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10.1101/19007526 | Quaternary Prevention: Is this Concept Relevant to Public Health? A Bibliometric and Descriptive Content Analysis. | Depallens, M. A.; Guimaraes, J. M. d. M.; Almeida Filho, N. | Miguel Andino Depallens | Federal University of the South of Bahia | 2019-11-02 | 2 | PUBLISHAHEADOFPRINT | cc_no | public and global health | https://www.medrxiv.org/content/early/2019/11/02/19007526.source.xml | ObjectiveTo measure and map research output on Quaternary Prevention (P4) and outline research trends; to assess the papers content, mainly regarding methods and subjects approached in order to contribute to the improvement of global knowledge about P4 and to evaluate its relevance for public health.
DesignBibliometric and descriptive content analysis.
Articles reviewedScientific articles about P4 recorded in Pubmed, LILACS, Scielo or CINAHL published until August 2018, with correspondent full articles available in Portuguese, English, Spanish, German or French.
Main outcome measuresYear of publication, first authors name and nationality, journals name, country and ranking, publication language, used methods and main reported subjects.
Results65 articles were included, published in 33 journals of 16 countries between 2003 and 2018 with a peak of publications in 2015. The first authors came from 17 different countries, 23% of them were Brazilian and Uruguay was the leading nation according to the scientific production per capita. 40% of all the selected articles were in English, 32% in Portuguese, 26% in Spanish. 28% of the papers were published in Q1 or Q2 journals. The research outputs on P4 begun first in the South of Europe, went to South America and then expanded worldwide. 88% of the articles were bibliographic research and 38% of all focused on specific examples of medical overuse (including several screening tests).
ConclusionsQuaternary prevention represents an ethical and valid approach to prevent occurence of iatrogenic events and to achieve equal and fair access to health services. Conceptual, geographical and linguistic elements, as well as WONCA conferences and type of healthcare systems in the authors country were fundamental factors that affected research output. The quality and quantity of available studies is still limited, therefore further investigations are recommended to assess the effective impact of P4 on public health. | 10.1590/0102-311X00231819 | medrxiv |
10.1101/19007526 | Quaternary Prevention: Is this Concept Relevant to Public Health? A Bibliometric and Descriptive Content Analysis. | Depallens, M. A.; Guimaraes, J. M. d. M.; Almeida Filho, N. | Miguel Andino Depallens | Federal University of the South of Bahia | 2019-11-05 | 3 | PUBLISHAHEADOFPRINT | cc_no | public and global health | https://www.medrxiv.org/content/early/2019/11/05/19007526.source.xml | ObjectiveTo measure and map research output on Quaternary Prevention (P4) and outline research trends; to assess the papers content, mainly regarding methods and subjects approached in order to contribute to the improvement of global knowledge about P4 and to evaluate its relevance for public health.
DesignBibliometric and descriptive content analysis.
Articles reviewedScientific articles about P4 recorded in Pubmed, LILACS, Scielo or CINAHL published until August 2018, with correspondent full articles available in Portuguese, English, Spanish, German or French.
Main outcome measuresYear of publication, first authors name and nationality, journals name, country and ranking, publication language, used methods and main reported subjects.
Results65 articles were included, published in 33 journals of 16 countries between 2003 and 2018 with a peak of publications in 2015. The first authors came from 17 different countries, 23% of them were Brazilian and Uruguay was the leading nation according to the scientific production per capita. 40% of all the selected articles were in English, 32% in Portuguese, 26% in Spanish. 28% of the papers were published in Q1 or Q2 journals. The research outputs on P4 begun first in the South of Europe, went to South America and then expanded worldwide. 88% of the articles were bibliographic research and 38% of all focused on specific examples of medical overuse (including several screening tests).
ConclusionsQuaternary prevention represents an ethical and valid approach to prevent occurence of iatrogenic events and to achieve equal and fair access to health services. Conceptual, geographical and linguistic elements, as well as WONCA conferences and type of healthcare systems in the authors country were fundamental factors that affected research output. The quality and quantity of available studies is still limited, therefore further investigations are recommended to assess the effective impact of P4 on public health. | 10.1590/0102-311X00231819 | medrxiv |
10.1101/19007500 | Isolated night cough in children: how does it differ from wheeze? | Jurca, M.; Goutaki, M.; Latzin, P.; Gaillard, E. A.; Spycher, B. D.; Kuehni, C. E. | Claudia E. Kuehni | University of Bern, Institute for Social and Preventive Medicine, Bern, Switzerland | 2019-10-10 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | respiratory medicine | https://www.medrxiv.org/content/early/2019/10/10/19007500.source.xml | BackgroundChildren with night cough but no wheeze might have a mild form of asthma (cough variant asthma), sharing risk factors with children who wheeze, and possibly developing wheeze later.
MethodsWe compared risk factors of children with isolated night cough and children with wheeze in the Leicester Respiratory Cohort study at ages 1, 4, 6, and 9 years. We also compared prognoses of children with isolated night cough, children with wheeze, and asymptomatic children.
ResultsAmong 4,101 children at age 1 year, 2,854 at 4, 2,369 at 6, and 1,688 at 9 years, the prevalence of isolated night cough was 10% at age 1 and 18% in older children, while prevalence of wheeze decreased from 35% at 1 year to 13% at age 9. Although many risk factors were the same for cough and wheeze, day care, reflux, and family history of bronchitis were more strongly associated with cough, and male sex and family history of asthma with wheeze. Over one-third of pre-schoolers with cough continued to cough at school age, but their risk of developing wheeze was similar to that of children asymptomatic at earlier surveys. Wheeze tracked more strongly throughout childhood than cough.
ConclusionsSome risk factors for cough and wheeze were shared and some were not; there was little evidence that children with isolated night cough have an increased risk of future wheeze. This suggests that only a fraction of children with isolated night cough might have a variant of asthma, if at all. | 10.1183/23120541.00217-2020 | medrxiv |
10.1101/19008615 | A Multiomics Approach to Heterogeneity in Alzheimer′s Disease: Focused Review and Roadmap | Badhwar, A.; McFall, G. P.; Sapkota, S.; Black, S. E.; Chertkow, H.; Duchesne, S.; Masellis, M.; Li, L.; Dixon, R.; Bellec, P. | AmanPreet Badhwar | CRIUGM, University of Montreal | 2019-10-10 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | neurology | https://www.medrxiv.org/content/early/2019/10/10/19008615.source.xml | Etiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimers disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput omics are unbiased data driven techniques that probe the complex etiology of Alzheimers disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimers disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimers disease. | 10.1093/brain/awz384 | medrxiv |
10.1101/19008227 | Molecular point-of-care testing for influenza A/B and respiratory syncytial virus: comparison of workflow parameters for the ID Now and cobas Liat systems | Young, S.; Phillips, J.; Christen Griego-Fullbright, C.; Wagner, A.; Jim, P.; Chaudhuri, S.; Tang, S.; Sickler, J. | Stephen Young | TriCore Reference Laboratories, Albuquerque, New Mexico, USA | 2019-10-10 | 1 | PUBLISHAHEADOFPRINT | cc_no | infectious diseases | https://www.medrxiv.org/content/early/2019/10/10/19008227.source.xml | AimsPoint-of-care (POC) tests for influenza and respiratory syncytial virus (RSV) offer the potential to improve patient management and antimicrobial stewardship. Studies have focused on performance; however, no workflow assessments have been published comparing POC molecular tests. This study compared the Liat and ID Now systems workflow, to assist end-users in selecting an influenza and/or RSV POC test.
MethodsStaffing, walk-away, and turnaround time (TAT) of the Liat and ID Now systems were determined using 40 nasopharyngeal samples, positive for influenza or RSV. The ID Now system requires separate tests for influenza and RSV, so parallel (two instruments) and sequential (one instrument) workflows were evaluated.
ResultsThe ID Now ranged 4.1-6.2 minutes for staffing, 1.9-10.9 minutes for walk-away and 6.4-15.8 minutes for TAT per result. The Liat ranged 1.1-1.8 minutes for staffing, 20.0-20.5 minutes for walk-away and 21.3-22.0 minutes for TAT. Mean walk-away time comprised 38.0% (influenza positive) and 68.1% (influenza negative) of TAT for ID Now and 93.7% (influenza/RSV) for Liat. The ID Now parallel workflow resulted in medians of 5.9 minutes for staffing, 9.7 minutes for walk-away, and 15.6 minutes for TAT. Assuming prevalence of 20% influenza and 20% RSV, the ID Now sequential workflow resulted in medians of 9.4 minutes for staffing, 17.4 minutes for walk-away, and 27.1 minutes for TAT.
ConclusionsThe ID Now and Liat systems offer different workflow characteristics. Key considerations for implementation include value of both influenza and RSV results, clinical setting, staffing capacity, and instrument(s) placement. | 10.1136/jclinpath-2019-206242 | medrxiv |
10.1101/19008516 | Does your address make the grade? The relationship between local socioeconomic status and the academic performance of paramedic students. | Hamel, L.; Procum, A.; Hunter, J.; Gridley, D.; O'Connor, K.; Fentress, T.; Goenner, C.; Khalsa, S.; Batt, A. M. | Alan M Batt | Fanshawe College | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_by | medical education | https://www.medrxiv.org/content/early/2019/10/11/19008516.source.xml | Research indicates students of lower socioeconomic status (SES) are educationally disadvantaged. We sought to examine differences in paramedic student academic performance from counties with varying SES in the United States. Student performance data and SES data were combined for counties within the states of California, Mississippi, Louisiana, Texas and Virginia. Linear multiple regression modelling was performed to determine the relationship between income, high school graduation rate, poverty and food insecurity with first-attempt scores on the Fisdap Paramedic Readiness Exam (PRE) versions 3 and 4. Linear regression models indicated that there was a significant relationship between county-level income, poverty, graduation rate, food insecurity, and paramedic student academic performance. It remains unclear what type of relationship exists between individual SES and individual academic performance of paramedic students. These findings support the future collection of individual student level SES data in order to identify issues and mitigate impact on academic performance. | 10.12968/ippr.2020.10.2.25 | medrxiv |
10.1101/19008516 | Local socioeconomic status and paramedic students' academic performance | Hamel, L.; Procum, A.; Hunter, J.; Gridley, D.; O'Connor, K.; Fentress, T.; Goenner, C.; Khalsa, S.; Batt, A. M. | Alan M Batt | Fanshawe College | 2020-06-17 | 2 | PUBLISHAHEADOFPRINT | cc_by | medical education | https://www.medrxiv.org/content/early/2020/06/17/19008516.source.xml | Research indicates students of lower socioeconomic status (SES) are educationally disadvantaged. We sought to examine differences in paramedic student academic performance from counties with varying SES in the United States. Student performance data and SES data were combined for counties within the states of California, Mississippi, Louisiana, Texas and Virginia. Linear multiple regression modelling was performed to determine the relationship between income, high school graduation rate, poverty and food insecurity with first-attempt scores on the Fisdap Paramedic Readiness Exam (PRE) versions 3 and 4. Linear regression models indicated that there was a significant relationship between county-level income, poverty, graduation rate, food insecurity, and paramedic student academic performance. It remains unclear what type of relationship exists between individual SES and individual academic performance of paramedic students. These findings support the future collection of individual student level SES data in order to identify issues and mitigate impact on academic performance. | 10.12968/ippr.2020.10.2.25 | medrxiv |
10.1101/19008524 | Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia | Karlsson, L.; Barbaro, M.; Ewing, E.; Gomez-Cabrero, D.; Lajic, S. | Svetlana Lajic | Karolinska Institutet | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_no | endocrinology | https://www.medrxiv.org/content/early/2019/10/11/19008524.source.xml | BackgroundPatients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome.
MethodsWe analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 {+/-}6.5 years [y]) and 37 population controls (mean age=17.0 {+/-}6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, {+/-}6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment.
ResultsWe identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035).
ConclusionIn conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH. | 10.1016/j.jsbmb.2020.105699 | medrxiv |
10.1101/19008524 | Genome-wide investigation of DNA methylation in congenital adrenal hyperplasia | Karlsson, L.; Barbaro, M.; Ewing, E.; Gomez-Cabrero, D.; Lajic, S. | Svetlana Lajic | Karolinska Institutet | 2020-02-10 | 2 | PUBLISHAHEADOFPRINT | cc_no | endocrinology | https://www.medrxiv.org/content/early/2020/02/10/19008524.source.xml | BackgroundPatients with congenital adrenal hyperplasia (CAH) are at risk of long-term cognitive and metabolic sequelae with some of the effects being attributed to the chronic glucocorticoid treatment that they receive. This study investigates genome-wide DNA methylation in patients with CAH to determine whether there is evidence for epigenomic reprogramming as well as any relationship to patient outcome.
MethodsWe analysed CD4+ T cell DNA from 28 patients with CAH (mean age=18.5 {+/-}6.5 years [y]) and 37 population controls (mean age=17.0 {+/-}6.1 y) with the Infinium-HumanMethylation450 BeadChip array to measure genome-wide locus-specific DNA methylation levels. Effects of CAH, phenotype and CYP21A2 genotype on methylation were investigated as well as the association between differentially methylated CpGs, glucose homeostasis, blood lipid profile and cognitive functions. In addition, we report data on a small cohort of 11 patients (mean age=19.1, {+/-}6.0 y) with CAH who were treated prenatally with dexamethasone (DEX) in addition to postnatal glucocorticoid treatment.
ResultsWe identified two CpGs to be associated with patient phenotype: cg18486102 (located in the FAIM2 gene; rho=0.58, adjusted p=0.027) and cg02404636 (located in the SFI1 gene; rho=0.58, adjusted p=0.038). cg02404636 was also associated with genotype (rho=0.59, adjusted p=0.024). Higher levels of serum C-peptide was also observed in patients with CAH (p=0.044). Additionally, levels of C-peptide and HbA1c were positively correlated with patient phenotype (p=0.044 and p=0.034) and genotype (p=0.044 and p=0.033), respectively. No significant association was found between FAIM2 methylation and cognitive or metabolic outcome. However, SFI1 TSS methylation was associated with fasting plasma HDL cholesterol levels (p=0.035).
ConclusionIn conclusion, higher methylation levels in CpG sites covering FAIM2 and SFI1 were associated with disease severity. Hypermethylation in these genes may have implications for long-term cognitive and metabolic outcome in patients with CAH. | 10.1016/j.jsbmb.2020.105699 | medrxiv |
10.1101/19008995 | Association of rs12722 COL5A1 with Pulmonary Tuberculosis infection: a preliminary case-control study in a Kazakhstani population. | Zhetkenev, S.; Khassan, A.; Khamzina, A.; Issanov, A.; Crape, B.; Akilzhanova, A.; Kozhamkulov, U.; Yerezhepov, D.; Chan, C. K. | Chee Kai Chan | School of Medicine, Nazarbayev University | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/10/11/19008995.source.xml | BackgroundLung cavitation is the classic hallmark of TB, which facilitates the disease development and transmission. It involves the degradation of lung parenchyma which is mainly made up of collagen fibers by metalloproteinases (MMPs) produced by activated monocyte-derived cells, neutrophils and stromal cells.
ObjectiveThe following population-based preliminary case-control study of adults with TB and controls without TB will check the possible association between rs1800012 in COL1A1, rs1272222 in COL5A1 genes to human TB susceptibility in Kazakhstan.
MethodsIn this case-control study including 165 samples we examined the associations between TB disease status and demographic variables along with single nucleotide polymorphisms related to COLA1 and COL5A1. The unadjusted {chi}2 and adjusted logistic regression was performed to find out relationships between SNPS and other predictors.
ResultsPreliminary findings suggest that there is a statistically significant association of age (OR=0.44, 95% CI:0.21-0.92, p-value=0.03), social status (OR=0.42, 95% CI:0.201 -0.87, p-value=0.020), HIV status(OR=6.9, 95% CI:1.86 - 25.6, p-value=0.004) and heterozygous rs12722 SNP (OR=2.45, 95% CI:1.16 -5.16 p-value=0.019) polymorphism of COL5A1 gene with TB susceptibility.
ConclusionThe association of collagen genes with TB pathogenesis indicates that anti TB programs should develop new drug regimens that include MMP inhibitors. Therapeutic targeting of MMPs will prevent extracellular matrix degradation and granuloma maturation. | 10.1007/s11033-020-06121-y | medrxiv |
10.1101/19008987 | Dynamic interactions of influenza viruses in Hong Kong during 1998-2018 | Yang, W.; Lau, E. H.; Cowling, B. J. | Wan Yang | Columbia University | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/10/11/19008987.source.xml | Influenza epidemics cause substantial morbidity and mortality every year worldwide. Currently, two influenza A subtypes, A(H1N1) and A(H3N2), and type B viruses co-circulate in humans and infection with one type/subtype could provide cross-protection against the others. However, it remains unclear how such ecologic competition via cross-immunity and antigenic mutations that allow immune escape impact influenza epidemic dynamics at the population level. Here we develop a comprehensive model-inference system and apply it to study the evolutionary and epidemiological dynamics of the three influenza types/subtypes in Hong Kong, a city of global public health significance for influenza epidemic and pandemic control. Utilizing long-term influenza surveillance data since 1998, we are able to estimate the strength of cross-immunity between each virus-pairs, the timing and frequency of punctuated changes in population immunity in response to antigenic mutations in influenza viruses, and key epidemiological parameters over the last 20 years including the 2009 pandemic. We find evidence of cross-immunity in all types/subtypes, with strongest cross-immunity from A(H1N1) against A(H3N2). Our results also suggest that A(H3N2) may undergo antigenic mutations in both summers and winters and thus monitoring the virus in both seasons may be important for vaccine development. Overall, our study reveals intricate epidemiological interactions and underscores the importance of simultaneous monitoring of population immunity, incidence rates, and viral genetic and antigenic changes. | 10.1371/journal.pcbi.1007989 | medrxiv |
10.1101/19008649 | Cardiac structure and function in schizophrenia: a cardiac MR imaging study | Osimo, E. F.; Brugger, S. P.; de Marvao, A.; Pillinger, T.; Whitehurst, T.; Statton, B.; Quinlan, M.; Berry, A.; Cook, S. A.; O'Regan, D. P.; Howes, O. D. | Emanuele Felice Osimo | Imperial College London | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_by | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/11/19008649.source.xml | BackgroundHeart disease is the leading cause of death in schizophrenia.
AimsWe investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.
Methods80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area.
ResultsPatients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume, end-systolic volume, stroke volume, right ventricular (RV) end-diastolic volume, end-systolic volume, and stroke volume but unaltered ejection fractions relative to controls. LV concentricity and septal thickness were significantly larger in schizophrenia. The findings were largely unchanged after adjusting for smoking or exercise levels and were independent of medication dose and duration.
ConclusionsPatients with schizophrenia show evidence of prognostically-adverse cardiac remodelling compared to matched controls, independent of conventional risk factors. | 10.1192/bjp.2019.268 | medrxiv |
10.1101/19008037 | Classifying post-traumatic stress disorder using the magnetoencephalographic connectome and machine learning | Zhang, J.; Richardson, J. D.; Dunkley, B. T. | Benjamin Thomas Dunkley | Hospital for Sick Children | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/11/19008037.source.xml | Given the subjective nature of conventional diagnostic methods for post-traumatic stress disorder (PTSD), an objectively measurable biomarker is highly desirable. Macroscopic neural circuits measured using magnetoencephalography (MEG) has previously been shown to be indicative of the PTSD phenotype and severity. In the present study, we employed a machine learning-based classification framework using MEG neural synchrony to distinguish combat-related PTSD from trauma-exposed controls. Support vector machine (SVM) was used as the core classification algorithm. A recursive random forest feature selection step was directly incorporated in the nested SVM cross validation process (CV-SVM-rRF-FS) for identifying the most important features for PTSD classification. For the five frequency bands tested, the nested CV-SVM-rRF-FS analysis selected the minimum numbers of edges per frequency that could serve as a PTSD signature and be used as the basis for SVM modelling. Many of the selected edges have been reported previously to be core in PTSD pathophysiology, with frequency-specific patterns also observed. Furthermore, the independent partial least squares discriminant analysis suggested low bias in the nested CV-SVM-rRF-FS process. The final SVM models built with selected features showed excellent PTSD classification performance (area-under-curve value up to 0.9). Testament to its robustness when distinguishing individuals from a heavily-traumatised control group, these developments for a classification model for PTSD also provide a comprehensive machine learning-based computational framework for classifying other mental health challenges using MEG connectome profiles. | 10.1038/s41598-020-62713-5 | medrxiv |
10.1101/19008896 | Prognostic value of the Residual Cancer Burden index according to breast cancer subtype: validation on a cohort of BC patients treated by neoadjuvant chemotherapy. | Hamy, A.-S.; Darrigues, L.; Laas, E.; De Croze, D.; Topciu, L.; Lam, G.-T.; Evrevin, C.; Rozette, S.; Laot, L.; Lerebours, F.; Pierga, J.-Y.; Osdoit, M.; Faron, M.; Feron, J.-G.; Lae, M.; Reyal, F. | Fabien Reyal | Institut Curie Paris | 2019-10-11 | 1 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2019/10/11/19008896.source.xml | IntroductionThe Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)).
MethodsWe retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes.
Results717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR=3.25 CI [2.1-5.1] p<0.001; RCB-III versus RCB-0: HR=5.6 CI [3.5-8.9] p<0.001). The prognostic impact of RCB index was significant for TNBC and HER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8 - 62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months.
ConclusionRCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies. | 10.1371/journal.pone.0234191 | medrxiv |
10.1101/19008284 | Analysis of online information available for treatment of depression | Ghezzi, P.; Clarke, Z. | Pietro Ghezzi | Brighon & Sussex Medical School | 2019-10-14 | 1 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/14/19008284.source.xml | The Internet has become a prime source of health information available to the public. Our aims were to assess the content and quality of online information for the treatment of depression.
We searched, "How to cure depression" on Google and analysed the first 200 websites according to the website typology and a standard health information assessment tool, the Journal of the American Medical Association (JAMA) criteria (presence of authorship, date, disclosure, and references). We also analyzed content in terms of treatments mentioned and developed a Quality Indicator Score (QIS) based on the guidelines for treating depression from the UK National Institute for Health and Care Excellence (NICE).
News websites were the most frequent typology followed by health portals, non-profit, professional and government; commercial websites were the least represented. In the top ten websites, news and health portals remained first and second respectively. Antidepressants were the most mentioned treatment, followed by psychotherapy, lifestyle & exercise, social support, diet. The least mentioned interventions were sunlight & light therapy, routine, and ketamine & psychedelics. Commercial websites preferentially mentioned supplements, while ketamine and psychedelic drugs were the most covered by news outlets. Analysing webpages according to our QIS showed the median of NICE recommended treatments was 2.5 out of 5 possible treatments: antidepressants, lifestyle & exercise, psychotherapy, social support and ECT. Government websites had the highest QIS, news and commercial websites the lowest. Webpages with high QIS ranked higher in Google. | null | medrxiv |
10.1101/19008706 | Mechanistic insights into heterogeneous radiofrequency ablation effects at the left atrial posterior wall during pulmonary vein isolation | Tomlinson, D. R. | David R Tomlinson | University Hospitals Plymouth NHS Trust | 2019-10-15 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/10/15/19008706.source.xml | BackgroundIndependent investigations demonstrate greater radiofrequency (RF) ablation effects at left- sided left atrial posterior wall (LAPW) sites.
ObjectiveTo investigate mechanisms underlying RF ablation heterogeneity during contact-force (CF) and VISITAG Module (Biosense Webster)-guided pulmonary vein isolation (PVI).
MethodsConsecutive patients undergoing PVI during atrial overdrive pacing comprised 2 cohorts: intermittent positive pressure ventilation (IPPV, 14-16/min, 6-8ml/kg); high frequency jet ventilation (HFJV, 150/min, Monsoon III, Acutronic). Temperature-controlled (17ml/min, 48{degrees}C) RF data was retrospectively assessed at first-annotated (target 15s) LAPW sites: 30W during IPPV; 20W at left-sided sites during HFJV.
ResultsTwenty-five and 15 patients underwent PVI during IPPV and HFJV, respectively. During IPPV, left versus right-sided median impedance drop (ImpD) was 13.6{Omega} versus 9.9{Omega} (p<0.0001) respectively and mean time to pure R unipolar electrogram (UE) morphology change 4.9s versus 6.7s (p=0.007) respectively. During HFJV, ImpD was greater at left-sided sites (9.7{Omega} versus 7.4{Omega}, p=0.21) and time to pure R UE significantly shorter: 4.3s versus 6.1s (p=0.02). Minimum case impedance subtracted from pre-RF baseline impedance (BI) generated site-specific {Delta}BI. Left-sided sites demonstrated significantly greater {Delta}BI, correlating strongly with Ln(ImpD) - IPPV r=0.84 (0.65 - 0.93), HFJV r=0.77 (0.35 - 0.93).
At right-sided sites, {Delta}BI and Ln(ImpD) were without correlation during IPPV, but correlation was modest during HFJV (r=0.54, -0.007 - 0.84).
Conclusions{Delta}BI may usefully indicate catheter-tissue contact surface area (SA). Consequently, greater left-sided LAPW RF effect may result from greater contact SA and in-phase catheter-tissue motion; HFJV may reduce right-sided out-of-phase catheter-tissue motion. Modifying RF delivery based on {Delta}BI may improve PVI safety and efficacy. | null | medrxiv |
10.1101/19008102 | How do World and European Standard Populations impact Burden of Disease studies? A case study of Disability-Adjusted Life Years in Scotland | Wyper, G. M.; Grant, I.; Fletcher, E.; McCartney, G.; Fischbacher, C.; Stockton, D. L. | Grant MA Wyper | Public Health Science Directorate, NHS Health Scotland, Glasgow, Scotland | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/10/16/19008102.source.xml | BackgroundDisability-Adjusted Life Years (DALYs) are an established method for quantifying population health needs and guiding prioritisation decisions. Global Burden of Disease (GBD) estimates aim to ensure comparability between countries and over time by using age-standardised rates (ASR) to account for differences in the age structure of different populations. Different standard populations are used for this purpose but it is not widely appreciated that the choice of standard may affect not only the resulting rates but also the rankings of causes of DALYs. We aimed to evaluate the impact of the choice of standard, using the example of Scotland.
MethodsDALY estimates were derived from the 2016 Scottish Burden of Disease (SBOD) study for an abridged list of 68 causes of disease/injury, representing a three-year annual average across 2014-16. Crude DALY rates were calculated using Scottish national population estimates. DALY ASRs standardised using the GBD World Standard Population (GBD WSP) were compared to those using the 2013 European Standard Population (ESP2013). Differences in ASR and in rank order within the cause list were summarised across all-causes and for each individual cause.
ResultsThe ranking of causes by DALYs were similar using crude rates or ASR (ESP2013). As expected, all-cause DALY rates using ASR (GBD WSP) were around 26% lower. Overall 58 out of 68 causes had a lower ASR using GBD WSP compared with ESP2013, with the largest falls occurring for leading causes of mortality observed in older ages. Gains in ASR were much smaller in scale and largely affected causes that operated early in life. These differences were associated with a substantial change to the ranking of causes when GBD WSP was used compared with ESP2013.
ConclusionDisease rankings based on DALY ASRs are strongly influenced by the choice of standard population. While GBD WSP offers international comparability, within-country analyses based on DALY ASRs should reflect local age structures. For European countries including Scotland, ESP2013 may better guide local priority setting. | 10.1186/s13690-019-0383-8 | medrxiv |
10.1101/19008672 | Efficacy and safety of Nab-paclitaxel in breast cancer: a meta-analysis | Yadav, U.; Kumar, P.; Rai, V. | Vandana Rai | VBS Purvanchal University | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | oncology | https://www.medrxiv.org/content/early/2019/10/16/19008672.source.xml | Worldwide breast cancer is the leading cause of cancer related death in women. Paclitaxel is an effective drug used for the treatment of breast cancer but it has many side effects. Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) is an FDA approved drug for the treatment of breast cancer. Currently many clinical trials are conducted to deliver nab-paclitaxel into the tumor cells. But the efficacy and safety of this nab-paclitaxel over conventional paclitaxel still remains questionable. So, we performed a meta-analysis to evaluate the efficacy and safety of nab-paclitaxel in breast cancer treatment.
Electronic databases were searched for the suitable studies using key terms "nab-paclitaxel", "paclitaxel", and "clinical trial" with the combination of "breast cancer" up to August 11, 2019. Risk ratio (RR) and odds ratio (OR) with corresponding 95% confidence intervals (CIs) were calculated. All statistical analyses were performed by the Open Meta-Analyst program. A total of eight studies which fulfilled our criteria were included in this study. For efficacy we retrieved data of 12 months progression free survival, 24 months progression free survival, and overall survival (up to 3 years) and for the safety we took data of nausea, anemia, leukopenia, neutropenia, fatigue, diarrhea and pain.
We did not found any difference in efficacy of nab-paclitaxel over paclitaxel (12 months progression free survival-RRFE= 0.86, 95%CI= 0.77-0.97, p= 0.02, I2= 25.07%; 24 months progression free survival-RRFE= 0.86, 95% CI= 0.64-1.16, p= 0.34, I2= 0%; and 3 years survival-RRFE= 1.20, 95%CI= 0.92-1.56, p= 0.16, I2= 37.55%). The meta-analysis of studies used nab-paclitaxel showed reduced adverse effect of anemia (ORFE= 1.66, 95% CI= 1.26-2.19; p= <0.001; I2= 0%) and leukopenia (ORFE= 1.37; 95%CI= 1.06-1.75; p= 0.01; I2= 48.63%). However, in case of other adverse effects no significant association was found with nab-paclitaxel (nausea-ORFE=1.15, 95%CI= 0.94-1.41, p= 0.15, I2= 50.12%; neutropenia-ORRE= 0.75, 95%CI= 0.30-1.87, p= 0.54, I2= 94.45%; fatigue-ORRE= 1.11, 95%CI= 0.77-1.62, p= 0.55, I2= 56.02; diarrhea-ORFE= 1.11, 95%CI= 0.77-1.62, p= 0.55; I2= 34.26; pain-ORRE= 1.15, 95%CI= 0.78-1.69, p= 0.45, I2= 52.96%).In conclusion the use of nab-paclitaxel has reduces the side effects of anemia and leukopenia in breast cancer treatment in comparison to paclitaxel but nab-paclitaxel has no effect on the overall survival of the patients. | null | medrxiv |
10.1101/19009431 | Association of polygenic risk scores for coronary artery disease with subsequent events amongst established cases | Howe, L. J.; Dudbridge, F.; Schmidt, A. F.; Finan, C.; Denaxas, S.; Asselbergs, F. W.; Hingorani, A. D.; Patel, R. S. | Riyaz S Patel | University College London | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_by | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/10/16/19009431.source.xml | BackgroundThere is growing evidence that polygenic risk scores (PRS) can be used to identify individuals at high lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain.
MethodsUsing two subsamples of UK Biobank, defined at baseline as prevalent CAD (N=10,287) and without CAD (N=393,108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes, during a median follow up of 7.8 years.
ResultsA 1 S.D. higher PRS was associated with increased risk of incident MI in participants without CAD (OR 1.33; 95% C.I. 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% C.I. 1.06, 1.25); heterogeneity P =0.0012. Additionally, among prevalent CAD cases, we found evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% C.I. 0.85, 0.98) compared to those without CAD (OR 1.01; 95% C.I. 0.99, 1.03); heterogeneity P =0.0041. A similar inverse association was found for ischaemic stroke (Prevalent CAD (OR 0.78; 95% C.I. 0.67, 0.90); without CAD (OR 1.09; 95% C.I. 1.04, 1.15), heterogeneity P <0.001).
ConclusionsBias induced by case stratification and survival into UK Biobank may attenuate, or reverse, associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Polygenic risk scores for subsequent events should be derived from new genome wide association studies conducted in patients with established disease.
Key messagesO_LICAD PRS are positively associated with incident myocardial infarction risk amongst established CAD cases.
C_LIO_LIHowever, the effect size is attenuated compared to estimates from CAD-free populations.
C_LIO_LICAD PRS are inversely associated with mortality and stroke risk amongst established CAD cases.
C_LIO_LIThese associations may reflect index event bias induced by stratifying on case status.
C_LIO_LIDedicated GWAS of coronary disease progression are required to improve prediction of subsequent event risk.
C_LI | 10.1093/hmg/ddaa052 | medrxiv |
10.1101/19009274 | BRAF mutation testing of MSI CRCs in Lynch syndrome diagnostics: performance and efficiency according to patient`s age | Bläker, H.; Haupt, S.; Morak, M.; Holinski-Feder, E.; Arnold, A.; Horst, D.; Sieber-Frank, J.; Seidler, F.; von Winterfeld, M.; Alwers, E.; Chang-Claude, J.; Brenner, H.; Roth, W.; Engel, C.; Löffler, M.; Möslein, G.; Schackert, H.-K.; Weitz, J.; Perne, C.; Aretz, S.; Hüneburg, R.; Schmiegel, W.; Vangala, D.; Rahner, N.; Steinke-Lange, V.; Heuveline, V.; von Knebel Doeberitz, M.; Ahadova, A.; Hoffmeister, M.; Kloor, M.; the German Consortium for Familial Intestinal Cancer, | Hendrik Bläker | Institute of Pathology, University Hospital Leipzig, Leipzig, Germany | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_no | gastroenterology | https://www.medrxiv.org/content/early/2019/10/16/19009274.source.xml | Background and aimsBRAF V600E mutations have been reported to be associated with sporadic microsatellite-unstable (MSI) colorectal cancer (CRC), while rarely detected in CRCs of Lynch syndrome (LS) patients. Therefore, current international diagnostic guidelines recommend somatic BRAF mutation testing in MLH1-deficient MSI CRC patients to exclude LS. As sporadic BRAF-mutant MSI CRC is a disease of the elderly, while LS-associated CRC usually occurs at younger age, we hypothesized that the efficacy of BRAF testing in LS diagnostics may be age-dependent.
MethodsWe systematically compared the prevalence of BRAF V600E mutations in LS-associated CRCs and MSI CRCs from population-based cohorts in different age groups as available from published studies, databases, and population-based patient cohorts. Cost calculations and sensitivity analysis of the BRAF testing for exclusion of LS was performed.
ResultsAmong 969 MSI CRCs from LS mutation carriers from the literature and German HNPCC Consortium, 15 (1.6%, 95% CI: 0.9-2.6%) harbored BRAF mutations. 6/7 LS patients with BRAF-mutant CRC and reported age were <50 years. Among unselected MSI CRCs, 44.8% (339/756) harbored BRAF mutations, 92.3% (313/339) of which were detected in patients >60 years. In MSI CRC patients <50, BRAF mutations were detected only in 0.6% (2/339), and the inclusion of BRAF testing led to increased costs and higher risk of missing LS patients (1.2%) compared to other age groups.
ConclusionBRAF testing in patients <50 years is cost-inefficient and carries the highest risk of missing LS patients among different age groups. We suggest direct referral of MSI CRC patients <50 years to genetic counseling without prior BRAF testing. | 10.1002/ijc.33273 | medrxiv |
10.1101/19008631 | NeuroMark: an adaptive independent component analysis framework for estimating reproducible and comparable fMRI biomarkers among brain disorders | Du, Y.; Fu, Z.; Sui, J.; Gao, S.; Xing, Y.; Lin, D.; Salman, M.; Rahaman, M. A.; Abrol, A.; Chen, J.; Hong, E.; Kochunov, P.; Osuch, E. A.; Calhoun, V. D. | Yuhui Du | Shanxi University | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/16/19008631.source.xml | Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. Standardized approaches for capturing reproducible and comparable biomarkers are greatly needed. Here, we propose a method, NeuroMark, which leverages a priori-driven independent component analysis to effectively extract functional brain network biomarkers from functional magnetic resonance imaging (fMRI) data. NeuroMark automatically estimates features adaptable to each individual and comparable across subjects by taking advantage of the replicated brain network templates extracted from 1828 healthy controls as guidance to initialize the individual-level networks. Four studies including 2454 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, depression, bipolar disorder, mild cognitive impairment and Alzheimers disease) to evaluate the proposed method from different perspectives (replication, cross-study comparison, subtle difference identification, and multi-disorder classification). Results demonstrate the great potential of NeuroMark in its feasibility to link different datasets/studies/disorders and enhance sensitivity in identifying biomarkers for patients with challenging mental illnesses.
Significance StatementIncreasing evidence highlights that features extracted from resting fMRI data can be leveraged as potential biomarkers of brain disorders. However, it has been difficult to replicate results using different datasets, translate findings across studies, and differentiate brain disorders sharing similar clinical symptoms. It is important to systematically characterize the degree to which unique and similar impaired patterns are reflective of brain disorders. We propose a fully automated method (called NeuroMark) that leverages priori-driven independent component analysis (ICA) using replicated brain network templates to estimate individual-subject network features. Evaluated by four studies involving six different brain disorders, we show that NeuroMark can effectively link the comparison of biomarkers across different studies/datasets/disorders and enable classification between complex brain disorders, while also providing information about relevant aspects of whole brain functional connectivity. | 10.1016/j.nicl.2020.102375 | medrxiv |
10.1101/19008631 | NeuroMark: a fully automated ICA method to identify effective fMRI markers of brain disorders | Du, Y.; Fu, Z.; Sui, J.; Gao, S.; Xing, Y.; Lin, D.; Salman, M.; Rahaman, M. A.; Abrol, A.; Chen, J.; Hong, E.; Kochunov, P.; Osuch, E. A.; Calhoun, V. D. | Yuhui Du | Shanxi University | 2019-12-16 | 2 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/12/16/19008631.source.xml | Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. Standardized approaches for capturing reproducible and comparable biomarkers are greatly needed. Here, we propose a method, NeuroMark, which leverages a priori-driven independent component analysis to effectively extract functional brain network biomarkers from functional magnetic resonance imaging (fMRI) data. NeuroMark automatically estimates features adaptable to each individual and comparable across subjects by taking advantage of the replicated brain network templates extracted from 1828 healthy controls as guidance to initialize the individual-level networks. Four studies including 2454 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, depression, bipolar disorder, mild cognitive impairment and Alzheimers disease) to evaluate the proposed method from different perspectives (replication, cross-study comparison, subtle difference identification, and multi-disorder classification). Results demonstrate the great potential of NeuroMark in its feasibility to link different datasets/studies/disorders and enhance sensitivity in identifying biomarkers for patients with challenging mental illnesses.
Significance StatementIncreasing evidence highlights that features extracted from resting fMRI data can be leveraged as potential biomarkers of brain disorders. However, it has been difficult to replicate results using different datasets, translate findings across studies, and differentiate brain disorders sharing similar clinical symptoms. It is important to systematically characterize the degree to which unique and similar impaired patterns are reflective of brain disorders. We propose a fully automated method (called NeuroMark) that leverages priori-driven independent component analysis (ICA) using replicated brain network templates to estimate individual-subject network features. Evaluated by four studies involving six different brain disorders, we show that NeuroMark can effectively link the comparison of biomarkers across different studies/datasets/disorders and enable classification between complex brain disorders, while also providing information about relevant aspects of whole brain functional connectivity. | 10.1016/j.nicl.2020.102375 | medrxiv |
10.1101/19008201 | Synthetic apparent diffusion coefficient for high b-value diffusion weighted MRI in Prostate | Sahoo, P.; Rockne, R. C.; Alexander, J.; Gupta, P. K.; Gupta, R. K. | Prativa Sahoo | City of Hope | 2019-10-16 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | radiology and imaging | https://www.medrxiv.org/content/early/2019/10/16/19008201.source.xml | PurposeIt has been reported that diffusion weighted imaging (DWI) with ultrahigh b-value increases the diagnostic power of prostate cancer. DWI imaging with higher b-values is challenging as it commonly suffers from low signal to noise ratio (SNR), distortion and longer scan time. The aim of our study was to develop a technique for quantification of apparent diffusion coefficient (ADC) for higher b-values from lower b-value DW images.
Materials and MethodsFifteen patient (7 malignant, 8 benign) with prostate cancer were included in this study retrospectively with the institutional ethical committee approval. All images were acquired at 3T MR scanner. The ADC values were calculated using mono-exponential model. Synthetic ADC (sADC) for higher b-value were computed using a log-linear model. Contrast ratio (CR) between prostate lesion and normal tissue on synthetic DWI (sDWI) was computed and compared with original DWI and ADC images.
ResultsNo significant difference was observed between actual ADC and sADC for b-2000 in all prostate lesions. However; CR increased significantly (p=0.002, paired t-test) in sDWI as compared to DWI. Malignant lesions showed significantly lower sADC as compared to benign lesion (p=0.0116, independent t-test). Mean ({+/-}standard deviation) of sADC of malignant lesions was 0.601{+/-}0.06 and for benign lesions was 0.92 {+/-} 0.09 (10-3mm2/s).
Discussion / ConclusionOur initial investigation suggests that the ADC values corresponding to higher b-value can be computed using log-linear relationship derived from lower b-values (b[≤]1000). Our method might help clinician to decide the optimal b-value for prostate lesion identification. | 10.1155/2020/5091218 | medrxiv |
10.1101/19006726 | Plasma proteomics reveals markers of metabolic stress in HIV infected children with severe acute malnutrition: call for more evidence-based nutritional intervention strategies | Gonzales, G. B.; Njunge, J. M.; Gichuki, B. M.; Wen, B.; Potani, I.; Voskuijl, W.; Bandsma, R.; Berkley, J. A. | Gerard Bryan Gonzales | Ghent University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2019/10/18/19006726.source.xml | HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p<0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc--2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p<0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM. | 10.1038/s41598-020-68143-7 | medrxiv |
10.1101/19006726 | Plasma proteomics reveals markers of metabolic stress in HIV infected children with severe acute malnutrition | Gonzales, G. B.; Njunge, J. M.; Gichuki, B. M.; Wen, B.; Potani, I.; Voskuijl, W.; Bandsma, R.; Berkley, J. A. | Gerard Bryan Gonzales | Ghent University | 2020-01-27 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | nutrition | https://www.medrxiv.org/content/early/2020/01/27/19006726.source.xml | HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p<0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc--2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p<0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM. | 10.1038/s41598-020-68143-7 | medrxiv |
10.1101/19008391 | Patient Preferences to Undergo Low-Value CT Coronary Angiography in the Emergency Department | Winkels, J. L.; Morrow Smith, C.; Iyengar, R.; Meka, A. P.; Porath, J. D.; Meurer, W. J. | Jessica L. Winkels | University of Michigan | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | emergency medicine | https://www.medrxiv.org/content/early/2019/10/18/19008391.source.xml | BackgroundLow-value diagnostic testing adds billions of dollars to the cost of health care in the US annually. Addressing patient preference for these tests is one possible strategy to limit overuse. In previous work, we showed that patient preference for testing can be influenced by test benefit, risk, and financial measures. Our objective was to examine the effect of these variables in another clinical scenario involving chest pain.
MethodsIn this cross-sectional survey of patients at the University of Michigan Emergency Department (ED), participants were given a hypothetical scenario involving an ED visit for chest pain, along with information regarding potential benefit (detecting a life-threatening condition; 0.1 or 1%) and risk (developing cancer; 0.1 or 1%) of CTCA, as well as an incentive of $0 or $100 to forego testing. Values for risk, benefit, and financial incentive varied across participants. Our primary outcome was patient preference to undergo testing. We also obtained demographic and numeracy information. Then, we used logistic regression to estimate odds ratios, adjusting for multiple potential confounders. Our sample size was designed to find at least 300 events (test acceptance) to allow for up to 30 covariates in fully adjusted models. We had 85-90% power to detect a 10% absolute difference in testing rate across groups, assuming a 95% significance level.
Results913 patients were surveyed. A $100 financial incentive (adjusted OR [AOR] 0.57; 95% Confidence Interval [CI] 0.42-0.78) and increased test risk (AOR 0.61; 95% CI 0.44-0.84) both significantly decreased test acceptance in fully adjusted models, whereas increased test benefit significantly increased test acceptance (AOR 2.45; 95% CI 1.79-3.36).
ConclusionsOffering a financial incentive deterred patients from accepting testing despite varying levels of risk and benefit. In the context of previous work, we provide preliminary evidence supporting that financial interventions may impact patient preference more than test risk and benefit. | null | medrxiv |
10.1101/19007724 | Reorganization of nurse scheduling reduces the risk of healthcare associated infections | Valdano, E.; Poletto, C.; Boelle, P.-Y.; Colizza, V. | Vittoria Colizza | INSERM, Sorbonne Universite, Institut Pierre Louis d\'Epidemiologie et de Sante Publique (IPLESP), Paris, France | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/10/18/19007724.source.xml | BackgroundEfficient prevention and control of healthcare associated infections (HAIs) is still an open problem.
ObjectiveTo design efficient hospital infection control strategies by reorganizing nurse scheduling.
Design, setting, and participantsProof-of-concept modeling study based on high-resolution contact data from wearable sensors between patients, nurses, doctors, and administrative staff at a short-stay geriatric ward of a University hospital.
MethodsWe considered isolation and contact removal to identify the most important class of individuals for HAI dissemination. We introduced a novel intervention based on the reorganization of nurse scheduling. This strategy switches and reassigns nurses tasks through the optimization of shift timelines, while respecting feasibility constraints and satisfying patient-care requirements. We evaluated the impact of interventions through a Susceptible-Colonized-Susceptible transmission model on the empirical and reorganized contacts.
ResultsIsolation and contact removal produced the largest risk reduction when acting on nurses. Reorganizing their schedules reduced HAI risk by 27% (95% confidence interval [24,29]%) while preserving the timeliness, number, and duration of contacts. More than 30% nurse-nurse contacts should be avoided to achieve an equivalent reduction through simple contact removal. No overall change in the number of nurses per patient resulted from the intervention.
ConclusionsReorganization of nurse scheduling offers an alternative change of practice that substantially limits HAI risk in the ward while ensuring the timeliness and quality of healthcare services. This calls for including optimization of nurse scheduling practices in programs for better infection control in hospitals. | 10.1038/s41598-021-86637-w | medrxiv |
10.1101/19005520 | Community gender systems and daughter's risk of female genital mutilation/cutting: New theory and application to Egypt | Yount, K. M.; Cheong, Y. F.; James-Hawkins, L.; Grose, R. G.; Hayford, S. | Kathryn M Yount | Emory University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/10/18/19005520.source.xml | We proposed and tested a feminist social-ecological theory about daughters experience of female genital mutilation/cutting (FGMC) in Egypt, where over 90% of women ages 15-49 are cut. FGMC has potential adverse effects on demographic and health outcomes and has been defined as a human-rights violation. Contextual factors are important determinants of FGMC, but an integrated theory is lacking, and quantitative multilevel research is limited. We theorized that more favorable community-level gender systems, including gender norms opposing FGMC and expanded opportunities for women outside of the family, would be associated with a daughters lower risk of FGMC and would strengthen the negative association of a mothers opposition to FGMC with her daughters risk of cutting. Using a national sample of 14,171 mother-daughter dyads from the 2014 Egypt Demographic and Health Survey, we estimated multilevel discrete-time hazard models to test these relationships. Community gender norms opposing FGMC had significant direct, negative associations with the hazard that a daughter was cut, but womens opportunities outside the family did not. Maternal opposition to FGMC was negatively associated with cutting a daughter, and these associations were stronger where community opposition to FGMC and opportunities for women were greater. Results provided good support for a gender-systems theory of the multilevel influences on FGMC. Integrated, multilevel interventions that address gender norms about FGMC and opportunities for women in the community, as well as beliefs about the practice among the mothers of at-risk daughters may be needed for sustainable declines in the practice. | 10.1371/journal.pone.0229917 | medrxiv |
10.1101/19008136 | Targeting the centromedian thalamic nucleus for deep brain stimulation | Warren, A. E. L.; Dalic, L. J.; Thevathasan, W.; Roten, A.; Bulluss, K. J.; Archer, J. S. | Aaron E.L. Warren | University of Melbourne | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | neurology | https://www.medrxiv.org/content/early/2019/10/18/19008136.source.xml | ObjectivesDeep brain stimulation (DBS) of the centromedian thalamic nucleus (CM) is an emerging treatment for multiple brain diseases, including the drug-resistant epilepsy Lennox-Gastaut syndrome (LGS). We aimed to improve neurosurgical targeting of the CM by (i) developing a structural MRI approach for CM visualisation, (ii) identifying the CMs neurophysiological characteristics, and (iii) mapping connectivity from CM-DBS sites using functional MRI (fMRI).
MethodsNineteen patients with LGS (mean age=28 years) underwent pre-surgical 3 tesla MRI using magnetisation-prepared 2 rapid acquisition gradient echoes (MP2RAGE) and fMRI sequences; 16 proceeded to bilateral CM-DBS implantation and intraoperative microelectrode recordings (MERs) from the thalamus. CM visualisation was achieved by highlighting intrathalamic borders on MP2RAGE using Sobel edge-detection. Mixed-effects analysis compared two MER features (spike firing rate, background noise) between ventrolateral, CM, and parafasicular nuclei. Resting-state fMRI connectivity was assessed using implanted CM-DBS electrode positions as regions-of-interest.
ResultsThe CM appeared as a hyperintense region bordering the comparatively hypointense pulvinar, mediodorsal, and parafasicular nuclei. At the group-level, reduced spike firing and background noise distinguished CM from the ventrolateral nucleus; however, these trends were not found in 20-25% of individual MER trajectories. Areas of fMRI connectivity included basal ganglia, brainstem, cerebellum, sensorimotor/premotor and limbic cortex.
ConclusionsIn the largest clinical trial cohort of LGS patients undergoing CM-DBS reported to date, we show that accurate targeting of the CM is achievable using 3 tesla MP2RAGE MRI. MERs may provide additional localising features in some cases, however their utility is limited by inter-patient variability. Therapeutic effects of CM-DBS may be mediated via connectivity with brain networks that support diverse arousal, cognitive, and sensorimotor processes. | 10.1136/jnnp-2019-322030 | medrxiv |
10.1101/19008342 | Genetic determinants of trehalose utilization are not associated with severe Clostridium difficile infection | Saund, K.; Rao, K.; Young, V. B.; Snitkin, E. S. | Evan S Snitkin | University of Michigan | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/10/18/19008342.source.xml | In a case-control study of patients with C. difficile infection we found no statistically significant association between the presence of trehalose utilization variants in infecting C. difficile strains and development of severe infection. These results do not support trehalose utilization conferring enhanced virulence in the context of human C. difficile infections. | 10.1093/ofid/ofz548 | medrxiv |
10.1101/19008276 | Sugar or Salt (SOS): a protocol for a UK multicentre randomised trial of mannitol and hypertonic saline in severe traumatic brain injury and intracranial hypertension | Rowland, M. J.; Veenith, T.; Scomparin, C.; Wilson, M. H.; Hutchinson, P. J.; Kolias, A. G.; Lall, R.; Regan, S.; Mason, J.; Andrews, P. J.; Horner, D.; Naisbitt, J.; Devrell, A.; Malins, A.; Dark, P.; McAuley, D. F.; Perkins, G. D. | Matthew James Rowland | Kadoorie Centre for Critical Care Research, Nuffield Division of Anaesthesia, University of Oxford, Oxford, UK | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | intensive care and critical care medicine | https://www.medrxiv.org/content/early/2019/10/18/19008276.source.xml | Hyperosmolar solutions are widely used to treat raised intracranial pressure (ICP) following severe traumatic brain injury (TBI). Although mannitol has historically been the most frequently administered, hypertonic saline (HTS) solutions are increasingly being used. However, definitive evidence regarding their comparative effectiveness is lacking. The Sugar or Salt (SOS) Trial is a UK randomised, allocation concealed open label multicentre pragmatic trial designed to determine the clinical and cost-effectiveness of hypertonic saline (HTS) compared with mannitol in the management of patients with severe TBI. Patients requiring intensive care unit admission and intracranial pressure (ICP) monitoring post-TBI will be allocated at random to receive equi-osmolar boluses of either mannitol or HTS following failure of routine first line measures to control ICP. The primary outcome for the study will be the Extended Glasgow Outcome Scale (GOS-E) assessed at 6 months after randomisation. Results will inform current clinical practice in the routine use of hyperosmolar therapy as well as assess the impact of potential side effects. Pre-planned longer term clinical and cost effectiveness analyses will further inform the use of these treatments. | 10.1177/1751143720901690 | medrxiv |
10.1101/19009159 | Bringing Proportional Recovery into Proportion: Bayesian Hierarchical Modelling of Post-Stroke Motor Performance | Bonkhoff, A. K.; Hope, T.; Bzdok, D.; Guggisberg, A. G.; Hawe, R. L.; Dukelow, S. P.; Rehme, A. K.; Fink, G. R.; Grefkes, C.; Bowman, H. | Anna K Bonkhoff | Department of Neurology, University Hospital Cologne, Cologne, Germany | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | neurology | https://www.medrxiv.org/content/early/2019/10/18/19009159.source.xml | Accurate predictions of motor performance after stroke are of cardinal importance for the patient, clinician, and health care system. More than ten years ago, the proportional recovery rule was introduced by promising just that: high-fidelity predictions of recovery following stroke based only on the initially lost motor performance, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than assumed by many.
We systematically revisited stroke outcome predictions by casting the data in a less confounded form and employing more integrative and flexible hierarchical Bayesian models. We jointly analyzed n=385 post-stroke trajectories from six separate studies - the currently largest overall dataset of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Finally, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data.
The first model comparison, relying on the conventional fraction of patients called fitters, pointed to a combination of constant and proportional to lost function recovery. Proportional to lost here describes the original notion of proportionality, indicating greater recovery in case of a more pronounced initial deficit. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analyzing the complete spectrum of subjects, model comparison selected a composite of constant and proportional to spared function recovery, implying a more significant improvement in case of more preserved function. Explained variance was at 53%.
Therefore, our data suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the levels of explanatory value were substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behavior scores to explain stroke recovery and establish robust single-subject predictions. | 10.1093/brain/awaa146 | medrxiv |
10.1101/19008763 | Implications of MGMT promoter methylation and its downstream hMSH2 mRNA in primary malignant glioma | Manuel, J.; K V L, N. R.; G K, C. | Chetan G K | NIMHANS,Bangalore, India | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | oncology | https://www.medrxiv.org/content/early/2019/10/18/19008763.source.xml | BackgroundHypermethylation of 06-methylguanine DNA methyltransferase (MGMT)promoter seen in high grade gliomas (HGG) leads to the accumulation of O6-meG DNA damage which mispairs with thymine, requiring recognition by mismatch repair protein dimer MutS, whose primary component is coded by Human MutS homolog protein 2 (hMSH2). O6-meG repair necessitates the interaction/combined action of MGMT andhMSH2 to maintain genomic stability. Analysis of the correlation between MGMT methylation and hMSH2mRNAexpression in HGG and their role in the prognosis was explored.
MethodsStudy was performed on 54 primary-frontal lobe HGG tumors, MGMT promoter methylation was detected by Q-MSP and Q-PCR was used to analyse hMSH2 m-RNA expression levels.
ResultsMGMT methylation was seen in 62%patients the mean percentage of methylation (PoM) being (17.62{+/-}17.20) %. MGMT PoM[≥]10% had improved Progression free survival (p=0.015) and [≥]8% had better Overall survival (p=0.043), indicating its predictive significance. Over expression of hMSH2 was seen in 50% patients with a median fold change of 2.74 (p=0.021). Univariate analysis of high hMSH2 expression with therapy(CT+RT) showed poor PFS (p=0.002). There was no correlation between MGMT methylation and hMSH2 expression.
ConclusionMGMT PoM of [≥]10% is a significant prognostic marker. Over expression of hMSH2 is prognostic marker for poor treatment response. Lack of/aberrant correlation between MGMT andhMSH2 could indicate impaired DNA repair of O6-meG in HGG, and this could be one of the factors responsible for both, gliomagenesis and variations in treatment response. | null | medrxiv |
10.1101/19008680 | Towards a differential diagnosis of cochlear synaptopathy and outer-hair-cell deficits in mixed sensorineural hearing loss pathologies | Vasilkov, V.; Verhulst, S. | Sarah Verhulst | Ghent University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | otolaryngology | https://www.medrxiv.org/content/early/2019/10/18/19008680.source.xml | Damage to the auditory periphery is more widespread than predicted by the gold-standard clinical audiogram. Noise exposure, ototoxicity and aging can destroy cochlear inner-hair-cell afferent synapses and result in a degraded subcortical representation of sound while leaving hearing thresholds unaffected. Damaged afferent synapses, i.e. cochlear synaptopathy, can be quantified using histology, but a differential diagnosis in living humans is difficult: histology cannot be applied and existing auditory evoked potential (AEP) metrics for synaptopathy become insensitive when other sensorineural hearing impairments co-exist (e.g., outer-hair-cell damage associated with elevated hearing thresholds). To develop a non-invasive diagnostic method which quantifies synaptopathy in humans and animals with normal or elevated hearing thresholds, we employ a computational model approach in combination with human AEP and psychoacoustics. We propose the use of a sensorineural hearing loss (SNHL) map which comprises two relative AEP-based metrics to quantify the respective degrees of synaptopathy and OHC damage and evaluate to which degree our predictions of AEP alterations can explain individual data-points in recorded SNHL maps from male and female listeners with normal or elevated audiometric thresholds. We conclude that SNHL maps can offer a more precise diagnostic tool than existing AEP methods for individual assessment of the synaptopathy and OHC-damage aspect of sensorineural hearing loss.
Significance StatementHearing loss ranks fourth in global causes for disability and risk factors include noise exposure, ototoxicity and aging. The most vulnerable parts of the cochlea are the inner-hair-cell afferent synapses and their damage (cochlear synaptopathy) results in a degraded subcortical representation of sound. While synaptopathy can be estimated reliably using histology, it cannot be quantified this way in living humans. Secondly, other co-existing sensorineural hearing deficits (e.g., outer-hair-cell damage) can complicate a differential diagnosis. To quantify synaptopathy in humans and animals with normal or elevated hearing thresholds, we adopt a theoretical and interdisciplinary approach. Sensitive diagnostic metrics for synaptopathy are crucial to assess its prevalence in humans, study its impact on sound perception and yield effective hearing restoration strategies. | null | medrxiv |
10.1101/19008680 | Towards a differential diagnosis of cochlear synaptopathy and outer-hair-cell deficits in mixed sensorineural hearing loss pathologies | Vasilkov, V.; Verhulst, S. | Sarah Verhulst | Ghent University | 2019-11-05 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | otolaryngology | https://www.medrxiv.org/content/early/2019/11/05/19008680.source.xml | Damage to the auditory periphery is more widespread than predicted by the gold-standard clinical audiogram. Noise exposure, ototoxicity and aging can destroy cochlear inner-hair-cell afferent synapses and result in a degraded subcortical representation of sound while leaving hearing thresholds unaffected. Damaged afferent synapses, i.e. cochlear synaptopathy, can be quantified using histology, but a differential diagnosis in living humans is difficult: histology cannot be applied and existing auditory evoked potential (AEP) metrics for synaptopathy become insensitive when other sensorineural hearing impairments co-exist (e.g., outer-hair-cell damage associated with elevated hearing thresholds). To develop a non-invasive diagnostic method which quantifies synaptopathy in humans and animals with normal or elevated hearing thresholds, we employ a computational model approach in combination with human AEP and psychoacoustics. We propose the use of a sensorineural hearing loss (SNHL) map which comprises two relative AEP-based metrics to quantify the respective degrees of synaptopathy and OHC damage and evaluate to which degree our predictions of AEP alterations can explain individual data-points in recorded SNHL maps from male and female listeners with normal or elevated audiometric thresholds. We conclude that SNHL maps can offer a more precise diagnostic tool than existing AEP methods for individual assessment of the synaptopathy and OHC-damage aspect of sensorineural hearing loss.
Significance StatementHearing loss ranks fourth in global causes for disability and risk factors include noise exposure, ototoxicity and aging. The most vulnerable parts of the cochlea are the inner-hair-cell afferent synapses and their damage (cochlear synaptopathy) results in a degraded subcortical representation of sound. While synaptopathy can be estimated reliably using histology, it cannot be quantified this way in living humans. Secondly, other co-existing sensorineural hearing deficits (e.g., outer-hair-cell damage) can complicate a differential diagnosis. To quantify synaptopathy in humans and animals with normal or elevated hearing thresholds, we adopt a theoretical and interdisciplinary approach. Sensitive diagnostic metrics for synaptopathy are crucial to assess its prevalence in humans, study its impact on sound perception and yield effective hearing restoration strategies. | null | medrxiv |
10.1101/19009464 | Immune response and endocytosis pathways are associated with the escape of Alzheimer's Disease | Tesi, N.; van der Lee, S.; Hulsman, M.; Jansen, I.; Stringa, N.; van Schoor, N.; Scheltens, P.; van der Flier, W.; Huisman, M.; Reinders, M.; Holstege, H. | Henne Holstege | Amsterdam UMC, Amsterdam | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/10/18/19009464.source.xml | Developing Alzheimers disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was {beta}-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to {beta}-amyloid metabolism. | 10.1038/s41398-020-01018-7 | medrxiv |
10.1101/19009464 | Immune response and endocytosis pathways are associated with the escape of Alzheimer's Disease | Tesi, N.; van der Lee, S.; Hulsman, M.; Jansen, I.; Stringa, N.; van Schoor, N.; Scheltens, P.; van der Flier, W.; Huisman, M.; Reinders, M.; Holstege, H. | Henne Holstege | Amsterdam UMC, Amsterdam | 2019-10-25 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/10/25/19009464.source.xml | Developing Alzheimers disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was {beta}-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to {beta}-amyloid metabolism. | 10.1038/s41398-020-01018-7 | medrxiv |
10.1101/19009464 | Immune response and endocytosis pathways are associated with the resilience against Alzheimer's Disease | Tesi, N.; van der Lee, S.; Hulsman, M.; Jansen, I.; Stringa, N.; van Schoor, N.; Scheltens, P.; van der Flier, W.; Huisman, M.; Reinders, M.; Holstege, H. | Henne Holstege | Amsterdam UMC, Amsterdam | 2020-07-16 | 3 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | genetic and genomic medicine | https://www.medrxiv.org/content/early/2020/07/16/19009464.source.xml | Developing Alzheimers disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was {beta}-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to {beta}-amyloid metabolism. | 10.1038/s41398-020-01018-7 | medrxiv |
10.1101/19008839 | The importance of adolescent girls and \"epidemic gearing\" on HIV prevalence across West Africa | Prudden, H.; Mukandavire, Z.; Gorgens, M.; Wilson, D.; Panovska-Griffiths, J.; Watts, C. | Jasmina Panovska-Griffiths | UCL | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | hiv aids | https://www.medrxiv.org/content/early/2019/10/18/19008839.source.xml | BackgroundIn West Africa HIV prevalence varies between 0.1-6% in female and between 0.1-4% in the male general population. Male circumcision is almost universal, and it is unclear what drives this variation. We use mathematical modelling to identify the determinants of this variation across fourteen West African countries.
MethodsWe developed a novel dynamic model of HIV transmission between population cohorts of female sex workers (FSWs), their clients, females with 2+ partners in the past year and other sexually active women and men in the general population. Parameter ranges were determined from the literature and sampled using Latin Hypercube sampling to identify parameter sets that fit West African HIV prevalence data. Partial-rank correlation coefficients between different model parameters and the HIV prevalence in general male and female population across 14 countries were calculated to determine to most significantly correlated model parameters to HIV prevalence.
ResultsThe key determinant of HIV in females when prevalence is between 0-3% is the size of the brothel and non-brothel FSW groups. When female HIV prevalence >3%, the percentage of sexually active adolescent females with 2+ partners has greater influence on HIV prevalence. The size of the FSW groups has the most significant impact on HIV prevalence for males.
ConclusionsOur findings confirm the role of FSWs in West Africa as an important determinant of HIV risk, but also identify, in countries with higher HIV prevalence, the emerging role of a group of adolescent girls with 2+ partners is an important determinant of risk. In fact, our findings suggest that this group may enable the epidemic to be effectively "geared up" when partnerships are formed with higher-risk males, indicating additional prevention needs amongst this group.
FundingThis study was funded by UNAIDS. | null | medrxiv |
10.1101/19009498 | A Network Analysis Framework to Improve the Delivery of Mosquito Abatement Services in Machala, Ecuador | Lippi, C. A.; Mao, L.; Stewart-Ibarra, A. M.; Heydari, N.; Beltran Ayala, E.; Burkett-Cadena, N. D.; Blackburn, J. K.; Ryan, S. J. | Catherine A Lippi | University of Florida | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | infectious diseases | https://www.medrxiv.org/content/early/2019/10/18/19009498.source.xml | BackgroundVector-borne disease places a high health and economic burden in the American tropics. Comprehensive vector control programs remain the primary method of containing local outbreaks. With limited resources, many vector control operations struggle to serve all affected communities within their districts. In the coastal city of Machala, Ecuador, vector control services, such as application of larvicides and truck-mounted fogging, are delivered through two deployment facilities managed by the Ecuadorian Ministry of Health. Public health professionals in Machala face several logistical issues when delivering mosquito abatement services, namely applying limited resources in ways that will most effectively suppress vectors of malaria, dengue, and encephalitis viruses.
MethodsUsing a transportation network analysis framework, we built models of service areas and optimized delivery routes based on distance costs associated with accessing neighborhoods throughout the city. Optimized routes were used to estimate the relative cost of accessing neighborhoods for mosquito control services in Machala, creating a visual tool to guide decision makers and maximize mosquito control program efficiency. Location-allocation analyses were performed to evaluate efficiency gains of moving service deployment to other available locations with respect to distance to service hub, neighborhood population, dengue incidence, and housing condition.
ResultsUsing this framework, we identified different locations for targeting mosquito control efforts, dependent upon management goals and specified risk factors of interest, including human population, housing condition, and reported dengue incidence. Our models indicate that neighborhoods on the periphery of Machala with the poorest housing conditions are the most costly to access. Optimal locations of facilities for deployment of control services change depending on pre-determined management priorities, increasing the population served via inexpensive routes up to 34.9%, and reducing overall cost of accessing neighborhoods up to 12.7%.
ConclusionsOur transportation network models indicate that current locations of mosquito control facilities in Machala are not ideal for minimizing driving distances or maximizing populations served. Services may be optimized by moving vector control operations to other existing public health facilities in Machala. This work represents a first step in creating a spatial tool for planning and critically evaluating the systematic delivery of mosquito control services in Machala and elsewhere. | 10.1186/s12942-020-0196-6 | medrxiv |
10.1101/19009282 | Phase I assessments of first-in-human administration of a novel malaria anti-sporozoite vaccine candidate, R21 in matrix-M adjuvant, in UK and Burkinabe volunteers | Venkatraman, N.; Tiono, A.; Bowyer, G.; Powlson, J.; Collins, K.; Coulibaly, S.; Datoo, M.; Silman, D.; Ouedraogo, A.; Nebie, I.; Imoukhuede, E.; Brod, F.; Folegatti, P.; Dickinson, E.; Jamieson, S.; Bougouma, E.; Wright, D.; Bellamy, D.; Diarra, A.; Bliss, C.; Morter, R.; Glenn, G.; Fries, L.; Reimer, J.; Lovgren-Bengtsson, K.; Baker, M.; Poulton, I.; Moyle, S.; Berrie, E.; Green, N.; Mukhopadhyay, E.; Viebig, N.; Angus, B.; Lawrie, A.; Roberts, R.; Gilbert, S.; Lewis, D.; Sirima, S.; Ewer, K.; Hill, A. | Katie Ewer | University of Oxford | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | infectious diseases | https://www.medrxiv.org/content/early/2019/10/18/19009282.source.xml | BackgroundImprovements in malaria control have stalled recently and new tools are needed. The R21 vaccine is comprised of the malaria circumsporozoite protein fused to hepatitis B surface antigen (HBsAg). It forms particles that lack the excess HBsAg in the frequently tested malaria vaccine candidate, RTS,S/AS01B.
MethodsWe conducted an open-label, first-in-human, Phase Ia study evaluating safety and immunogenicity of R21 administered alone and with the saponin-based adjuvant, Matrix-M (MM). Twenty-eight healthy adults received three doses of R21 given intramuscularly 4 weeks apart. We subsequently conducted a Phase Ib randomised, controlled trial in West African adults.
FindingsVaccinations were well tolerated, and the majority of local and systemic adverse events were mild. Reactogenicity was significantly lower in Burkinabe than UK vaccinees (p<0.0001). Antibody responses increased significantly 28 days after the 2nd vaccination in UK volunteers. Antibody responses to R21 in all dose groups (2g, 10g and 50g) were comparable to those of 50g RTS,S/AS01B in malaria-naive adults at 28 days after final vaccination. The 10g dose induced more durable responses, with 2-fold higher NANP-specific IgG titres at 6 months compared with the 2g and 50g dose groups. R21 also boosted baseline humoral responses in Burkinabe adults with well-maintained responses suggesting natural boosting.
InterpretationR21 adjuvanted with MM is safe and has comparable immunogenicity to RTS,S/AS01B, even when administered at a five-fold lower 10g dose in UK and African populations. This forms the basis for efficacy testing of this vaccine which could prove to be particularly cost-effective to manufacture and deploy. | null | medrxiv |
10.1101/19009175 | Eligibility for Subcutaneous Implantable Cardioverter Defibrillator in Congenital Heart Disease | Wang, L.; Javadekar, N.; Rajagopalan, A.; Rogovoy, N.; Haq, K. T.; Broberg, C.; Tereshchenko, L. G. | Larisa G Tereshchenko | Oregon Health & Science University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/10/18/19009175.source.xml | BackgroundThe goals of this study were: assess left-and right-sided subcutaneous implantable cardioverter-defibrillator (S-ICD) eligibility in adult congenital heart disease (ACHD) patients, use machine learning to predict S-ICD eligibility in ACHD patients, and transform 12-lead ECG to S-ICD 3-lead ECG, and vice versa.
MethodsACHD outpatients (n=101; age 42{+/-}14 y; 52% female; 85% white; left ventricular ejection fraction (LVEF) 56{+/-}9%) were enrolled in a prospective study. Supine and standing 12-lead ECG was recorded simultaneously with a right- and left-sided S-ICD 3-lead ECG. Peak-to-peak QRS and T amplitudes, RR, PR, QT, QTc, QRS intervals, Tmax, and R/Tmax (31 predictor variables) were tested. Model selection, training, and testing were performed using supine ECG datasets. Validation was performed using standing ECG datasets and out-of-sample non-ACHD population (n=68; age 54{+/-}16 y; 54% female; 94% white; LVEF 61{+/-}8%).
ResultsA 40% of participants were ineligible for S-ICD. Tetralogy of Fallot patients passed right-sided screening (57%) more often than left-sided (21%; McNemars {chi}2 P=0.025). The ridge model demonstrated the best cross-validation function. Validation of the ridge models was satisfactory for standing left-sided [ROC AUC 0.687 (95%CI 0.582-0.791)] and right-sided [ROC AUC 0.655(95%CI 0.549-0.762)] S-ICD eligibility prediction. Out-of-sample validation in the non-ACHD population yielded a 100% sensitivity of the pre-selected threshold for the elastic net model. Validation of the transformation matrices showed satisfactory agreement (<0.1 mV difference).
ConclusionNearly half of the contemporary ACHD population is ineligible for S-ICD. Machine-learning prediction of S-ICD eligibility can be used for screening of S-ICD candidates. | 10.1016/j.hrthm.2020.01.016 | medrxiv |
10.1101/19008771 | Investigation of an estimate of daily resting heart rate using a consumer wearable device | Heneghan, C.; Venkatraman, S.; Russell, A. | Conor Heneghan | Fitbit | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/10/18/19008771.source.xml | Resting heart rate is accepted as a valid overall indicator of cardiovascular risk and is a low-cost easy-to-measure metric that can be collected in both home and clinical settings. Wearable devices such as smartwatches and trackers can measure heart rate continuously using optical technology. This study reports initially on the agreement between the resting heart rate reported by a wearable device (Fitbit Charge HR and Fitbit Blaze) and a chest-based consumer electrocardiogram (Polar H7). In 45 subjects, the reported resting heart rates agreed within 0.89 bpm over a resting period of 5 mins. The same device and algorithm was then used in a population of 168 subjects (45.9{+/-} 15.6 yrs) who were asked to collect their resting heart rate for four days under seven different conditions and times (at wake sitting/lying down, pre-breakfast, pre-lunch, pre-dinner, and before bed sitting/lying down). The reported values were compared with the Daily Resting Heart Rate (DRHR) reported by the wearable device. The measurement lying down before wake were closest to the DRHR (mean error of 0.0 bpm with a 25-75th percentile spread of {+/-}3.5bpm. There was a significant circadian variation in the reported resting heart rate across subjects, with the highest values reported in the middle of the day. Within individual subjects, the median standard deviation of heart rate at rest was 3-5bpm even measured under nominally similar conditions over four days. | null | medrxiv |
10.1101/19008748 | Trends and variation in prescribing of suboptimal statin treatment regimes: a cohort study in English primary care | Curtis, H. J.; Walker, A. J.; MacKenna, B.; Croker, R.; Goldacre, B. | Ben Goldacre | University of Oxford | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/10/18/19008748.source.xml | ObjectivesWe set out to describe trends and variation in statin prescribing in England that breaches 2014 national guidance on "high-intensity" statins. We identify factors associated with breaching; and assess the feasibility of rapid prescribing behaviour change.
Design, Setting and ParticipantsRetrospective cohort study in NHS primary care in England, including all 8,142 standard general practices from August 2010 to March 2019.
Main Outcome MeasuresWe categorised statins as high or low/medium-intensity based on two different thresholds, and calculated the proportion prescribed below these thresholds across all practices. We plotted trends and geographical variation, carried out mixed effects logistic regression to identify practice characteristics associated with breaching guidance, and used indicator saturation to identify practices exhibiting sudden changes in prescribing.
ResultsWe included all 8,142 practices across the study period. The proportion of statin prescriptions below the recommended 40% LDL-lowering threshold decreased gradually since 2012 from 80% to 45%; the proportion below a pragmatic 37% threshold decreased from 30% to 18%. The 2014 guidance had minimal impact on these trends. We found wide variation between practices (interdecile ranges 20% to 85% and 10% to 30% respectively in 2018). Mixed effects logistic regression did not identify practice characteristics strongly associated with breaching guidance. Indicator saturation identified several practices exhibiting sudden changes in prescribing towards greater guideline compliance.
ConclusionsBreaches of English guidance on choice of statin remain common, with substantial variation between GP practices. Some practices and regions have implemented rapid change, indicating the feasibility of rapid prescribing behaviour change. We discuss the potential for a national strategic approach, using data and evidence to optimise care, including targeted education alongside audit and feedback to outliers through services such as OpenPrescribing.
SummaryO_ST_ABSWhat is already known on this topicC_ST_ABSEnglish national guidance recommends the use of a high-intensity statin, capable of reducing LDL (low-density lipoprotein) cholesterol by 40% or more. Adherence at the time of guideline release was low, but has not been documented since.
What this study addsAdherence is improving, but breaches of national guidance remain common, with 45% of prescriptions below the recommended strength, and there is very substantial variation between practices. Some practices have exhibited rapid positive change in prescribing, which indicates that better adherence could readily be achieved. We have produced a live data tool allowing anyone to explore any practices current statin prescribing behaviour. | 10.3399/bjgp20x710873 | medrxiv |
10.1101/19009605 | Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization | Yang, Q.; Sanderson, E.; Tilling, K.; Borges, M. C.; Lawlor, D. A. | Qian Yang | University of Bristol | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by | epidemiology | https://www.medrxiv.org/content/early/2019/10/18/19009605.source.xml | BackgroundOur aim is to produce guidance on exploring and mitigating possible bias when genetic instrumental variables (IVs) associate with traits other than the exposure of interest in Mendelian randomization (MR) studies.
MethodsWe use causal diagrams to illustrate scenarios that could result in IVs being related to (non-exposure) traits. We recommend that MR studies explore possible IV-non-exposure associations across a much wider range of traits than is usually the case. Where associations are found, confounding by population stratification should be assessed through adjusting for relevant population structure variables. To distinguish vertical from horizontal pleiotropy we suggest using bidirectional MR between the exposure and non-exposure traits and MR of the effect of the non-exposure traits on the outcome of interest. If vertical pleiotropy is plausible, standard MR methods should be unbiased. If horizontal pleiotropy is plausible, we recommend using multivariable MR to control for observed pleiotropic traits and conducting sensitivity analyses which do not require prior knowledge of specific invalid IVs or pleiotropic paths.
ResultsWe applied our recommendations to an illustrative example of the effect of maternal insomnia on offspring birthweight in the UK Biobank. We found little evidence that unexpected IV-non-exposure associations were driven by population stratification. Three out of six observed non-exposure traits plausibly reflected horizontal pleiotropy. Multivariable MR and sensitivity analyses suggested an inverse association of insomnia with birthweight, but effects were imprecisely estimated in some of these analyses.
ConclusionsWe provide guidance for MR studies where genetic IVs associate with non-exposure traits.
Key messagesO_LIGenetic variants are increasingly found to associate with more than one social, behavioural or biological trait at genome-wide significance, which is a challenge in Mendelian randomization (MR) studies.
C_LIO_LIFour broad scenarios (i.e. population stratification, vertical pleiotropy, horizontal pleiotropy and reverse causality) could result in an IV-non-exposure trait association.
C_LIO_LIPopulation stratification can be assessed through adjusting for population structure with individual data, while two-sample MR studies should check whether the original genome-wide association studies have used robust methods to properly account for it.
C_LIO_LIWe apply currently available MR methods for discriminating between vertical and horizontal pleiotropy and mitigating against horizontal pleiotropy to an example exploring the effect of maternal insomnia on offspring birthweight.
C_LIO_LIOur study highlights the pros and cons of relying more on sensitivity analyses without considering particular pleiotropic paths versus systematically exploring and controlling for potential pleiotropic paths via known characteristics.
C_LI | 10.1007/s10654-022-00874-5 | medrxiv |
10.1101/19008722 | A Markov Chain approach for ranking treatments in network meta-analysis | Chaimani, A.; Porcher, R.; Sbidian, E.; Mavridis, D. | Anna Chaimani | Universite de Paris, Research Center of Epidemiology and Statistics Sorbonne Paris Cite (CRESS-UMR1153), INSERM, INRA, F-75004 Paris, France | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/10/18/19008722.source.xml | When interpreting the relative effects from a network meta-analysis (NMA), researchers are usually aware of the potential limitations that may render the results for some comparisons less useful or meaningless. In the presence of sufficient and appropriate data, some of these limitations (e.g. risk of bias, small-study effects, publication bias) can be taken into account in the statistical analysis. Very often, though, the necessary data for applying these methods are missing and data limitations cannot be formally integrated into ranking. In addition, there are other important characteristics of the treatment comparisons that cannot be addressed within a statistical model but only through qualitative judgements; for example, the relevance of data to the research question, the plausibility of the assumptions, etc. Here, we propose a new measure for treatment ranking called the Probability of Selecting a Treatment to Recommend (POST-R). We suggest that the order of treatments should represent the process of considering treatments for selection in clinical practice and we assign to each treatment a probability of being selected. This process can be considered as a Markov chain model that allows the end-users of NMA to select the most appropriate treatments based not only on the NMA results but also to information external to the NMA. In this way, we obtain rankings that can inform decision-making more efficiently as they represent not only the relative effects but also their potential limitations. We illustrate our approach using a NMA comparing treatments for chronic plaque psoriasis and we provide the Stata commands. | 10.1002/sim.8784 | medrxiv |
10.1101/19009076 | An Environment-Wide Study of Adult Cognitive Performance in the 23andMe Cohort | Huang, Y.; Filshtein, T.; 23andMe Research Team, ; Gentleman, R.; Aslibekyan, S. | Stella Aslibekyan | 23andMe | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/10/18/19009076.source.xml | BACKGROUNDWith the emergence of web-based data collection methods, large digital health cohorts offer the opportunity to conduct behavioral and epidemiologic research at an unprecedented scale. The size and breadth of such data sets enable discovery of novel associations across the phenotypic spectrum.
METHODSWe deployed the digital symbol substitution test (DSST) online to consented 23andMe research participants 50-85 years of age. We tested cross-sectional associations between DSST performance and 824 phenotypes using linear regression models adjusted for age, sex, age*sex interaction, device, time of cohort entry, and ancestry, separately among discovery (n=144,786) and replication (n=93,428) samples; additional analyses further adjusted for education. We post-stratified association estimates on age, sex, and education to adjust for discrepancies across subsamples. Leveraging the rich genetic and phenotypic data available at 23andMe, we also estimated genetic and environmental correlations between DSST and its top correlates using linkage disequilibrium score regression.
RESULTS97 phenotypes were significantly (false discovery rate < 0.05) and strongly (standardized effect size > |0.5|) associated with DSST performance in the discovery phase. Of those, 60 (38 with additional adjustment for education) demonstrated both statistical significance and consistent direction of association in the replication sample. The significantly associated phenotypes largely clustered into the following categories: psychiatric traits (e.g. anxiety, {beta} per 1 SD = -0.74, P-value=3.9x10-169), education (e.g. highest math class completed, {beta} per 1 SD = 2.11, P-value<1 x 10-300), leisure activities (e.g. solitary activities like puzzles, {beta} per 1 SD = 1.85, P-value<1.0x10-300), social determinants (e.g. household income, {beta} per 1 SD = 1.20, P-value= 8.9x10-245, and lifestyle (e.g. years smoked, {beta} per 1 SD = -0.98, P-value= 2.2x10-78). We identified several reproducible genetic correlations between DSST and its top associated exposures (e.g. 0.48 for leisure activities like puzzles, 0.28 for years of education, and -0.24 for anxiety; all P [≤] 7.9x10-26). For almost all exposures, genetic correlations with DSST were considerably stronger than environmental correlations.
CONCLUSIONSWe have conducted the largest study of cognitive performance to date, building evidence supporting its correlations with many social, lifestyle, and clinical exposures. We established that the observed associations are in part underpinned by shared genetic architecture. Our study illustrates the potential of large-scale digital cohorts to contribute to epidemiologic discovery. | null | medrxiv |
10.1101/19009076 | An Environment-Wide Study of Adult Cognitive Performance in the 23andMe Cohort | Huang, Y.; Filshtein, T.; 23andMe Research Team, ; Gentleman, R.; Aslibekyan, S. | Stella Aslibekyan | 23andMe | 2019-11-02 | 2 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/11/02/19009076.source.xml | BACKGROUNDWith the emergence of web-based data collection methods, large digital health cohorts offer the opportunity to conduct behavioral and epidemiologic research at an unprecedented scale. The size and breadth of such data sets enable discovery of novel associations across the phenotypic spectrum.
METHODSWe deployed the digital symbol substitution test (DSST) online to consented 23andMe research participants 50-85 years of age. We tested cross-sectional associations between DSST performance and 824 phenotypes using linear regression models adjusted for age, sex, age*sex interaction, device, time of cohort entry, and ancestry, separately among discovery (n=144,786) and replication (n=93,428) samples; additional analyses further adjusted for education. We post-stratified association estimates on age, sex, and education to adjust for discrepancies across subsamples. Leveraging the rich genetic and phenotypic data available at 23andMe, we also estimated genetic and environmental correlations between DSST and its top correlates using linkage disequilibrium score regression.
RESULTS97 phenotypes were significantly (false discovery rate < 0.05) and strongly (standardized effect size > |0.5|) associated with DSST performance in the discovery phase. Of those, 60 (38 with additional adjustment for education) demonstrated both statistical significance and consistent direction of association in the replication sample. The significantly associated phenotypes largely clustered into the following categories: psychiatric traits (e.g. anxiety, {beta} per 1 SD = -0.74, P-value=3.9x10-169), education (e.g. highest math class completed, {beta} per 1 SD = 2.11, P-value<1 x 10-300), leisure activities (e.g. solitary activities like puzzles, {beta} per 1 SD = 1.85, P-value<1.0x10-300), social determinants (e.g. household income, {beta} per 1 SD = 1.20, P-value= 8.9x10-245, and lifestyle (e.g. years smoked, {beta} per 1 SD = -0.98, P-value= 2.2x10-78). We identified several reproducible genetic correlations between DSST and its top associated exposures (e.g. 0.48 for leisure activities like puzzles, 0.28 for years of education, and -0.24 for anxiety; all P [≤] 7.9x10-26). For almost all exposures, genetic correlations with DSST were considerably stronger than environmental correlations.
CONCLUSIONSWe have conducted the largest study of cognitive performance to date, building evidence supporting its correlations with many social, lifestyle, and clinical exposures. We established that the observed associations are in part underpinned by shared genetic architecture. Our study illustrates the potential of large-scale digital cohorts to contribute to epidemiologic discovery. | null | medrxiv |
10.1101/19008854 | Mosquito exposure and malaria morbidity; a micro-level analysis of household mosquito populations and malaria in a population-based longitudinal cohort in western Kenya | Prudhomme O'Meara, W.; Simmons, R.; Bullins, P.; Freedman, B.; Abel, L.; Mangeni, J.; Taylor, S. M.; Obala, A. A. | Wendy Prudhomme O'Meara | Duke University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/10/18/19008854.source.xml | BackgroundMalaria morbidity is highly overdispersed in the population. Fine-scale differences in mosquito exposure may partially explain this heterogeneity. However, exposure variability has not been related to individual malaria outcomes.
MethodsWe established a cohort of 38 households to explore the effect of household-level mosquito exposure and individual insecticide treated net(ITN) use on relative risk(RR) of diagnostically-confirmed malaria. We conducted monthly active surveillance (n=254; 2,624 person-months) and weekly mosquito collection in all households (2,092 household-days of collection). We used molecular techniques to confirm human blood feeding and exposure to infectious mosquitoes.
ResultsOf 1,494 female anopheles (89.8% Anopheles gambiae s.l.). 88.3% were fed, 51.9% had a human bloodmeal, and 9.2% were sporozoite-infected. 168 laboratory-confirmed malaria episodes were reported (incidence rate 0.064 episodes per person-month at risk, 95% confidence interval [CI]:0.055,0.074). Malaria risk was directly associated with exposure to sporozoite-infected mosquitoes (RR=1.24, 95%CI:1.11,1.38). No direct effect was measured between ITN use and malaria morbidity, however, ITN use did moderate the effect of mosquito exposure on morbidity.
ConclusionsMalaria risk increases linearly with vector density and feeding success for persons with low ITN use. In contrast, malaria risk among high ITN users is consistently low and insensitive to variation in mosquito exposure.
SummaryIn this study, we measure the relationship between fine-scale spatio-temporal heterogeneity in exposure to infected and successfully-fed malaria vectors, the incidence of malaria, and their interaction with ITN use in a population-based cohort. | 10.1093/infdis/jiz561 | medrxiv |
10.1101/19009647 | Development of population and Bayesian models for applied use in patients receiving cefepime | Liu, J.; Neely, M.; Lipman, J.; Sime, F.; Roberts, J.; Kiel, P. J.; Avedissian, S. A.; Rhodes, N. J.; Scheetz, M. | Marc Scheetz | Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA; Northwestern Memorial Hospital, Chicago, IL, USA; Midwestern University Chicago Colle | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nd | pharmacology and therapeutics | https://www.medrxiv.org/content/early/2019/10/18/19009647.source.xml | Understanding exposures of cefepime, a {beta}-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of twelve pediatric and two separate adult populations were assessed. Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n=34) on average weighed 82.7 kg and displayed a mean creatinine clearance (CrCL) of 106.7 mL/min. All pediatric subjects (n=36) had mean weight and CrCL of 16.0 kg and 195.64 mL/min, respectively. A covariate-adjusted two compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). The identified model serves well for population dosing and as a Bayesian prior for precision dosing.
Key pointsO_LIA unified cefepime population pharmacokinetic model has been developed from adult and pediatric patients and evaluates well in independent populations.
C_LIO_LIWhen paired with real time beta-lactam assays, precision dosing approach will optimize drug exposure and improve clinical outcomes.
C_LI | 10.1007/s40262-020-00873-3 | medrxiv |
10.1101/19009639 | Trade Study of Population Age Groups for a Clinical Trial in Attention Deficit Hyperactivity Disorder | Lodder, R. A.; Lovins, D. B. | Robert A. Lodder | University of Kentucky | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | pharmacology and therapeutics | https://www.medrxiv.org/content/early/2019/10/18/19009639.source.xml | ADHD is a neurodevelopmental disorder characterized by difficulty paying attention, impulsivity, and hyperactivity that is treated by an array of different modalities in order to decrease functional impairment. Despite the variety of available pharmacologic treatment options and their widespread use, there still remains a strong need to create innovative therapies. Game Based Therapy (GBT) is a type of cognitive behavioral therapy that seeks to increase the efficacy of currently available pharmacological treatments through improving cognitive deficits and reducing the current dose of such treatments. At the University of Kentucky, a clinical trial was implemented to assess the effects of combining stimulant pharmacotherapy with the popular video game Minecraft as Game Based Therapy on ADHD symptoms in children ages 10-15. However, the low subject recruitment played a large role in the trial failing to produce conclusive data from that site.
This trade study serves to address the difficulties of subject recruitment and determine an optimal population and location for future adoption of the clinical trial. Through statistical analysis of state, national, and survey data it was found that in Lexington, Kentucky, 18-21 year olds are the optimal population for future GBT with pharmacotherapy clinical trials. | null | medrxiv |
10.1101/19008433 | A target product profile for electronic clinical decision support algorithms combined with point-of-care diagnostic test results to support evidence-based decisions during patient consultations by health workers | Pelle, K. G.; Rambaud-Althaus, C.; D'Acremont, V.; Moran, G.; Sampath, R.; Katz, Z.; Moussy, F. G.; Mehl, G. L.; Dittrich, S. | Karell G. Pellé | Foundation for Innovative New Diagnostic | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/18/19008433.source.xml | Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point of care diagnostics with evidence-based clinical protocols, can help improve the quality of care, the rational use of resources (humans, diagnostics and medicines) and save patient lives. The development of a target product profile for electronic clinical decision support algorithms (CDSAs) aimed at guiding preventive or curative consultations, and that integrate diagnostic test results will help align developer and implementer processes and specifications with the needs of end-users, in terms of quality, safety, performance and operational functionality. To identify characteristics for a CDSA, experts from academia, research institutions, and industry as well as policy makers with expertise in diagnostic and CDSA development, and implementation in LMICs were convened. Experts discussed the critical characteristics of a draft TPP which was revised and finalised through a Delphi process to facilitate consensus building. Experts were in overwhelming agreement that, given that CDSAs provide patients management recommendations, the underlying clinical algorithms should be available in human readable format and evidence-based. Whenever possible, the algorithm output should take into account pre-test disease probabilities, diagnostic likelihood ratios of clinical or laboratory predictors and disease probability thresholds to test and to treat. Validation processes should at a minimum ensure the CDSA are implementing faithfully the evidence-based algorithm they are based on (internal validation through clinical association and analytical validation). Additionally, clinical validation, bringing practice evidence about the impact of the CDSA use on health outcomes, was recognized as a good to have. The CDSAs should be designed to fit within clinic workflows, connectivity challenges and high volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards. | 10.1136/bmjgh-2019-002067 | medrxiv |
10.1101/19008433 | A target product profile for electronic clinical decision support algorithms combined with point-of-care diagnostic test results to support evidence-based decisions during patient consultations by health workers | Pelle, K. G.; Rambaud-Althaus, C.; D'Acremont, V.; Moran, G.; Sampath, R.; Katz, Z.; Moussy, F. G.; Mehl, G. L.; Dittrich, S. | Karell G. Pellé | Foundation for Innovative New Diagnostic | 2019-10-29 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/29/19008433.source.xml | Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point of care diagnostics with evidence-based clinical protocols, can help improve the quality of care, the rational use of resources (humans, diagnostics and medicines) and save patient lives. The development of a target product profile for electronic clinical decision support algorithms (CDSAs) aimed at guiding preventive or curative consultations, and that integrate diagnostic test results will help align developer and implementer processes and specifications with the needs of end-users, in terms of quality, safety, performance and operational functionality. To identify characteristics for a CDSA, experts from academia, research institutions, and industry as well as policy makers with expertise in diagnostic and CDSA development, and implementation in LMICs were convened. Experts discussed the critical characteristics of a draft TPP which was revised and finalised through a Delphi process to facilitate consensus building. Experts were in overwhelming agreement that, given that CDSAs provide patients management recommendations, the underlying clinical algorithms should be available in human readable format and evidence-based. Whenever possible, the algorithm output should take into account pre-test disease probabilities, diagnostic likelihood ratios of clinical or laboratory predictors and disease probability thresholds to test and to treat. Validation processes should at a minimum ensure the CDSA are implementing faithfully the evidence-based algorithm they are based on (internal validation through clinical association and analytical validation). Additionally, clinical validation, bringing practice evidence about the impact of the CDSA use on health outcomes, was recognized as a good to have. The CDSAs should be designed to fit within clinic workflows, connectivity challenges and high volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards. | 10.1136/bmjgh-2019-002067 | medrxiv |
10.1101/19009589 | Dengue importation into Europe: a network connectivity-based approach | Salami, D.; Capinha, C.; Martins, M. d. R. O.; Sousa, C. A. | Donald Salami | Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa, Lisbon, Portugal | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by | public and global health | https://www.medrxiv.org/content/early/2019/10/18/19009589.source.xml | The spread of dengue through global human mobility is a major public health concern. A key challenge is understanding the transmission pathways and mediating factors that characterized the patterns of dengue importation into non-endemic areas. Utilizing a network connectivity-based approach, we analyze the importation patterns of dengue fever into European countries.
Seven connectivity indices were developed to characterize the role of the air passenger traffic, seasonality, incidence rate, geographical proximity, epidemic vulnerability, and wealth of a source country, in facilitating the transport and importation of dengue fever. We used generalized linear mixed models (GLMMs) to examine the relationship between dengue importation and the connectivity indices while accounting for the air transport network structure. We also incorporated network autocorrelation within a GLMM framework to investigate the propensity of a European country to receive an imported case, by virtue of its position within the air transport network.
The connectivity indices and dynamical processes of the air transport network were strong predictors of dengue importation in Europe. With more than 70% of the variation in dengue importation patterns explained. We found that transportation potential was higher for source countries with seasonal dengue activity, high passenger traffic, high incidence rates, lower economic status, and geographical proximity to a destination country in Europe. We also found that position of a European country within the air transport network was a strong predictor of the countrys propensity to receive an imported case.
Our findings provide evidence that the importation patterns of dengue into Europe can be largely explained by appropriately characterizing the heterogeneities of the source, and topology of the air transport network. This contributes to the foundational framework for building integrated predictive models for bio-surveillance of dengue importation. | 10.1371/journal.pone.0230274 | medrxiv |
10.1101/19009258 | A spatio-temporal approach to short-term forecasting of visceral leishmaniasis diagnoses in India | Nightingale, E. S.; Chapman, L. A. C.; Srikantiah, S.; Subramanian, S.; Purushothaman, J.; Cameron, M.; Medley, G. | Emily S Nightingale | London School of Hygiene and Tropical Medicine | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/10/18/19009258.source.xml | BackgroundThe elimination programme for visceral leishmaniasis (VL) in India has seen great progress, with total cases decreasing by over 80% since 2010 and many blocks now reporting zero cases from year to year. Prompt diagnosis and treatment is critical to continue progress and avoid epidemics in the increasingly susceptible population. Short-term forecasts could be used to highlight anomalies in incidence and support health service logistics. The model which best fits the data is not necessarily most useful for prediction, yet little empirical work has been done to investigate the balance between fit and predictive performance.
Methodology/Principal FindingsWe developed statistical models of monthly VL case counts at block level. By evaluating a set of randomly-generated models, we found that fit and one-month-ahead prediction were strongly correlated and that rolling updates to model parameters as data accrued were not crucial for accurate prediction. The final model incorporated auto-regression over four months, spatial correlation between neighboring blocks, and seasonality. Ninety-four percent of 10-90% prediction intervals from this model captured the observed count during a 24-month test period. Comparison of one-, three-and four-month-ahead predictions from the final model fit demonstrated that a longer time horizon yielded only a small sacrifice in predictive power for the vast majority of blocks.
Conclusions/SignificanceThe model developed is informed by routinely-collected surveillance data as it accumulates, and predictions are sufficiently accurate and precise to be useful. Such forecasts could, for example, be used to guide stock requirements for rapid diagnostic tests and drugs. More comprehensive data on factors thought to influence geographic variation in VL burden could be incorporated, and might better explain the heterogeneity between blocks and improve uniformity of predictive performance. Integration of the approach in the management of the VL programme would be an important step to ensuring continued successful control.
Author summaryThis paper demonstrates a statistical modelling approach for forecasting of monthly visceral leishmaniasis (VL) incidence at block level in India, which could be used to tailor control efforts according to local estimates and monitor deviations from the currently decreasing trend. By fitting a variety of models to four years of historical data and assessing predictions within a further 24-month test period, we found that the model which best fit the observed data also showed the best predictive performance, and predictive accuracy was maintained when making rolling predictions up to four months ahead of the observed data. Since there is a two-month delay between reporting and processing of the data, predictive power more than three months ahead of current data is crucial to make forecasts which can feasibly be acted upon. Some heterogeneity remains in predictive power across the study region which could potentially be improved using unit-specific data on factors believed to be associated with reported VL incidence (e.g. age distribution, socio-economic status and climate). | 10.1371/journal.pntd.0008422 | medrxiv |
10.1101/19009258 | A spatio-temporal approach to short-term forecasting of visceral leishmaniasis diagnoses in India | Nightingale, E. S.; Chapman, L. A. C.; Srikantiah, S.; Subramanian, S.; Purushothaman, J.; Bracher, J.; Cameron, M.; Medley, G. | Emily S Nightingale | London School of Hygiene and Tropical Medicine | 2019-11-05 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/11/05/19009258.source.xml | BackgroundThe elimination programme for visceral leishmaniasis (VL) in India has seen great progress, with total cases decreasing by over 80% since 2010 and many blocks now reporting zero cases from year to year. Prompt diagnosis and treatment is critical to continue progress and avoid epidemics in the increasingly susceptible population. Short-term forecasts could be used to highlight anomalies in incidence and support health service logistics. The model which best fits the data is not necessarily most useful for prediction, yet little empirical work has been done to investigate the balance between fit and predictive performance.
Methodology/Principal FindingsWe developed statistical models of monthly VL case counts at block level. By evaluating a set of randomly-generated models, we found that fit and one-month-ahead prediction were strongly correlated and that rolling updates to model parameters as data accrued were not crucial for accurate prediction. The final model incorporated auto-regression over four months, spatial correlation between neighboring blocks, and seasonality. Ninety-four percent of 10-90% prediction intervals from this model captured the observed count during a 24-month test period. Comparison of one-, three-and four-month-ahead predictions from the final model fit demonstrated that a longer time horizon yielded only a small sacrifice in predictive power for the vast majority of blocks.
Conclusions/SignificanceThe model developed is informed by routinely-collected surveillance data as it accumulates, and predictions are sufficiently accurate and precise to be useful. Such forecasts could, for example, be used to guide stock requirements for rapid diagnostic tests and drugs. More comprehensive data on factors thought to influence geographic variation in VL burden could be incorporated, and might better explain the heterogeneity between blocks and improve uniformity of predictive performance. Integration of the approach in the management of the VL programme would be an important step to ensuring continued successful control.
Author summaryThis paper demonstrates a statistical modelling approach for forecasting of monthly visceral leishmaniasis (VL) incidence at block level in India, which could be used to tailor control efforts according to local estimates and monitor deviations from the currently decreasing trend. By fitting a variety of models to four years of historical data and assessing predictions within a further 24-month test period, we found that the model which best fit the observed data also showed the best predictive performance, and predictive accuracy was maintained when making rolling predictions up to four months ahead of the observed data. Since there is a two-month delay between reporting and processing of the data, predictive power more than three months ahead of current data is crucial to make forecasts which can feasibly be acted upon. Some heterogeneity remains in predictive power across the study region which could potentially be improved using unit-specific data on factors believed to be associated with reported VL incidence (e.g. age distribution, socio-economic status and climate). | 10.1371/journal.pntd.0008422 | medrxiv |
10.1101/19009258 | A spatio-temporal approach to short-term forecasting of visceral leishmaniasis diagnoses in India | Nightingale, E. S.; Chapman, L. A. C.; Srikantiah, S.; Subramanian, S.; Purushothaman, J.; Bracher, J.; Cameron, M.; Medley, G. | Emily S Nightingale | London School of Hygiene and Tropical Medicine | 2020-04-24 | 3 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2020/04/24/19009258.source.xml | BackgroundThe elimination programme for visceral leishmaniasis (VL) in India has seen great progress, with total cases decreasing by over 80% since 2010 and many blocks now reporting zero cases from year to year. Prompt diagnosis and treatment is critical to continue progress and avoid epidemics in the increasingly susceptible population. Short-term forecasts could be used to highlight anomalies in incidence and support health service logistics. The model which best fits the data is not necessarily most useful for prediction, yet little empirical work has been done to investigate the balance between fit and predictive performance.
Methodology/Principal FindingsWe developed statistical models of monthly VL case counts at block level. By evaluating a set of randomly-generated models, we found that fit and one-month-ahead prediction were strongly correlated and that rolling updates to model parameters as data accrued were not crucial for accurate prediction. The final model incorporated auto-regression over four months, spatial correlation between neighboring blocks, and seasonality. Ninety-four percent of 10-90% prediction intervals from this model captured the observed count during a 24-month test period. Comparison of one-, three-and four-month-ahead predictions from the final model fit demonstrated that a longer time horizon yielded only a small sacrifice in predictive power for the vast majority of blocks.
Conclusions/SignificanceThe model developed is informed by routinely-collected surveillance data as it accumulates, and predictions are sufficiently accurate and precise to be useful. Such forecasts could, for example, be used to guide stock requirements for rapid diagnostic tests and drugs. More comprehensive data on factors thought to influence geographic variation in VL burden could be incorporated, and might better explain the heterogeneity between blocks and improve uniformity of predictive performance. Integration of the approach in the management of the VL programme would be an important step to ensuring continued successful control.
Author summaryThis paper demonstrates a statistical modelling approach for forecasting of monthly visceral leishmaniasis (VL) incidence at block level in India, which could be used to tailor control efforts according to local estimates and monitor deviations from the currently decreasing trend. By fitting a variety of models to four years of historical data and assessing predictions within a further 24-month test period, we found that the model which best fit the observed data also showed the best predictive performance, and predictive accuracy was maintained when making rolling predictions up to four months ahead of the observed data. Since there is a two-month delay between reporting and processing of the data, predictive power more than three months ahead of current data is crucial to make forecasts which can feasibly be acted upon. Some heterogeneity remains in predictive power across the study region which could potentially be improved using unit-specific data on factors believed to be associated with reported VL incidence (e.g. age distribution, socio-economic status and climate). | 10.1371/journal.pntd.0008422 | medrxiv |
10.1101/19009191 | Increasing Firearm Deaths in The Youngest Americans:Ecologic Correlation with Firearm Prevalence | Bleyer, A.; Siegel, S. E.; Thomas, C. R. | Archie Bleyer | Oregon Health and Science University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/18/19009191.source.xml | BackgroundIn the United States (U.S.), the overall death rate in 1-4 year-olds had been steadily declining until 2011, after which it ceased to improve. To understand this trend reversal, we investigated trends in the causes of their deaths.
MethodsMortality data were obtained from the U.S. Centers for Disease Control and Institute for Health Metrics and Evaluation, firearm background check data from the National Instant Criminal Background Check System, and civilian firearm prevalence from the Small Arms Survey.
FindingsIn 1-4 year-olds, the rate of fatal firearm accidents during 2002-2017 increased exponentially at an average rate of 6.0%/year (p=0.0003). The rate of increase was the greatest of all evaluable causes of death in the age group. Both the rate increase and most recent absolute rate in firearm accidental deaths in young children were correlated with the concurrent corresponding rate of firearm background checks (p = 0.0002 and 0.003, respectively). Also, the firearm accidental death rate in countries with high civilian firearm prevalence was correlated with the number of guns per civilian population (p=0.002).
InterpretationPrior to 2004, the childhood firearm death rate did not increase during the Federal Assault Weapons Ban. Since 2004 when the Ban ended, the steadily increasing rate of sales and concomitant availability of, and access to, firearms in the U.S. has been associated with an increase in fatal firearm accidents in its youngest children. The acceleration of firearm deaths and injuries among young Americans requires urgent, definitive solutions that address firearm prevalence.
FundingNo external funding.
KEY POINTSO_ST_ABSQuestionC_ST_ABSIn the U.S., how has the escalation of both firearm sales and firearm death rates affected the countrys youngest population?
FindingsWhile the steadily increasing rate of sales and concomitant availability of, and access to, firearms in the U.S. has increased since 2004, fatal firearm accidents in 1 to 4 year-olds increased exponentially and at a rate greater than all other evaluable causes of death in the age group.
InterpretationThe ominous acceleration of firearm deaths and injuries among young Americans requires urgent, definitive solutions from multiple stakeholders to effectively reduce firearm access. | 10.1016/j.jnma.2020.12.005 | medrxiv |
10.1101/19009191 | Increasing Firearm Deaths in The Youngest Americans: Ecologic Correlation with Firearm Prevalence | Bleyer, A.; Siegel, S. E.; Thomas, C. R. | Archie Bleyer | Oregon Health and Science University | 2019-10-25 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/25/19009191.source.xml | BackgroundIn the United States (U.S.), the overall death rate in 1-4 year-olds had been steadily declining until 2011, after which it ceased to improve. To understand this trend reversal, we investigated trends in the causes of their deaths.
MethodsMortality data were obtained from the U.S. Centers for Disease Control and Institute for Health Metrics and Evaluation, firearm background check data from the National Instant Criminal Background Check System, and civilian firearm prevalence from the Small Arms Survey.
FindingsIn 1-4 year-olds, the rate of fatal firearm accidents during 2002-2017 increased exponentially at an average rate of 6.0%/year (p=0.0003). The rate of increase was the greatest of all evaluable causes of death in the age group. Both the rate increase and most recent absolute rate in firearm accidental deaths in young children were correlated with the concurrent corresponding rate of firearm background checks (p = 0.0002 and 0.003, respectively). Also, the firearm accidental death rate in countries with high civilian firearm prevalence was correlated with the number of guns per civilian population (p=0.002).
InterpretationPrior to 2004, the childhood firearm death rate did not increase during the Federal Assault Weapons Ban. Since 2004 when the Ban ended, the steadily increasing rate of sales and concomitant availability of, and access to, firearms in the U.S. has been associated with an increase in fatal firearm accidents in its youngest children. The acceleration of firearm deaths and injuries among young Americans requires urgent, definitive solutions that address firearm prevalence.
FundingNo external funding.
KEY POINTSO_ST_ABSQuestionC_ST_ABSIn the U.S., how has the escalation of both firearm sales and firearm death rates affected the countrys youngest population?
FindingsWhile the steadily increasing rate of sales and concomitant availability of, and access to, firearms in the U.S. has increased since 2004, fatal firearm accidents in 1 to 4 year-olds increased exponentially and at a rate greater than all other evaluable causes of death in the age group.
InterpretationThe ominous acceleration of firearm deaths and injuries among young Americans requires urgent, definitive solutions from multiple stakeholders to effectively reduce firearm access. | 10.1016/j.jnma.2020.12.005 | medrxiv |
10.1101/19008961 | The prevalence and risk factors for phantom limb pain in people with amputations: a systematic review and meta-analysis. | Limakatso, K.; Bedwell, G. J.; Madden, V. J.; Parker, R. | Katleho Limakatso | Department of Anaesthesia and Perioperative Medicine, University of Cape Town | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | rehabilitation medicine and physical therapy | https://www.medrxiv.org/content/early/2019/10/18/19008961.source.xml | Background and objectivePhantom limb pain (PLP) is a common complication in people with limb amputations. There are conflicting reports in the literature regarding the prevalence of PLP in people with limb amputations. Therefore, this review aimed to determine the estimated pooled prevalence of PLP, and risk factors associated with this complication.
MethodsArticles published between 1980 and July 2019 were identified through a systematic search of the following electronic databases: MEDLINE/PubMed, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature, Africa-Wide Information, Health Source: Nursing/Academic Edition, SCOPUS, Web of Science and Academic Search Premier. Grey literature was searched on databases for preprints. Two reviewers independently performed the screening of articles, data extraction and risk of bias assessment. The meta-analyses were conducted using the random-effects model. A statistically significant level for the analyses was set at p>0.05.
ResultsThe pooling of all studies demonstrated a prevalence estimate of 63% [95% CI: 58.23-67.05] with high heterogeneity [I2=95.70% (95% CI: 95.10-96.20)]. The prevalence of PLP was significantly lower in developing countries compared to developed countries [53.98% vs 64.55%; p=0.04]. Persistent pre-operative pain, proximal site of amputation, lower limb amputation, stump pain and phantom sensations were identified as risk factors for PLP.
ConclusionThis systematic review and meta-analysis estimates that six of every 10 people with an amputation report PLP - a high and important prevalence of PLP. Health care professionals ought to be aware of the high rates of PLP and implement strategies to reduce PLP by addressing known risk factors, specifically those identified by the current study. | 10.1371/journal.pone.0240431 | medrxiv |
10.1101/19009233 | Female genital schistosomiasis and reproductive tract infections. A cross-sectional study in rural adolescents in South Africa | Shukla, J. D.; Kleppa, E.; Holmen, S.; Ndhlovu, P. D.; Mtshali, A.; Sebitloane, M. H.; Vennervald, B. J.; Gundersen, S. G.; Taylor, M.; Kjetland, E. F. | Eyrun F Kjetland | Oslo University Hospital | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | sexual and reproductive health | https://www.medrxiv.org/content/early/2019/10/18/19009233.source.xml | Background and objectivesThe aim of the current study was to establish the relative prevalences of Female Genital Schistosomiasis (FGS) and sexually transmitted infections (STIs). We hypothesised that due to the use of syndromic management for STIs it is possible that FGS is being misdiagnosed and mismanaged as an STI. We therefore wanted to examine the relationship between FGS and the individual STIs in schistosomiasis endemic areas.
MethodsBetween 2011 and 2013, a cross-sectional study was performed in 32 randomly selected secondary schools in rural KwaZulu-Natal, South Africa, where each school had at least 300 pupils. In a research clinic, FGS diagnosis, STI testing, and face-to-face interviews were performed in sexually active, young women aged 16 - 22 years.
ResultsFGS was the second most prevalent current genital infection (23%). There were significantly more women who had presented FGS among those who had detectable urinary schistosomiasis (35%), compared to those without (19%, p< 0.001). In the FGS positive group 35% were positive for HPV infection, compared to 24 % in the FGS negative group (p=0.010). In the FGS positive group 37% were sero-positive for HSV infection, compared to 30% in the FGS negative group (p=0.079). There were significantly fewer chlamydia infections amongst women with FGS (20%, p=0.018) compared with those who did not have FGS (28%).
ConclusionsFGS was the second most common genital infection after HSV but the two were not significantly associated. HPV infection was significantly associated with FGS. Surprisingly Chlamydia infection were negatively associated with FGS. The results show the importance of the inclusion of FGS in the management protocols for genital infections in areas endemic for urinary schistosomiasis, and highlight the importance for more research on suitable differential diagnostic tools and disease management.
Key messages boxO_LIFGS was the second most common genital infection in this rural population after HSV.
C_LIO_LIFGS was positively associated with HPV.
C_LIO_LIFGS was negatively associated with genital chlamydia infections.
C_LIO_LIFGS should be included in the syndromic management of genital infections.
C_LI | null | medrxiv |
10.1101/19009712 | Computational Modeling of Ovarian Cancer: Implications for Therapy and Screening | Gu, S. S.; Lheureux, S.; Sayad, A.; Cybulska, P.; Ben-David Hogen, L.; Vyarvelska, I.; Tu, D.; Parulekar, W.; Levine, D. A.; Bernardini, M. Q.; Rosen, B.; Oza, A.; Neel, B. G. | Benjamin G Neel | New York University Langone Medical Center | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2019/10/18/19009712.source.xml | High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Whether treatment order--primary debulking surgery followed by adjuvant chemotherapy (PDS) or neo-adjuvant chemotherapy with interval surgery (NACT)--affects outcome is controversial. We developed a mathematical framework that holds for hierarchical or stochastic models of tumor initiation and reproduces HGSC clinical course. After estimating parameter values, we infer that most patients harbor chemo-resistant HGSC cells at diagnosis, and that if complete debulking (<1 mm residual tumor) can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. Our predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.
Significance StatementThe optimal order and timing of surgery and chemotherapy, and the potential benefits of earlier diagnosis of HGSC, remain controversial. We developed a mathematical framework of tumor dynamics to address such issues, populated the model with primary clinical data and reliably recapitulated clinical observations. Our model prospectively predicts that: (1) PDS is superior to NACT when complete debulking is feasible; (2) timely adjuvant chemotherapy is critical for the outcome of PDS with <1mm, but not >1mm, residual tumors; (3) earlier detection of relapse is unlikely to be beneficial with current therapies; (4) earlier detection of primary HGSC, followed by complete debulking, could have substantial benefit. Our model provides insights into the evolutionary dynamics of HGSC, argues for new clinical trials to optimize HGSC therapy, and is potentially applicable to other tumor types. | 10.1073/pnas.2026663118 | medrxiv |
10.1101/19009712 | Computational Modeling of Ovarian Cancer Reveals Optimal Strategies for Therapy and Screening | Gu, S. S.; Lheureux, S.; Sayad, A.; Cybulska, P.; Ben-David Hogen, L.; Vyarvelska, I.; Tu, D.; Parulekar, W.; Nankivell, M.; Kehoe, S.; Chi, D.; Levine, D. A.; Bernardini, M. Q.; Rosen, B.; Oza, A.; Neel, B. G. | Benjamin G Neel | New York University Langone Medical Center | 2020-06-09 | 2 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2020/06/09/19009712.source.xml | High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Whether treatment order--primary debulking surgery followed by adjuvant chemotherapy (PDS) or neo-adjuvant chemotherapy with interval surgery (NACT)--affects outcome is controversial. We developed a mathematical framework that holds for hierarchical or stochastic models of tumor initiation and reproduces HGSC clinical course. After estimating parameter values, we infer that most patients harbor chemo-resistant HGSC cells at diagnosis, and that if complete debulking (<1 mm residual tumor) can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. Our predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.
Significance StatementThe optimal order and timing of surgery and chemotherapy, and the potential benefits of earlier diagnosis of HGSC, remain controversial. We developed a mathematical framework of tumor dynamics to address such issues, populated the model with primary clinical data and reliably recapitulated clinical observations. Our model prospectively predicts that: (1) PDS is superior to NACT when complete debulking is feasible; (2) timely adjuvant chemotherapy is critical for the outcome of PDS with <1mm, but not >1mm, residual tumors; (3) earlier detection of relapse is unlikely to be beneficial with current therapies; (4) earlier detection of primary HGSC, followed by complete debulking, could have substantial benefit. Our model provides insights into the evolutionary dynamics of HGSC, argues for new clinical trials to optimize HGSC therapy, and is potentially applicable to other tumor types. | 10.1073/pnas.2026663118 | medrxiv |
10.1101/19009522 | Genetic profile and functional proteomics of anal squamous cell carcinoma: proposal for a molecular classification | Trilla-Fuertes, L.; Ghanem, I.; Gamez-Pozo, A.; Maurel, J.; G-Pastrian, L.; Mendiola, M.; Pena, C.; Lopez-Vacas, R.; Prado-Vazquez, G.; Lopez-Camacho, E.; Zapater-Moros, A.; Heredia, V.; Cuatrecasas, M.; Garcia-Alfonso, P.; Capdevila, J.; Conill, C.; Garcia-Carbonero, R.; Ramos-Ruiz, R.; Fortes, C.; Llorens, C.; Nanni, P.; Fresno, J. A.; Feliu, J. | Jaime Feliu | Hospital Universitario La Paz | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2019/10/18/19009522.source.xml | BackgroundAnal squamous cell carcinoma is a rare tumor. Chemo-radiotherapy yields a 50% 3-year relapse-free survival rate in advanced anal cancer, so improved predictive markers and therapeutic options are needed.
MethodsHigh-throughput proteomics and whole-exome sequencing were performed in 46 paraffin samples from anal squamous cell carcinoma patients. Hierarchical clustering was used to establish groups de novo. Then, probabilistic graphical models were used to study the differences between groups of patients at the biological process level.
ResultsA molecular classification into two groups of patients was established, one group with increased expression of proteins related to adhesion, T lymphocytes and glycolysis; and the other group with increased expression of proteins related to translation and ribosomes. The probabilistic graphical model showed that these two groups presented differences in metabolism, mitochondria, translation, splicing and adhesion processes. Additionally, these groups showed different frequencies of genetic variants in some genes, such as ATM, SLFN11 and DST. Finally, genetic and proteomic characteristics of these groups suggested the use of some possible targeted therapies, such as PARP inhibitors or immunotherapy.
ConclusionsIn this study, a molecular classification of anal squamous cell carcinoma using high-throughput proteomics and whole-exome sequencing data was proposed. Moreover, differences between the two established groups suggested some possible therapies. | 10.1074/mcp.RA120.001954 | medrxiv |
10.1101/19009456 | Olanzapine Combined with 5-HT3 RA Plus Dexamethasone for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in High and Moderate Emetogenic Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | Zhou, j.; HUang, L.; Jin, S.-H.; Xc, C.; Ma, H. | jianguo Zhou Sr. | Affiliated Hospital of Zunyi Medical University | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2019/10/18/19009456.source.xml | ObjectivesWe performed a pooled analysis to evaluate the efficacy and adverse events (AEs) of olanzapine combined with dexamethasone plus compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomized controlled trials (RCTs).
MethodsPubMed, EMBASE, Web of Science, the Cochrane Library, China Biomedical Literature database (CBM), WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (from their inception to April 2019) were searched to capture relevant articles. Relative risk (RR) with 95% confidence intervals (CIs) for CINV and AEs were all extracted or calculated.
ResultEleven studies with 1107 cancer patients were involved in this review. The pooled RR of delayed CINV (RR=0.50, 95%CI: 0.38-0.66, P<0.01) were significant decreased in olanzapine group. Besides, the occurrence of insomnia was statistically decreased. The rate of acute CINV (RR=0.60, 95%CI: 0.48-0.75, P<0.01) was also significant decreased. However only the percent of CINV {square} and CINV {square} were significant deceased in acute and delayed phase. Subgroup analysis demonstrated that the efficacy was no statistically significant difference between 5mg and 10mg for olanzapine.
ConclusionOlanzapine significant decreased the occurrence of CINV {square} and {square} and insomnia in high and moderately emetogenic chemotherapy. Compared with 10mg per day, 5mg oral may be more appropriate for patients with cancer. | 10.1093/annonc/mdz261.007 | medrxiv |
10.1101/19009456 | Olanzapine Combined with 5-HT3 RA Plus Dexamethasone for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in High and Moderate Emetogenic Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | Zhou, j.; HUang, L.; Jin, S.-H.; Xc, C.; Ma, H. | jianguo Zhou Sr. | Affiliated Hospital of Zunyi Medical University | 2019-11-18 | 2 | PUBLISHAHEADOFPRINT | cc_no | oncology | https://www.medrxiv.org/content/early/2019/11/18/19009456.source.xml | ObjectivesWe performed a pooled analysis to evaluate the efficacy and adverse events (AEs) of olanzapine combined with dexamethasone plus compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomized controlled trials (RCTs).
MethodsPubMed, EMBASE, Web of Science, the Cochrane Library, China Biomedical Literature database (CBM), WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (from their inception to April 2019) were searched to capture relevant articles. Relative risk (RR) with 95% confidence intervals (CIs) for CINV and AEs were all extracted or calculated.
ResultEleven studies with 1107 cancer patients were involved in this review. The pooled RR of delayed CINV (RR=0.50, 95%CI: 0.38-0.66, P<0.01) were significant decreased in olanzapine group. Besides, the occurrence of insomnia was statistically decreased. The rate of acute CINV (RR=0.60, 95%CI: 0.48-0.75, P<0.01) was also significant decreased. However only the percent of CINV {square} and CINV {square} were significant deceased in acute and delayed phase. Subgroup analysis demonstrated that the efficacy was no statistically significant difference between 5mg and 10mg for olanzapine.
ConclusionOlanzapine significant decreased the occurrence of CINV {square} and {square} and insomnia in high and moderately emetogenic chemotherapy. Compared with 10mg per day, 5mg oral may be more appropriate for patients with cancer. | 10.1093/annonc/mdz261.007 | medrxiv |
10.1101/19009183 | Improving parents knowledge of early signs of pediatric eye disease: A double-blind RCT | Staffieri, S. E.; Rees, G.; Sanfilippo, P. G.; Cole, S.; Mackey, D. A.; Hewitt, A. W. | Sandra E Staffieri | Centre for Eye Research Australia | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | ophthalmology | https://www.medrxiv.org/content/early/2019/10/18/19009183.source.xml | Background and ObjectivesEarly diagnosis and intervention is essential to achieve optimal outcomes for most pediatric eye diseases. Educating parents/caregivers to recognize early signs of disease and consult a healthcare professional is critical to achieving this aim. We evaluate the effectiveness of an eye-health information pamphlet on parents level of concern and their help-seeking intention if they observed leukocoria or strabismus.
MethodsPregnant women attending a metropolitan antenatal clinic were recruited to the study. Participants were randomly assigned to receive a pamphlet on either pediatric eye health (intervention) or strategies for play (control). The primary outcome measure was a change in the parents level of concern if they observed leukocoria or strabismus. The secondary outcome measure was a change in their help-seeking intention if either sign was observed.
ResultsOf the 518 women enrolled, 382 (73.7%) completed the post-test survey. At follow-up, women who received the intervention were more likely to report a higher level of concern if they observed leukocoria (OR 1.711 [CI: 1.176-2.497] p=0.005]) and were less likely to have a delayed help-seeking intention. (OR 0.560 [CI 0.382-0.817] p =0.003) No change in the level of concern for strabismus was identified between the groups; however, at follow-up, women who received the intervention were less likely to delay help-seeking (OR 0.318 [CI 0.125-0.806] p=0.016).
ConclusionProviding parents with relevant, evidence-based information can significantly improve their knowledge and positively influence help-seeking intentions if leukocoria or strabismus are observed.
Trial registrationANZCTR.org.au identifier: ACTRN12617001431314p;
World Health Organization Universal Trial Number: U1111-1203-0485
Table of Contents SummaryThis study reports the results of a randomised controlled trial evaluating a novel, evidence-based, theory-informed pediatric eye-health information pamphlet for parents.
What is known on this subjectLack of parental awareness of signs of pediatric eye disease (leukocoria and strabismus) delays consultation with healthcare professionals (help-seeking), contributing to late diagnosis and poor outcomes. Providing parents with relevant health information can improve their childs health outcomes.
What this study addsUsing an RCT to evaluate a novel health intervention, this study demonstrates that providing parents with evidence-based, theory informed pediatric eye-health information can improve their knowledge and help-seeking intentions if leukocoria or strabismus are observed in their child. | 10.1111/ceo.13866 | medrxiv |
10.1101/19009332 | AN OPEN-SOURCE DATASET OF ANTI-VEGF THERAPY IN DIABETIC MACULAR OEDEMA PATIENTS OVER FOUR YEARS & THEIR VISUAL OUTCOMES | Kern, C.; Fu, D. J.; Huemer, J.; Faes, L.; Wagner, S. K.; Kortuem, K.; Patel, P.; Balaskas, K.; Hamilton, R.; Sim, D. A.; Keane, P. | Pearse Keane | Moorfields Eye Hospital, NHS Trust, London, UK | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | ophthalmology | https://www.medrxiv.org/content/early/2019/10/18/19009332.source.xml | PURPOSETo evaluate visual acuity (VA) outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) in diabetic macular oedema (DMO).
METHODSIn this retrospective cohort study, electronic medical records for all patients undergoing intravitreal injections (IVI) in a tertiary referral centre between March 2013 and October 2018 were analysed. Treatment response in terms of visual acuity outcomes were reported for all eyes over a 4-year observation period.
RESULTSOur cohort includes 2616 DMO eyes of 1965 patients over 48 months. Cox proportional hazards modelling identified injection number (hazard ratio [HR] = 1.18), male gender (HR = 1.13), and baseline VA (HR = 1.09) as independent predictors to reach a favorable visual outcome of more than 70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Half of our cohort reached 70 letters 1.9 months after starting anti-VEGF therapy. Of those that reached 70 letters, 50% fell below 70 by 14.7 months.
CONCLUSIONTo date, this is the largest single centre cohort study and over the longest observation period reporting on real-life outcomes of anti-VEGF in DMO. We have made an anonymised version of our dataset available on an open-source data repository as a resource for all clinical researchers globally.
SYNOPSISUsing time-to-event analysis in patients receiving anti-VEGF for DMO: age, baseline visual acuity and injection number are independent predictors of visual outcomes. | 10.1038/s41433-020-1048-0 | medrxiv |
10.1101/19009332 | AN OPEN-SOURCE DATASET OF ANTI-VEGF THERAPY IN DIABETIC MACULAR OEDEMA PATIENTS OVER FOUR YEARS & THEIR VISUAL OUTCOMES | Kern, C.; Fu, D. J.; Huemer, J.; Faes, L.; Wagner, S. K.; Kortuem, K.; Patel, P.; Balaskas, K.; Hamilton, R.; Sim, D. A.; Keane, P. | Pearse Keane | Moorfields Eye Hospital, NHS Trust, London, UK | 2019-10-29 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | ophthalmology | https://www.medrxiv.org/content/early/2019/10/29/19009332.source.xml | PURPOSETo evaluate visual acuity (VA) outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) in diabetic macular oedema (DMO).
METHODSIn this retrospective cohort study, electronic medical records for all patients undergoing intravitreal injections (IVI) in a tertiary referral centre between March 2013 and October 2018 were analysed. Treatment response in terms of visual acuity outcomes were reported for all eyes over a 4-year observation period.
RESULTSOur cohort includes 2616 DMO eyes of 1965 patients over 48 months. Cox proportional hazards modelling identified injection number (hazard ratio [HR] = 1.18), male gender (HR = 1.13), and baseline VA (HR = 1.09) as independent predictors to reach a favorable visual outcome of more than 70 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Half of our cohort reached 70 letters 1.9 months after starting anti-VEGF therapy. Of those that reached 70 letters, 50% fell below 70 by 14.7 months.
CONCLUSIONTo date, this is the largest single centre cohort study and over the longest observation period reporting on real-life outcomes of anti-VEGF in DMO. We have made an anonymised version of our dataset available on an open-source data repository as a resource for all clinical researchers globally.
SYNOPSISUsing time-to-event analysis in patients receiving anti-VEGF for DMO: age, baseline visual acuity and injection number are independent predictors of visual outcomes. | 10.1038/s41433-020-1048-0 | medrxiv |
10.1101/19009662 | Unmasking selective path integration deficits in Alzheimer's disease risk carriers | Bierbrauer, A.; Kunz, L.; Gomes, C. A.; Luhmann, M.; Deuker, L.; Getzmann, S.; Wascher, E.; Gajewski, P. D.; Hengstler, J. G.; Fernandez-Alvarez, M.; Atienza, M.; Cammisuli, D. M.; Bonatti, F.; Pruneti, C.; Percesepe, A.; Bellaali, Y.; Hanseeuw, B.; Strange, B. A.; Cantero, J. L.; Axmacher, N. | Anne Bierbrauer | Department of Neuropsychology, Institute of Cognitive Neuroscience, Faculty of Psychology, Ruhr University Bochum, Bochum, Germany | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_no | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/10/18/19009662.source.xml | Alzheimers disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE {varepsilon}4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE {varepsilon}4-carriers during a virtual navigation task. We report a selective impairment in APOE {varepsilon}4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE {varepsilon}4-carriers. Furthermore, retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset. | 10.1126/sciadv.aba1394 | medrxiv |
10.1101/19009555 | Simulation models of dengue transmission in Funchal, Madeira Island: influence of seasonality | Salami, D.; Capinha, C.; Sousa, C. A.; Martins, M. d. R. O.; Lord, C. | Donald Salami | Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2019/10/18/19009555.source.xml | The recent emergence and established presence of Aedes aegypti in the Autonomous Region of Madeira, Portugal, was responsible for the first autochthonous outbreak of dengue in Europe. The island has not reported any dengue cases since the outbreak in 2012. However, there is a high risk that an introduction of the virus would result in another autochthonous outbreak given the presence of the vector and permissive environmental conditions. Understanding the dynamics of a potential epidemic is critical for targeted local control strategies.
Here, we adopt a deterministic model for the transmission of dengue in Aedes aegypti mosquitoes. The model integrates empirical and mechanistic parameters for virus transmission, under seasonally varying temperatures for Funchal, Madeira Island. We examine the epidemic dynamics as triggered by the arrival date of an infectious individual; the influence of seasonal temperature mean and variation on the epidemic dynamics; and performed a sensitivity analysis on the following quantities of interest: the epidemic peak size, time to peak and the final epidemic size.
Our results demonstrate the potential for summer to early winter transmission of dengue, with the arrival date significantly affecting the distribution of the timing and peak size of the epidemic. Mid-summer to early autumn arrivals are more likely to produce larger epidemics within a short peak time. Epidemics within this favorable period had an average of 18% of the susceptible population infected at the peak, at an average peak time of 70 days. We also demonstrated that seasonal temperature variation dramatically affects the epidemic dynamics, with warmer starting temperatures producing peaks more quickly after an introduction and larger epidemics. Overall, our quantities of interest were most sensitive to variance in the date of arrival, seasonal temperature, biting rate, transmission rates, and the mosquito population; the magnitude of sensitivity differs across quantities.
Our model could serve as a useful guide in the development of effective local control and mitigation strategies for dengue fever in Madeira Island.
Author SummaryThe presence of Aedes aegypti mosquitoes in Madeira Island had recently caused the first local outbreak of dengue in Europe. The island is at risk of another local transmission if triggered by the introduction of the dengue virus by an infected person. Using a mathematical model for the transmission of dengue, we examine the dynamics of a potential epidemic triggered by the arrival of an infected person on the island. We also examine the impact of seasonal temperature variation on the epidemic dynamics. Our results show the potential for summer to early winter transmission of dengue on the island, and that the arrival date of an infectious person affects the distribution of the timing and peak size of the epidemic. Arrival dates during mid-summer to early autumn were more likely to produce larger epidemic peak size within a short time. We also show that seasonal temperature variation dramatically affects the epidemic dynamics. With warmer starting temperatures, epidemics peak more rapidly and produce a larger epidemic size. Our model could be useful to estimate the risk of an epidemic outbreak and as a guide for local control and mitigation strategies for dengue on the island. | 10.1371/journal.pntd.0008679 | medrxiv |
10.1101/19009555 | Simulation models of dengue transmission in Funchal, Madeira Island: influence of seasonality | Salami, D.; Capinha, C.; Sousa, C. A.; Martins, M. d. R. O.; Lord, C. | Donald Salami | Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal | 2020-04-15 | 2 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2020/04/15/19009555.source.xml | The recent emergence and established presence of Aedes aegypti in the Autonomous Region of Madeira, Portugal, was responsible for the first autochthonous outbreak of dengue in Europe. The island has not reported any dengue cases since the outbreak in 2012. However, there is a high risk that an introduction of the virus would result in another autochthonous outbreak given the presence of the vector and permissive environmental conditions. Understanding the dynamics of a potential epidemic is critical for targeted local control strategies.
Here, we adopt a deterministic model for the transmission of dengue in Aedes aegypti mosquitoes. The model integrates empirical and mechanistic parameters for virus transmission, under seasonally varying temperatures for Funchal, Madeira Island. We examine the epidemic dynamics as triggered by the arrival date of an infectious individual; the influence of seasonal temperature mean and variation on the epidemic dynamics; and performed a sensitivity analysis on the following quantities of interest: the epidemic peak size, time to peak and the final epidemic size.
Our results demonstrate the potential for summer to early winter transmission of dengue, with the arrival date significantly affecting the distribution of the timing and peak size of the epidemic. Mid-summer to early autumn arrivals are more likely to produce larger epidemics within a short peak time. Epidemics within this favorable period had an average of 18% of the susceptible population infected at the peak, at an average peak time of 70 days. We also demonstrated that seasonal temperature variation dramatically affects the epidemic dynamics, with warmer starting temperatures producing peaks more quickly after an introduction and larger epidemics. Overall, our quantities of interest were most sensitive to variance in the date of arrival, seasonal temperature, biting rate, transmission rates, and the mosquito population; the magnitude of sensitivity differs across quantities.
Our model could serve as a useful guide in the development of effective local control and mitigation strategies for dengue fever in Madeira Island.
Author SummaryThe presence of Aedes aegypti mosquitoes in Madeira Island had recently caused the first local outbreak of dengue in Europe. The island is at risk of another local transmission if triggered by the introduction of the dengue virus by an infected person. Using a mathematical model for the transmission of dengue, we examine the dynamics of a potential epidemic triggered by the arrival of an infected person on the island. We also examine the impact of seasonal temperature variation on the epidemic dynamics. Our results show the potential for summer to early winter transmission of dengue on the island, and that the arrival date of an infectious person affects the distribution of the timing and peak size of the epidemic. Arrival dates during mid-summer to early autumn were more likely to produce larger epidemic peak size within a short time. We also show that seasonal temperature variation dramatically affects the epidemic dynamics. With warmer starting temperatures, epidemics peak more rapidly and produce a larger epidemic size. Our model could be useful to estimate the risk of an epidemic outbreak and as a guide for local control and mitigation strategies for dengue on the island. | 10.1371/journal.pntd.0008679 | medrxiv |
10.1101/19009563 | Hepatitis B virus resistance to tenofovir: fact or fiction? A synthesis of the evidence to date | Mokaya, J.; McNaughton, A. L.; Bester, P. A.; Goedhals, D.; Barnes, E.; Marsden, B. D.; Matthews, P. C. | Philippa C Matthews | Nuffield Department of Medicine, Medawar Building, South Parks Road, Oxford OX1 3SY, UK | 2019-10-18 | 1 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2019/10/18/19009563.source.xml | BackgroundTenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into the mechanisms of resistance and potential clinical significance.
MethodsWe carried out a systematic literature search in PubMed to identify clinical, in vitro and in silico evidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.
ResultsWe identified a long-list of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. Based on quality and quantity of supporting data, we generated a short-list of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.
ConclusionThere is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets. | null | medrxiv |
10.1101/19009563 | Hepatitis B virus resistance to tenofovir: fact or fiction? A synthesis of the evidence to date | Mokaya, J.; McNaughton, A. L.; Bester, P. A.; Goedhals, D.; Barnes, E.; Marsden, B. D.; Matthews, P. C. | Philippa C Matthews | Nuffield Department of Medicine, Medawar Building, South Parks Road, Oxford OX1 3SY, UK | 2020-04-23 | 2 | PUBLISHAHEADOFPRINT | cc_by | infectious diseases | https://www.medrxiv.org/content/early/2020/04/23/19009563.source.xml | BackgroundTenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into the mechanisms of resistance and potential clinical significance.
MethodsWe carried out a systematic literature search in PubMed to identify clinical, in vitro and in silico evidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.
ResultsWe identified a long-list of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. Based on quality and quantity of supporting data, we generated a short-list of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.
ConclusionThere is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets. | null | medrxiv |
10.1101/19008045 | Predicting the required pre-surgery blood volume in surgical patients based on machine learning | Li, R.; Han, X.; Sun, L.; Feng, Y.; Sun, X.; He, X.; Zhang, Y.; Zhu, H.; Zhao, D.; Dai, C.; He, Z.; Chen, S.; Wang, X.; Li, W.; Chi, X.; Yu, Y.; Niu, B.; Wang, D. | Beifang Niu | Computer Network Information Center, Chinese Academy of Sciences; University of Chinese Academy of Sciences | 2019-10-19 | 1 | PUBLISHAHEADOFPRINT | cc_no | hematology | https://www.medrxiv.org/content/early/2019/10/19/19008045.source.xml | Precisely predicting the required pre-surgery blood volume (PBV) in surgical patients is a formidable challenge in China. Inaccurate estimation is associate with excessive costs, postponed surgeries and adverse outcome after surgery due to in sufficient supply or inventory. This study aimed to predict required PBV based on machine learning techniques. 181,027 medical documents over 6 years were cleaned and finally obtained 92,057 blood transfusion records. The blood transfusion and surgery related factors of perioperative patients, surgeons experience volumes and the actual volumes of transfused RBCs were extracted. 6 machine learning algorithms were used to build prediction models. The surgery patients received allogenic RBCs or without transfusion, had total volume less than 10 units, or had the latest laboratory examinations of pre-surgery within 7 days were included, providing 118,823 data points. 39 predictive factors related to the RBCs transfusion were identified. Random forest model was selected to predict the required PBV of RBCs with 72.9% accuracy and strikingly improved the accuracy by 30.4% compared with surgeons experience, where 90% of data was used for training. We tested and demonstrated that both the data-driven models and the random forest model achieved higher accuracy than surgeons experience. Furthermore, we developed a computational tool, PTRBC, to precisely estimate the required PBV in surgical patients and we believe this tool will find more applications in assisting clinician decisions, not only confined to making accurate pre-surgery blood requirement predicting. | null | medrxiv |
10.1101/19009449 | Seroprevalence of Varicella Zoster virus in China: an age-stratifed systematic review and meta-analysis | Wang, L.; Sun, F.; Liu, S.; Zhang, H.; Lu, B.; Shao, X.; Zhang, M.; Li, Z. | Zhengwei Li | The First Affiliated Hospital of Xian Medical University | 2019-10-21 | 1 | PUBLISHAHEADOFPRINT | cc_by_nd | dermatology | https://www.medrxiv.org/content/early/2019/10/21/19009449.source.xml | OBJECTIVESthe aim of this meta-analysis was pooled on the comprehensive information of the epidemiology of VZV infection and analyzed the seropositivity of VZV-IgG antibodies in different age groups in China, so as to arouse peoples attention on VZV.
DESIGNSystematic review
DATA SOURCESSources included on PubMed, the China National Knowledge Infrastructure (CNKI) database, WANFANG database and the Chinese Scientific Journals Full-Text Database (CQVIP) from 1997 to 2019.
ELIGIBILITY CRITERIA(1) the Chinese and English literatures of study on varicella-zoster virus immunization epidemics in different regions of China; (2) The literature has obvious age stratification; (3) The subjects are general people; (4) VZV sero-prevalence in the population investigated by the literature research institute. Exclusion criteria: Any study that did not contain these information was excluded.
DATA EXTRACTION AND SYNTHESISTwo evaluators independently retrieved documents and extracted data. Information about the study design, eligible population, age and gender distribution, inclusion and exclusion criteria were checked. When they disagreed, they could solve the problem by discussion or by soliciting opinions from third parties.
RESULTSLiteratures were screened according to the inclusion criteria and 10 studies from 1997 to 2019 with a total of 11666 individuals were included. The overall VZV seroprevalence in the Chinese population was 65.80% (95% CI; 56.5% - 75.1%), and the peak prevalence was seen in the age 36-45 93.50% (95% CI; 0.917-0.953) while the VZV seroprevalence rate (82.20%, 95% CI: 0.544-1.099) was not increased in individuals of 45 and older.
CONCLUSIONThe incidence of VZV increases with age, and there was no significant difference between different genders or regions. This results can provide epidemiological evidence for the prevention and treatment of VZV.
Strengths and limitations of this studyO_LIA broad search strategy and systematic review methodology were used to generate this comprehensive review on advice for prevention and treatment of VZV.
C_LIO_LIEvery inclusion article was assessed with a risk of bias tool and/or a quality assessment tool.
C_LIO_LIBecause of relatively small sample size, the incomplete data, and the different research objects, there are some bias in the outcomes, which limits the ability to make discrete conclusions.
C_LIO_LIThere were not enough articles identified to perform a meta-analysis.
C_LI | null | medrxiv |
10.1101/19008409 | The role of prison-based interventions for hepatitis C virus (HCV) micro-elimination among people who inject drugs in Montreal, Canada | Godin, A.; Kronfli, N.; Cox, J.; Alary, M.; Maheu-Giroux, M. | Arnaud Godin | McGill University | 2019-10-21 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | health policy | https://www.medrxiv.org/content/early/2019/10/21/19008409.source.xml | BackgroundIn Canada, hepatitis C virus (HCV) transmission primarily occurs among people who inject drugs (PWID) and people with experience in the prison system bare a disproportionate HCV burden. These overlapping groups of individuals have been identified as a priority populations for HCV micro-elimination in Canada, a country currently not on track to achieve its elimination targets. Considering the missed opportunities to intervene in provincial prisons, this study aims to estimate the population-level impact of prison-based interventions and post-release risk reduction strategies on HCV transmission among PWID in high HCV-burdened Canadian city, Montreal.
MethodsA dynamic HCV transmission model among PWID was developed and calibrated to community and prison bio-behavioural surveys in Montreal. The, the relative impact of prison-based testing and treatment or post-release linkage to care, alone or in combination with risk reduction strategies, was estimated from 2018 to 2030, and compared to counterfactual status quo scenario.
ResultsTesting and linkage to care interventions implemented over 2018-30 could lead to the greatest declines in prevalence (23%; 95% Credible interval(CrI):17-31%), incidence (20%; 95%CrI: 10-28%), and prevent the most new chronic infections (8%; 95%CrI: 4-11%). Testing and treatment in prison could decrease prevalence, incidence, and fraction of prevented new chronic infections. Combining test and linkage to care with risk reduction measures could further its epidemiological impact, preventing 10% (95%CrI: 5-16%) of new chronic infections. When implemented concomitantly with community-based treatment scale-up, both prison-based interventions had synergistic effects, averting a higher fraction of new chronic infections.
ConclusionOffering HCV testing and post-release linkage to care in provincial prisons, where incarcerations are frequent and sentences short, could change the course of the HCV epidemic in Montreal. Integration of post-release risk reduction measures and community-based treatment scale-up could also increase the impact of these interventions. | 10.1016/j.drugpo.2020.102738 | medrxiv |
10.1101/19009134 | Dissecting the association of C-reactive protein levels with PTSD, traumatic events, and social support | Muniz Carvalho, C.; Wendt, F.; Maihofer, A.; Stein, D.; Stein, M.; Sumner, J.; Hemmings, S.; Nievergelt, C.; Koenen, K.; Gelernter, J.; Belangero, S.; Polimanti, R. | Renato Polimanti | Yale University | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_no | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/22/19009134.source.xml | Inflammatory markers like C-reactive protein (CRP) have been associated with posttraumatic stress disorder (PTSD) and traumatic experience, but the underlying mechanisms are unclear. We investigated the association among CRP, PTSD, and traits related to traumatic events and social support using genome-wide data from the Psychiatric Genomics Consortium (30,000 cases and 170,000 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg=0.16, p=0.026) and behavioral and emotional response to trauma, exposure to traumatic events, and the presence of social support (-0.28<rg<0.20; p<0.008). We observed a bidirectional association between CRP and PTSD (CRP[->]PTSD: {beta}=0.065, p=0.015; PTSD[->]CRP: {beta}=0.008, p=0.009). CRP also showed a negative association on the "felt loved as a child" trait (UKB, {beta}=-0.017, p=0.008). Due to the known association of socioeconomic status (SES) on PTSD and social support, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: {beta}=-0.22, p=1.57x10-7; multivariate MR: {beta}=-0.17, p=0.005) and deprivation index (univariate MR: {beta}=0.38, p=1.63x10-9; multivariate MR: {beta}=0.27, p=0.016) were driving the causal estimates of "felt loved as a child" and CRP on PTSD. The present findings highlight a bidirectional association between PTSD and CRP levels, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk. | 10.1038/s41386-020-0655-6 | medrxiv |
10.1101/19008813 | Spatial versus angular resolution for tractography-assisted planning of deep brain stimulation | Liebrand, L.; van Wingen, G. A.; Vos, F. M.; Denys, D.; Caan, M. W. A. | Luka Liebrand | Dept. of Psychiatry, Amsterdam UMC | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/22/19008813.source.xml | Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b=2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization. | 10.1016/j.nicl.2019.102116 | medrxiv |
10.1101/19008953 | German Recommendations for Physical Activity and Physical Activity Promotion in Adults with Noncommunicable Diseases | Geidl, W.; Abu-Omar, K.; Weege, M.; Messing, S.; Pfeifer, K. | Wolfgang Geidl | Friedrich-Alexander University Erlangen-Nuernberg | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | public and global health | https://www.medrxiv.org/content/early/2019/10/22/19008953.source.xml | BackgroundThe objective of this study was to develop evidence-based recommendations for physical activity (PA) and PA promotion for German adults (18-65 years) with noncommunicable diseases (NCDs).
MethodsThe PA recommendations were developed based on existing PA recommendations and using a three-phased process. In phase 1, systematic literature searches were conducted for current PA recommendations for seven chronic conditions (osteoarthrosis of the hip and knee, chronic obstructive pulmonary disease, stable ischemic heart disease, stroke, clinical depression, and chronic non-specific back pain). In phase 2, the PA recommendations were evaluated on the basis of 28 quality criteria. High-quality recommendations were identified, and a content analysis was conducted on these recommendations. In phase 3, the findings of the content analysis were summarised, and PA recommendations for seven chronic conditions were deducted. The seven recommendations were then synthesised to generate generic German PA recommendations for adults with noncommunicable diseases (NCDs). In relation to the recommendations for PA promotion, a systematic literature review was conducted on papers that reviewed the efficacy/effectiveness of interventions for PA promotion in adults with NCDs.
ResultsThe German Recommendations for Physical Activity state that adults with NCDs should, over the course of a week, should do at least 150 minutes of moderate-intensity aerobic PA, or 75 minutes of vigorous-intensity aerobic PA, or a combination of both. Furthermore, muscle-strengthening activities should be performed at least twice a week. The promotion of PA among adults with NCDs should be theory-based, specifically target PA behaviour, and be tailored to the respective target group. In this context, and as an intervention method, exercise referral schemes are one of the more promising methods of promoting PA in adults with NCDs.
ConclusionThe development of evidence-based recommendations for PA and PA promotion is an important step in terms of the initiation and implementation of actions for PA-related health promotion in Germany. The German Recommendations for PA and PA promotion inform adults affected by NCDs and health professionals on how much PA would be optimal for adults with NCDs. Additionally, the recommendations provide professionals entrusted in PA promotion the best strategies and interventions to raise low PA levels in adults with NCDs. The formulation of specific PA recommendations for adults with NCDs and their combination with recommendations on PA promotion is a unique characteristic of the German recommendations. | 10.1186/s12966-020-0919-x | medrxiv |
10.1101/19009126 | Diffusion Histology Imaging to Improve Lesion Detection and Classification in Multiple Sclerosis | Ye, Z.; George, A.; Wu, A. T.; Niu, X.; Lin, J.; Adusumilli, G.; Cross, A. H.; Sun, P.; Song, S.-K. | Peng Sun | Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | neurology | https://www.medrxiv.org/content/early/2019/10/22/19009126.source.xml | BackgroundDiagnosing MS through magnetic resonance imaging (MRI) requires extensive clinical experience and tedious work. Furthermore, MRI-indicated MS lesion locations rarely align with the patients symptoms and often contradict with pathology studies. Our lab has developed and modified a novel diffusion basis spectrum imaging (DBSI) technique to address the shortcomings of MRI-based MS diagnoses. Although primary DBSI metrics have been demonstrated to be associated with axonal injury/loss, demyelination and inflammation, a more detailed analysis using multiple DBSI-structural metrics to improve the accuracy of MS lesion detection and differentiation is still needed. Here we report that Diffusion Histology Imaging (DHI), an improved approach that combines a deep neural network (DNN) algorithm with improved DBSI analyses, accurately detected and classified various MS lesion types.
MethodsThirty-eight multiple sclerosis patients were scanned with T2-weighted imaging (T2WI) using fluid attenuated inversion recovery (FLAIR), T1-weighted imaging (T1WI) using magnetization-prepared rapid acquisition with gradient echo (MPRAGE), magnetization transfer contrast (MTR) imaging and diffusion-weighted imaging. The imaging results identified 43,261 voxels from 91 persistent black hole (PBH) lesions, 89 persistent gray hole (PGH) lesions, 16 acute gray hole (AGH) lesions, 189 non-black hole (NBH) lesions and 113 normal-appearing white matter (NAWM) areas. Data extracted from these lesions were randomly split into training, validation, and testing groups with an 8:1:1 ratio. The DNN was constructed with 10 fully-connected hidden layers using TensorFlow 2.0 in Python. Batch normalization and dropout regularization were used for model optimization.
ResultsEach MS lesion type had unique DBSI derived diffusion metric profiles. Based on these DBSI diffusion metric profiles, DHI achieved a 93.6% overall concordance with neurologist determinations of all five MS lesions, compared with 74.3% from conventional MRI (cMRI)-DNN model, 78.2% from MTR-DNN model, and 80% from DTI-DNN model. DHI also achieved greater performances on detecting individual MS lesion types compared to other models. Specifically, DHI showed great performances on prediction of PBH (AUC: 0.991; F1-score: 0.923), PGH (AUC: 0.977; F1-score: 0.823) and AGH (AUC: 0.987; F1-score: 0.887), which significantly outperformed other models.
ConclusionsDHI significantly improves the detection and classification accuracy for various MS lesion types, which could greatly aid the clinical decisions of neurologists and neuroradiologists. The efficacy and efficiency of this DNN model shows great promise for clinical application. | 10.1002/acn3.51037 | medrxiv |
10.1101/19009704 | Impact of a natural disaster on access to care and biopsychosocial outcomes among Hispanic/Latino cancer survivors | Rodriguez, M.; Hernandez-Torres, R.; Rodriguez, Z.; Colon-Echevarria, C. B.; Maldonado, L.; Tollinchi, N.; Torres, E.; Mulero, A.; Albors, D.; Perez-Morales, J.; Flores, I.; Jim, H.; Castro, E. M.; Armaiz-Pena, G. N. | Guillermo N Armaiz-Pena | Ponce Health Sciences University | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | oncology | https://www.medrxiv.org/content/early/2019/10/22/19009704.source.xml | Cancer is the leading cause of death in Puerto Rico (PR). Hurricane Maria (HM) and its aftermath lead to widespread devastation in the island, including the collapse of the healthcare system. Medically fragile populations, such as cancer survivors, were significantly affected. The goal of this study was to assess the impact of HM on barriers to care, emotional distress, and inflammatory biomarkers among cancer survivors in PR. This exploratory longitudinal study was conducted in health care facilities and community support groups from PR. Cancer survivors (n=50) and non-cancer participants (n=50) completed psychosocial questionnaires and provided blood samples that were used to assess inflammatory cytokines levels. Data were analyzed through descriptive, frequencies, correlational, and linear regression analyses. Cancer survivors that were affected by HM reported increased barriers in accessing medical care, which were directly associated with anxiety, perceived stress, and post-traumatic symptomatology. Moreover, being a cancer survivor, along with closeness in time from HM predicted more barriers to receiving health care. Several inflammatory cytokines, such as CD31, BDNF, TFF3, Serpin E-1, Vitamin D BP, VCAM-1, Osteopontin, Chitinase 3 like 1, MMP-9 and MIF were significantly upregulated in cancer survivors while BDNF, MMP9 and Osteopontin had significant positive correlations with barriers to care. HM significantly impacted Puerto Ricans psychosocial well-being. Cancer survivors had significant barriers to care and showed increased serum inflammatory cytokines, but didnt show differences in anxiety, stress and post-traumatic symptoms compared to non-cancer participants. | 10.1038/s41598-020-66628-z | medrxiv |
10.1101/19006932 | Resilience to dominant genetic disease in the healthy elderly | Lacaze, P.; Sebra, R.; Riaz, M.; Tiller, J.; Revote, J.; Phung, J.; Parker, E. J.; Orchard, S. G.; Lockery, J. E.; Wolfe, R.; Strahl, M.; Wang, Y. C.; Chen, R.; Sisco, D.; Arnold, T.; Thompson, B. A.; Buchanan, D. D.; Macrae, F.; James, P. A.; Abhayaratna, W. P.; Lockett, T. J.; Gibbs, P.; Tonkin, A. M.; Nelson, M. R.; Reid, C. M.; Woods, R. L.; Murray, A. M.; Winship, I.; McNeil, J. J.; Schadt, E. | Paul Lacaze | Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | genetic and genomic medicine | https://www.medrxiv.org/content/early/2019/10/22/19006932.source.xml | Here we describe genomic screening of the healthy elderly to identify those resilient to adult-onset genetic disease, despite being at exceptionally high genetic risk. We sequenced 13,131 individuals aged 70 or older (mean age 75 years) from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no prior history of cardiovascular disease, life-threatening cancer, persistent physical disability or dementia. We compared the prevalence of pathogenic variants in medically actionable autosomal dominant disease genes with that from the UK Biobank population, and assessed their clinical impact using personal medical history and adjudicated study outcomes during 4.5 years of follow-up. The frequency of pathogenic variants was less than reported among the younger UK Biobank population, suggesting these variants confer a survival disadvantage during the middle years of life. Yet we identified 141 individuals with pathogenic variants free of any associated disease up to average age 79.5 years. Further study of these elderly resilient individuals might help uncover genetic mechanisms that protect against the development of disease. | null | medrxiv |
10.1101/19009118 | A Comprehensive Typing System for Information Extraction from Clinical Narratives | Caufield, J. H.; Zhou, Y.; Bai, Y.; Liem, D. A.; Garlid, A. O.; Chang, K.-W.; Sun, Y.; Ping, P.; Wang, W. | J. Harry Caufield | University of California, Los Angeles | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by | health informatics | https://www.medrxiv.org/content/early/2019/10/22/19009118.source.xml | We have developed ACROBAT (Annotation for Case Reports using Open Biomedical Annotation Terms), a typing system for detailed information extraction from clinical text. This resource supports detailed identification and categorization of entities, events, and relations within clinical text documents, including clincal case reports (CCRs) and the free-text components of electronic health records. Using ACROBAT and the text of 200 CCRs, we annotated a wide variety of real-world clinical disease presentations. The resulting dataset, MACCROBAT2018, is a rich collection of annotated clinical language appropriate for training biomedical natural language processing systems. | null | medrxiv |
10.1101/19008821 | Estimating Real World Performance of a Predictive Model: A Case-Study in Predicting End-of-Life | Major, V. J.; Jethani, N.; Aphinyanaphongs, Y. | Vincent J Major | NYU Langone Health | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_no | health informatics | https://www.medrxiv.org/content/early/2019/10/22/19008821.source.xml | ObjectiveThe main criteria for choosing how models are built is the subsequent effect on future (estimated) model performance. In this work, we evaluate the effects of experimental design choices on both estimated and actual model performance.
Materials and MethodsFour years of hospital admissions are used to develop a 1 year end-of-life prediction model. Two common methods to select appropriate prediction timepoints (backwards-from-outcome and forwards-from-admission) are introduced and combined with two ways of separating cohorts for training and testing (internal and temporal). Two models are trained in identical conditions, and their performances are compared. Finally, operating thresholds are selected in each test set and applied in a final, real-world cohort consisting of one year of admissions.
ResultsBackwards-from-outcome cohort selection discards 75% of candidate admissions (n=23,579), whereas forwards-from-admission selection includes many more (n=92,148). Both selection methods produce similar global performances when applied to an internal test set. However, when applied to the temporally defined real-world set, forwards-from-admission yields higher areas under the ROC and precision recall curves (88.3 and 56.5% vs. 83.2 and 41.6%).
DiscussionA backwards-from-outcome experiment effectively transforms the training data such that it no longer resembles real-world data. This results in optimistic estimates of test set performance, especially at high precision. In contrast, a forwards-from-admission experiment with a temporally separated test set consistently and conservatively estimates real-world performance.
ConclusionExperimental design choices impose bias upon selected cohorts. A forwards-from-admission experiment, validated temporally, can conservatively estimate real-world performance. | 10.1093/jamiaopen/ooaa008 | medrxiv |
10.1101/19009167 | Bringing Critical Race Praxis into the Study of Electrophysiological Substrate of Sudden Cardiac Death: The Atherosclerosis Risk in Communities (ARIC) Study | Jensen, K.; Howell, S.; Phan, F.; Khayyat-Kholghi, M.; Wang, L.; Haq, K. T.; Johnson, J.; Tereshchenko, L. G. | Larisa G Tereshchenko | Oregon Health & Science University | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_no | cardiovascular medicine | https://www.medrxiv.org/content/early/2019/10/22/19009167.source.xml | Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological (EP) substrate with SCD varies between black and white individuals. Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,408; age 54{+/-}6 y; 74% white) were included. EP substrate was characterized by traditional 12-lead ECG and vectorcardiographic metrics. Two competing outcomes were adjudicated SCD and non-sudden cardiac death (nonSCD). Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease (CVD), risk factors, and incident non-fatal CVD. At the baseline visit linear regression analysis, adjusted for age, sex, and study center, showed black individuals had larger Spatial Ventricular Gradient magnitude by 0.30 (95%CI 0.25-0.34) mV, SAI QRST by 18.4 (13.7-23.0) mV*ms, Cornell voltage by 0.30 (95%CI 0.25-0.35) mV than white individuals. Over a median follow-up of 24.4 years, SCD incidence was higher in black (2.86; 95%CI 2.50-3.28 per 1000 person-years) than white individuals (1.37; 95%CI 1.22-1.53 per 1000 person-years). Black individuals with hypertension had the highest rate of SCD: 4.26; 95%CI 3.66-4.96 per 1000 person-years. Race did not modify associations of EP substrate with SCD and nonSCD. EP substrate does not explain racial disparities in SCD rate. | 10.1161/JAHA.119.015012 | medrxiv |
10.1101/19009886 | COST-EFFECTIVENESS ANALYSIS FOR HPV MITIGATION STRATEGIES IMPLEMENTED IN 2018 IN THE REPUBLIC OF MOLDOVA BASED ON INFECTIOUS DISEASE MODELLING | Jarynowski, A. | Andrzej Jarynowski | Institute for Interdisciplinary Research | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/10/22/19009886.source.xml | Human papillomavirus (HPV), is a sexually transmittable virus infection, which is necessary risk factor for developing cervical cancer, first killer in working age women in Moldova. Since 2018 Moldova has modified screening program and vaccination program (mainly externally funded). To assess the performance of the mitigation policy we propose cost-effectiveness analysis according to 2 already implemented strategies. (1) Vaccination of a single age-cohort, although vaccinating a single cohort may not have a substantial effect in other countries with distinct socio-economic situation. (2) Transition to more technologically advance screening ecosystem (changing from Romanowski to Pap smear), which might not necessary be cost-efficient in low resource settings (if GDP per capita will not growth substantially at the same time).
O_LIWe verified that single cohort vaccination is both cost-beneficial (total costs reduction will balance intervention costs around the year 2040) and cost-efficient (with incremental impact in 20 years perspective on the level of 2300 EUR/QALY). Moreover, we found out that single year cohort is more beneficial than 5-years cohort vaccination scenarios in our mathematical model. This behaviour could be explained by a transitional situation in Moldova (HPV epidemic is near outbreak threshold), still small changes of model parameters and initial conditions could cause strong effect in the epidemiology. However, a definitive answer cannot be given with the chosen methodology.
C_LIO_LITransition between Romanowski -> Pap smear cytology in screening benefits unquestionably in epidemiology e.g. due to higher specificity. However, further maintenance and higher procedure costs could exceed treatment costs, hence intervention costs would gather unacceptable share in whole national limited resources dedicated to public health.
C_LI | null | medrxiv |
10.1101/19009837 | Presence of additional P. vivax malaria in Duffy negative individuals from Southwestern Nigeria | Oboh, M. A.; Singh, U. S.; Ndiaye, D.; Badiane, A. S.; Ali, N. A.; Bharti, P. K.; Das, A. | Mary Aigbiremo Oboh | Parasitology and Mycology Laboratory, Universite Cheikh Anta Diop, Dakar, Senegal | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/10/22/19009837.source.xml | Malaria in sub-Saharan Africa (sSA) is thought to be hugely caused by Plasmodium falciparum and very infrequently by P. ovale, P. malariae, with P. vivax not even being considered to be of any significant role. However, with the availability of very sensitive diagnostic tool, it has become more clear that, the percentage of non-falciparum malaria in this sub-region has been underestimated. P. vivax was historically thought to be absent in sSA due to the high prevalence of the Duffy null antigen in individuals residing here. Nevertheless, recent studies reporting the detection of vivax malaria in Duffy-negative individuals challenges this notion. Following our earlier report of P. vivax in Duffy-negative individuals, we have re-assessed all previous samples following the classical PCR method and sequencing to confirm both single/mixed infections as well as the Duffy status of the individuals.
Interestingly, fifteen additional Plasmodium infections were detected, representing 5.9% in prevalence from our earlier work. In addition, P. vivax represents 26.7% (4/15) of the new isolates collected in Nigeria. Sequencing results confirmed, all vivax isolates as truly vivax malaria and their Duffy status to be that of the Duffy-negative genotype. The identification of more vivax isolates among these Duffy-negative individuals from Nigeria, substantiate the expanding body of evidence of the ability of P. vivax to infect RBCs that do not express the DARC gene. Hence, such geno-epidemiological study should be conducted at the national level in order to evaluate the actual burden of P. vivax in the country. | 10.1186/s12936-020-03301-w | medrxiv |
10.1101/19009241 | Evaluation of a brief intervention to reduce cell phone use in college students | Piper, B. J.; Daily, S. M.; Martin, S. L.; Martin, M. W. | Maurice W Martin | University of Maine, Farmington | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | epidemiology | https://www.medrxiv.org/content/early/2019/10/22/19009241.source.xml | BackgroundExcessive cell phone use contributes to distracted driving, may increase risk for automobile accidents, and a minority of mobile phone users exhibit behaviors consistent with technological addiction. The purpose of this study was to determine whether cell phone beliefs and behaviors could be changed by a brief educational encounter. The Theory of Reasoned Action provided a lens for viewing attitudes and behavior.
MethodsA one-week pre-post design with a thirty-day follow-up was used with participants (N = 215, 67.0% female, age = 20.0 + 1.6) assigned to a peer led intervention or comparison groups. The intervention included cell-phone educational materials. A short index of cell phone behavior was developed which showed good internal consistency with a Cronbachs alpha of .81.
ResultsThe intervention group "agreed" or "strongly-agreed" more than the comparison group on five of the seven areas of cell phone beliefs and behaviors (p < 0.05, item Cohens d = .32 to .47, total d = .50) at one-week following receipt of informational materials.
DiscussionWe conclude that attitudes and behaviors regarding cell phones are malleable and susceptible to change in young-adults following a brief psychoeducational intervention. | 10.53481/001c.35547 | medrxiv |
10.1101/19009738 | Independent and Joint Associations of Sedentary Behavior and Physical Activity with Cardiometabolic Health Markers in the 1970 British Birth Cohort | Huang, B.-H.; Hamer, M.; Chastin, S.; Koster, A.; Pearson, N.; Stamatakis, E. | Emmanuel Stamatakis | University of Sydney | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_no | epidemiology | https://www.medrxiv.org/content/early/2019/10/22/19009738.source.xml | ObjectiveTo examine the independent and joint associations thigh-worn accelerometry assessed sedentary time and moderate to vigorous physical activity with cardiometabolic health markers.
DesignCross-sectional study embedded in the age-46 wave an established birth cohort, the 1970 British Birth Cohort.
SettingPopulation-based sample from Great Britain (England, Scotland, and Wales).
MethodsOutcome measures included: body mass index, waist-to-hip ratio, blood pressure, glycated hemoglobin, high-density lipoprotein cholesterol, total cholesterol, triglycerides, and c-reactive protein. Sedentary behavior and other physical activity exposures, recorded by a thigh-worn activPAL3 accelerometry, included: daily sedentary time, breaks in sedentary time, daily time spent in moderate-to-vigorous physical activity. Multiple linear regression analyses, multiple logistic regression analyses, and general linear models were conducted as applicable.
Results4,634 participants were available for the final analysis. After adjusting for potential confounders and moderate-to-vigorous physical activity, daily sedentary time was positively associated with triglycerides ({beta}=0.052 [0.015, 0.089]) and inversely associated with high-density lipoprotein cholesterol ({beta}=-0.015 [-0.022, -0.010]). Daily prolonged sedentary time ([≥] 60 minutes) was positively associated with both glycated hemoglobin and log-transformed c-reactive protein ({beta}=0.240 [0.030, 0.440] and 0.026 [0.007, 0.045], respectively) and inversely associated with systolic blood pressure and high-density lipoprotein cholesterol ({beta}=-0.450 [-0.760, -0.150] and -0.013 [-0.022, -0.003], respectively). After adjusting for potential confounders and daily sedentary time, daily breaks in sedentary time were inversely associated with glycated hemoglobin ({beta}=-0.020 [-0.037, -0.003]), and positively associated with both triglycerides and systolic blood pressure ({beta}=0.006 [0.002, 0.010] and 0.030 [0.002, 0.050], respectively). The joint associations of prolonged sedentary time and moderate-to-vigorous physical activity with the prevalence of diabetes were not statistically significant.
ConclusionProlonged sedentary time ([≥] 60 minutes) and daily breaks in sedentary time were deleteriously associated with glycated hemoglobin, although we found no evidence that there were joint moderate-to-vigorous physical activity and sitting associations. | 10.1111/dme.14392 | medrxiv |
10.1101/19009423 | Point-of-care serodiagnostic test for early-stage Lyme disease using a multiplexed paper-based immunoassay and machine learning | Joung, H.-A.; Ballard, Z. S.; Wu, J.; Tseng, D. K.; Teshome, H.; Zhang, L.; Horn, E. J.; Arnaboldi, P. M.; Dattwyler, R. J.; Garner, O. B.; Carlo, D. D.; Ozcan, A. | Aydogan Ozcan | UCLA | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | pathology | https://www.medrxiv.org/content/early/2019/10/22/19009423.source.xml | Caused by the tick-borne spirochete, Borrelia burgdorferi, Lyme disease (LD) is the most common vector-borne infectious disease in North America and Europe. Though timely diagnosis and treatment are effective in preventing disease progression, current tests are insensitive in early-stage LD, with a sensitivity <50%. Additionally, the serological testing currently recommended by the US Center for Disease Control has high costs (>$400/test) and extended sample-to-answer timelines (>24 hours). To address these challenges, we created a cost-effective and rapid point-of-care (POC) test for early-stage LD that assays for antibodies specific to seven Borrelia antigens and a synthetic peptide in a paper-based multiplexed vertical flow assay (xVFA). We trained a deep learning-based diagnostic algorithm to select an optimal subset of antigen/peptide targets, and then blindly-tested our xVFA using human samples (N(+) = 42, N(-)= 54), achieving an area-under-the-curve (AUC), sensitivity, and specificity of 0.950, 90.5%, and 87.0% respectively, outperforming previous LD POC tests. With batch-specific standardization and threshold tuning, the specificity of our blind-testing performance improved to 96.3%, with an AUC and sensitivity of 0.963 and 85.7%, respectively. | 10.1021/acsnano.9b08151 | medrxiv |
10.1101/19009696 | Profiles of cognitive change in preclinical Alzheimer's disease using change-point analysis | Williams, O. A.; An, Y.; Armstrong, N. M.; Kitner-Triolo, M.; Ferrucci, L.; Resnick, S. M. | Owen A Williams | National Institute on Aging, NIH | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc0 | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/22/19009696.source.xml | IntroductionChange-point analyses are increasingly used to identify the temporal stages of accelerated cognitive decline in the preclinical stages of Alzheimers Disease (AD). However, statistical comparisons of change-points between specific cognitive measures have not been reported.
Methods165 older adults (baseline age range: 61.1-91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures.
ResultsChange-points followed by accelerated decline ranged from 15.5 years (Card Rotations) to 1.9 years (Trail-Making A) before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures.
DiscussionResults suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD. | 10.3233/JAD-191268 | medrxiv |
10.1101/19009621 | Increased Mortality in Patients with Standard EEG Findings of \"Diffuse Slowing\" | Wanzek, R.; Bormann, N.; Shabbir, Y.; Saito, T.; Yamada, T.; Shinozaki, G. | Gen Shinozaki | University of Iowa | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc_nd | psychiatry and clinical psychology | https://www.medrxiv.org/content/early/2019/10/22/19009621.source.xml | Background/ObjectivesWe aim to confirm the association between the high risk score on bispectral electroencephalogram (BSEEG) and mortality by comparing outcomes for those with "diffuse slowing" and normal findings on standard EEG.
DesignThis is a retrospective study conducted with patient chart data from March 2015 to March 2017.
SettingSingle center study at a tertiary care academic hospital in the Midwest region of the USA.
Participants1069 subjects aged 55 years and older who were on an inpatient floor or intensive care unit and received a standard 24-hour EEG.
MeasurementsPrimary outcome was all-cause mortality at 30-, 90-, 180-, and 365-days. Secondary outcomes were time-to-discharge, and discharge to home.
ResultsPatients with "diffuse slowing" on standard EEG was significantly associated with 30-, 90-, 180-, and 365-day mortality (P < .001) compared to those with normal EEG findings when controlling for age, sex, and Carlson Comorbidity Index. Those with diffuse slowing also had a longer time to discharge (P < 0.001) and were less likely to discharge to home (P < 0.001) when controlling for the same factors. Findings were similar when limiting the study to only patients whose clinical status indicated "awake" at time of EEG, except for 30-day mortality.
ConclusionOur findings show that a standard EEG finding of "diffuse slowing" for inpatients 55 year or older is associated with greater mortality. This study strengthens the importance of the association found between high BSEEG score and mortality. | 10.12788/acp.0018 | medrxiv |
10.1101/19009977 | Cost-effectiveness of the next generation of RSV intervention strategies | Hodgson, D.; Panovska-Griffiths, J.; Pebody, R.; Baguelin, M.; Atkins, K. | David Hodgson | UCL | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/22/19009977.source.xml | BackgroundWith a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued.
MethodsTo compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to seven years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes.
FindingsOur transmission model suggests that maternal protection of infants is seasonal, with 2-14% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than {pound}80.
InterpretationsIn a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal.
FundingMedical Research Council and National Institute for Health Research
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA recent systematic review identified RSV prophylactic candidates currently in clinical trials, including a maternal vaccine (RSV F-nanoparticles vaccine), long-acting monoclonal antibodies aimed at neonates (MEDI8897), and an active adenovirus vector-based vaccine aimed at infants and/or the elderly (ChAd155-RSV). Given the significant observed health burden due to RSV in children, these products, which are mainly aimed at children, are likely to be effective at preventing RSV disease. However, uncertainties surrounding i) the dynamics of maternally-derived protection in neonates, ii) the impact of herd immunity, and iii) the purchasing cost of these prophylactics, means it is not clear if these products are cost-effective. Therefore, evaluating the purchasing price required for these prophylactics to remain cost-effective using a dynamic transmission model, in which the herd immunity is included and the dynamics of maternally-derived immunity is determined by calibrating the model to data, is a public health priority.
Added-value of this studyOur study finds that in a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal. In addition, our study estimates the maximum purchasing price per course for various potential RSV intervention programmes to be cost-effective in England, assuming a cost-effectiveness threshold of {pound}20,000/QALY as recommended by the National Institute of Clinical Excellence (NICE). We find that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, and vaccinating the elderly is not likely to be affordable.
Implications of all the available evidenceThe seasonal protection conferred to newborns is consistent with empirical immunological data from maternal cord blood and ecological evidence from hospital records. Further, extending a monoclonal antibody programme would be possible if there is a considerable drop in price and maternal vaccination remains the only realistic vaccination strategy in the UK. With further clinical trials planned for RSV F-nanoparticles vaccine to evaluate its efficacy, and with clinical trial completion dates set at the end of 2021 for the other two prophylactic candidates, the results of this study provide a comprehensive overview of the impact of potential RSV intervention programmes both in the present and in the coming years. | 10.1186/s12916-020-01802-8 | medrxiv |
10.1101/19009977 | Cost-effectiveness of the next generation of RSV intervention strategies | Hodgson, D.; Panovska-Griffiths, J.; Pebody, R.; Baguelin, M.; Atkins, K. | David Hodgson | UCL | 2019-10-29 | 2 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/10/29/19009977.source.xml | BackgroundWith a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued.
MethodsTo compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to seven years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes.
FindingsOur transmission model suggests that maternal protection of infants is seasonal, with 2-14% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than {pound}80.
InterpretationsIn a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal.
FundingMedical Research Council and National Institute for Health Research
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA recent systematic review identified RSV prophylactic candidates currently in clinical trials, including a maternal vaccine (RSV F-nanoparticles vaccine), long-acting monoclonal antibodies aimed at neonates (MEDI8897), and an active adenovirus vector-based vaccine aimed at infants and/or the elderly (ChAd155-RSV). Given the significant observed health burden due to RSV in children, these products, which are mainly aimed at children, are likely to be effective at preventing RSV disease. However, uncertainties surrounding i) the dynamics of maternally-derived protection in neonates, ii) the impact of herd immunity, and iii) the purchasing cost of these prophylactics, means it is not clear if these products are cost-effective. Therefore, evaluating the purchasing price required for these prophylactics to remain cost-effective using a dynamic transmission model, in which the herd immunity is included and the dynamics of maternally-derived immunity is determined by calibrating the model to data, is a public health priority.
Added-value of this studyOur study finds that in a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal. In addition, our study estimates the maximum purchasing price per course for various potential RSV intervention programmes to be cost-effective in England, assuming a cost-effectiveness threshold of {pound}20,000/QALY as recommended by the National Institute of Clinical Excellence (NICE). We find that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, and vaccinating the elderly is not likely to be affordable.
Implications of all the available evidenceThe seasonal protection conferred to newborns is consistent with empirical immunological data from maternal cord blood and ecological evidence from hospital records. Further, extending a monoclonal antibody programme would be possible if there is a considerable drop in price and maternal vaccination remains the only realistic vaccination strategy in the UK. With further clinical trials planned for RSV F-nanoparticles vaccine to evaluate its efficacy, and with clinical trial completion dates set at the end of 2021 for the other two prophylactic candidates, the results of this study provide a comprehensive overview of the impact of potential RSV intervention programmes both in the present and in the coming years. | 10.1186/s12916-020-01802-8 | medrxiv |
10.1101/19009977 | Cost-effectiveness of the next generation of RSV intervention strategies | Hodgson, D.; Panovska-Griffiths, J.; Pebody, R.; Baguelin, M.; Atkins, K. | David Hodgson | UCL | 2019-11-05 | 3 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2019/11/05/19009977.source.xml | BackgroundWith a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued.
MethodsTo compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to seven years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes.
FindingsOur transmission model suggests that maternal protection of infants is seasonal, with 2-14% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than {pound}80.
InterpretationsIn a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal.
FundingMedical Research Council and National Institute for Health Research
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA recent systematic review identified RSV prophylactic candidates currently in clinical trials, including a maternal vaccine (RSV F-nanoparticles vaccine), long-acting monoclonal antibodies aimed at neonates (MEDI8897), and an active adenovirus vector-based vaccine aimed at infants and/or the elderly (ChAd155-RSV). Given the significant observed health burden due to RSV in children, these products, which are mainly aimed at children, are likely to be effective at preventing RSV disease. However, uncertainties surrounding i) the dynamics of maternally-derived protection in neonates, ii) the impact of herd immunity, and iii) the purchasing cost of these prophylactics, means it is not clear if these products are cost-effective. Therefore, evaluating the purchasing price required for these prophylactics to remain cost-effective using a dynamic transmission model, in which the herd immunity is included and the dynamics of maternally-derived immunity is determined by calibrating the model to data, is a public health priority.
Added-value of this studyOur study finds that in a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal. In addition, our study estimates the maximum purchasing price per course for various potential RSV intervention programmes to be cost-effective in England, assuming a cost-effectiveness threshold of {pound}20,000/QALY as recommended by the National Institute of Clinical Excellence (NICE). We find that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, and vaccinating the elderly is not likely to be affordable.
Implications of all the available evidenceThe seasonal protection conferred to newborns is consistent with empirical immunological data from maternal cord blood and ecological evidence from hospital records. Further, extending a monoclonal antibody programme would be possible if there is a considerable drop in price and maternal vaccination remains the only realistic vaccination strategy in the UK. With further clinical trials planned for RSV F-nanoparticles vaccine to evaluate its efficacy, and with clinical trial completion dates set at the end of 2021 for the other two prophylactic candidates, the results of this study provide a comprehensive overview of the impact of potential RSV intervention programmes both in the present and in the coming years. | 10.1186/s12916-020-01802-8 | medrxiv |
10.1101/19009977 | Cost-effectiveness of the next generation of RSV intervention strategies | Hodgson, D.; Pebody, R.; Panovska-Griffiths, J.; Baguelin, M.; Atkins, K. | David Hodgson | UCL | 2020-01-23 | 4 | PUBLISHAHEADOFPRINT | cc_by_nc | public and global health | https://www.medrxiv.org/content/early/2020/01/23/19009977.source.xml | BackgroundWith a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued.
MethodsTo compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to seven years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes.
FindingsOur transmission model suggests that maternal protection of infants is seasonal, with 2-14% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than {pound}80.
InterpretationsIn a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal.
FundingMedical Research Council and National Institute for Health Research
RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSA recent systematic review identified RSV prophylactic candidates currently in clinical trials, including a maternal vaccine (RSV F-nanoparticles vaccine), long-acting monoclonal antibodies aimed at neonates (MEDI8897), and an active adenovirus vector-based vaccine aimed at infants and/or the elderly (ChAd155-RSV). Given the significant observed health burden due to RSV in children, these products, which are mainly aimed at children, are likely to be effective at preventing RSV disease. However, uncertainties surrounding i) the dynamics of maternally-derived protection in neonates, ii) the impact of herd immunity, and iii) the purchasing cost of these prophylactics, means it is not clear if these products are cost-effective. Therefore, evaluating the purchasing price required for these prophylactics to remain cost-effective using a dynamic transmission model, in which the herd immunity is included and the dynamics of maternally-derived immunity is determined by calibrating the model to data, is a public health priority.
Added-value of this studyOur study finds that in a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal. In addition, our study estimates the maximum purchasing price per course for various potential RSV intervention programmes to be cost-effective in England, assuming a cost-effectiveness threshold of {pound}20,000/QALY as recommended by the National Institute of Clinical Excellence (NICE). We find that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around {pound}4,350 but dropping to {pound}200 for vaccinated heightened risk infants or {pound}90 for all infants. A seasonal maternal vaccine would have to be priced less than {pound}85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, and vaccinating the elderly is not likely to be affordable.
Implications of all the available evidenceThe seasonal protection conferred to newborns is consistent with empirical immunological data from maternal cord blood and ecological evidence from hospital records. Further, extending a monoclonal antibody programme would be possible if there is a considerable drop in price and maternal vaccination remains the only realistic vaccination strategy in the UK. With further clinical trials planned for RSV F-nanoparticles vaccine to evaluate its efficacy, and with clinical trial completion dates set at the end of 2021 for the other two prophylactic candidates, the results of this study provide a comprehensive overview of the impact of potential RSV intervention programmes both in the present and in the coming years. | 10.1186/s12916-020-01802-8 | medrxiv |
10.1101/19009787 | Beware (surprisingly common) left-right flips in your MRI data: an efficient and robust method to check using AFNI | Glen, D. R.; Taylor, P. A.; Buchsbaum, B.; Cox, R. W.; Reynolds, R. C. | Daniel R Glen | NIMH | 2019-10-22 | 1 | PUBLISHAHEADOFPRINT | cc0 | radiology and imaging | https://www.medrxiv.org/content/early/2019/10/22/19009787.source.xml | Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets. | 10.3389/fninf.2020.00018 | medrxiv |
10.1101/19009787 | Beware (surprisingly common) left-right flips in your MRI data: an efficient and robust method to check MRI dataset consistency using AFNI | Glen, D. R.; Taylor, P. A.; Buchsbaum, B.; Cox, R. W.; Reynolds, R. C. | Daniel R Glen | NIMH | 2019-12-31 | 2 | PUBLISHAHEADOFPRINT | cc0 | radiology and imaging | https://www.medrxiv.org/content/early/2019/12/31/19009787.source.xml | Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets. | 10.3389/fninf.2020.00018 | medrxiv |
10.1101/19009787 | Beware (surprisingly common) left-right flips in your MRI data: an efficient and robust method to check MRI dataset consistency using AFNI | Glen, D. R.; Taylor, P. A.; Buchsbaum, B.; Cox, R. W.; Reynolds, R. C. | Daniel R Glen | NIMH | 2020-01-24 | 3 | PUBLISHAHEADOFPRINT | cc0 | radiology and imaging | https://www.medrxiv.org/content/early/2020/01/24/19009787.source.xml | Knowing the difference between left and right is generally assumed throughout the brain MRI research community. However, we note widespread occurrences of left-right orientation errors in MRI open database repositories where volumes have contained systematic left-right flips between subject EPIs and anatomicals, due to having incorrect or missing file header information. Here we present a simple method in AFNI for determining the consistency of left and right within a pair of acquired volumes for a particular subject; the presence of EPI-anatomical inconsistency, for example, is a sign that dataset header information likely requires correction. The method contains both a quantitative evaluation as well as a visualizable verification. We test the functionality using publicly available datasets. Left-right flipping is not immediately obvious in most cases, so we also present visualization methods for looking at this problem (and other potential problems), using examples from both FMRI and DTI datasets. | 10.3389/fninf.2020.00018 | medrxiv |