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10.1101/2022.04.20.22274073 | Heterozygous and homozygous variants in STX1A cause a neurodevelopmental disorder with or without epilepsy | The neuronal SNARE complex drive synaptic vesicle exocytosis. Therefore, one of its core proteins syntaxin 1A (STX1A) has long been suspected to play a role in neurodevelopmental disorders. We assembled eight individuals harboring rare variants in STX1A who present with a spectrum of intellectual, autism and epilepsy. Causative variants comprise a homozygous splice variant, three de novo missense variants and two inframe deletions of a single amino acid. We observed a phenotype mainly driven by epilepsy in the individuals with missense variants in contrast to intellectual disability and autistic behavior in individuals with single amino acid deletions and the splicing variant. In silico modeling of missense variants and single amino acid deletions show different impaired protein-protein interactions. We hypothesize the two phenotypic courses of affected individuals to be dependent on two different pathogenic mechanisms: (1) a weakened inhibitory STX1A-STXBP1 interaction due to missense variants results in an STX1A-related developmental epileptic encephalopathy and (2) a hampered SNARE complex formation due to inframe deletions causes an STX1A-related intellectual disability and autism phenotype. | genetic and genomic medicine |
10.1101/2022.04.19.22273994 | SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy | Introductory ParagraphElevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and epilepsy1-5. We performed a genome-wide association, colocalization and pathway analysis of impulsivity in juvenile myoclonic epilepsy (JME). We identify genome-wide associated SNPs at 8q13.3 (p=7.5 x 10-9) and 10p11.21 (p=3.6 x 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (p=9.5 x 10-3). SLCO5A1 codes for a membrane-bound organic anion transporter6 and upregulates synapse assembly/organisation genes7. Pathway analysis also demonstrates 9.3-fold enrichment for synaptic assembly genes (p=0.03) including NRXN1, NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila homolog of SLCO5A1, causes both over-reactive startling behaviour (p=8.7 x 10-3) and increased seizure-like events (p=6.8 x 10-7). Polygenic risk score for ADHD correlates with impulsivity scores (p=1.60 x 10-3), demonstrating shared genetic contributions. SLCO5A1 loss-of-function represents a novel impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease. | genetic and genomic medicine |
10.1101/2022.04.19.22273994 | SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy | Introductory ParagraphElevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and epilepsy1-5. We performed a genome-wide association, colocalization and pathway analysis of impulsivity in juvenile myoclonic epilepsy (JME). We identify genome-wide associated SNPs at 8q13.3 (p=7.5 x 10-9) and 10p11.21 (p=3.6 x 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (p=9.5 x 10-3). SLCO5A1 codes for a membrane-bound organic anion transporter6 and upregulates synapse assembly/organisation genes7. Pathway analysis also demonstrates 9.3-fold enrichment for synaptic assembly genes (p=0.03) including NRXN1, NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila homolog of SLCO5A1, causes both over-reactive startling behaviour (p=8.7 x 10-3) and increased seizure-like events (p=6.8 x 10-7). Polygenic risk score for ADHD correlates with impulsivity scores (p=1.60 x 10-3), demonstrating shared genetic contributions. SLCO5A1 loss-of-function represents a novel impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease. | genetic and genomic medicine |
10.1101/2022.04.20.22274099 | Minimal algorithms for knowledge representation in clinical decision support systems research: a theoretical and empirical analysis | Clinical decision support systems (CDSS) figures out as one of the most promising technologies for data-centered and AI-prompted healthcare. Its current developments are mainly guided by two disparate mindsets, namely a machine learning-centered framework and a classical rule-based framework. These respective approaches presents contrastive pros and cons. In the present study we provide an analysis showing that these two mindsets are actually related to each other, and straightforward algorithms are feasible by combining current standards for machine learning and classic decision tables algorithms. A theoretical analysis are provided, as well a computational implementation (in python). A real case scenario on radiological immaging exam prescription is used to ilustrate the successfully application of our results. Future work on benchmarking the proposed algorithms embodied in a fully operational clinical decision support system could extend our findings towards daily used systems. | health informatics |
10.1101/2022.04.20.22274033 | Reporting of patient involvement: A mixed-methods analysis of current practice in health research publications | ObjectivesTo evaluate the extent and quality of patient involvement reporting in examples of current practice in health research.
DesignMixed-methods study. We used a targeted search strategy across three cohorts to identify health research publications that reported patient involvement: publications published in The BMJ, publications listed in the PCORI database, and publications citing the GRIPP2 reporting checklist for patient involvement or a critical appraisal guideline for user involvement. Publications were coded according to three coding schemes: "Phase of involvement", the GRIPP2-SF reporting checklist, and the critical appraisal guideline.
Outcome measuresThe phase of the study in which patients were actively involved. For the BMJ sample, the proportion of publications that reported patient involvement. The quality of reporting based on the GRIPP2 short form reporting guideline. The quality of patient involvement based on the critical appraisal guideline. Quantitative and qualitative results are reported.
ResultsWe included 87 publications that reported patient involvement. Patients were most frequently involved in study design (90% of publications, n=78), followed by study conduct (70%, n=61), and dissemination (40%, n=35). Reporting of patient involvement was often incomplete, e.g., only 39% of publications (n=34) reported the aim of patient involvement. While the methods (56%, n=49) and results (59%, n=51) of involvement were reported more frequently, qualitative analyses showed that reporting was often unspecific and the influence of patients input remained vague. Therefore, a systematic assessment of the quality and impact of patient involvement according to the critical appraisal guideline was not feasible across samples.
ConclusionsAs patient involvement is increasingly seen as an integral part of the research process and requested by funding bodies, it is essential that researchers receive specific guidance on how to report patient involvement activities. Complete reporting builds the foundation for assessing the quality of patient involvement and its impact on research.
PROTOCOLThe protocol was published on the Open Science Framework: https://osf.io/vntgu/
STRENGTHS AND LIMITATIONSO_LIA targeted search strategy was used to identify examples of patient involvement reporting in a variety of publication types and study designs in health research
C_LIO_LIA mixed-methods approach allowed for an analysis of both the completeness and quality of patient involvement reporting
C_LIO_LIIn this study, we coded statements reporting on patient involvement in 87 health research publications that may be adapted for further use
C_LIO_LIReporting of patient involvement was insufficiently detailed to allow for a systematic assessment of the quality of patient involvement
C_LI | health systems and quality improvement |
10.1101/2022.04.19.22273931 | The Prevalence of Mental Health Disorders in people with HIV and the effects on the HIV Care Continuum | ObjectiveTo describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHD).
DesignObservational study of participants in the NA-ACCORD.
MethodsPWH ([≥]18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008-2018 based on ICD code mapping. MH multimorbidity was defined as having [≥] 2 MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care ([≥] 1 visit/year) and viral suppression (HIV RNA [≤] 200 copies/mL) by presence vs. absence of each MHD between 2016-2018.
ResultsAmong 122,896 PWH, 67,643 (55.1%) were diagnosed with [≥] 1 MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008-2018, while bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016-2018 (N=64,684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR=0.98 [0.98-0.99]) as did PWH with MH multimorbidity (aPR=0.99 [0.99-1.00]) compared with PWH without MHD.
ConclusionThe prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity. | hiv aids |
10.1101/2022.04.19.22274050 | The impact of community asymptomatic rapid antigen testing on COVID-19 hospital admissions: a synthetic control study | ObjectiveTo analyse the impact on hospital admissions for COVID-19 of large-scale, voluntary, public open access rapid testing for SARS-CoV-2 antigen in Liverpool (UK) between 6th November 2020 and 2nd January 2021.
DesignSynthetic control analysis comparing hospital admissions for small areas in the intervention population to a group of control areas weighted to be similar in terms of prior COVID-19 hospital admission rates and socio-demographic factors.
InterventionCOVID-SMART (Systematic Meaningful Asymptomatic Repeated Testing), a national pilot of large-scale, voluntary rapid antigen testing for people without symptoms of COVID-19 living or working in the City of Liverpool, deployed with the assistance of the British Army from the 6th November 2020 in an unvaccinated population. This pilot informed the UK roll-out of SARS-CoV-2 antigen rapid testing, and similar policies internationally.
Main outcome measureWeekly COVID-19 hospital admissions for neighbourhoods in England.
ResultsThe intensive introduction of COVID-SMART community testing was associated with a 43% (95% confidence interval: 29% to 57%) reduction in COVID-19 hospital admissions in Liverpool compared to control areas for the initial period of intensive testing with military assistance in national lockdown from 6th November to 3rd December 2020. A 25% (11% to 35%) reduction was estimated across the overall intervention period (6th November 2020 to 2nd January 2021), involving fewer testing centres, before Englands national roll-out of community testing, after adjusting for regional differences in Tiers of COVID-19 restrictions from 3rd December 2020 to 2nd January 2021.
ConclusionsThe worlds first voluntary, city-wide SARS-CoV-2 rapid antigen testing pilot in Liverpool substantially reduced COVID-19 hospital admissions. Large scale asymptomatic rapid testing for SARS-CoV-2 can help reduce transmission and prevent hospital admissions.
Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABS- Previous studies on managing the spread of SARS-CoV-2 have identified asymptomatic transmission as significant challenges for controlling the pandemic.
- Along with non-pharmaceutical measures, many countries rolled out population-based asymptomatic testing programmes to further limit transmission.
- Evidence is required on whether large scale voluntary testing of communities for COVID-19 reduces severe disease, by breaking chains of transmission.
What this study adds- The findings of this study suggest that large scale rapid antigen testing of communities for SARS-CoV-2, within an agile local public health campaign, can reduce transmission and prevent hospital admissions.
- The results indicate that policy makers should integrate such testing into comprehensive, local public health programmes targeting high risk groups, supporting those required to isolate and adapting promptly to prevailing biological, behavioural and environmental circumstances. | infectious diseases |
10.1101/2022.04.19.22269518 | MICNet: Prediction of antibiotic susceptibility from microscopic images using transfer learning | Rapid susceptibility testing of bacterial isolates is crucial for anti-infective therapy, especially in critical cases such as bacteriaemia and sepsis. Nevertheless, empiric therapy is often initiated immediately and without testing because two days and more pass between a positive blood culture and a susceptibility profile, so in the meantime, the most likely pathogens are treated. However, current empiric recommendations are very generic. They often remain unmodified even in light of incoming, early data specific to a patients case, such as positive blood culture microscopy. Part of the hesitancy to change treatments presumably stems from a lack of systematic integration of early information beyond expert intuition. To enable targeted antimicrobial therapy earlier in a cases progression, we developed a method to predict antimicrobial susceptibility from microscopy images of bacteria alone. Our proof-of-concept MICNet combines two neural nets in a new chimerical architecture. It is pre-trained on about 100 thousand antibiograms and fine-tuned with only five thousand microscopic images through transfer learning. Predicting susceptibility profiles of four representative species, we show high predictive performance with a mean F-score of nearly 85%. In addition, several qualitative assessments show that our chimerical net has learned substantial expert knowledge. Therefore, MICNet is the first step towards personalized empiric therapy, combining prior pathogen probabilities with patient-specific data. | infectious diseases |
10.1101/2022.04.20.22274090 | Monoclonal Antibodies for Treatment of SARS-CoV-2 Infection During Pregnancy | IMPORTANCEMonoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19. However, no studies have evaluated adverse events and effectiveness of mAbs in pregnant persons compared to no mAb treatment.
OBJECTIVETo determine the frequency of drug-related adverse events and obstetric-associated safety outcomes after treatment with mAb compared to no mAb treatment, and the association between mAb treatment and a composite of 28-day COVID-19-related hospital admission or emergency department visit, COVID-19-associated delivery, or mortality.
DESIGN, SETTING, PARTICIPANTSPropensity-score matched cohort study of persons aged 12 years of age or older with a pregnancy episode and any documented positive SARS-CoV-2 test (polymerase chain reaction or antigen test) in the UPMC health system from April 30, 2021 to January 21, 2022.
EXPOSURESBamalanivmab and etesevimab, casirivimab and imdevimab, or sotrovimab treatment compared to no mAb treatment.
MAIN OUTCOMES AND MEASURESDrug-related adverse events, obstetric-associated safety outcomes among persons who delivered, and a risk-adjusted composite of 28-day COVID-19-related hospital admission or ED visit, COVID-19-associated delivery, or mortality.
RESULTSAmong 944 pregnant persons (median [IQR] age 30 [26, 33] years, White (79.5%, N=750), median [IQR] Charlson Comorbidity Index Score 0 (0,0)), 552 persons received mAb treatment (58%). Median gestational age at COVID-19 diagnosis or treatment was 179 days (IQR: 123, 227), and most persons received sotrovimab (69%, N=382). Of those with known vaccination status, 178 (62%) were fully vaccinated. Drug-related adverse events were uncommon (N=8, 1.4%), and there were no differences in any obstetric-associated outcome among 276 persons who delivered. After propensity score matching, the frequency of the composite 28-day COVID-19-associated outcome was 4.0 per 100 persons (95% CI 1.9, 6.2) in mAb-treated compared to 3.7 per 100 persons (95% CI 1.7, 5.8) in non-treated controls (risk difference = 0.31 per 100 persons [95% CI -2.6, 3.3). There were no deaths among mAb-treated patients compared to 1 death in the non-treated controls (p = 0.24). There were more non-COVID-19-related hospital admissions in the mAb-treated persons (risk difference 2.8 per 100 persons (95% CI 1.1, 4.5)).
CONCLUSIONS AND RELEVANCEIn pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were mild and rare. There was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment among persons who delivered. MAb treatment was associated with similar 28-day COVID-19-associated outcomes and more non-COVID-19-related hospital admissions compared to no mAb treatment.
Key PointsO_ST_ABSQUESTIONC_ST_ABSAmong pregnant persons with COVID-19, is monoclonal antibody (mAb) treatment associated with drug-related adverse events, similar frequency of obstetric-associated safety outcomes, and improved COVID-19-related clinical outcomes compared to no mAb treatment?
FINDINGSIn 944 pregnant persons with COVID-19, drug-related adverse events were mild and infrequent. Obstetric-associated safety outcomes were similar between mAb treatment and no treatment. There was no evidence of difference in risk of COVID-19-related hospital admission, COVID-19-associated delivery, or mortality between mAb treatment and no mAb treatment.
MEANINGIn pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were uncommon, and there was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment. MAb treatment was associated with similar 28-day risk of a COVID-19-associated outcome and more non-COVID-19-related hospital admissions compared to no mAb treatment. | infectious diseases |
10.1101/2022.04.21.22274025 | Determinants of SARS-CoV-2 anti-spike antibody levels following BNT162b2 vaccination: cross-sectional analysis of 6,000 SIREN study participants | BackgroundUnderstanding immunological responses to SARS-CoV-2 vaccinations is integral to the management of SARS-CoV-2. We aimed to investigate determinants of antibody response to the BNT162b2 vaccine.
MethodsA cross-sectional analysis of anti-spike binding antibodies in serum samples from healthcare workers after one or two doses. Post-vaccination interval was restricted to [≥]21 days after dose 1, [≥]14 days after dose 2. The primary outcome was anti-S titres with explanatory variables dose, previous infection, dosing interval, age, ethnicity, and comorbidities. Multivariable linear regression was also conducted.
ResultsParticipants (n=5,871) included 3,989 post-dose 1, 1,882 post-dose 2. In SARS-CoV-2 infection naive, 99.65% seroconverted after dose 1 and >99.9% seroconverted after dose 2. Geometric mean anti-S titre in the naive cohort was 75.48 Binding Antibody Units/ml after dose 1, 7,049 BAU/ml after dose 2. Anti-S titres were higher in those with previous infection (2,111 BAU/ml post-dose 1, 16,052 BAU/ml post-dose 2), and increased with time between infection and vaccination: 3 months 1,970 (1,506-2,579) vs 9 months; 13,759 (8,097-23,379). Longer dosing intervals increased antibody response post-dose 2: 11-fold higher with a longer interval (>10 weeks) than those with shorter intervals, across all age-groups. Younger participants had higher mean titres (>2.2-fold higher). Multivariable regression modelling corroborated the above associations, and also found higher titres associated with being female or from an ethnic minority but lower titres among immunocompromised participants.
ConclusionThe number of antigen exposures and timing between vaccinations plays a significant role in the magnitude of the post-vaccination antibody response, with implications for long-term protection and post-booster antibody responses. | infectious diseases |
10.1101/2022.04.19.22273488 | Variation in the Incidence of ventriculostomy related infection in critically ill patients | IntroductionVentriculostomy related infection (VRI) or ventriculitis is a common and serious complication related to the placement of an external ventricular drain. Numerous sets of diagnostic criteria for VRI have been reported. We sought to estimate the variation in the incidence of VRI in a cohort of patients according to published diagnostic criteria.
Materials and MethodsWe conducted a retrospective cohort study. We included adult patients admitted to the Neuroscience intensive care unit with traumatic brain injury (TBI), subarachnoid haemorrhage (SAH) and intracerebral haemorrhage (ICH) who required an EVD. We estimated the incidence of VRI according to published diagnostic criteria. We compared the incidence to clinicians diagnoses of VRI. The primary outcome was the estimated incidence of VRI.
ResultsThere were 190 study participants, median age (interquartile range) of 58 (48 - 72), 106 (55.8%) were female. Admitting diagnoses was ICH in 30 (15.8%), TBI in 49 (25.8%) and SAH in 111 (58.4%) of cases respectively. There were 158 (83.2%) who required mechanical ventilation for a median of 6 (2-13) days. There were 29 (15.3%) who were treated for VRI by clinicians, with 6 (3.2%) having a positive culture. Variation in the diagnostic criteria led to an estimated incidence of VRI that ranged from 1 (0.5%) to 178 (93.7%).
ConclusionIn this critically ill cohort, the estimated incidence of VRI varied widely depending on which diagnostic criteria for VRI were applied. A comprehensive, consistent, objective and universal set of diagnostic criteria for ventriculostomy related infection is needed. | intensive care and critical care medicine |
10.1101/2022.04.20.22274046 | Elevated plasma Complement Factor H Regulating Protein 5 is associated with venous thromboembolism and COVID-19 severity | Venous thromboembolism (VTE), comprising both deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. We used multiplex proteomics profiling to screen plasma from patients with suspected acute VTE, and a case-control study of patients followed up after ending anticoagulant treatment for a first VTE. With replication in 5 independent studies, together totalling 1137 patients and 1272 controls, we identify Complement Factor H Related Protein (CFHR5), a regulator of the alternative pathway of complement activation, as a novel VTE associated plasma biomarker. Using GWAS analysis of 2967 individuals we identified a genome-wide significant pQTL signal on chr1q31.3 associated with CFHR5 levels. We showed that higher CFHR5 levels are associated with increased thrombin generation in patient plasma and that recombinant CFHR5 enhances platelet activation in vitro. Thrombotic complications are a frequent feature of COVID-19; in hospitalised patients we found CFHR5 levels at baseline were associated with short-time prognosis of disease severity, defined as maximum level of respiratory support needed during hospital stay. Our results indicate a clinically important role for regulation of the alternative pathway of complement activation in the pathogenesis of VTE and pulmonary complications in acute COVID-19. Thus, CFHR5 is a potential diagnostic and/or risk predictive plasma biomarker reflecting underlying pathology in VTE and acute COVID-19. | cardiovascular medicine |
10.1101/2022.04.20.22274101 | Assessing Depression and Suicidality Among Recently Unemployed Persons with Obstructive Sleep Apnea and Socioeconomic Inequality | BackgroundObstructive Sleep Apnea (OSA) is a common sleep-related breathing disorder that often is associated with several psychiatric conditions. Job loss is a stressful life event that can also affect mental health and socioeconomic status (SES). We investigated whether there was an association between the prevalence of OSA and several psychiatric conditions within a cohort of persons who recently became unemployed and whether SES was a contributing factor.
MethodsData from 292 participants who completed the screening evaluation of the Assessing Daily Activity Patterns through occupational Transitions (ADAPT) Study were used to assess the association between the prevalence of OSA, and current and past depression, and past suicidality. A type III sleep home sleep monitor was used to identify the presence of OSA and assess its severity. Depression and suicidality were ascertained using the Mini-international neuropsychiatric interview. Years of education was used as a proxy for SES.
ResultsThere were no significant associations between severity of OSA, SES and current depression, past depression, and suicidality. Past suicidality was noted to be more common among those who were single/widowed (17.4%) or those who were divorced or separated (11.1%) (p=0.027). Current depression was more common among Hispanics in comparison to non-Hispanics. Furthermore, prevalence rates of both depression and past suicidality were higher than previous reports in general populations.
ConclusionsWithin a cohort of individuals who experienced recent job loss, there was no association between OSA and depression or past suicidality. Prevalence rates of both depression and past suicidality were higher than previous reports in the general population. | epidemiology |
10.1101/2022.04.19.22274026 | A Platform for Data-centric, Continuous Epidemiological Analyses | Guaranteeing durability, provenance, accessibility, and trust in open datasets can be challenging for researchers and organizations that rely on public repositories of data critical to epidemiology and other health analytics. Not only are the required repositories sometimes difficult to locate, and nearly always require conversion into a compatible format, they may move or change unpredictably. Any single change of the rules in one repository can hinder updating of a public dashboard reliant on pulling data from external sources. These concerns are particularly challenging at the international level, because systems aimed at harmonizing health and related data are typically dictated by national governments to serve their individual needs. In this paper, we introduce a comprehensive public health data platform, the EpiGraphHub, that aims to provide a single interoperable repository for open health and related data, curated by the international research community, which allows secure local integration of sensitive databases whilst facilitating the development of data-driven applications and reports for decision-makers. The platform development is co-funded by the World Health Organization and is fully open-source to maximize its value for large-scale public health studies. | epidemiology |
10.1101/2022.04.19.22274026 | A Platform for Data-centric, Continuous Epidemiological Analyses | Guaranteeing durability, provenance, accessibility, and trust in open datasets can be challenging for researchers and organizations that rely on public repositories of data critical to epidemiology and other health analytics. Not only are the required repositories sometimes difficult to locate, and nearly always require conversion into a compatible format, they may move or change unpredictably. Any single change of the rules in one repository can hinder updating of a public dashboard reliant on pulling data from external sources. These concerns are particularly challenging at the international level, because systems aimed at harmonizing health and related data are typically dictated by national governments to serve their individual needs. In this paper, we introduce a comprehensive public health data platform, the EpiGraphHub, that aims to provide a single interoperable repository for open health and related data, curated by the international research community, which allows secure local integration of sensitive databases whilst facilitating the development of data-driven applications and reports for decision-makers. The platform development is co-funded by the World Health Organization and is fully open-source to maximize its value for large-scale public health studies. | epidemiology |
10.1101/2022.04.19.22274036 | A Statistical Argument Against Vaccine Injury | Vaccine hesitancy is a major threat to public health. While the root causes of vaccine hesitancy are numerous, they largely revolve around some form of perceived risk to the self. In particular, the unknown long-term risks are amongst the most frequently cited concerns. In this work, we show that regardless of their peak onset following vaccination, the incidence of adverse outcomes will follow some distribution f (x| {micro}, {sigma}2) of mean onset {micro}, and standard deviation{sigma} , and variance{sigma} 2. Despite the small proportion of events at the tails of these distributions, the large-scale public deployment of vaccines would imply that any signal for a given adverse outcome would be observed soon after distribution begins, even in cases where tx < t{micro}-3{sigma}. The absence of such an early signal, however low, would suggest that long term effects are unlikely and that vaccine safety is therefore likely. Indeed, when enough individuals have been exposed to a new therapy - even if the majority of adverse outcomes only manifest at a future time t{micro}, the number of adverse outcomes given by the cumulative density function (CDF) near t0 + dt > 0. Otherwise stated:
O_FD O_INLINEFIG[Formula 1]C_INLINEFIGM_FD(1)C_FD
We evoke the theory behind normal (Gaussian) and skew-normal distributions and use Chebyshevs Theorem to evaluate the COVID-19 vaccine data as an example. The findings of this study are not vaccine-specific and can be applied to assess the health effects of the mass distribution of any good, treatment or policy at large. | epidemiology |
10.1101/2022.04.20.22274084 | Genetic diversity and spatiotemporal distribution of SARS-CoV-2 alpha variant in India | After the spill to humans, in the timeline of SARS-CoV-2, several positively selected variants have emerged. A phylogeographic study on these variants can reveal their spatial and temporal distribution. In December 2020, the alpha variant of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which has been designated as a variant of concern (VOC) by WHO, was discovered in the southeastern United Kingdom (UK). Slowly, it expanded across India, with a considerable number of cases, particularly in North India. The study focuses on determining the prevalence and expansion of the alpha variants in various parts of India. The genetic diversity estimation helped us understand various evolutionary forces that have shaped the spatial distribution of this variant during the peak. Overall, our study paves the way to understand the evolution and expansion of a virus variant. | epidemiology |
10.1101/2022.04.20.22274068 | Association of Sedentary and Physical Activity Behaviors with Body Composition: a Genome-Wide Association and Mendelian Randomization Study | ObjectivesStudies suggest that body composition can be independently improved through physical activity (PA). We performed a Mendelian randomization (MR) study to test the incremental benefits of sedentary behavior and various physical activity (PA) exposures on body composition outcomes as assessed by anthropometric indices, lean body mass (LBM) (kg), body fat (%), and visceral adipose tissue (VAT) (kg).
MethodsGenetic instruments were identified for both self-reported and accelerometer-measured sedentary behavior and PA. Outcomes included anthropometric and dual-energy X-ray absorptiometry measures of adiposity, extracted from the UK Biobank and the largest available consortia. Multivariable MR (MVMR) included educational attainment as a covariate to address potential confounding. Sensitivity analyses were evaluated for weak instrument bias and pleiotropic effects.
ResultsWe did not identify consistent associations between genetically-predicted self-reported and accelerometer-measured sedentary behavior and body composition outcomes. All analyses for self-reported moderate PA were null for body composition outcomes. Genetically-predicted PA at higher intensities was protective against VAT in MR and MVMR analyses of both accelerometer-measured vigorous PA (MVMR {beta} = -0.15, 95% Confidence Interval (CI): -0.24, -0.07, p<0.001) and self-reported participation in strenuous sports or other exercises (MVMR {beta} = -0.27, 95%CI: -0.52, -0.01, p=0.034) was robust across several sensitivity analyses.
ConclusionsWe did not identify evidence of a causal relationship between genetically-predicted PA and body composition, with the exception of a putatively protective effect of higher-intensity PA on VAT. Protective effects of PA against VAT may support prior evidence of biological pathways through which PA decreases risk of downstream cardiometabolic diseases. | epidemiology |
10.1101/2022.04.19.22274042 | An epidemiological and intervention assessment of the malaria epidemic in Bolivar, Venezuela: a modelling study | BackgroundVenezuela has experienced an explosive resurgence in Plasmodium falciparum and Plasmodium vivax malaria incidence over the last decade due to various social, political, and economic factors. To ensure national and regional progress towards malaria elimination, there is an urgent need to better understand the epidemiological dynamics of this malaria outbreak at its epicenter in the southern state of Bolivar and to identify the sets of interventions that may be necessary to reduce transmission and incidence.
MethodsWe fitted transmission models of P. falciparum and P. vivax to weekly incidence data in Bolivar, Venezuela during 2000-2018. We estimated the magnitude of local transmission for both Plasmodium spp. and inferred the contribution of relapses and reinfections to P. vivax incidence in the region. Compared to a business-as-usual scenario, we projected the impact of different interventions on Plasmodium spp. incidence during the period 2021-2023.
FindingsWe estimated that 63{middle dot}7 - 73{middle dot}3% of all P. vivax infections in Bolivar are relapses, leading to as many as 51,800 observed relapses misclassified per year as reinfections in the routine surveillance data. Our estimates suggest that the reproduction number remains close to one for both Plasmodium spp., pointing towards the feasibility of control. Long-lasting insecticidal nets (LLINs) were projected to cause greater proportional reductions in P. falciparum incidence than P. vivax incidence, and mass drug administration (MDA) with an 8-aminoquinoline and a blood-stage partner drug was projected to cause the greatest reduction in P. vivax incidence, provided that adherence rates were high.
InterpretationControl of the malaria outbreak in Southeastern Venezuela is feasible, should appropriate resources to support surveillance and control be brought to bear. Coupling the distribution of LLINs and a focal MDA with an 8-aminoquinoline and a blood-stage partner drug may lead to the greatest reduction in malaria incidence.
FundingNational Science Foundation and the University of Notre Dame
RESEARCH IN CONTEXTO_ST_ABSEvidence before the studyC_ST_ABSWe searched PubMed, bioRxiv, and medRxiv for articles in English published on or before May 25th, 2021 using the following keywords: "Venezuela", "malaria", AND "model*". Previous studies have applied statistical models to characterize the relationship between malaria incidence and climate in Venezuela, concluding that the reproduction number is low and suggesting the feasibility of control. A study fitting a mechanistic transmission model to epidemiological data to allow for projecting the impact of alternative approaches to control has not been performed.
Added value of the studyWe fitted Plasmodium falciparum and Plasmodium vivax transmission models to 20 years of weekly incidence data to estimate the transmission of both Plasmodium spp. and characterize the contribution of relapses and reinfections to P. vivax incidence in Bolivar, Venezuela. We also projected the likely impact of interventions in the region under alternative scenarios about control.
Implications of the available evidenceThe burden of Plasmodium vivax relapses in Bolivar is underestimated from routine surveillance data, so control interventions must target the hypnozoite reservoir in the region. Mass drug administration (MDA) is projected to be impactful for both Plasmodium spp., though tradeoffs between coverage and adherence suggest that a focal MDA with an 8-aminoquinoline and a blood-stage partner drug may yield the greatest impact. | epidemiology |
10.1101/2022.04.19.22273872 | Immune response to 2-dose BNT162b2 vaccination and risk of SARS-CoV-2 breakthrough infection: The Shieldvacc-2 study | It is uncertain to which extent antibody and T-cell responses after vaccination against SARS-CoV-2 are associated with reduced risk of breakthrough infection and whether their measurement enhances risk prediction. We conducted a phase-4 open-label clinical trial in the pre-omicron era, enrolling 2,760 individuals aged [≥]16 years 35{+/-}8 days after having received the second dose of BNT162b2 (baseline 15-21 May 2021). Over a median 5.9-month of follow-up, we identified incident SARS-CoV-2 breakthrough infections using weekly antigen tests, a confirmatory PCR test, and/or serological evidence for incident infection. We quantified relative risks adjusted for age, sex, and prior SARS-CoV-2 infection for different immunological parameters and assessed improvements in risk discrimination. In contrast to the T-cell response, higher plasma levels of binding antibodies and antibodies in a surrogate neutralization assay were associated with reduced risk of breakthrough infection. Furthermore, assessment of anti-spike IgG levels enhanced prediction of breakthrough infection and may therefore be a suitable measurable correlate of protection in practice. | epidemiology |
10.1101/2022.04.20.22274062 | Weakly supervised and transfer learning for adenocarcinoma classification in transurethral resection of the prostate whole slide images | The transurethral resection of the prostate (TUR-P) is generally considered an option for benign prostatic diseases especially nodular hyperplasia patients who have moderate to severe urinary problems that have not responded to medication. Importantly, incidental prostate cancer are diagnosed at the time of TUR-P for benign prostatic disease. Since diagnosing a large number of cases containing TUR-P specimens which are characterized by a very large volume of tissue fragments by pathologists using a conventional microscope is time-consuming and limited in terms of human resources. Thus, it is necessary to develop new techniques which can rapidly and accurately screen large numbers of TUR-P specimens. Computational pathology applications which can assist pathologists in detecting prostate adenocarcinoma from TUR-P whole slide images (WSIs) would be of great benefit for routine histopathological workflow. In this study, we trained deep learning models to classify TUR-P WSIs into prostate adenocarcinoma and benign (non-neoplastic) lesions using transfer and weakly supervised learning. We evaluated the models on TUR-P, needle biopsy, and The Cancer Genome Atlas (TCGA) public dataset test sets, achieving an ROC-AUC up to 0.984 in TUR-P test sets for adenocarcinoma. The results demonstrate the high promising potential of deployment in a practical TUR-P histopathological diagnostic workflow system. | pathology |
10.1101/2022.04.19.22274027 | Diabetes and neuroaxonal damage in Parkinson's disease | Patients with Parkinsons disease (PD) with coexistent type 2 diabetes (T2DM) can manifest with more severe motor and cognitive phenotypes. The precise reasons for this remain unclear though underlying pathophysiological differences are increasingly implicated. More severe neuroaxonal injury in PD patients with T2DM was recently proposed as a potential mechanism for this. We explored this in the tracking Parkinsons study and confirmed these findings. Cases with T2DM had higher serum neurofilament light levels and this remained significant after correction for age and vascular risk factor burden. Disentangling the underlying mechanism for more rapid axonal damage will be important in the development of disease modifying therapies for PD. | neurology |
10.1101/2022.04.20.22274092 | Optical coherence tomography assessment of axonal and neuronal damage of the retina in patients with familial and sporadic multiple sclerosis | ObjectiveOptical coherence tomography (OCT) assessment of axonal and neuronal damage of the retina in patients with familial and sporadic multiple sclerosis.
Methods45 patients with familial MS (fMS), 58 patients with sporadic MS (sMS) and 35 healthy controls were included in the study. OCT was performed with the spectral domain optical coherence tomography (SD-OCT, Heidelberg Engineering, Germany). The retinal nerve fiber layer (RNFL) thickness and macular volume (MV) were measured.
ResultsA significant thinning of the global RNFL thickness was detected in both forms of MS compared to control group, (86,61 (+/- 14,74) {micro}m in sMS, 85,8 (+/- 12,7) {micro}m in fMS, 97,96 (+/- 7,6) {micro}m in control group; p <0,001). There was no significant difference in the global RNFL thickness between sMS and fMS. A significant reduction of the MV was shown in sMS and fMS compared to control group (8,12 (+/- 1,14) mm3 in sMS, 8,1 (+/- 1,12) mm3 in fMS, and 8,81 (+/- 0,31) mm3 in control group; p = 0,003). No difference in MV between sMS and fMS was found. However, in eyes with history of optic neuritis (ON) MV was significantly reduced in sMS versus fMS (8,12 (+/- 2,87) mm3 vs. 8,42 (+/- 0,54) mm3; p=0,05).
ConclusionWe confirmed the presence of axonal and neuronal damage of the retina in sMS and fMS. ON induced a significantly greater reduction of MV in sMS compared to fMS, indicating a stronger neuronal damage in ON eyes in sMS than in fMS.
KEY MESSAGESThe familial MS accounts for a significant proportion of MS patients and there is still ongoing discussion on the distinction between familial (fMS) and sporadic (sMS) forms of this disease. Using OCT, we confirmed the presence of axonal and neuronal damage in the retina in both forms of MS. We found that optic neuritis (ON) induced a greater retinal neuronal damage in sMS than in fMS. These results support the conclusion that there are some discrete differences in pathological processes occurring in the retina in sMS and fMS. | neurology |
10.1101/2022.04.20.22274066 | Geospatial distribution of Hepatitis B prevention services in Wakiso District, Central Uganda | IntroductionDespite global and national efforts in place for the prevention and control of Hepatitis B, there remains a gap in access to hepatitis B prevention services such as testing and vaccination. Nonetheless, there is limited evidence of the geospatial distribution of Hepatitis B services. This study established the geospatial distribution of HBV vaccination services in Wakiso District, Uganda.
Materials and methodsA cross-sectional quantitative descriptive study was conducted among 55 healthcare facilities including 6 hospitals, and 49 primary care facilities in Wakiso district. Data were collected using the KoboCollect application. Quantitative data were analysed using STATA 14.0. A chi-square test was performed to establish the relationship between healthcare facility characteristics and the availability of hepatitis B services. ArcGIS (version 10.1) was used for analysis of geospatial data.
ResultsThe hepatitis B vaccine was available in only 27.3 % (15) of the facilities, and 60% (33) had testing services. Receipt of the hepatitis B vaccine doses in the last 12 months was associated with the level of healthcare facility (p=[≤]0.001) and location (p=0.030). Availability of the Hepatitis B vaccines at the time of the survey was associated with the level of healthcare facility (p=0.002) and location (p=0.010). Availability of hepatitis B testing services was associated with level of healthcare facility (p=0.031), ownership (p[≤]0.001) and location (p=0.010). Healthcare facilities offering vaccination and testing services were mostly in urban healthcare facilities, and close to Kampala, Ugandas capital.
ConclusionHepatitis B services were sub-optimal across all healthcare facility levels, locations, and ownership. The majority of the hepatitis B prevention services were provided in urban settings, close to major towns, municipalities, and the city. This calls a extension of hepatitis B prevention services to rural, public and PNFP healthcare facilities. | infectious diseases |
10.1101/2022.04.19.22274047 | COVID-19 outcomes by cancer status, type, treatment, and vaccination | BackgroundObservational studies have identified patients with cancer as a potential subgroup of individuals at elevated risk of severe SARS-CoV-2 (COVID-19) disease and mortality. Early studies showed an increased risk of COVID-19 mortality for cancer patients, but it is not well understood how this association varies by cancer site, cancer treatment, and vaccination status.
MethodsUsing electronic health record data from an academic medical center, we identified 259,893 individuals who were tested for or diagnosed with COVID-19 from March 10, 2020, to February 2, 2022. Of these, 41,218 tested positive for COVID-19 of whom 10,266 had a past or current cancer diagnosis. We conducted Firth-corrected, covariate-adjusted logistic regression to assess the association of cancer status, cancer type, and cancer treatment with four COVID-19 outcomes: hospitalization, intensive care unit (ICU) admission, mortality, and a composite "severe COVID-19" outcome which is the union of the first three outcomes. We examine the effect of the timing of cancer diagnosis and treatment relative to COVID diagnosis, and the effect of vaccination.
ResultsCancer status was associated with higher rates of severe COVID-19 infection [OR (95% CI): 1.18 (1.08, 1.29)], hospitalization [OR (95% CI): 1.18 (1.06, 1.28)], and mortality [OR (95% CI): 1.22 (1.00, 1.48)]. These associations were driven by patients whose most recent initial cancer diagnosis was within the past three years. Chemotherapy receipt was positively associated with all four COVID-19 outcomes (e.g., severe COVID [OR (95% CI): 1.96 (1.73, 2.22)], while receipt of either radiation or surgery alone were not associated with worse COVID-19 outcomes. Among cancer types, hematologic malignancies [OR (95% CI): 1.62 (1.39, 1.88)] and lung cancer [OR (95% CI): 1.81 (1.34, 2.43)] were significantly associated with higher odds of hospitalization. Hematologic malignancies were associated with ICU admission [OR (95% CI): 1.49 (1.11, 1.97)] and mortality [OR (95% CI): 1.57 (1.15, 2.11)], while melanoma and breast cancer were not associated with worse COVID-19 outcomes. Vaccinations were found to reduce the frequency of occurrence for the four COVID-19 outcomes across cancer status but those with cancer continued to have elevated risk of severe COVID [cancer OR (95% CI) among those fully vaccinated: 1.69 (1.10, 2.62)] relative to those without cancer even among vaccinated.
ConclusionOur study provides insight to the relationship between cancer diagnosis, treatment, cancer type, vaccination, and COVID-19 outcomes. Our results indicate that it is plausible that specific diagnoses (e.g., hematologic malignancies, lung cancer) and treatments (e.g., chemotherapy) are associated with worse COVID-19 outcomes. Vaccines significantly reduce the risk of severe COVID-19 outcomes in individuals with cancer and those without, but cancer patients are still at higher risk of breakthrough infections and more severe COVID outcomes even after vaccination. These findings provide actionable insights for risk identification and targeted treatment and prevention strategies. | epidemiology |
10.1101/2022.04.19.22274047 | COVID-19 outcomes by cancer status, type, treatment, and vaccination | BackgroundObservational studies have identified patients with cancer as a potential subgroup of individuals at elevated risk of severe SARS-CoV-2 (COVID-19) disease and mortality. Early studies showed an increased risk of COVID-19 mortality for cancer patients, but it is not well understood how this association varies by cancer site, cancer treatment, and vaccination status.
MethodsUsing electronic health record data from an academic medical center, we identified 259,893 individuals who were tested for or diagnosed with COVID-19 from March 10, 2020, to February 2, 2022. Of these, 41,218 tested positive for COVID-19 of whom 10,266 had a past or current cancer diagnosis. We conducted Firth-corrected, covariate-adjusted logistic regression to assess the association of cancer status, cancer type, and cancer treatment with four COVID-19 outcomes: hospitalization, intensive care unit (ICU) admission, mortality, and a composite "severe COVID-19" outcome which is the union of the first three outcomes. We examine the effect of the timing of cancer diagnosis and treatment relative to COVID diagnosis, and the effect of vaccination.
ResultsCancer status was associated with higher rates of severe COVID-19 infection [OR (95% CI): 1.18 (1.08, 1.29)], hospitalization [OR (95% CI): 1.18 (1.06, 1.28)], and mortality [OR (95% CI): 1.22 (1.00, 1.48)]. These associations were driven by patients whose most recent initial cancer diagnosis was within the past three years. Chemotherapy receipt was positively associated with all four COVID-19 outcomes (e.g., severe COVID [OR (95% CI): 1.96 (1.73, 2.22)], while receipt of either radiation or surgery alone were not associated with worse COVID-19 outcomes. Among cancer types, hematologic malignancies [OR (95% CI): 1.62 (1.39, 1.88)] and lung cancer [OR (95% CI): 1.81 (1.34, 2.43)] were significantly associated with higher odds of hospitalization. Hematologic malignancies were associated with ICU admission [OR (95% CI): 1.49 (1.11, 1.97)] and mortality [OR (95% CI): 1.57 (1.15, 2.11)], while melanoma and breast cancer were not associated with worse COVID-19 outcomes. Vaccinations were found to reduce the frequency of occurrence for the four COVID-19 outcomes across cancer status but those with cancer continued to have elevated risk of severe COVID [cancer OR (95% CI) among those fully vaccinated: 1.69 (1.10, 2.62)] relative to those without cancer even among vaccinated.
ConclusionOur study provides insight to the relationship between cancer diagnosis, treatment, cancer type, vaccination, and COVID-19 outcomes. Our results indicate that it is plausible that specific diagnoses (e.g., hematologic malignancies, lung cancer) and treatments (e.g., chemotherapy) are associated with worse COVID-19 outcomes. Vaccines significantly reduce the risk of severe COVID-19 outcomes in individuals with cancer and those without, but cancer patients are still at higher risk of breakthrough infections and more severe COVID outcomes even after vaccination. These findings provide actionable insights for risk identification and targeted treatment and prevention strategies. | epidemiology |
10.1101/2022.04.19.22274053 | Public attitudes towards COVID-19 vaccines in Africa: a systematic review | BackgroundAs COVID-19 vaccine acquisition and deployment accelerates, tensions also increase. This review aims to identify and understand the significance of population attitudes toward COVID-19 vaccines in Africa.
MethodsA systematic review was conducted. Searches were conducted in MEDLINE, CINAHL, EMBASE, and Global Health databases. Database searches began on June 23, 2021, and the last search date was June 30, 2021. The methodological quality of the studies included in this review was assessed using the Mixed methods appraisal tool.
ResultsA total of 609 articles were retrieved, and 23 met the eligibility criteria. All 23 included studies were cross-sectional. Three attitudes were identified: acceptance, reluctance, and refusal to be vaccinated. Acceptance of vaccination was motivated by confidence in the accuracy of the governments response to COVID-19 and the fact that relatives had been diagnosed with or died from COVID-19. Reluctance was based on fear of vaccine quality and side effects, and insufficient clinical trials. Finally, refusal to be vaccinated was justified by reasons such as the unreliability of clinical trials and insufficient data regarding the vaccines adverse effects.
ConclusionThis review revealed common attitudes of African populations toward COVID-19 vaccines. The results indicate that research needs to focus more on identifying facilitators of COVID-19 vaccination. However, they also provide essential elements for health personnel in charge of vaccination to develop strategies to achieve satisfactory coverage rates | public and global health |
10.1101/2022.04.20.22274085 | Systematic review of food insecurity and violence against women and girls: mixed methods findings from low- and middle-income settings | IntroductionViolence against women and girls (VAWG) is a global human rights and public health concern. Food insecurity is a sign of severe poverty, and likely to heighten womens vulnerability to VAWG and mens perpetration of it. However, the extent of the association and the multiple pathways between food insecurity and VAWG are not well understood.
MethodsWe systematically assessed peer reviewed quantitative and qualitative literature to explore this in low- and middle-income countries (LMIC). Fixed effects meta-analysis was used to synthesize quantitative evidence. Qualitative data was analyzed using thematic analysis.
ResultsWe identified 23 quantitative and 19 qualitative or mixed-methods peer-reviewed manuscripts. In a meta-analysis of 21 cross-sectional studies with 20,378 participants, food insecurity was associated with doubled odds of reported VAWG (odds ratio [OR]=2.38, 95% confidence interval [CI]=1.82-3.10). This finding was consistent for both womens experience or male perpetration of VAWG. Qualitative and mixed-methods papers offered insight that underlying conditions of inequitable gender norms, economic deprivation, and social isolation frame both food insecurity and VAWG. Food insecurity may trigger survival behaviors due to household stress and lack of meeting expected gender roles, which leads to VAWG. VAWG exposure may lead to food insecurity if women are more impoverished after leaving a violent household. Potential protective factors include financial stability, the involvement of men in VAWG programming, transformation of gender norms, and supporting women to develop new networks and social ties.
ConclusionStrong evidence exists for a relationship between food security and IPV. Future funding should target causal directions and preventive options through longitudinal and interventional research. Strategies to ensure households have access to sufficient food and safe relationships are urgently needed to prevent VAWG. | public and global health |
10.1101/2022.04.20.22274096 | A pipeline for tabular dataset formation from unstructured data provided by ACR Appropriateness Criteria guidelines | Currently, data performns a critical concept for disparate human activities, from law to technology. Among data-centric technologies, clinical decision support systems (CDSS) figures out as one of the most promising for healthcare. Despite the technological advances facilitating its implementation, the maintainance of knowledge base for CDSS remains open to improvements. Here, we argue that the Appropriateness Criteria provided by ACR guidelines can be used as a open data-source that, combined with appropriate algorithms, can push forward basic research and technological developments regarding knowledge base for CDSS. Therefore, we developed a pipeline capable of forming tabular datasets from ACR guidelines, stored in a web site as textual PDF files. We also experimentally demonstrate that the proposed pipeline successfully recorvers the interested contents, and the best composition, in terms of its component algorithms, is discussed. Future research focused on algorithms flexibility in the face of PDF template updates could improve our work. | health informatics |
10.1101/2022.04.20.22274097 | Accuracy of US CDC COVID-19 Forecasting Models | Accurate predictive modeling of pandemics is essential for optimally distributing resources and setting policy. Dozens of case predictions models have been proposed but their accuracy over time and by model type remains unclear. In this study, we analyze all US CDC COVID-19 forecasting models, by first categorizing them and then calculating their mean absolute percent error, both wave-wise and on the complete timeline. We compare their estimates to government-reported case numbers, one another, as well as two baseline models wherein case counts remain static or follow a simple linear trend. The comparison reveals that more than one-third of models fail to outperform a simple static case baseline and two-thirds fail to outperform a simple linear trend forecast. A wave-by-wave comparison of models revealed that no overall modeling approach was superior to others, including ensemble models, and error in modeling has increased over time during the pandemic. This study raises concerns about hosting these models on official public platforms of health organizations including the US-CDC which risks giving them an official imprimatur and further raising concerns if utilized to formulate policy. By offering a universal evaluation method for pandemic forecasting models, we expect this work to serve as the starting point towards the development of more sophisticated models. | public and global health |
10.1101/2022.04.20.22274081 | Investigating Attitudes, Motivations and Key Influencers for vaccine uptake among late adopters of COVID-19 vaccination in Africa | BackgroundThe rapid development of vaccines in response to the COVID-19 pandemic has provided an effective tool for the management of COVID-19. However, in Africa there has been a poor uptake of COVID-19 vaccines with only 15% vaccine coverage compared to the WHO global target of 70%. One of the important drivers has been vaccine hesitancy, understanding late adopters of vaccination can provide insights into the attitudes, motivations and influences that can enhance vaccine uptake.
MethodsBetween January 4 - February 11, 2022, we conducted a survey among adults presenting for their first dose of a COVID-19 vaccine almost 12-months after the vaccination program began. Vaccines were free and provided at clinics and outreach centers in Harare, Zimbabwe. The questionnaire assessed environmental and individual factors (attitudes, barriers, motivations, key influencers, and information sources) that influenced the decision to present for vaccination. Baseline socio-demographic data and responses to survey questions were summarized using descriptive statistics. Binary logistic regression models were developed to understand factors associated with vaccine confidence.
Results1016 adults were enrolled into the study, 508 (50%) were female, 126 (12.4%) had HIV co-infection. The median age was 30 years (IQR 22 - 39). Women were more likely to have negative views about the COVID-19 vaccine compared to men (OR 1.51 (95%CI 1.16, 1.97, p=0.002). Women compared to men and older adults ([≥] 40 years) compared with youth (18-25 years) were more likely to have major concerns about vaccines. Most concerns were about safety with 602 (59.3%) concerned about immediate and 520 (51.2%) about long-term health effects of vaccines. People living with HIV (PLWH) were more likely to perceive vaccines as safe (OR 1.71 (95%CI: 1.07, 2.74, p=0.025), effective (1.68 (95%CI: 1.07, 2.64, p=0.026) and to trust regulatory systems for approving vaccines (OR 1.79 (95% CI: 1.11, 2.89, p=0.017) compared to those without HIV. Internet users were less likely to perceive vaccines as safe (OR 0.72 (95% CI: 0.55, 0.95, p=0.021), effective (OR 0.61 (95% CI: 0.47, 0.80, p<0.001) or trust regulatory processes for approving vaccines (OR 0.64 (95% CI: 0.48, 0.85, p=0.002) compared to non-internet users. Social influence was a key factor in the decision to be vaccinated with family members being the primary key influencers for 560 (55.2%) participants. The most important reason for receiving the COVID-19 vaccine today for 715 (70.4%) participants was the protection of individual health. The most trusted source of information regarding the vaccine was the Ministry of Health (79.7%) and the radio, television and social media were the preferred sources for obtaining this information. Social media was a more likely source for youth and those with higher levels of education.
ConclusionImproving vaccine coverage will need targeted communication strategies that address negative perceptions of vaccines and associated safety and effectiveness concerns. Leveraging normative behavior as a social motivator for vaccination will be important as close social networks are key influences of vaccination. Traditional media remains important for health communication in Africa and should be strengthened to counter social media-based misinformation that drives concerns about safety and effectiveness particularly among internet users. | public and global health |
10.1101/2022.04.19.22274038 | Assessing the effectiveness of malaria interventions at the regional level in Ghana using a mathematical modelling Application | BackgroundSupporting malaria control with interfaced applications of mathematical models that enables investigating effectiveness of various interventions as well as their cost implications could be supportive. Through their usage for planning, these applications may improve the chances of attaining various set targets such as those of the National Strategic Plan policy for malaria control 2014-2020 in Ghana. This approach could boost the fight against malaria and accelerate the achievement of pre-elimination in a shorter time
MethodsA single patch malaria model was adapted and used for simulating the incidence of malaria in all ten administrative regions of Ghana. The model and its application were developed by the Modelling and Simulation Hub Africa (MASHA) and calibrated using aggregated district level data captured on the District Health Information Management System (DHIMS) in Ghana from 2012 to 2018. Average monthly rainfall at the zonal level was fitted to trigonometric functions for each zone using least squares approach. These zonal functions were then used as forcing functions for all the regions within their respective zones. Various intervention packages such as increasing insecticide treated bednets coverage and usage, increasing indoor residual spraying coverage and effectiveness, improving the health system effectiveness, increasing seasonal malaria chemotherapy coverage among children were investigated to observe the their impact on averting malaria incidence by 2030.
ResultsIncreased usage of bednets but not only coverage levels, predicted to lead to significant proportion of cases of malaria averted in all regions. Whereas, improvements in the health systems by way of health seeking, testing and treatment predicted to lead to a decline in incidence largely in all regions, it allows more incidence cases to be detected in the Upper East, Upper West and Brong-Ahafo regions. With an increased coverage of SMC, to include higher age groups, a modest proportion of cases could be averted in populations of the Guinea savannah. Indoor residual spraying could also benefit populations of the Transitional forest and Coastal savannah as its impact is significant in averting incidence.
ConclusionsHaving achieved relatively high bednet coverage, enhancing bednet usage to at least a doubling of the current usage levels and deployed in combination with various interventions in all the regions predicted a significant reductions, ranging from 44.0% - 97.0%, in malaria incidence. Regions of the Transitional forest and Coastal savannah could also benefit from a drastic decline in incidence following a gradual introduction of indoor residual spraying on a sustained basis. A much improved health system in all regions could potentially cater for all incident cases that were not prevented through vector control activities. The modelling application has shown to be beneficial given the opportunity to be able to study in relatively more detail, the regional differences in malaria morbidity in Ghana. | public and global health |
10.1101/2022.04.20.22273878 | Spinal cord damage in Friedreich's ataxia: Results from ENIGMA-Ataxia | ObjectiveSpinal cord damage is a hallmark of Friedreich ataxia (FRDA), but its progression and clinical correlates remain unclear. Here we performed a characterization of cervical spinal cord structural abnormalities in a large multisite FRDA cohort.
MethodsWe performed a cross-sectional analysis of cervical spinal cord (C1 to C4) cross-sectional area (CSA) and eccentricity using MRI data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched controls. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.
ResultsIndividuals with FRDA, relative to controls, had significantly reduced CSA at all examined levels, with large effect sizes (d>2.1) and significant correlations with disease severity (r<-0.4). Similarly, we found significantly increased eccentricity (d>1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, while CSA appears to decrease progressively, eccentricity remains stable over time.
InterpretationPrevious research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. | neurology |
10.1101/2022.04.21.22274143 | Improving the Diagnosis of SIBO Using an At-Home Handheld App Connected Breath Analysis Device (AIRE) | INTRODUCTIONSmall Intestinal Bacterial Overgrowth (SIBO) is a common yet underdiagnosed condition. Lactulose hydrogen breath tests (LHBT) are typically used to detect SIBO; however, current breath testing methods require specialised, expensive equipment and technical support and are either done at a point-of-care facility and/or have to be mailed to a central laboratory. To address these issues a novel hand-held breath analyzer (AIRE(R), FoodMarble) was tested. The aims of this study were first, to perform a technical assessment of the AIRE device, second to compare the performance of the AIRE device against a commercially available mail-in LHBT kit using a zero-inflated negative binomial mixed effect model.
METHODSThree AIRE devices were tested with certified test gases covering a diagnostically meaningful range (hydrogen mixed with air at 3 ppm, 10 ppm and 50 ppm). For the clinical study, 36 patients suspected to have SIBO presenting to a tertiary level clinic were provided with an AIRE device and performed concurrent LHBTs at home with a mail-in LHBT kit.
RESULTSThe overall average readings (mean {+/-} SD) for the AIRE devices tested at 3 ppm, 10 ppm and 50 ppm H2 were: 3.5 {+/-} 0.7 ppm; 10.7 {+/-} 1.1 ppm and 49.5 {+/-} 2.6 ppm respectively. The overall mean absolute error across the tested devices was 1.2 ppm. A significant positive correlation (r = 0.78, p < 0.001) was demonstrated between AIRE and mail-in kit H2 values.
DISCUSSIONThe AIRE device is a compelling alternative to mail-in LHBT kits for the diagnosis of SIBO. The AIRE device may also offer advantages over other traditional breath testing methods. | gastroenterology |
10.1101/2022.04.21.22274143 | Improving the Diagnosis of SIBO Using an At-Home Handheld App Connected Breath Analysis Device (AIRE) | INTRODUCTIONSmall Intestinal Bacterial Overgrowth (SIBO) is a common yet underdiagnosed condition. Lactulose hydrogen breath tests (LHBT) are typically used to detect SIBO; however, current breath testing methods require specialised, expensive equipment and technical support and are either done at a point-of-care facility and/or have to be mailed to a central laboratory. To address these issues a novel hand-held breath analyzer (AIRE(R), FoodMarble) was tested. The aims of this study were first, to perform a technical assessment of the AIRE device, second to compare the performance of the AIRE device against a commercially available mail-in LHBT kit using a zero-inflated negative binomial mixed effect model.
METHODSThree AIRE devices were tested with certified test gases covering a diagnostically meaningful range (hydrogen mixed with air at 3 ppm, 10 ppm and 50 ppm). For the clinical study, 36 patients suspected to have SIBO presenting to a tertiary level clinic were provided with an AIRE device and performed concurrent LHBTs at home with a mail-in LHBT kit.
RESULTSThe overall average readings (mean {+/-} SD) for the AIRE devices tested at 3 ppm, 10 ppm and 50 ppm H2 were: 3.5 {+/-} 0.7 ppm; 10.7 {+/-} 1.1 ppm and 49.5 {+/-} 2.6 ppm respectively. The overall mean absolute error across the tested devices was 1.2 ppm. A significant positive correlation (r = 0.78, p < 0.001) was demonstrated between AIRE and mail-in kit H2 values.
DISCUSSIONThe AIRE device is a compelling alternative to mail-in LHBT kits for the diagnosis of SIBO. The AIRE device may also offer advantages over other traditional breath testing methods. | gastroenterology |
10.1101/2022.04.19.22274057 | Exploring biomarkers of processing speed and executive function: the role of the anterior thalamic radiations | IntroductionProcessing speed and executive functioning are often impaired after stroke and in typical aging. However, there are no reliable neurological markers of these cognitive impairments. The trail making test (TMT) is a common index of processing speed and executive function. Here, we tested candidate MRI markers of TMT performance in a cohort of older adults and individuals with chronic stroke.
MethodsIn 61 older adults and 32 individuals with chronic stroke, we indexed white matter structure with region-specific lesion load (WMH and stroke lesions) and diffusion tensor imaging (DTI) from four regions related to TMT performance: the anterior thalamic radiations (ATR), superior longitudinal fasciculus (SLF), forceps minor, and cholinergic pathways. Regression modelling was used to identify the marker(s) that best predicted TMT performance.
ResultsDTI metrics of the ATR predicted processing speed in both the older adult (TMT A: {beta}=-3.431, p<0.001) and chronic stroke (TMT A: {beta}=11.282, p<0.001) groups. In the stroke group executive function was best predicted by a combination of ATR and forceps minor DTI metrics in the chronic stroke group (TMT B: adjustedR2=0.438, p<0.001); no significant predictors of executive function (TMT B) emerged in the older adult group. No imaging metrics related to set shifting (TMT B-A). For all TMT outcome measures with significant imaging predictors, regional DTI metrics predicted TMT performance above and beyond whole-brain stroke and WMH volumes and removing whole-brain lesion volumes improved model fits.
ConclusionsIn this comprehensive assessment of candidate imaging markers, we demonstrate an association between ATR microstructure and processing speed and executive function performance. Regional DTI metrics provided better predictors of cognitive performance than whole-brain lesion volumes or regional lesion load, emphasizing the importance of lesion location in understanding cognition. We propose ATR DTI metrics as novel candidate imaging biomarker of post-stroke cognitive impairment. | rehabilitation medicine and physical therapy |
10.1101/2022.04.19.22274057 | Exploring biomarkers of processing speed and executive function: the role of the anterior thalamic radiations | IntroductionProcessing speed and executive functioning are often impaired after stroke and in typical aging. However, there are no reliable neurological markers of these cognitive impairments. The trail making test (TMT) is a common index of processing speed and executive function. Here, we tested candidate MRI markers of TMT performance in a cohort of older adults and individuals with chronic stroke.
MethodsIn 61 older adults and 32 individuals with chronic stroke, we indexed white matter structure with region-specific lesion load (WMH and stroke lesions) and diffusion tensor imaging (DTI) from four regions related to TMT performance: the anterior thalamic radiations (ATR), superior longitudinal fasciculus (SLF), forceps minor, and cholinergic pathways. Regression modelling was used to identify the marker(s) that best predicted TMT performance.
ResultsDTI metrics of the ATR predicted processing speed in both the older adult (TMT A: {beta}=-3.431, p<0.001) and chronic stroke (TMT A: {beta}=11.282, p<0.001) groups. In the stroke group executive function was best predicted by a combination of ATR and forceps minor DTI metrics in the chronic stroke group (TMT B: adjustedR2=0.438, p<0.001); no significant predictors of executive function (TMT B) emerged in the older adult group. No imaging metrics related to set shifting (TMT B-A). For all TMT outcome measures with significant imaging predictors, regional DTI metrics predicted TMT performance above and beyond whole-brain stroke and WMH volumes and removing whole-brain lesion volumes improved model fits.
ConclusionsIn this comprehensive assessment of candidate imaging markers, we demonstrate an association between ATR microstructure and processing speed and executive function performance. Regional DTI metrics provided better predictors of cognitive performance than whole-brain lesion volumes or regional lesion load, emphasizing the importance of lesion location in understanding cognition. We propose ATR DTI metrics as novel candidate imaging biomarker of post-stroke cognitive impairment. | rehabilitation medicine and physical therapy |
10.1101/2022.04.20.22274114 | Physiotherapists use different motivational strategies tailored to an individual's condition: a qualitative study | QuestionHow do physiotherapists use different motivational strategies for individuals in stroke rehabilitation?
DesignA qualitative study using in-depth semi-structured online interviews.
ParticipantsA criterion sample of 15 physiotherapists who have worked in rehabilitation for over 10 years and have an interest in an individuals motivation.
InterventionNot applicable.
Outcome measuresPhysiotherapists perspectives and experiences regarding motivational strategies used depending on the individuals condition.
ResultsA total of nine themes emerged from the data upon thematic analysis and inductive coding. The participants used different strategies to encourage individuals active participation in physiotherapy depending on their (1) mental health problems, (2) physical difficulties, (3) level of cognitive function, (4) personality, (5) activities and participation, (6) age, (7) human environment, and (8) type of rehabilitation service where the individual undergoes treatment. For example, in cases where an individual lost self-confidence, participants offered practice tasks that the individual could achieve with little effort to make them experience success. Conversely, for individuals with overconfidence, participants would provide them with a relatively difficult practice task to help them realize the necessity of practice through the experience of failure. The interviews also revealed (9) motivational strategies used regardless of the individuals condition. For instance, patient-centred communication was used to build a rapport with individuals, irrespective of their condition.
ConclusionThis qualitative study is the first to demonstrate motivational strategies that physiotherapists use based on the individuals condition. Our findings provide a deeper understanding of the selection of motivational strategies in stroke rehabilitation. | rehabilitation medicine and physical therapy |
10.1101/2022.04.20.22273998 | Clinical measures of balance and gait cannot differentiate somatosensory impairments in people with lower-limb amputation. | BackgroundIn addition to a range of functional impairments seen in individuals with a lower-limb amputation, this population is at a substantially elevated risk of falls [1,2]. Studies postulate that the lack of sensory feedback from the prosthetic limb contributes heavily to these impairments, but the extent to which sensation affects functional measures remains unclear [3,4].
Research QuestionThe purpose of this study is to determine how sensory impairments in the lower extremities relate to performance with common clinical functional measures of balance and gait in individuals with a lower-limb amputation. Here we evaluate the effects of somatosensory integrity to both clinical and lab measures of static, reactive and dynamic balance, and gait stability.
MethodsIn 20 individuals with lower-limb amputation (AMP) and 20 age and gender-matched able-bodied controls (CON), we evaluated the relationship of measures of sensation (pressure, proprioception, and vibration) to measures of balance and gait. Static, reactive, and dynamic balance were assessed using the Sensory Organization Test (SOT), Motor Control Test (MCT), and Functional Gait Assessment (FGA), respectively. Gait stability was assessed through measures of step length asymmetry and step width variability. Sensation was categorized into intact or impaired sensation by pressure thresholds and differences across groups were analyzed.
ResultsThere were significant differences between AMP and CON groups for the reliance on vision for static balance in the SOT, MCT, and FGA (p<0.01). Despite these differences across groups, there were no significant differences within the AMP group based on intact or impaired sensation across all functional measures.
SignificanceDespite being able to detect differences between able-bodied individuals and individuals with an amputation, these functional measures are unable to distinguish between levels of impairment within participants with an amputation. These findings suggest that more challenging and robust metrics are needed to evaluate the relationship of sensation and function in individuals with an amputation.
Research reported in this publication was supported by the National Institutes of Health [NINDS Award Number UH3NS100541 and NICHD Award Number F30HD098794]. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. | rehabilitation medicine and physical therapy |
10.1101/2022.04.19.22274054 | Rasch Validation of the Revised Body Awareness Rating Questionnaire (BARQ-R) in Adults with Musculoskeletal Pain, Adults with Spinal Cord Injury, and Community-Dwelling Adults in the US | BackgroundTo establish Rasch validation of the Revised Body Awareness Rating Questionnaire (BARQ-R) in adults with musculoskeletal pain, community-dwelling adults without pain, and adults with spinal cord injury (SCI) who have neuropathic pain.
Materials and MethodThe BARQ-R has 12 items with scores ranging from 0 (completely disagree) to 3 (completely agree). Through Rasch analysis, we evaluated unidimensionality through item and person fit, targeting of the population, person separation reliability (PSR), local item dependence (LID), and principal components analysis of residuals (PCAR).
ResultsThe BARQ-R in adults with musculoskeletal pain (n=152; average age = 52.26{+/-}16.13 years) showed good targeting (person mean location: -0.36{+/-}0.88 logits), minimal floor effect (0.01%), and no ceiling effect (0.00%) and had good reliability (PSR=0.75). The BARQ-R in community-dwelling adults (n=471; average age = 49.63{+/-}17.57 years) had a person mean location of -0.62{+/-}1.09 logits, minimal floor (2.63%), and minimal ceiling effect (0.43%) after rescoring 2 items and deleting 3 items and had good reliability (PSR=0.74). The BARQ-R in adults with SCI-related neuropathic pain (n=44; average age = 55.45{+/-}13.47 years) showed good targeting after rescoring 7 items (person mean location: -0.33{+/-}0.71 logits), no floor effect (0.00%) or ceiling effect (0.00%) but had poor reliability (PSR=0.65).
ConclusionsThe BARQ-R shows sufficient fit to be used in clinical settings for group decision-making for both adults with musculoskeletal pain and community-dwelling adults. However, in adults with SCI-related neuropathic pain, preliminary Rasch analysis of the BARQ-R showed low reliability and therefore the BARQ-R is not recommended for clinical use in that population. Validation in larger groups of adults with SCI as well as more diverse samples are needed. | rehabilitation medicine and physical therapy |
10.1101/2022.04.21.22274148 | Trends in TSH, free T4, and anti-thyroid peroxidase and treatment status: Canadian Health Measures Survey 2012 to 2015 | BackgroundPrevious studies in Canada focused on the prevalence of thyroid conditions have not reported on the levels of the thyroid-stimulating hormone (TSH) and thyroid hormones. To address this issue, the present study describes the trends in TSH, free T4, and anti-thyroid peroxidase and their treatment status for the patients who have clinically high or low levels.
MethodsWe used data from the Canadian Health Measures Survey (CHMS) cycles 3 and 4 conducted between 2012 and 2015. The thyroid measures studied were TSH, free T4, and anti-thyroid peroxidase. We used clinical reference ranges to identify abnormality in these measures. We labelled abnormality in these measures as treated if relevant conditions were diagnosed or a disease-specific prescription was reported. Untreated individuals were those with an abnormality in thyroid measures without any medication use or relevant diagnoses. We presented the trends of thyroid measures in mean values and ratios, compared to the values first measured.
ResultsThe levels of TSH, free T4, and anti-peroxidase in cycle 4 were not significantly different from those in cycle 3. The proportions of Canadians with clinically high levels of free T4, anti-thyroid peroxidase, and TSH were 0.03 to 0.017, 0.005 to 0.005, and 0.30 to 0.43 for cycles 3 to 4, respectively. The proportions of Canadians with clinically low levels of TSH and free T4 were 0.02 to 0.021 and 0.18 to 0.11 for cycles 3 to 4, respectively. The change in the proportions of treatment statuses varied across the thyroid measures of the Canadians studied.
ConclusionThis descriptive study demonstrates the trends in TSH, free T4, and anti-thyroid peroxidase; their distributions in the population; and the proportions of Canadians with clinically high or low levels. We believe the information on the treatment status of those with uncontrolled high levels can be used to design patient screening programs. | endocrinology |
10.1101/2022.04.20.22274020 | Understanding the cultural environment of the outpatient care setting for patients with dementia receiving cancer treatment: a qualitative study | IntroductionPeople with dementia have poorer cancer outcomes than those without, and experience inequalities in access to, and quality of, care. Outpatient environments, where radiotherapy, chemotherapy and immunotherapy cancer treatments typically take place, have largely been excluded from research. This study was conducted to understand provision of treatment and support and experiences of care for people with dementia undergoing cancer treatment in the outpatient setting.
Materials and methodsUsing observation, interviews and document analysis, data were collected to scrutinise the cultural environment of ambulatory care, comprising the physical fabric of the care setting; interactions, behaviours and perceptions of those in the care setting; and the organizational, clinical and interactional processes involved in care delivery. The study was conducted in the outpatient oncology departments of two large teaching hospitals in England between January 2019-July 2021.
ResultsData were gathered from a wide range of sources, including 15 hours of observation, and interviews with patients (n=2), caregivers (n=7) and staff (n=20). Evidence from this study suggests the cultural environment of the outpatient care setting reflects and supports the standardised processing of people for cancer treatment. Dementia introduces a wider set of care requirements not catered for by this standardised treatment model and associated processes. Data showed the needs of patients with dementia could be addressed most effectively when individualised, as opposed to standardised care, was offered.
ConclusionThere is work to be done in outpatient cancer services to ensure responsiveness to individual patient need. This could be achieved by having an established way (or ways) of eliciting needs, preferences and expectations, a belief that a persons needs and expectations are legitimate, and that effort should be made to address them, with the ability to accommodate these needs and expectations.
Patient or public contributionpatients and caregivers were involved in the study design and development of study materials including the interview topic guide. They also assisted with discussion and clarification of study findings. | oncology |
10.1101/2022.04.17.22269308 | The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study | Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk. | epidemiology |
10.1101/2022.04.22.22274032 | Antibody Responses In Non-Severe SARS-CoV-2 Infections Are Driven By CD4+ T cells and Age. | SARS-CoV-2 infection causes a spectrum of clinical outcomes and diverse memory responses. Population studies indicate that viral neutralizing antibody responses are protective, but do not always develop post-infection. Other antiviral antibody effector functions, T-cell responses, or immunity to seasonal coronaviruses (OC43, 229E) have been implicated but not defined in all ages. Here, we identify that children and adult subjects generate polyfunctional antibodies to the spike protein after asymptomatic infection or mild disease, with some subjects developing cellular responses without seroconversion. Diversity in immunity was explained by two clusters distinguished by CD4+ T-cell cytokines, age, and antibodies to seasonal coronaviruses. Post-vaccination neutralizing responses were predicted by specific post-infection immune measures, including IL-2, spike-IgA, OC43-IgG1, 229E-IgM. We confirm a key role for CD4+ T cell cytokines in functionality of anti-spike antibodies, and show that antibody diversity is impacted by age, Th/Th2 cytokine biases, and antibody isotypes to SARS-CoV-2 and seasonal coronaviruses. | allergy and immunology |
10.1101/2022.04.21.22273340 | Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review | BackgroundChildhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises.
MethodsRealist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised.
Results50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n=17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited.
ConclusionA number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge. | public and global health |
10.1101/2022.04.21.22273340 | Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review | BackgroundChildhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises.
MethodsRealist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised.
Results50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n=17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited.
ConclusionA number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge. | public and global health |
10.1101/2022.04.21.22274150 | Epidemiological impact and cost-effectiveness analysis of COVID-19 vaccination in Kenya | BackgroundFew studies have assessed the benefits of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection.
MethodsWe conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (> 18 years) population prioritizing roll-out in over 50-year olds (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at $7 per dose and vaccine delivery costs of $3.90-$6.11 per dose. The cost-effectiveness threshold was USD 919.
FindingsSlow roll-out at 30% coverage largely targets over 50-year-olds and resulted in 54% fewer deaths (8,132(7,914 to 8,373)) than no vaccination and was cost-saving (ICER=US$-1,343 (-1,345 to - 1,341) per DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757 to 872) and 5% (282 (251 to 317) but was not cost-effective, using Kenyas cost-effectiveness threshold ($ 919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=$-1,607 (-1,609 to -1,604) per DALY averted) compared to slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective.
InterpretationWith prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective.
KEY QUESTIONSO_ST_ABSWhat is already known?C_ST_ABSO_LIThe COVID-19 pandemic has led to a substantial number of cases and deaths in low-and middle-income countries.
C_LIO_LICOVID-19 vaccines are considered the main strategy of curtailing the pandemic. However, many African nations are still at the early phase of vaccination.
C_LIO_LIEvidence on the cost-effectiveness of COVID-19 vaccines are useful in estimating value for money and illustrate opportunity costs. However, there is a need to balance these economic outcomes against the potential impact of vaccination.
C_LI
What are the new findings?O_LIIn Kenya, a targeted vaccination strategy that prioritizes those of an older age and is deployed at a rapid rollout speed achieves greater marginal health impacts and is better value for money.
C_LIO_LIGiven the existing high-level population protection to COVID-19 due to prior exposure, vaccination of younger adults is less cost-effective in Kenya.
C_LI
What do the new findings imply?O_LIRapid deployment of vaccines during a pandemic averts more cases, hospitalisations, and deaths and is more cost-effective.
C_LIO_LIAgainst a context of constrained fiscal space for health, it is likely more prudent for Kenya to target those at severe risk of disease and possibly other vulnerable populations rather than to the whole population.
C_LI | health economics |
10.1101/2022.04.22.22274137 | A within-host model of SARS-CoV-2 infection | Within-host models have been used to successfully describe the dynamics of multiple viral infections, however, the dynamics of SARS-CoV-2 virus infection remain poorly understood. A greater understanding of how the virus interacts with the host can contribute to more realistic epidemiological models and help evaluate the effect of antiviral therapies and vaccines. Here, we present a within-host model to describe SARS-CoV-2 viral dynamics in the upper respiratory tract of individuals enrolled in the UK COVID-19 Human Challenge Study. Using this model, we investigate the viral dynamics and provide timescales of infection that independently verify key epidemiological parameters important in the management of an epidemic. In particular, we estimate that an infected individual is first capable of transmitting the virus after approximately 2.1 days, remains infectious for a further 8.3 days, but can continue to test positive using a PCR test for up to 27 days. | infectious diseases |
10.1101/2022.04.21.22274014 | Can process mapping and a multi-site Delphi of perioperative professionals inform our understanding of system-wide factors that may impact operative risk? | ObjectivesTo examine whether the use of process mapping and a multidisciplinary Delphi can identify potential contributors to perioperative risk. We hypothesised that this approach may identify factors not represented in common perioperative risk tools and give insights of use to future research in this area.
DesignMultidisciplinary modified Delphi study
SettingTwo centres (one tertiary, one secondary) in the United Kingdom during 2020 amidst coronavirus pressures.
Participants91 stakeholders from 23 professional groups involved in the perioperative care of older patients. Key stakeholder groups were identified through the use of process mapping of local perioperative care pathways.
ResultsResponse rate ranged from 51% in round one to 19% in round three. After round one, free text suggestions from the panel were combined with variables identified from perioperative risk scores. This yielded a total of 410 variables that were voted on in subsequent rounds. Including new suggestions from round two, 468/519 (90%) of the statements presented to the panel reached a consensus decision by the end of round three. Identified risk factors included patient level factors (such as ethnicity and socio-economic status); and organisational or process factors related to the individual hospital (such as policies, staffing, and organisational culture). 66/160 (41%) of the new suggestions did not feature in systematic reviews of perioperative risk scores or key process indicators. No factor categorised as organisational is currently present in any perioperative risk score.
ConclusionsThrough process mapping and a modified Delphi we gained insights into additional factors that may contribute to perioperative risk. Many were absent from currently used risk stratification scores. These results enable an appreciation of the contextual limitations of currently used risk tools and could support future research into the generation of more holistic datasets for the development of perioperative risk assessment tools.
Strengths and Weaknesses- Novel use of process mapping to identify key perioperative stakeholders
- Multidisciplinary Delphi panel to gain breadth of perspective
- Performed across two sites
- Comprehensive results may be of use to other researchers designing perioperative research databases
- Results may be limited by low response rate in final round (although majority of consensus decisions made in round two) | anesthesia |
10.1101/2022.04.22.22274163 | Predicting past and future SARS-CoV-2-related sick leave using discrete time Markov modelling | BackgroundPrediction of SARS-CoV-2-induced sick leave among healthcare workers (HCWs) is essential for being able to plan the healthcare response to the epidemic.
MethodsDuring first wave of the SARS-Cov-2 epidemic (April 23rd to June 24th, 2020), the HCWs in the greater Stockholm region in Sweden were invited to a study of past or present SARS-CoV-2 infection. We develop a discrete time Markov model using a cohort of 9449 healthcare workers (HCWs) who had complete data on SARS-CoV-2 RNA and antibodies as well as sick leave data for the calendar year 2020. The one-week and standardized longer term transition probabilities of sick leave and the ratios of the standardized probabilities for the baseline covariate distribution were compared with the referent period (an independent period when there were no SARS-CoV-2 infections) in relation to PCR results, serology results and gender.
ResultsThe one-week probabilities of transitioning from healthy to partial sick leave or full sick leave during the outbreak as compared to after the outbreak were highest for healthy HCWs testing positive for large amounts of virus (3.69, (95% confidence interval, CI: 2.44-5.59) and 6.67 (95% CI: 1.58-28.13), respectively). The proportion of all sick leaves attributed to COVID-19 during outbreak was at most 55% (95% CI: 50%-59%).
ConclusionsA robust Markov model enabled use of simple SARS-CoV-2 testing data for quantifying past and future COVID-related sick leave among HCWs, which can serve as a basis for planning of healthcare during outbreaks. | epidemiology |
10.1101/2022.04.19.22274028 | SARS-CoV-2 testing of aircraft wastewater shows that mandatory tests and vaccination pass before boarding did not prevent massive importation of Omicron variant in Europe | BackgroundMost new SARS-CoV-2 epidemics in France occurred following importation from abroad of emerging viral variants. Currently, the control of such risk of new variant importation is based on the negativity of a screening test (PCR or antigenic) and on an up-to-date vaccine status, such as International Air Transport Association travel pass.
MethodsWastewater of 2 planes arriving in Marseille (France) from Addis-Ababa (Ethiopia) on December 2021 were i) tested by RT-PCR for SARS-CoV2 detection, and variants screening; these tests were carried out between landing and custom clearance, ii)sequenced by MiSeq Illumina.
Antigenic tests and sequencing by NovaSeq were carried out on respiratory samples collected from the 56 passengers of the second flight.
ResultsSARS-CoV-2 RNA suspected of being from the Omicron BA.1 variant was detected on the aircrafts wastewater.,
SARS-CoV2 RNA was detected for 11 (20%) passengers and the Omicron BA.1 variant was identified.
ConclusionOur work shows the efficiency of aircraft wastewater testing to detect SARS-CoV-2 cases among travelers and identify the viral genotype. It also highlights the low performance for incoming flights from outside Europe to France of the current filter strategy that combines requirement for a vaccine pass and a negative testing before boarding. | epidemiology |
10.1101/2022.04.21.22274139 | How time-scale differences in asymptomatic and symptomatic transmission shape SARS-CoV-2 outbreak dynamics | Asymptomatic and symptomatic SARS-CoV-2 infections can have different characteristic time scales of transmission. These time-scale differences can shape outbreak dynamics as well as bias population-level estimates of epidemic strength, speed, and controllability. For example, prior work focusing on the initial exponential growth phase of an outbreak found that larger time scales for asymptomatic vs. symptomatic transmission can lead to under-estimates of the basic reproduction number as inferred from epidemic case data. Building upon this work, we use a series of nonlinear epidemic models to explore how differences in asymptomatic and symptomatic transmission time scales can lead to changes in the realized proportion of asymptomatic transmission throughout an epidemic. First, we find that when asymptomatic transmission time scales are longer than symptomatic transmission time scales, then the effective proportion of asymptomatic transmission increases as total incidence decreases. Moreover, these time-scale-driven impacts on epidemic dynamics are enhanced when infection status is correlated between infector and infectee pairs (e.g., due to dose-dependent impacts on symptoms). Next we apply these findings to understand the impact of time-scale differences on populations with age-dependent assortative mixing and in which the probability of having a symptomatic infection increases with age. We show that if asymptomatic generation intervals are longer than corresponding symptomatic generation intervals, then correlations between age and symptoms lead to a decrease in the age of infection during periods of epidemic decline (whether due to susceptible depletion or intervention). Altogether, these results demonstrate the need to explore the role of time-scale differences in transmission dynamics alongside behavioural changes to explain outbreak features both at early stages (e.g., in estimating the basic reproduction number) and throughout an epidemic (e.g., in connecting shifts in the age of infection to periods of changing incidence). | epidemiology |
10.1101/2022.04.21.22272868 | Waning of PCV13 vaccine-induced antibody levels within the first year of life, using a 3+0 schedule: an observational population-level serosurveillance study among children under 5 years old in Blantyre, Malawi | BackgroundPneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibody, effectively reducing vaccine-serotype (VT) carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty around correlate of protection (CoP) estimates and with persistent VT carriage and VT-IPD following PCV13 introduction, we undertook population-level immunogenicity profiling among children <5 years in Blantyre, Malawi.
MethodsFor 638 children, capsule-specific IgG to PCV13 VTs, two non-VTs, and IgG to three pneumococcal proteins were measured using an enzyme-linked immunosorbent assay and a direct-binding electrochemiluminescence-based multiplex assay. A linear spline regression model estimated population-level, serotype-specific immunogenicity profiles. A linear regression model was used to validate putative CoPs.
FindingsImmunogenicity profiles revealed a consistent pattern among VTs except serotype 3: a vaccine-induced IgG peak followed by waning to a nadir and subsequent increase in titre. For serotype 3 there was no apparent vaccine-induced increase. Heterogeneity in parameters included age range at post-vaccination-nadir (11{middle dot}2 [19F, 23F] to 27{middle dot}3 [7F] months). Titres dropped below IPD CoPs among 9 VTs and below carriage CoPs for 10 VTs. Study data estimated a range of carriage CoPs (0{middle dot}50g/mL to 2{middle dot}5g/mL). Increasing antibody among older children and seroincident events were consistent with ongoing VT exposure.
InterpretationA 3+0 PCV13 schedule with high uptake has not led to sustained population-level antibody immunity beyond the first year of life. Indeed, post-vaccine antibody concentrations dropped below putative CoPs for several VTs, potentially contributing to persistent VT carriage and residual VT-IPD in Malawi and other similar settings.
FundingBill & Melinda Gates Foundation, Wellcome UK, and National Institute for Health & Care Research. | epidemiology |
10.1101/2022.04.21.22274111 | Prevalence and associated factors of khat chewing among pregnant women: A Systematic Review and Meta-analysis | BackgroundKhat (Catha edulis) is a stimulant plant, broadly cultivated and consumed in the Horn of Africa and the Arabian Peninsula. It contains Cathinone, which is an amphetamines-like chemical and causes various adverse outcomes for pregnant women and babies when it is consumed during pregnancy. Decisive estimates of the prevalence of khat chewing and related risk factors which may increase this practice have not been determined.
AimTo determine the pooled prevalence and associated factors of khat chewing among pregnant women in the Horn Africa and the Arabian Peninsula countries with a view to informing targeted interventions for the region.
MethodThe study protocol was prepared and registered on PROSPERO, ID CRD42021190837. A database search including Gray literature and Google scholar was explored to identify 667 studies. Finally, 14 studies were considered relevant for meta-analysis, after removing 259 duplicates, 388 unrelated topics and 6 studies with full text examination. The Newcastle-Ottawa Scale quality assessment tool was used to assess the quality of the studies. The pooled prevalence was determined by using the random-effect model and the p- values of [≤] 0.05 were considered stastically significant to examine associations. Statistical heterogeneity amongst the studies was assessed by Cochrane chi-square and the I2 statistical test.
Main FindingsFrom the meta-analysis of 14 studies with 15,343 study participants, the pooled prevalence of khat chewing among pregnant women was 21.42%, 95% CI (14.49 - 29.29); (I 2=99.05% (p<0.0001). The results of the meta-analysis demonstrated that pregnant women who had a khat chewing partner [OR 6.50 (95% CI 5.01, 8.43)]; low educational status [OR 2.53 (95% CI 2.24 - 2.85)], lived in rural area [OR 1.69 (95% CI 1.52 - 1.88)] or had a low level of income [OR 1.70 (95% CI 1.55 - 1.87)] were significantly more likely to chew khat during pregnancy.
ConclusionThe prevalence of khat chewing amongst pregnant women in the Horn of Africa and the Arabian Peninsula has never been measured before and was found to be high. Partners khat chewing status, maternal low educational and economic status were the main factors associated with the problem. Designing intervention strategies to specifically target these risk factors and reduce the burden of the problem for women and their babies is urgently needed. | epidemiology |
10.1101/2022.04.22.22274176 | Association between household composition and severe COVID-19 outcomes in older people by ethnicity: an observational cohort study using the OpenSAFELY platform | Ethnic differences in the risk of severe COVID-19 may be linked to household composition. We quantified the association between household composition and risk of severe COVID-19 by ethnicity for older individuals. With the approval of NHS England, we analysed ethnic differences in the association between household composition and severe COVID-19 in people aged 67 or over in England. We defined households by number of generations living together, and used multivariable Cox regression stratified by location and wave of the pandemic and accounted for age, sex, comorbidities, smoking, obesity, housing density and deprivation. We included 2 692 223 people over 67 years in wave 1 (01/02/2020-31/08/2020) and 2 731 427 in wave 2 (01/09/2020-31/01/2021). Multigenerational living was associated with increased risk of severe COVID-19 for White and South Asian older people in both waves (e.g. wave 2, 67+ living with 3 other generations vs 67+ year olds only: White HR 1{middle dot}61 95% CI 1{middle dot}38-1{middle dot}87, South Asian HR 1{middle dot}76 95% CI 1{middle dot}48-2{middle dot}10), with a trend for increased risks of severe COVID-19 with increasing generations in wave 2. Multigenerational living was associated with severe COVID-19 in older adults. Older South Asian people are over-represented within multigenerational households in England, especially in the most deprived settings. The number of generations in a household, number of occupants, ethnicity and deprivation status are important considerations in the continued roll-out of COVID-19 vaccination and targeting of interventions for future pandemics.
FundingThis research was funded in part, by the Wellcome Trust. For the purpose of open access, the author has applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. | epidemiology |
10.1101/2022.04.21.22273836 | Subcortical brain volumes in young infants exposed to antenatal maternal depression: Findings from a South African birth cohort | BackgroundSeveral studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants first weeks of life, following exposure in utero. We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort.
MethodsAMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28-32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II20) and unexposed (BDI-II<14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance.
ResultsLarger volumes were observed in AMD-exposed (N=49) compared to unexposed infants (N=75) for the right amygdala (1.98% difference, p=0.039) and bilateral caudate nucleus (left: 5.78% difference, p=0.001; right: 6.06% difference, p<0.001). A significant AMD-by-sex interaction was found for the hippocampus (left: F(1,118)=4.80, p=0.030; right: F(1,118)=5.16, p=0.025), reflecting greater volume in AMD-exposed females (left: 5.09% difference, p=0.001, right: 3.53% difference, p=0.010), but not males.
ConclusionsVolumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation. | pediatrics |
10.1101/2022.04.22.22273055 | How do primary care providers perceive their role at ensuring opioid safety? A qualitative exploration from those on the front lines | IntroductionPrescribing naloxone is recommended by the Centers for Disease Control and Prevention to reduce the risk of death from an opioid overdose. Naloxone is rarely prescribed, even when indicated; improving our understanding of how primary care providers (PCP) perceive their role in naloxone prescribing is essential to increase opioid medication safety. The objectives of this study were to: (1) describe how PCPs perceive their role in prescribing naloxone for patients who are at high risk of an overdose and (2) describe PCP-reported barriers and facilitators of naloxone prescribing.
MethodsCurrently practicing providers completed semi-structured interviews, based on Theory of Planned Behavior, to understand their attitudes toward naloxone, their perceived role in naloxone prescribing, and facilitators/barriers to prescribing naloxone.
ResultsEleven interviews were conducted with physicians (n=2), physician assistants (n=8), and a nurse practitioner (n=1). Providers held generally positive attitudes toward naloxone as a rescue medication. Negative attitudes toward naloxone include the perception of facilitating risky opioid use. Providers suggested that whomever prescribes the opioid pain medication should be primarily responsible for prescribing naloxone. Providers noted that stigma may prevent them from discussing naloxone during clinic visits. Increasing visit time and receiving support/education from organizational and professional society leadership were identified as important facilitators of naloxone prescribing.
ConclusionsWhile providers were aware of what naloxone was used for, there was reticence in discussing this medication with patients. Providers reported that whomever prescribes a pain medication should be primarily responsible for ensuring medication safety. If primary care organizations would like to improve opioid medication safety, ensuring that providers feel supported and receive needed education are essential. | primary care research |
10.1101/2022.04.22.22274164 | Disruption of long-term psychological distress trajectories during the COVID-19 pandemic: evidence from three British birth cohorts | ImportanceMental health disorders were among the leading global contributors to years lived with disability prior to the COVID-19 pandemic onset, and growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until mid-life and then falls in both sexes, is unknown.
ObjectiveTo analyse whether long-term pre-pandemic psychological distress trajectories have altered during the pandemic, and whether these changes have been different across generations and by sex.
DesignCross-cohort study with prospective data collection over a 40-year period (earliest time point: 1981; latest time point: February/March 2021).
SettingPopulation-based (adult general population), Great Britain.
ParticipantsMembers of three nationally representative birth cohorts which comprised all people born in Great Britain in a single week of 1946, 1958, or 1970, and who participated in at least one of the data collection waves conducted after the start of the pandemic (40.6%, 42.8%, 39.4%, respectively).
Exposure(s)Time, COVID-19 pandemic.
Main Outcome(s) and Measure(s)Psychological distress factor scores, as measured by validated self-reported questionnaires.
Results16,389 participants (2,175 from the 1946 birth cohort, 52.8% women; 7,446 from the 1958 birth cohort, 52.4% women; and 6,768 from the 1970 birth cohort, 56.2% women) participated in the study. By September/October 2020, psychological distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts: Standardised Mean Differences (SMD) and 95% confidence intervals (CIs) of -0.02 [-0.07, 0.04], 0.05 [0.02, 0.07], and 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively. Increases in distress were larger among women than men, widening the pre-existing inequalities observed in the pre-pandemic peak and in the most recent pre-pandemic assessment.
Conclusions and RelevancePre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems. | psychiatry and clinical psychology |
10.1101/2022.04.22.22274142 | The impact of sexual violence in mid-adolescence on girls' mental health: evidence from a longitudinal population-based study | BackgroundA large gender gap appears in internalising mental health during adolescence. There is little high-quality longitudinal population-based research investigating the role of sexual violence experiences, which are disproportionately experienced by females. This study estimates the impact of sexual violence experiences in adolescent girls on mental ill-health.
MethodsLongitudinal data from girls in the UK Millennium Cohort Study are used. The impact of sexual violence experiences on psychological distress, self-harm and attempted suicide at age 17 is examined using both multivariable confounder adjusted and propensity matching approaches.
FindingsThe analytic samples for multivariable and matched analyses were, respectively, 5,134 and 4,355 participants. In the final adjusted model, sexual violence was associated with greater mean psychological distress (mean difference 2.23 [1.67 - 2.79])), and higher risk of high distress (RR 1.74 [1.44 - 2.09]), self-harming (RR 2.04 [1.70 - 2.45]), and attempting suicide (RR 2.26 [1.64 - 3.11]) at age 17 years. Similar results were found for the matched analyses for all mental health outcomes: psychological distress (mean difference 1.97 [1.58 - 2.36]; RR 1.60 [1.41 - 1.81]), self-harm (RR 1.64 [1.48 - 1.82]), and attempted suicide (RR 1.81 [1.47 - 2.22]). Estimates of population attributable fractions suggested that, in a scenario with no sexual violence, we could expect 25-37% fewer incident mental health problems at this age.
InterpretationOur findings highlight the substantial role of sexual violence experiences in the poorer mental health outcomes experienced by adolescent girls and the substantial changes needed at societal and policy levels to prevent sexual violence and its impacts.
FundingMedical Research Council. | psychiatry and clinical psychology |
10.1101/2022.04.22.22274159 | Adults' self-reported barriers and enablers to riding a bike for transport: a systematic review | Riding a bike for transport purposes is an effective way to improve population and environmental health. Despite this, participation levels in many countries are low. Identifying the barriers and enablers to riding a bike for transport is essential to developing interventions that encourage bike riding. In this mixed-methods systematic review, we aimed to identify the perceived barriers and enablers to adults riding a bike for transport in Organisation for Economic Development (OECD) countries. A systematic database search was conducted to identify relevant peer-reviewed and grey literature. Fifty-five papers/reports met eligibility criteria. There were 34 barriers and 21 enablers identified. The leading barriers related to riding on the road alongside motor vehicles. Other factors identified included the provision and quality of cycling infrastructure, personal factors such as physical fitness, attitudinal factors such as community perceptions of cyclists, and environmental factors. While this review highlights the complexity of factors that influence the uptake of riding a bike for transport, many of the leading factors could be overcome through the provision of high-quality protected infrastructure for bike riders. Other interventions to address other known barriers and enablers are needed to increase the uptake of bike riding. | public and global health |
10.1101/2022.04.21.22274110 | Prosocial motivation for vaccination | Vaccination has both private and public benefits. We ask whether social preferences--concerns for the well-being of other people--influence ones decision regarding vaccination. We measure these social preferences for 549 online subjects: We give each subject $4 to play a public-good game and make contributions to public welfare. To the extent that one gets vaccinated out of concern for the health of others, contribution in this game is analogous to an individuals decision to obtain vaccination. We collect COVID-19 vaccination history separately to avoid experimenter-demand effects. We find a strong result: Contribution in the public-good game is associated with greater demand to voluntarily receive a first dose, and thus also to vaccinate earlier. Compared to a subject who contributes nothing, one who contributes the maximum ($4) is 48% more likely to obtain a first dose voluntarily in the four-month period that we study (April through August 2021). People who are more pro-social are indeed more likely to take a voluntary COVID-19 vaccination. | public and global health |
10.1101/2022.04.19.22273510 | ClearSpeechTogether: a rater blinded, single, controlled feasibility study of speech intervention for speakers with progressive ataxia | BackgroundProgressive ataxias frequently lead to speech disorders and consequently impact on communication participation and psychosocial wellbeing. Whilst recent studies demonstrate the potential for improvements in these areas, these treatments generally require intensive input which can reduce acceptability of the approach.
A new model of care - ClearSpeechTogether - is proposed which maximises treatment intensity whilst minimising demands on clinician. This study aimed to establish feasibility and accessibility of this approach and at the same time determine the potential benefits and adverse effects on people with progressive ataxias.
MethodThe study targeted people with progressive ataxia and mild-moderate speech and gross motor impairment. ClearSpeechTogether consisted of four individual sessions over two weeks followed by 20 patient-led group sessions over four weeks. All sessions were provided online. Quantitative and qualitative data were collected for evaluation.
ResultsNine participants completed treatment. Feasibility and acceptability were high and no adverse effects were reported. Statistical tests found significantly reduced vocal strain, improved intelligibility for reading, and increased participation and confidence. Participant interviews highlighted the value of group support, from psychosocial perspectives and in supporting speech strategy internalisation and generalisation.
DiscussionClearSpeechTogether presented an effective intervention in a small group of people with progressive ataxia. It matched or exceeded the outcomes previously reported for intensive, individual therapy while minimising clinician time demands. Furthermore, its unique peer led group intervention design appeared effective in addressing intractable psychosocial issues. ClearSpeechTogether is potentially cost-effective, providing intensive delivery with few clinician sessions, thus maximising the input available from health care providers. | rehabilitation medicine and physical therapy |
10.1101/2022.04.22.22274158 | Comparison of immunogenicity and safety of inactivated, adenovirus-vectored and heterologous adenovirus-vectored/mRNA vaccines in patients with systemic lupus erythematosus and rheumatoid arthritis: a prospective cohort study | BackgroundImpaired immune response to COVID-19 vaccines have been observed in autoimmune rheumatic disease patients. Determining the most effective and safe vaccine regimen is critically needed in such a population. We aim to compare the immunogenicity and safety of three COVID-19 vaccine regimens in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
MethodsSLE and RA patients aged 18-65 years who received inactivated (CoronaVac or COVILO), adenovirus-vectored (AZD1222), or heterogeneous (AZD1222/BNT162b2) vaccines were enrolled. Humoral and cellular immune responses were assessed at day 28 after the second vaccination. This was performed using the serum binding antibody level against receptor-binding domain of the SARS-CoV-2 spike protein (anti-RBD Ig) and IFNy-ELISpot assay (ELISpot) respectively. Reactogenicity was reviewed on day 7 following each vaccination. Disease activity was assessed before and on day 28 after the second vaccination.
ResultsThe cohort consisted of 94 patients (64 SLE and 30 RA). Inactivated, AZD1222, and AZD1222/BNT162b2 vaccines were administered to 23, 43, and 28 patients, respectively. Anti-RBD titers were lowest in the inactivated vaccine group (2.84 AU/mL; 95% CI 0.96-8.44), followed by AZD1222 (233.7 AU/mL; 95% CI 99.0 - 505.5) and AZD1222/BNT162b2 (688.6 AU/mL; 95% CI 271 - 1745), p 0<0.0001. After adjusting for relevant factors, the inactivated vaccine was associated with the lowest humoral response, while adenovirus-vectored/mRNA vaccine was the highest. The proportion of positive ELISpot test was also lowest in the inactivated vaccine group (27%), followed by the adenovirus-vectored vaccine (67%), and adenovirus-vectored/mRNA vaccine (73%)(p = 0.03). All types of vaccine were well-tolerated. There was no flare of autoimmune disease post-vaccination.
ConclusionAdenovirus-vectored and adenovirus-vectored/mRNA vaccines elicited a stronger humoral and cellular immune response than inactivated vaccines, suggesting that they may be more suitable in SLE and RA patients receiving immunosuppressive therapy. | rheumatology |
10.1101/2022.04.21.22274011 | Ambulatory detection of isolated REM sleep behavior disorder combining actigraphy and clinical questionnaire | ImportanceIsolated rapid-eye-movement sleep behavior disorder (iRBD) is in most cases a prodrome of neurodegenerative synucleinopathies, affecting 1-2 % of middle-aged and older adults, however accurate ambulatory diagnostic methods are lacking. Questionnaires lack specificity in non-clinic populations. Wrist actigraphy can detect characteristic features in individuals with RBD, however high frequency actigraphy has rarely been used.
ObjectiveTo develop a machine learning classifier using high frequency (1-second resolution) actigraphy and a short patient survey for detecting iRBD with high accuracy and precision.
DesignAnalysis of [≥]7 nights home actigraphy data and 9-item questionnaire (RBD Innsbruck inventory and 3 prodromal synucleinopathy symptoms) in a dataset including patients with iRBD, sleep clinic patients with other sleep disorders, and community controls.
SettingSingle-center study at the Stanford Sleep Center.
ParticipantsOf 108 participants, 83 completed the study, including 41 definitive iRBD cases, and 42 age- and sex-matched controls, including 21 sleep clinic patients with RBD mimics (other parasomnias, sleep apnea, periodic limb movements) or other sleep disorders, and 21 community controls.
ExposureNo intervention
Main OutcomesSensitivity, specificity, accuracy, and precision of classifiers based on actigraphy, on questionnaire data, and both.
ResultsThe actigraphy classifier achieved 95.1% (95 % CI: 88.1 - 98.7) sensitivity and 92.9% (95 % CI: 84.9 - 97.3) precision using all nights recorded, and 88.5 % sensitivity and 90.1 % precision over one night, with performance plateauing after 7 to 10 nights. The questionnaire classifier achieved 91.6 % accuracy and 92.5 % precision, exceeding performance of questionnaire alone. Concordant predictions between actigraphy and questionnaire reached specificity and precision of 100 % (95 % CI: 95.7 - 100.0) with 87.8 % sensitivity (95 % CI: 79.0 - 94.1).
Conclusions and RelevanceActigraphy detected iRBD with high accuracy in a mixed clinical and community cohort. Combined with a short clinical questionnaire, performance reached 100% precision and 87.8% sensitivity. This fully remote procedure can be used to diagnose iRBD in specialty outpatient settings. This cost-effective method has potential for large scale screening of iRBD in the general population.
Key pointsO_ST_ABSQuestionC_ST_ABSCan ambulatory actigraphy and a short prodromal synucleinopathy questionnaire increase the accuracy of RBD screening?
FindingIn a dataset of 41 iRBD cases and 42 clinic and community controls, the combination of actigraphy and a 9-item questionnaire reached specificity of 100 % (95% CI: 95.7 - 100.0) and sensitivity of 87.8 % (95% CI: 79.0 - 94.1).
MeaningCombination of ambulatory actigraphy and questionnaire can be used in both general and specialty outpatient settings for detecting individuals at high risk of having iRBD. This cost-effective, multimodal strategy has potential for large scale screening in the general population. | neurology |
10.1101/2022.04.21.22274011 | Ambulatory detection of isolated REM sleep behavior disorder combining actigraphy and clinical questionnaire | ImportanceIsolated rapid-eye-movement sleep behavior disorder (iRBD) is in most cases a prodrome of neurodegenerative synucleinopathies, affecting 1-2 % of middle-aged and older adults, however accurate ambulatory diagnostic methods are lacking. Questionnaires lack specificity in non-clinic populations. Wrist actigraphy can detect characteristic features in individuals with RBD, however high frequency actigraphy has rarely been used.
ObjectiveTo develop a machine learning classifier using high frequency (1-second resolution) actigraphy and a short patient survey for detecting iRBD with high accuracy and precision.
DesignAnalysis of [≥]7 nights home actigraphy data and 9-item questionnaire (RBD Innsbruck inventory and 3 prodromal synucleinopathy symptoms) in a dataset including patients with iRBD, sleep clinic patients with other sleep disorders, and community controls.
SettingSingle-center study at the Stanford Sleep Center.
ParticipantsOf 108 participants, 83 completed the study, including 41 definitive iRBD cases, and 42 age- and sex-matched controls, including 21 sleep clinic patients with RBD mimics (other parasomnias, sleep apnea, periodic limb movements) or other sleep disorders, and 21 community controls.
ExposureNo intervention
Main OutcomesSensitivity, specificity, accuracy, and precision of classifiers based on actigraphy, on questionnaire data, and both.
ResultsThe actigraphy classifier achieved 95.1% (95 % CI: 88.1 - 98.7) sensitivity and 92.9% (95 % CI: 84.9 - 97.3) precision using all nights recorded, and 88.5 % sensitivity and 90.1 % precision over one night, with performance plateauing after 7 to 10 nights. The questionnaire classifier achieved 91.6 % accuracy and 92.5 % precision, exceeding performance of questionnaire alone. Concordant predictions between actigraphy and questionnaire reached specificity and precision of 100 % (95 % CI: 95.7 - 100.0) with 87.8 % sensitivity (95 % CI: 79.0 - 94.1).
Conclusions and RelevanceActigraphy detected iRBD with high accuracy in a mixed clinical and community cohort. Combined with a short clinical questionnaire, performance reached 100% precision and 87.8% sensitivity. This fully remote procedure can be used to diagnose iRBD in specialty outpatient settings. This cost-effective method has potential for large scale screening of iRBD in the general population.
Key pointsO_ST_ABSQuestionC_ST_ABSCan ambulatory actigraphy and a short prodromal synucleinopathy questionnaire increase the accuracy of RBD screening?
FindingIn a dataset of 41 iRBD cases and 42 clinic and community controls, the combination of actigraphy and a 9-item questionnaire reached specificity of 100 % (95% CI: 95.7 - 100.0) and sensitivity of 87.8 % (95% CI: 79.0 - 94.1).
MeaningCombination of ambulatory actigraphy and questionnaire can be used in both general and specialty outpatient settings for detecting individuals at high risk of having iRBD. This cost-effective, multimodal strategy has potential for large scale screening in the general population. | neurology |
10.1101/2022.04.22.22274175 | Psychometric properties of the Copenhagen Burnout Inventory (CBI) in Italian physicians | BackgroundAssessing burnout in physicians is relevant as it can adversely affect both their mental and physical health by also decreasing the quality of care, especially since the onset of the COVID-19 pandemic. This study aimed at standardizing the Copenhagen Burnout Inventory (CBI), a psychometrically sound, worldwide-spread tool, in Italian physicians.
MethodsNine-hundred and fifteen Italian physicians were web-administered the CBI, Patient Health Questionnaire-8 (PHQ-8), Generalized Anxiety Disorder-7 (GAD-7) and General Self-Efficacy Scale (GSE). The present CBI is a self-report questionnaire including 18 Likert items (range=19-90) assessing Personal, Work-related and Client-related Burnout. Client-related adaptation was performed. Construct validity, factorial structure (Confirmatory Factor Analysis) and internal consistency were tested. Diagnostic accuracy was assessed simultaneously against the PHQ-8, GAD-7 and GSE.
ResultsAll CBI measures yielded optimal internal consistency (Cronbachs =.90-.96). The CBI met its original three-factor model (CFI=.94; TLI=.93; RMSEA=.09; SRMR=.04), was positively related with the PHQ-8 (r=.76) and GAD-7 (r.=73), whereas negatively with the GSE (r=-.39), and yielded optimal diagnostics (AUC=.93; sensitivity=.91 and specificity=.85 at the optimal cut-off of 69/90).
DiscussionThe CBI is a valid, reliable and normed tool to assess burnout levels in physicians, whose use is encouraged in both clinical practice and research as being short-lived, easy to use and openly accessible. | occupational and environmental health |
10.1101/2022.04.22.22274166 | Strategies to investigate and mitigate collider bias in genetic and Mendelian randomization studies of disease progression | Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors which influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomization analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and Mendelian Randomization studies using both individual and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-hunter and Dudbridges index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, whilst our second example investigates genetic associations with breast cancer mortality. | genetic and genomic medicine |
10.1101/2022.04.22.22274167 | Unhealthy Lifestyle Mediates the Adverse Influence of Childhood Traumas on Acceleration of Aging: Analysis of 110,596 UK Biobank Participants | BackgroundAccelerated aging makes adults more vulnerable to chronic diseases and death. This study evaluates the association of childhood traumas with a phenotypic aging measure that captures mortality and morbidity risk, and the role of unhealthy lifestyle in mediating these associations.
MethodsWe assembled data from 110,596 members of the UK Biobank aged 40-69 years who participated in the baseline survey (2006-2010) and online mental health questionnaire (2016). A phenotypic aging measure--Phenotypic Age Acceleration (PhenoAgeAccel) was calculated, with the higher value indicating the acceleration of aging. Body mass index, smoking status, alcohol consumption, physical activity, and diet were combined to construct an unhealthy lifestyle score (range: 0-5). Childhood traumas including physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse were assessed. General linear regression and formal mediation analysis were performed.
ResultsEach individual childhood trauma and cumulative childhood traumas were significantly associated with PhenoAgeAccel. For instance, compared with participants who did not experience childhood traumas, those who experienced four ({beta}=0.292, standard error [SE]: 0.091) or five childhood traumas had higher PhenoAgeAccel ({beta}=0.669, SE: 0.169) in fully adjusted models. The formal mediation analysis revealed that unhealthy lifestyle partially mediated the associations of childhood traumas with PhenoAgeAccel (26.1%-42.6%).
ConclusionsIn a large sample from UKB, childhood traumas were positively associated with acceleration of aging; and more importantly, unhealthy lifestyle partially mediated these associations. These findings reveal a novel pathway from childhood traumas to late-life health through lifestyle and underscore the potential of more psychological strategies beyond lifestyle interventions to promote healthy aging. | geriatric medicine |
10.1101/2022.04.21.22274122 | Examining the association between genetic risk for depression, wellbeing and schizophrenia, and proximity to greenspace | It is unclear whether associations between between greenspace and mental health reflects those with better mental health seeking out greener environments.
To examine this we 1) test associations between depression, wellbeing and schizophrenia polygenic scores (PGS) with two greenspace measures in UK Biobank (N=238,306 and 293,922), 2) estimate multilevel-models (MLM), clustering individuals by local geography and, 3) conduct one-sample Mendelian randomisation (MR) to estimate causal effects.
Depression and schizophrenia PGS were associated with lower greenspace, whilst wellbeing PGS was associated with higher greenspace. Locally-clustered MLM demonstrated attenuation for the individual wellbeing PGS association and a reversal of effect for the schizophrenia PGS association. MR revealed evidence of a causal effect of increased depression liability on decreased greenspace.
Therefore, greater liability to depression may cause selection into less green neighbourhoods. Our results also highlight how individual-level PGS associations can be biased by contextual, between-area differences in outcome. | epidemiology |
10.1101/2022.04.21.22274131 | Risks and challenges in COVID-19 infection prevention and control in a hospital setting: perspectives of healthcare workers in Thailand | In hospital settings, awareness of, and responsiveness to, COVID-19 are crucial to reducing the risk of transmission among healthcare workers (HCWs) and protecting them from infection. Healthcare professionals can offer insights into the practicalities of infection prevention and control measures and on how the protective equipment and training could best be delivered during the pandemic. This study aimed to inform the development of future recommendations to optimise compliance with appropriate use of these measures, and to improve the guidance to reduce their risk of the disease. Drawing on in-depth interviews with HCWs in a hospital in Thailand, several factors influence the use of multiple prevention measures: concerns about infection, availability of the equipment supply, barriers to work performance, and physical limitations in the hospital setting. Setting a ventilated outdoor space for screening and testing, and interaction through mobile technology, were perceived to reduce the transmission risk for staff and patients. Adequate training, clear guidelines, streamlined communications, and management support are crucial to encourage appropriate use of, and adherence to, implementation of infection prevention and control (IPC) measures among HCW. Further study should explore the perceptions and experience of health professionals in local health facilities and community-based workers during the pandemic, particularly in resource-limited settings. | infectious diseases |
10.1101/2022.04.21.22274060 | Effectiveness of the neutralizing antibody sotrovimab among high-risk patients with mild to moderate SARS-CoV-2 in Qatar | Effectiveness of sotrovimab against severe, critical, or fatal COVID-19 was investigated in Qatar using a case-control study design at a time when BA.2 Omicron subvariant dominated incidence. Adjusted odds ratio of progression to severe, critical, or fatal COVID-19, comparing those sotrovimab-treated to those untreated, was 2.67-fold higher (95% CI: 0.60-11.91). | infectious diseases |
10.1101/2022.04.22.22274170 | A protein signature associated with active tuberculosis identified by plasma profiling and network-based analysis | ObjectivesTuberculosis (TB) is a bacterial infectious disease caused by Mycobacterium tuberculosis. Annually, an estimated 10 million people are diagnosed with active TB, and approximately 1.4 million dies of the disease. If left untreated, each person with active TB will infect 10 to 15 new individuals every year. Therefore, interrupting disease transmission by accurate early detection and diagnosis, paired with appropriate treatment is of major importance. In this study, we aimed to identify biomarkers associated with the development of active TB that can then be further developed for clinical testing.
MethodsWe assessed the relative plasma concentration of 92 proteins associated with inflammation in individuals with active TB (n=19), latent TB (n=13), or healthy controls (n=10). We then constructed weighted protein co-expression networks to reveal correlations between protein expression profiles in all samples. After clustering the networks into four modules, we assessed their association with active TB.
ResultsOne module consisting of 16 proteins was highly associated with active TB. We used multiple independent transcriptomic datasets from studies investigating respiratory infections and non-TB diseases. We then identified and removed genes encoding proteins within the module that were low expressed in active TB or associated with non-TB diseases, resulting in a 12-protein plasma signature associated with active TB.
ConclusionWe identified a plasma protein signature that is highly enriched in patients with active TB but not in individuals with latent TB or healthy controls and that also had minimal cross-reactivity with common viral or bacterial lower respiratory tract infections. | infectious diseases |
10.1101/2022.04.21.22274155 | Usage and awareness of antiviral medications for COVID-19 | We surveyed people that recently tested positive for SARS-CoV-2 to assess the frequency and correlates of early treatment seeking behavior. Among high risk respondents, 66.0% were aware of treatment for COVID-19 and 36.3% had sought treatment, however only 1.7% reported use of an antiviral for SARS-CoV-2 infection. More public outreach is needed to raise awareness of the benefits of treatment for COVID-19. | infectious diseases |
10.1101/2022.04.21.22274155 | Usage and awareness of antiviral medications for COVID-19 | We surveyed people that recently tested positive for SARS-CoV-2 to assess the frequency and correlates of early treatment seeking behavior. Among high risk respondents, 66.0% were aware of treatment for COVID-19 and 36.3% had sought treatment, however only 1.7% reported use of an antiviral for SARS-CoV-2 infection. More public outreach is needed to raise awareness of the benefits of treatment for COVID-19. | infectious diseases |
10.1101/2022.04.21.22273975 | Radiologist observations of chest X-rays (CXR) predict sputum smear microscopy status in TB Portals, a real-world database of tuberculosis (TB) cases | The Tuberculosis (TB) Portals is an international program of 14 countries connecting clinical, genomic, and radiologist specialists to develop an openly available repository of deidentified TB cases with multi-modal data such as case clinical characteristics, pathogen genomics, and radiomics. This real-world data resource contains over 4000 TB cases, principally drug resistant cases, with over 4000 chest X-rays (CXR) images. The scope of curated data offers a case-focused perspective into the drivers of disease incorporating the chronological context of the presented CXR data. Here, we analyze a cohort consisting of new TB cases to understand the relationship between baseline sputum microscopy status and nearby Chest X rays images. The Timika score, a lung biomarker of disease severity, was derived for each CXR using available radiologist observations. The Timika score along with the radiologist observations were compared for predictive performance of baseline sputum microscopy status. Baseline sputum microscopy status is a useful marker of pre-treatment disease severity and infectiousness. The modeling results support that both the radiologist observations as well as Timika score are predictive of smear status and that Timika score performs similarly to the top 5 radiologist features by feature selection. Moreover, inferential statistical analysis identifies the factors having the greatest association with sputum smear positivity such as presence of radiologist observations in both lungs, presence of cavity, presence of nodule, and Timika score itself. The results are consistent with prior reports showing Timika Score utility for predicting baseline sputum smear and disease status. We report testing of Timika Score on the largest, openly available real-world dataset of TB cases that can serve as a reference to explore extant and new TB disease severity scores bridging radiological, microbiological, and clinical data. To illustrate, we visualize Timika score from images in our database with other cases characteristics demonstrating that this score captures lung biomarker status consistent with known clinical risk factors. | infectious diseases |
10.1101/2022.04.21.22273941 | A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteraemia | Outcomes for patients with severe bacterial infections are determined by the interplay between host, pathogen, and treatments. Most notably, patient age and antibiotic resistance contributes significantly to poor outcomes. While human genomics studies have provided insights into the host genetic factors impacting outcomes of Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the idea that bacterial pathoadaptation is a key driver of clinical outcomes, we develop a new genome-wide association study (GWAS) framework to identify adaptive bacterial mutations associated with clinical treatment failure and mortality in three large and independent S. aureus bacteraemia cohorts, comprising 1358 episodes. We discovered S. aureus loci with previously undescribed convergent mutations linked to both poorer infection outcomes and reduced susceptibility to vancomycin. Our research highlights the potential of vancomycin-selected mutations and vancomycin MIC as key explanatory variables to predict SAB severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability < 5%), however, GWAS allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine-learning, we were able to quantify the predictive potential of these adaptive S. aureus signatures, along with host determinants of bacteraemia outcomes. The statistical genomics framework we have developed is a powerful means to capture adaptive mutations and find bacterial factors that influence and predict severe infections. Our findings underscore the importance of systematically collected, rich clinical and microbiological data to understand bacterial mechanisms promoting treatment failure. | infectious diseases |
10.1101/2022.04.21.22274082 | COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds | Patients suffering from coronavirus disease-2019 (COVID-19) are at high risk for deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM). Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood (WB) stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, WB from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-{gamma}, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients. | infectious diseases |
10.1101/2022.04.21.22274138 | Epidemiological investigation of the COVID-19 outbreak in Vellore district in South India using Geographic Information Surveillance (GIS) | Objectives: Geographical Information Surveillance (GIS) is an advanced digital technology tool that maps location-based data and helps in epidemiological modeling. We applied GIS to analyze patterns of spread and hotspots of COVID-19 cases in Vellore district in South India. Methods: Laboratory-confirmed COVID-19 cases from the Vellore district and neighboring taluks from March 2020 to June 2021 were geo-coded and spatial maps were generated. Time trends exploring urban-rural burden with an age-sex distribution of cases and other variables were correlated with outcomes. Results: A total of 45,401 cases of COVID-19 were detected with 20730 cases during the first wave and 24671 cases during the second wave. The overall incidence rates of COVID-19 were 462.8 and 588.6 per 100,000 populations during the first and second waves respectively. The pattern of spread revealed epicenters in densely populated urban areas with radial spread sparing rural areas in the first wave. The case fatality rate was 1.89% and 1.6% during the first and second waves that increased with advancing age. Conclusions: Modern surveillance systems like GIS can accurately predict the trends and pattern of spread during future pandemics. A real-time mapping can help design risk mitigation strategies thereby preventing the spread to rural areas. | infectious diseases |
10.1101/2022.04.21.22274138 | Epidemiological investigation of the COVID-19 outbreak in Vellore district in South India using Geographic Information Surveillance (GIS) | Objectives: Geographical Information Surveillance (GIS) is an advanced digital technology tool that maps location-based data and helps in epidemiological modeling. We applied GIS to analyze patterns of spread and hotspots of COVID-19 cases in Vellore district in South India. Methods: Laboratory-confirmed COVID-19 cases from the Vellore district and neighboring taluks from March 2020 to June 2021 were geo-coded and spatial maps were generated. Time trends exploring urban-rural burden with an age-sex distribution of cases and other variables were correlated with outcomes. Results: A total of 45,401 cases of COVID-19 were detected with 20730 cases during the first wave and 24671 cases during the second wave. The overall incidence rates of COVID-19 were 462.8 and 588.6 per 100,000 populations during the first and second waves respectively. The pattern of spread revealed epicenters in densely populated urban areas with radial spread sparing rural areas in the first wave. The case fatality rate was 1.89% and 1.6% during the first and second waves that increased with advancing age. Conclusions: Modern surveillance systems like GIS can accurately predict the trends and pattern of spread during future pandemics. A real-time mapping can help design risk mitigation strategies thereby preventing the spread to rural areas. | infectious diseases |
10.1101/2022.04.22.22274160 | Regional replacement of SARS-CoV-2 variant BA.1 with BA.2 as observed through wastewater surveillance | An understanding of circulating SARS-CoV-2 variants can inform pandemic response, vaccine development, disease epidemiology, and use of monoclonal antibody treatments. We developed custom assays targeting characteristic mutations in SARS-CoV-2 variants Omicron BA.1 and BA.2 and confirmed their sensitivity and specificity in silico and in vitro. We then applied these assays to daily wastewater solids samples from eight publicly owned treatment works in the greater Bay Area of California, USA, over four months to obtain a spatially and temporally intensive data set. We documented regional replacement of BA.1 with BA.2 in agreement with, and ahead of, clinical sequencing data. This study highlights the utility of wastewater surveillance for real time tracking of SARS-CoV-2 variant circulation.
SynopsisWastewater surveillance was used to document regional emergence of SARS-CoV-2 variant Omicron BA.2 ahead of clinical surveillance.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/22274160v2_ufig1.gif" ALT="Figure 1">
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10.1101/2022.04.22.22274160 | Regional replacement of SARS-CoV-2 variant BA.1 with BA.2 as observed through wastewater surveillance | An understanding of circulating SARS-CoV-2 variants can inform pandemic response, vaccine development, disease epidemiology, and use of monoclonal antibody treatments. We developed custom assays targeting characteristic mutations in SARS-CoV-2 variants Omicron BA.1 and BA.2 and confirmed their sensitivity and specificity in silico and in vitro. We then applied these assays to daily wastewater solids samples from eight publicly owned treatment works in the greater Bay Area of California, USA, over four months to obtain a spatially and temporally intensive data set. We documented regional replacement of BA.1 with BA.2 in agreement with, and ahead of, clinical sequencing data. This study highlights the utility of wastewater surveillance for real time tracking of SARS-CoV-2 variant circulation.
SynopsisWastewater surveillance was used to document regional emergence of SARS-CoV-2 variant Omicron BA.2 ahead of clinical surveillance.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/22274160v2_ufig1.gif" ALT="Figure 1">
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10.1101/2022.04.21.22274140 | Snotwatch COVID-Toes: An ecological study of chilblains and COVID-19 diagnoses in Victoria, Australia | BackgroundThe COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions.
AimsWe conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two.
Study DesignOur study collated data from three Primary Health Networks across Victoria, Australia, from 2017-2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations.
ResultsWe found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria.
ConclusionOur study statistically demonstrates that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data and its potential application to monitoring the spread of COVID-19 infections across the state, supporting current epidemiological efforts for COVID-19 tracking. | infectious diseases |
10.1101/2022.04.22.22274195 | Monitoring One Heart to Help Two: Heart Rate Variability and Resting Heart Rate using Wearable Technology in Active Women Across the Perinatal Period | BACKGROUNDCharacterizing normal heart rate variability (HRV) and resting heart rate (RHR) in healthy women over the course of a pregnancy allows for further investigation into disease states, as pregnancy is the ideal time period for these explorations due to known decreases in cardiovascular health. To our knowledge, this is the first study to continuously monitor HRV and RHR using wearable technology in healthy pregnant women.
METHODSA total of eighteen healthy women participated in a prospective cohort study of HRV and RHR while wearing a WHOOP(R) strap prior to conception, throughout pregnancy, and into postpartum. The study lasted from March 2019 to July 2021; data were analyzed using linear mixed models with splines for non-linear trends.
RESULTSEighteen women were followed for an average of 405.8 days (SD=153). Minutes of logged daily activity decreased from 28 minutes pre-pregnancy to 14 minutes by third trimester. A steady decrease in daily HRV and increase in daily RHR were generally seen during pregnancy (HRV Est. = -0.10, P<0.0001; RHR Est. = 0.05, P<0.0001). The effect was moderated by activity minutes for both HRV and RHR. However, at 49 days prior to birth there was a reversal of these indices with a steady increase in daily HRV (Est.=0.38, P< 0.0001) and decrease in daily RHR (Est. = -0.23, P< 0.0001), regardless of activity level, that continued into the postpartum period.
CONCLUSIONSIn healthy women, there were significant changes to HRV and RHR throughout pregnancy, including a rapid improvement in cardiovascular health prior to birth that was not otherwise known. Physical activity minutes of any type moderated the known negative consequences of pregnancy on cardiovascular health. By establishing normal changes using daily data, future research can now evaluate disease states as well as physical activity interventions during pregnancy and their impact on cardiovascular fitness. | obstetrics and gynecology |
10.1101/2022.04.19.22273757 | Computational analysis of peripheral blood smears detects disease-associated cytomorphologies | Many hematological diseases are characterized by altered abundance and morphology of blood cells and their progenitors. Myelodysplastic syndromes (MDS), for example, are a type of blood cancer manifesting via a range of cytopenias and dysplastic changes of blood and bone marrow cells. While experts analyze cytomorphology to diagnose MDS, similar alterations can be observed in other conditions such as haematinic deficiency anemias, and definitive diagnosis requires complementary information such as blood counts, karyotype and molecular testing. However, recent works demonstrated that computational analysis of bone marrow slides predicts not only MDS or AML but also the presence of specific mutations. Here, we present and make available Haemorasis, a computational method that detects and characterizes white and red blood cells (WBC and RBC, respectively) in peripheral blood slides, and apply it to over 300 individuals with different conditions (SF3B1-mutant and SF3B1-wildtype MDS, megaloblastic anemia and iron deficiency anemia), where Haemorasis detects over half a million WBC and millions of RBC. We then show how these large sets of cell images can be used in diagnosis and prognosis, whilst identifying novel associations between computational morphotypes and disease. We find that hypolobulated neutrophils and large RBC are characteristic of SF3B1-mutant MDS, and, while prevalent in both iron deficiency and megaloblastic anemia, hyperlobulated neutrophils are larger in the latter. Finally, we externally validate these methods, showing they generalize to other centers and scanners. | hematology |
10.1101/2022.04.20.22274108 | Japanese Encephalitis emergence in Australia: the potential population at risk | In Australia, Japanese Encephalitis virus circulated in tropical north Queensland between 1995 and 2005. In 2022, a dramatic range expansion across the southern states resulted in 24 confirmed human cases and three deaths. We discuss the outbreak drivers and estimate the potential size of the human population at risk. | infectious diseases |
10.1101/2022.04.22.22274198 | Estimation of the Ascertainment Bias in Covid Case Detection During the Omicron Wave | Covid cases in the general population have been historically underreported due to a variety of reasons including limited access to PCR testing at the start of the pandemic, lack of nation-wide surveillance testing, and discouraged testing unless symptomatic. Concerns about underreporting have increased during the Omicron surge due to the expanded use of at-home rapid tests which are not required to be officially reported. For the state of Illinois, we have found that reported cases constituted only 50%-70% of the actual cases during the pre-Omicron waves (August 2020-December 2021). During the first Omicron (BA1) wave, this fraction dropped to 20-25% (i.e., only 1 in 4 to 1 in 5 cases are reported). During the ongoing second Omicron (BA2) surge, this fraction has further decreased to 10-15% (i.e., only 1 in 7 to 1 in 10 cases are reported). These estimates have important implications on understanding the extent of the Omicron surge at the state and national levels. | epidemiology |
10.1101/2022.04.22.22274198 | Estimation of the Ascertainment Bias in Covid Case Detection During the Omicron Wave | Covid cases in the general population have been historically underreported due to a variety of reasons including limited access to PCR testing at the start of the pandemic, lack of nation-wide surveillance testing, and discouraged testing unless symptomatic. Concerns about underreporting have increased during the Omicron surge due to the expanded use of at-home rapid tests which are not required to be officially reported. For the state of Illinois, we have found that reported cases constituted only 50%-70% of the actual cases during the pre-Omicron waves (August 2020-December 2021). During the first Omicron (BA1) wave, this fraction dropped to 20-25% (i.e., only 1 in 4 to 1 in 5 cases are reported). During the ongoing second Omicron (BA2) surge, this fraction has further decreased to 10-15% (i.e., only 1 in 7 to 1 in 10 cases are reported). These estimates have important implications on understanding the extent of the Omicron surge at the state and national levels. | epidemiology |
10.1101/2022.04.22.22274185 | Asian Lung Cancer Absolute Risk Models for lung cancer mortality based on China Kadoorie Biobank | BackgroundLung cancer is the leading cause of cancer mortality globally. Early detection through screening can markedly improve prognosis and prediction models can identify high-risk individuals for screening. However, most models have been developed in North American cohorts of smokers and much less is known about risk factors for never-smokers, which represent a growing proportion of lung cancers, particularly for Asian populations.
MethodsBased on the China Kadoorie Biobank, a population-based prospective cohort study of 512,714 adults age 30-79 recruited between 2004-2008 with up to 12 years of follow-up, we built an Asian Lung Cancer Absolute Risk Model (ALARM) for lung cancer mortality using flexible parametric survival models, separately for ever- and never-smokers. Model performance was evaluated in a 25% held-out test set using the time-dependent area under the receiver operating characteristic curve (AUC) and by comparing the model-predicted and observed risks for agreement (i.e. calibration).
ResultsPredictors assessed in the never-smoker lung cancer mortality model were age, sex, household income, lung function, history of emphysema/bronchitis, family history of cancer, personal cancer history, BMI, passive smoking, and indoor air pollution. The ever-smoker model additionally assessed smoking status (former vs. current), duration, intensity, and years since cessation. The 5-year AUC based on the hold-out test set for the never and ever-smoker models were 0.77 (95% CI: 0.73-0.81) and 0.81 (95% CI: 0.79-0.84), respectively. The maximum 5-year risk for never and ever smokers were 2.7% and 14.0%, respectively.
ConclusionsThis study is among the first to develop and test risk models specifically for Asian population, separately for never (ALARM-NS) and ever-smokers (ALARM-ES). Our models identify Asian never- and ever-smokers at high-risk of death due to lung cancer with a high degree of accuracy, and may identify those with risks exceeding common eligibility thresholds who would likely benefit from lung cancer screening. | epidemiology |
10.1101/2022.04.19.22274030 | Estimating the distribution of COVID-19-susceptible, -recovered, and -vaccinated individuals in Germany up to April 2022 | After having affected the population for two years, the COVID-19 pandemic has reached a phase where a considerable number of people in Germany have been either infected with a SARS-CoV-2 variant, vaccinated, or both. Yet the full extent to which the population has been in contact with either virus or vaccine remains elusive, particularly on a regional level, because (a) infection counts suffer from under-reporting, and (b) the overlap between the vaccinated and recovered subpopulations is unknown. Since previous infection, vaccination, or especially a combination of both reduce the risk of severe disease, a high share of individuals with SARS-CoV-2 immunity lowers the probability of severe outbreaks that could potentially overburden the public health system once again, given that emerging variants do not escape this reduction in susceptibility. Here, we estimate the share of immunologically naive individuals by age group for each of the 16 German federal states by integrating an infectious disease model based on weekly incidences of SARS-CoV-2 infections in the national surveillance system and vaccine uptake, as well as assumptions regarding under-ascertainment. We estimate a median share of 7.0% of individuals in the German population have neither been in contact with vaccine nor any variant as of March 31, 2022 (quartile range [3.6%- 9.8%]). For the adult population at higher risk of severe disease, this figure is reduced to 3.5% [1.3%-5.5%] for ages 18-59 and 4.3% [2.7%-5.8%] for ages 60 and above. However, estimates vary between German states mostly due to heterogeneous vaccine uptake. Excluding Omicron infections from the analysis, 16.1% [14.0%-17.8%] of the population in Germany, across all ages, are estimated to be immunologically naive, highlighting the large impact the Omicron wave had until the beginning of spring in 2022. | public and global health |
10.1101/2022.04.22.22274074 | Human health effects of recycling and reusing plastic packaging in the food system: a systematic review and meta-analysis of life cycle assessments. | Circular strategies, including recycling and reuse of food packaging, are critical responses to the plastic pollution crisis and could provide co-benefits and trade-offs for human health. Our meta-analysis of life cycle assessment (LCA) data quantifies possible health effects using Disability-Adjusted Life Years (DALYs) mediated by climate change, ozone, air pollution, toxicity, and water scarcity. We found strong evidence for reduced health risks with both a higher percentage of recycled content and a greater end-of-life recycling rate, resulting in around a day of healthy life saved per tonne of plastic packaging recycled. On average, reusable packaging reduced the health impacts associated with single use plastics after 30 uses, which is unlikely reflected in current consumer behaviour. Data from low- and middle-income countries, and greater use of health indicators in LCA, are urgently needed. LCA is a unique tool that could be optimised for interdisciplinary public health research on circular economies.
TeaserLife cycle assessment meta-analysis shows recycling and reusing plastic food packaging could provide human health co-benefits, and some risks. | public and global health |
10.1101/2022.04.19.22273864 | Immune and pathophysiologic profiling of antenatal COVID-19 in the GIFT cohort: A Singaporean case-control study. | BackgroundCOVID-19 has been a major public health threat for the past two years, with disproportionate effects on the elderly, immunocompromised, and pregnant women. While much has been done in delineating immune dysfunctions and pathogenesis in the former two groups, less is known about the diseases progression in expectant women and children born to them. To address this knowledge gap, we profiled the immune responses in maternal and child sera as well as breast milk in terms of antibody and cytokine expression and performed histopathological studies on placentae obtained from mothers convalescent from antenatal COVID-19.
Methods and findingsA total of 17 mother-child dyads (8 cases of antenatal COVID-19 and 9 healthy unrelated controls; 34 individuals in total) were recruited to the Gestational Immunity For Transfer (GIFT) study. Maternal and infant sera, and breast milk samples were collected over the first year of life. All samples were analyzed for IgG and IgA against whole SARS-CoV-2 spike protein, the spike receptor-binding domain (RBD), and previously reported immunodominant epitopes, with conventional ELISA approaches. Cytokine levels were quantified in maternal sera using multiplex microbead-based Luminex arrays. The placentae were examined microscopically. We found high levels of virus-specific IgG in convalescent mothers and similarly elevated titers in newborn children. Virus-specific IgG in infant circulation waned within 3-6 months of life. Virus-specific IgA levels were variable among convalescent individuals sera and breast milk. Convalescent mothers also showed a blood cytokine signature indicative of a persistent pro-inflammatory state. Four placentae presented signs of acute inflammation marked by neutrophil infiltration even though >50 days had elapsed between virus clearance and delivery. Administration of a single dose of BNT162b2 mRNA vaccine to mothers convalescent from antenatal COVID-19 increased virus-specific IgG and IgA titers in breast milk.
ConclusionsAntenatal SARS-CoV-2 infection led to high plasma titres of virus-specific antibodies in infants postnatally. However, this was not reflected in milk; milk-borne antibody levels varied widely. Additionally, placentae from COVID-19 positive mothers exhibited signs of acute inflammation with neutrophilic involvement, particularly in the subchorionic region. Virus neutralisation by plasma was not uniformly achieved, and the presence of antibodies targeting known immunodominant epitopes did not assure neutralisation. Antibody transfer ratios and the decay of transplacentally transferred virus-specific antibodies in neonatal circulation resembled that for other pathogens. Convalescent mothers showed signs of chronic inflammation marked by persistently elevated IL17RA levels in their blood. A single dose of the Pfizer BNT162b2 mRNA vaccine provided significant boosts to milk-borne virus-specific antibodies, highlighting the importance of receiving the vaccine even after natural infection with the added benefit of enhanced passive immunity. The study is registered at clinicaltrials.gov under the identifier NCT04802278. | pediatrics |
10.1101/2022.04.20.20225664 | Comparison of tests done and Tuberculosis cases detected by Xpert MTB/RIF and Xpert MTB/RIF-Ultra in Uganda | BackgroundUganda introduced Xpert(R) MTB/RIF assay into its TB diagnostic algorithm in January 2012. In July 2018, this assay was replaced with Xpert(R) MTB/RIF Ultra assay. We set out to compare the tests done and tuberculosis cases detected by Xpert(R) MTB/RIF and Xpert(R) MTB/RIF Ultra assay in Uganda.
MethodsThis was a before and after study, with the tests done and TB cases detected between Jan-June 2019 when using Xpert(R) MTB/RIF Ultra assay compared to those done between Jan-June 2018 while using Xpert(R) MTB/RIF assay. This data was analyzed using Stata version 13, it was summarized into measures of central tendency and the comparison between Xpert(R) MTB/RIF Ultra and Xpert(R) MTB/RIF was explored using a two-sided T-test which was considered significant if p <0.05.
ResultsOne hundred and twelve (112) GeneXpert sites out of a possible 239 were included in the study. 128,476 (M: 1147.11, SD: 842.88) tests were performed with Xpert(R) MTB/RIF Ultra assay, with 9693 drug-susceptible TB (DS-TB) cases detected (M: 86.54, SD: 62.12) and 144 (M: 1.28, SD: 3.42) Rifampicin Resistant TB cases (RR-TB). Whilst 107, 890 (M: 963.30, SD: 842.88) tests were performed with Xpert(R) MTB/RIF assay between, 8807 (M: 78.63, SD: 53.29) DS-TB cases were detected, and 147 (M: 1.31, SD: 2.39) RR-TB cases. The Number Need to Test (NNT) to get one TB case was 12 for Xpert(R) MTB/RIF and 13 for Xpert (R)MTB/RIF Ultra. On comparing the two assays in terms of test performance (p=0.75) and case detection both susceptible TB (p=0.31) and RR-TB (p=0.95) were not found statistically significant.
ConclusionsThis study found no significant difference in test performance and overall detection of DS-TB and RR-TB when using Xpert(R) MTB/RIF Ultra and Xpert(R) MTB/RIF assays. The health systems approach should be used to elucidate all the probable potential of Xpert(R) MTB/RIF Ultra. | public and global health |
10.1101/2022.04.19.22273976 | Do Some Super-Spreaders Spread Better? Effects of individual heterogeneity in epidemiological traits | Many high-profile outbreaks are driven by super-spreading, including HIV, MERS, Ebola, and the SARS-Cov-2 pandemic. That super-spreading is a common feature of epidemics is immutable, however, the relative importance of 2super-spreaders to the outcome of an epidemic, and the individual-level traits that lead to super-spreading, is less clear. For example, an individual may contribute disproportionately to transmission by way of an extremely high contact rate or by way of low recovery, but how these two super-spreaders differ in their effect on epidemiological dynamics is unclear. Furthermore, epidemiological traits may often covary with one another in ways that promote or inhibit super-spreading. What patterns of covariation, and between what traits, are most likely to lead to large epidemics driven by super-spreading? Using stochastic individual-based simulations of an SIR epidemiological model, we explore how variation and covariation between transmission-related traits (contact rate and infectiousness) and duration-related traits (virulence and recovery) of infected individuals affects super-spreading and peak epidemic size. We show that covariation matters when contact rate and infectiousness covary: peak epidemic size is largest when they covary positively and smallest when they covary negatively. We did not see that more super-spreading always leads to larger epidemics, rather, we show that the relationship between super-spreading and peak epidemic size is dependent on which traits are covarying. This suggests that there may not necessarily be any general relationship between the frequency of super-spreading and the size of an epidemic. | epidemiology |
10.1101/2022.04.20.22273997 | Genetic variations in EIF2AK3 are associated with neurocognitive impairment in people living with HIV | Coding and noncoding single-nucleotide variants (SNVs) of EIF2AK3, which encodes an integrated stress response (ISR) kinase, may play a role in neurodegenerative disorders. We used a candidate gene approach to determine the correlation of EIF2AK3 SNVs with neurocognitive (NC) impairment (NCI), which can persist with viral suppression from antiretroviral therapy (ART) in people with HIV (PWH). This retrospective study of prospectively collected data included participants of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, after excluding participants with severe neuropsychiatric comorbidities. Genome-wide data previously obtained in the CHARTER cohort participants (n=1,047) were analyzed to interrogate the association of three noncoding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global NCI (GDS[≥]0.5). Targeted sequencing (TS) was performed in 992 participants with available genomic DNA to determine the association of three coding EIF2AK3 SNVs with GDS and NCI. Analyses included univariable and multivariable methods such as analysis of variance and regression. Multivariable models covaried demographic, disease-associated, and treatment characteristics. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4+ T cell counts, 175/{micro}L (nadir) and 428/{micro}L (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA [≤] 200 copies/mL. A minority of participants had at least one risk allele for rs6739095 (T,41.7%), rs1913671 (C,41.4%), and rs11684404 (C,39.4%). All three noncoding EIF2AK3 SNVs were associated with significantly worse GDS and more NCI (all p<0.05). By TS, fewer participants had at least one risk allele for rs1805165 (G,30.9%), rs867529 (G,30.9%), and rs13045 (A,41.2%). Homozygosity for all three coding SNVs was associated with significantly worse GDS and more NCI (all p<0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II (BDI) > 13 were independently associated with GDS and NCI (p<0.001). The other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were specifically associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but were present in multivariable analyses. Specific SNVs in EIF2AK3 may be an important component of genetic vulnerability to NC complications in PWH. Identification of host factors that predict NCI could allow for earlier interventions, including those directly modulating the ISR, to improve NC outcomes. | hiv aids |
10.1101/2022.04.19.22274029 | Transcriptome and DNA methylome analysis of peripheral blood samples reveals incomplete restoration and transposable element activation after 3-month recovery of COVID-19 | Comprehensive analyses showed that SARS-CoV-2 infection caused COVID-19 and induced strong immune responses and sometimes severe illnesses. However, cellular features of recovered patients and long-term health consequences remain largely unexplored. In this study, we collected peripheral blood samples from recovered COVID-19 patients (average age of 35.7 years old) from Hubei province, China, 3 months after discharge; and carried out RNA-seq and whole-genome bisulfite sequencing (WGBS) to identify hallmarks of recovered COVID-19 patients. Our analyses showed significant changes both in expression and DNA methylation of genes and transposable elements (TEs) in recovered COVID-19 patients. We identified 639 misregulated genes and 18516 differentially methylated regions (DMRs) in total. Genes with aberrant expression and DMRs were found to be associated with immune responses and other related biological processes, implicating prolonged overreaction of the immune system in response to SARS-CoV-2 infection. Notably, a significant amount of TEs were aberrantly activated and TE activation was positively correlated with COVID-19 severity. Moreover, differentially methylated TEs may regulate adjacent gene expression as regulatory elements. Those identified transcriptomic and epigenomic signatures define and drive the features of recovered COVID-19 patients, helping determine the risks of long COVID-19, and providing guidance for clinical intervention. | infectious diseases |
10.1101/2022.04.21.22274129 | Survival rate of positive peritoneal cytology in endometrial cancer; a systematic review and meta-analysis | BackgroundThe impact of positive peritoneal cytology on survival rate of endometrial cancer patients in different stages and histopathology is still controversial. We performed a systematic review and meta-analysis to investigate the influence of positive peritoneal cytology (PPC) on survival rate of patients with endometrial carcinoma.
MethodsA systematic literature search of PubMed, Embase, Scopus, and Cochrane databases was conducted up to November 24, 2020. The quality of included studies was evaluated by Quality in prognosis study (QUIPS) tool.
ResultsInitially, 3014 articles were found, of which 65 met the inclusion criteria for qualitative analysis and 27 studies on 75897 patients with endometrial cancer were included in the meta-analysis. PPC was associated with a lower overall survival in endometrial cancer (HR= 2.102; 95% CI:1.629-2.711; P< 0.001). The findings also identified PPC as an independent prognostic factor for both disease-free survival (HR= 3.052; 95% CI: 2.348-2967; P< 0.001) and cancer specific survival (HR= 3.461; 95% CI: 2.280-5.254; P< 0.001). In addition, we meta-analyzed the studies in 21 subgroups based on staging and histopathology of the endometrial cancer which all identified PPC as a non-prognostic factor for cancer of endometrium.
ConclusionPPC is an independent prognostic factor for endometrial cancer survival rate in all staging and histopathologic subgroups. | obstetrics and gynecology |
10.1101/2022.04.21.22273952 | Seasonal patterns of SARS-CoV-2 transmission in secondary schools: a modelling study | BackgroundThe Omicron variant has caused a new wave of SARS-CoV-2 infections worldwide. We explore crucial epidemiological parameters driving seasonal patterns of SARS-CoV-2 transmission in secondary schools and assess various infection control interventions over a 2.5-year time frame.
MethodsWe developed an agent-based model parameterised with data from secondary schools in the Netherlands. We modelled the circulation of Omicron assuming a stable introduction rate of infections and accounted for uncertainty in epidemiological parameters describing virus transmissibility, susceptibility to reinfection, vaccine immune escape, and waning of sterilising immunity. We quantified the SARS-CoV-2 health burden defined as number of symptomatic student days. We further evaluated the cost-benefit (number of prevented infected students per absent student) for reactive quarantine interventions, regular screening using antigen tests, and annual booster vaccinations.
FindingsDurability of sterilising immunity is a key parameter that governs temporal SARS-CoV-2 transmission patterns in secondary schools. Our model predicts pronounced within-school seasonal patterns with dominant autumn outbreaks and smaller winter outbreaks and a maximum prevalence of 2.9% (95% CI: 0.7%-6.6%) symptomatic students during infection peaks. Regular screening and annual booster vaccination may reduce the health burden up to 15% (95% CI: 1.5%-27.8%) and have a higher cost-benefit ratio than reactive quarantine interventions (reduction: 4.3%; 95% CI: -10.1% to 17.6%).
InterpretationImmunity waning will determine the intensity and pattern of SARS-CoV-2 transmission in secondary schools in the medium-term future. If mitigation strategies are needed, screening and annual booster vaccination have the highest cost-benefit by reducing viral transmission with little educational disruption. | epidemiology |
10.1101/2022.04.20.22270880 | Whole-Genome Sequencing Of Omicron Identified Multiple Outbreaks And Introduction Events In India During November 2021 and January 2022 | The variant of Concern(VOC), Omicron is the predominant variant circulating throughout the world of the SARS COV2 pandemic during the third wave including India. The World Health Organisation has designated this highly mutated variant as a VOC due to its high transmissibility and risk of reinfection. Whole-genome sequencing and analysis were performed for SARS-CoV2 PCR positive samples between Dec21 to Jan22. From the 133 omicron variants detected, genomic analysis was carried out by contextualizing them with 1586 complete genomes of Omicron from India obtained from GISAID.
The Omicron variant prevalence in India has increased in a log phase within 3 months in most of the metropolitan cities. The sublineage BA.1 was first observed in the country, while the BA.2 sublineage was introduced to Delhi in the mid of December 2021. The two outbreaks observed were of BA.2 variant and were observed to spread to multiple cities in a short time. The rapid spread and specific mutations in the outbreak samples of Omicron indicate that the variant is highly transmissible when compared to previous variants. The study shows the importance of genomic sequence to identify the emergence of clusters and take actions to prevent further spreading events. | epidemiology |
10.1101/2022.04.20.22273895 | Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior | Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. Here we dramatically relax GWAS stringency by orders of magnitude and apply GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks from diverse lines of evidence. From multiple GWAS summary statistics of suicide attempt, a complex psychiatric phenotype, GRIN identified additional genes that replicated across independent cohorts and retained genes that were more biologically interrelated despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways to influence suicidal behavior and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate that GRIN is a useful community resource for improving the signal to noise ratio of GWAS results. | genetic and genomic medicine |
10.1101/2022.04.20.22273895 | Digging deeper into GWAS signal using GRIN implicates additional genes contributing to suicidal behavior | Genome-wide association studies (GWAS) identify genetic variants underlying complex traits but are limited by stringent genome-wide significance thresholds. Here we dramatically relax GWAS stringency by orders of magnitude and apply GRIN (Gene set Refinement through Interacting Networks), which increases confidence in the expanded gene set by retaining genes strongly connected by biological networks from diverse lines of evidence. From multiple GWAS summary statistics of suicide attempt, a complex psychiatric phenotype, GRIN identified additional genes that replicated across independent cohorts and retained genes that were more biologically interrelated despite a relaxed significance threshold. We present a conceptual model of how these retained genes interact through neurobiological pathways to influence suicidal behavior and identify existing drugs associated with these pathways that would not have been identified under traditional GWAS thresholds. We demonstrate that GRIN is a useful community resource for improving the signal to noise ratio of GWAS results. | genetic and genomic medicine |