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10.1101/2022.04.14.22273858 | The methodologies to assess the effects of non-pharmaceutical interventions during COVID-19: a systematic review | Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around the world to control the spread of SARS-CoV-2. Their effects on health-related outcomes have been the subject of numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflecting the absence of an established methodological framework. On the one hand, variation in methodologies may be desirable to assess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. To establish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessing the effects of non-pharmaceutical interventions on health-related outcomes between January 1, 2020 and January 12, 2021 (n=248). We identified substantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach, and effect assessment. On this basis, we point to shortcomings of existing studies and make recommendations for the design of future studies. | health policy |
10.1101/2022.04.13.22273200 | Pre-procedural testing improves estimated COVID-19 prevalence and trends | BackgroundCOVID-19 positivity rates reported to the public may provide a distorted view of community trends because they tend to be inflated by high-risk groups, such as symptomatic patients and individuals with known exposures to COVID-19. This positive bias within high-risk groups has also varied over time, depending on testing capability and indications for being tested. In contrast, throughout the pandemic, routine COVID-19 screening tests for elective procedures and operations unrelated to COVID-19 risk have been administered by medical facilities to reduce transmission to medical staffing and other patients. We propose the use of these pre-procedural COVID-19 patient datasets to reduce biases in community trends and better understand local prevalence.
MethodsUsing patient data from the Maui Medical Group clinic, we analyzed 12,640 COVID-19 test results from May 1, 2020 to March 16, 2021, divided into two time periods corresponding with Mauis outbreak.
ResultsMean positivity rates were 0.1% for the pre-procedural group, 3.9% for the symptomatic group, 4.2% for the exposed group, and 2.0% for the total study population. Post-outbreak, the mean positivity rate of the pre-procedural group was significantly lower than the aggregate group (all other clinic groups combined). The positivity rates of both pre-procedural and aggregate groups increased over the study period, although the pre-procedural group showed a smaller rise in rate.
ConclusionsPre-procedural groups may produce different trends compared to high-risk groups and are sufficiently robust to detect small changes in positivity rates. Considered in conjunction with high-risk groups, pre-procedural marker groups used to monitor understudied, low-risk subsets of a community may improve our understanding of community COVID-19 prevalence and trends. | infectious diseases |
10.1101/2022.04.15.22273918 | Treatment group outcome variance difference after dropout as an indicator of missing-not-at-random bias in randomized clinical trials | Randomized controlled trials (RCTs) are considered the gold standard for assessing the causal effect of an exposure on an outcome, but are vulnerable to bias from missing data. When outcomes are missing not at random (MNAR), estimates from complete case analysis (CCA) will be biased. There is no statistical test for distinguishing between outcomes missing at random (MAR) and MNAR, and current strategies rely on comparing dropout proportions and covariate distributions, and using auxiliary information to assess the likelihood of dropout being associated with the outcome. We propose using the observed variance difference across treatment groups as a tool for assessing the risk of dropout being MNAR. In an RCT, at randomization, the distributions of all covariates should be equal in the populations randomized to the intervention and control arms. Under the assumption of homogeneous treatment effects, the variance of the outcome will also be equal in the two populations over the course of followup. We show that under MAR dropout, the observed outcome variances, conditional on the variables included in the model, are equal across groups, while MNAR dropout may result in unequal variances. Consequently, unequal observed conditional group variances are an indicator of MNAR dropout and possible bias of the estimated treatment effect. Heterogeneity of treatment effect affects the intervention group variance, and is another potential cause of observing different outcome variances. We show that, for longitudinal data, we can isolate the effect of MNAR outcome-dependent dropout by considering the variance difference at baseline in the same set of patients that are observed at final follow-up. We illustrate our method in simulation and in applications using individual-level patient data and summary data. | epidemiology |
10.1101/2022.04.17.22273947 | From menarche to menopause: the impact of reproductive factors on the metabolic profile of over 65,000 women | We explored the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits, measured using nuclear magnetic resonance (NMR), in up to 65,487 UK Biobank women using multivariable regression (MV), Mendelian randomization (MR) and a male negative control (parity only). Older age of menarche was related to a more atherogenic metabolic profile in MV and MR, which was largely attenuated when accounting for adult body mass index. In MV, higher parity related to complex changes in lipoprotein-related traits; these were not observed in male negative controls and were imprecisely estimated in MR. In MV and MR, older age at natural menopause was related to lower concentrations of inflammation markers, but inconsistent results were observed for LDL-related traits. Our findings support a role of reproductive traits on later life metabolic profile and provide insights into identifying novel markers for the prevention of adverse cardiometabolic outcomes in women. | epidemiology |
10.1101/2022.04.14.22273896 | COVID-19 vaccine effectiveness against severe disease from the Omicron BA.1 and BA.2 subvariants: surveillance results from southern Sweden, December 2021 to March 2022 | We compared vaccine effectiveness (VE) against severe COVID-19 during calendar periods from December 2021 to March 2022 when Omicron BA.1 and BA.2, respectively, were the dominating virus variants in Scania county, Sweden. We used continuous density case-control sampling matched for sex and age, and with further adjustment for differences in comorbidities and prior infection. VE remained relatively stable after the transition from BA.1 to BA.2 among people with at least three doses but decreased markedly among those with only two doses. Protection from prior infection was also lower after the transition to BA.2. These findings suggest that booster vaccination is needed to maintain sufficient protection against severe COVID-19. | epidemiology |
10.1101/2022.04.14.22273865 | Genetic risk and incident venous thromboembolism in middle-aged and older adults following 1 Covid-19 vaccination | BACKGROUNDCovid-19 vaccination has been associated with an increased risk of venous thromboembolism (VTE). However, it is unknown whether genetic predisposition to VTE is associated with an increased risk of thrombosis following vaccination.
METHODSUsing data from the UK Biobank, which contains in-depth genotyping data and linked vaccination and health outcomes information, we generated a polygenic risk score (PRS) using 299 genetic variants identified from a previous large genome-wide association study. We prospectively assessed associations between PRS and incident VTE after first and the second-dose vaccination separately. We conducted sensitivity analyses stratified by vaccine type (adenovirus- and mRNA-based) and using two historical unvaccinated cohorts. We estimated hazard ratios (HR) for PRS-VTE associations using Cox models.
RESULTSOf 359,310 individuals receiving one dose of a Covid-19 vaccine, 160,327 (44.6%) were males, and the mean age at the vaccination date was 69.05 (standard deviation [SD] 8.04) years. After 28- and 90-days follow-up, 88 and 299 individuals developed VTE respectively, equivalent to an incidence rate of 0.88 (95% confidence interval [CI] 0.70 to 1.08) and 0.92 (95% CI 0.82 to 1.04) per 100,000 person-days. The PRS was significantly associated with a higher risk of VTE (HR per 1 SD increase in PRS, 1.41 (95% CI 1.15 to 1.73) in 28 days and 1.36 (95% CI 1.22 to 1.52) in 90 days). Similar associations were found after stratification by vaccine type, in the two-dose cohort and across the historical unvaccinated cohorts.
CONCLUSIONSThe genetic determinants of post-Covid-19-vaccination VTE are similar to those seen in historical data. This suggests that, at the population level, post-vaccine VTE has similar aetiology to conventional VTE. Additionally, the observed PRS-VTE associations were equivalent for adenovirus- and mRNA-based vaccines. | epidemiology |
10.1101/2022.04.13.22273833 | Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study | BackgroundType 2 diabetes (T2D) and coronary artery disease (CAD) both have roots in disordered metabolism and known genetic determinants. The mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD.
MethodsWe performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466) using 167 and 145 genetic instruments, respectively. We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses.
ResultsUsing inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Moreover, higher T2D liability uniquely increased the odds of using metformin, whereas higher CAD liability uniquely increased the odds of using statins. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common.
ConclusionsOur results support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently protective effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood. | epidemiology |
10.1101/2022.04.18.22273971 | Genetic variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis | Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. | pathology |
10.1101/2022.04.18.22273971 | Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis | Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. | pathology |
10.1101/2022.04.14.22273867 | The Cerebellum Plays More Than One Role in Appetite Control: Evidence From Typical and Pathological Populations | BackgroundDysregulated appetite control is characteristic of anorexia nervosa (AN) and obesity (OB). Studies using a broad range of methods suggest the cerebellum plays an important role in appetite control, and it is implicated in both AN and OB with reports of aberrant grey matter volume (GMV) compared to non-clinical populations. As functions of the cerebellum are anatomically segregated, specific localization of aberrant anatomy may indicate how it affects appetite control in different states.
ObjectiveTo determine if there were consistencies in regions of cerebellar GMV changes affected in AN and OB, and across normative variation.
Methodsystematic review and meta-analysis using Ginger ALE.
ResultsTwenty publications were identified as either case-control studies (with total n=619) or regressed weight from normative data against brain volume (with total n=3,518). AN and OB analyses both showed consistently decreased GMV within the left cerebellum, but volume reduction was anterior for AN and posterior for OB, with minimal overlap. Analysis of the normative dataset identified a cluster in right posterior lobe.
DiscussionThese findings suggest that more than one area of the cerebellum is involved in control of eating behaviour and is differentially affected in normal variation and pathological conditions. Specifically, we hypothesise an association with sensorimotor and emotional learning in AN, but with executive function in OB. | psychiatry and clinical psychology |
10.1101/2022.04.15.22273917 | The Validity of the Parsley Symptom Index: an e-PROM designed for Telehealth | Background / PurposeThe Parsley Symptom Index (PSI) is a recently developed symptom assessment for adults with chronic disease in telehealth settings. The purpose of this study was to validate the PSI against the Self-Rated Health (SRH) item.
Materials and MethodsThis prospective cohort study took place from January 15, 2021 to December 15, 2021 among a sample of 10,519 adult patients at Parsley Health, a subscription based holistic medical practice. The PSI and the SRH were completed by patients via an online portal. The association between the PSI and SRH was assessed via polyserial and polychoric correlations, while weighted kappa scores provided information related to agreement between the PSI and SRH.
ResultsFrom 22,748 responses, there were moderate levels of association (polyserial r=0.51; polychoric r=0.52) and agreement (weighted {square} = 0.46) between the PSI and SRH. In total 74.2% (16865) of responses between the PSI and SRH were relatively congruent while 36.2% (8229) were literally congruent.
ConclusionsThe PSI demonstrates validity with the SRH for adults with chronic disease in a telehealth setting. | public and global health |
10.1101/2022.04.14.22273332 | Functional Magnetic Resonance Imaging of the amygdala and subregions at 3 Tesla: A scoping review protocol | BackgroundFunctional Magnetic Resonance Imaging (fMRI) is a widely accepted and utilised method of investigating neural activation within the brain. There has been increasing awareness and understanding in the field of neuropsychology over the last 10-15 years that the amygdala plays an important role in many mental health conditions. Functional connectivity (FC) of the amygdala with other parts of the brain is well-documented in the literature; however the role of the amygdala and its reported connections is still not well understood and this can be attributed, in part, to its very small size. It is challenging to achieve adequate spatial resolution to visualise amygdala activation using 3T MRI systems that are in widespread use for this type of clinical research. Optimisation of protocols for improved data accuracy and reproducibility may potentially lead to standardisation and subsequent advancements in overall image quality in this field.
MethodsThe protocol for this scoping review was developed in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and registered with the Open Science Framework (OSF). A literature search of five databases (Medline, Embase, Web of Science, Google Scholar and Scopus) will be undertaken using a refined search strategy; peer-reviewed publications identified as being relevant will then be imported into Covidence software for abstract screening and data extraction by two reviewers working independently. The quantitative findings will be tabulated to provide an overview of the current methodologies for comparison. This will be accompanied by a narrative report summarising the extracted data in relation to the stated research questions.
DiscussionThe objective of this scoping review is to identify and map the range of existing protocols used in fMRI for imaging the activation and FC patterns of the amygdala at 3 Tesla. This will be achieved by collating and presenting quantitative data relating to protocol parameter choices as well as other qualitative aspects of the data acquisition process.
RegistrationOpen Science Framework (OSF) - Registration type: OSF Pre-registration
Registration: https://osf.io/e3c28, DOI: 10.17605/OSF.IO/KW58P | radiology and imaging |
10.1101/2022.04.18.22273958 | Ukrainian refugee integration and flows analysis with an approach of Big Data: Social media insights | BackgroundThe Ukrainian refugee crisis shows a lack of reliable data about refugee flows, demographic structure, and integration. But those data are necessary for the UNHCR and governments in preparing high-quality projections for emergencies and the conditions for the integration of refugees who intend to stay in immigration societies. Although Facebook, Instagram and YouTube are social platforms with the most users, very few studies have been written about their potential for migration studies and integration.
ObjectiveThe objective was to test the usefulness of Big Data insights from social network platforms to gain first demographic insights into refugees age and gender structure, migration flows, and integration trends.
MethodsThe primary methodological concept of our approach is to monitor the so-called "digital trace" of refugees left on social networks Facebook, Instagram and YouTube and their geo-locations. We focus on users that use social network platforms in Ukrainian and Russian language. We sampled the data before and during the war outbreak, standardised the data and compared it with the first official data from UNHCR and national governments. We selected specific keywords, i.e. migration and integration-related queries, using YouTube insight tools. Using FB and Instagram, we collected our own data archive because Meta offers data only for the present day with the ability to compare this day with the average of the past 12 months. In the next step, we collected signals that indicate integration willingness.
ResultsOur approach shows that the number of Facebook and Instagram users is growing rapidly in Ukrainian neighbouring countries and Germany after the war outbreak in Ukraine. Testing performed matches the trend of immigration of Ukrainian refugees in Poland and Germany, as well in the cities and the German Bundeslander. The tested correlation between the number of Ukrainian refugees in Poland and FB and Instagram users in Ukrainian in Poland shows that the increase in frequency index is correlated with stepped-up emigration from Ukraine. R2 is 0.1324 and shows a positive correlation, and a p-value is statistically significant. The analysis of the FB group of Ukrainian in the EU shows that those groups can be a valuable source for studying integration. Ukrainians are increasingly expressing interest in learning the German language, which is a good indication of integration willingness. One of the contributions of the second used method, YouTube insights, is that it shows that by searching for video material on the YouTube platform, the intention of users to migrate, or in this case, to flee from Ukraine, can be estimated.
ConclusionThe usefulness and the main advantage of this approach are enabling first insights into integration willingness and identification of trends in the movement and intentions of refugees when there is no official data. On the one side, this method allows governments to estimate how many refugees intend to enter the labour market and integrate into the immigration society and, on the other, better respond to the recent humanitarian crisis. Despite its beneficiaries, this approach has many limitations, and there is a need for many more studies to perfect this method. | occupational and environmental health |
10.1101/2022.04.14.22270303 | The testing of the DAC algorithm for classifying Lymphoma Cell of Origin samples using HTG's targeted gene expression system | An implementation of the windows based DLBCL automatic classification (DAC) algorithm for determining cell of origin (COO) written in the R language and designed for use with the HTG EdgeSeq Reveal Software package is described. Classifications using the new implementation (DAC-R) were compared to the those using the original version (DAC-Win), the HTG DLBCL COO classifier, the HTG EdgeSeq Reveal DLBCL algorithm. Classifications made using HTG data were tested for concordance with those made using WG-DASL data for the same samples. To analyse small numbers of samples a background dataset was developed to allow for the reliable classification of individual cases. Classification accuracy was assessed using percentage of agreement of discrete classification groups and Pearson correlation of probability scores where appropriate. In the data tested it was seen that the correlation of probability scores for DAC-R and DAC-Win was 0.9985 or higher. Agreement with the HTG DLBCL COO classifier was 85.1% and agreement with the HTG EdgeSeq Reveal DLBCL algorithm was also high (Pearson correlation of GCB probabilities = 0.91). Agreement between classifications made using HTG and WG-DASL data was also high (83.7%). In summary, the R based algorithm of DAC successfully replicates the functionality of the original routine and produces comparable COO calls in data produced from the HTG Pan B-Cell Lymphoma Panel to the other methods listed. | oncology |
10.1101/2022.04.13.22273573 | Data and care integration for post-acute intensive care program of stroke patients: effectiveness assessment using a disease-matched comparator cohort | PurposeTo assess the effectiveness of an integrated care program for post-acute care of stroke patients, the return home program (RHP program), deployed in Barcelona (North-East Spain) between 2016 and 2017 in a context of health and social care information systems integration.
DesignThe health outcomes and resource use of the RHP program participants were compared with a population-based matched control group built from central healthcare records of routine care data.
FindingsThe study included 92 stroke patients attended within the RHP program and their matched-controls. Patients in the intervention group received domiciliary care service, home rehabilitation, and telecare significantly earlier than the matched-controls. Within the first two years after the stroke episode, recipients of the RHP program were less frequently institutionalized in a long-term care facility (5% vs. 15%). The use of primary care services, non-emergency transport, and telecare services were more frequent in the RHP group.
OriginalityOur analysis shows that an integrated care program can effectively promote and accelerate delivery of key domiciliary care services, reducing institutionalization of stroke patients in the mid-term. The integration of health and social care information allows not only a better coordination among professionals but also to monitor health and resource use outcomes of care delivery | health systems and quality improvement |
10.1101/2022.04.13.22273843 | Association of Covid-19 Vaccine Hesitancy with Demographics, Mental Health, and Disability | BackgroundThe world is witnessing a pandemic caused by the novel coronavirus named Covid-19 by WHO that has claimed millions of lives since its advent in December 2019. Several vaccine candidates and treatments have emerged to mitigate the effect of virus, along with came an increased confusion, mistrust on their development, emergency authorization and approval process. Increased job losses, jump in divorce rate, and the generic nature of staying home has also led to various mental health issues.
MethodsWe analyzed two publicly available datasets to better understand vaccine hesitancy. The first dataset was extracted from ICPSR Covid-19 database (https://doi.org/10.3886/E130422V1).[1].This cross-sectional survey was conducted to assess the prevalence of vaccine hesitancy in the US, India, and China. The second dataset was obtained from the United States Census Bureaus Household Pulse Survey (HPS) Phase 3.2.
For the ICPSR dataset, proportions and summary statistics are reported to give an overview of the global picture of vaccine hesitancy. The HPS dataset was analyzed using multinomial and binary logistic regression. Chi-square test of independence and exploratory data analysis supplemented provided insight into the casual factors involved in vaccine hesitancy.
ResultsO_ST_ABSICPSR Global DataC_ST_ABSFor India, 1761 participants completed the survey as of November, 2020 of which 90.2% indicated acceptance of a Covid-19 vaccine. 66.4% are parents of 18 years old or younger, and 79.0% respondent has a parent 50 years or older. Vaccine acceptance rate was 99.8% among 928 out of 1761 participants who had a child. 1392 participants either had a parent or child of which 83.4% will encourage their parents and 90.5% will encourage their children to get the covid-19 vaccine. In this Indian survey, 16.2% identified as belonging to the rural population of which 51.2% showed vaccine hesitancy. A binary logistic regression model with vaccine hesitancy as a dichotomous variable showed that rural population had an odds ratio (OR) of 3.45 (p-value<0.05). Income seems to influence vaccine hesitancy, with income level of (7501-15,000 Indian Rupees (INR)/month) having an OR of 1.41 as compared to other income groups.
In the US, 1768 individuals participated in the survey from August-November 2020. 67.3% respondents indicated the will to accept the vaccine. 1129 of them either had a parent or a child, of which 67.6% will take the vaccine; 66% will encourage their parents and 83% will encourage their children for taking the vaccination. 40.3% responded as vaccine hesitant, 31% identified as staying in rural areas, of which 52.5% are vaccine hesitant. In the binary logistic regression analysis, race, past flu shot history, rural living, income turned out to be significant. White race had OR >1 as compared to other races, low-income group (US dollar $2000-4999/month) had an OR of 1.03.
In China, there were 1727 participants, of which 1551(90.0%) indicated that they will accept a vaccine. 90.1% of them who had either a parent or child will accept vaccine, 80.4% will influence parents, and 83.4% will encourage children to get vaccination needle in the arm. 30% had vaccine hesitancy. 262 belonged to the rural population, of which 34.8% are vaccine hesitant. Income and Northern region (OR = 3.17) were significant in saying "yes" to a vaccine. High income groups were least resistant (OR=0.96) as compared to other groups.
HPS USA dataData used in this study was collected from United States Census Bureaus Household Pulse Survey (HPS) Phase 3.2 Weeks 34-39, which covers data collected from July 21, 2021, to October 11, 2021. The HPS data helped to understand the effect of several demographic and psychological, and health-related factors upon which responses were provided, thus helping to understand the social and economic effects during the COVID-19 pandemic.
ConclusionAmong the three countries, it appears based on this survey that US has the highest rate of vaccine hesitancy. may contribute towards this result gender, education, religious beliefs, disbelief in science, government which remains unexplored due to data limitation. | infectious diseases |
10.1101/2022.04.14.22273860 | Comprehensive analyses reveal the impacts of vaccination status and physiological variables in early infection on viral persistence in COVID-19 patients: a retrospective single-center cohort study | BACKGROUNDViral persistence is a crucial factor that influences the communicability of SARS-CoV-2 infection. However, the impacts of vaccination status and physiological variables on viral RNA shedding have not been adequately clarified.
METHODSIn this study, we retrospectively collected the clinical records of 377 hospitalized COVID-19 patients, which contained unvaccinated patients and patients received two doses of an inactivated vaccine or an mRNA vaccine. Firstly, we analyzed the impacts of vaccination on disease severity and viral RNA persistence. Next, to clarify the impacts of physiological variables on viral RNA shedding in COVID-19 patients, we retrieved 49 laboratory variables and analyzed their correlations with the duration of viral RNA shedding. Finally, we established a multivariate regression model to predict the duration of viral RNA shedding.
RESULTSOur results showed that both inactivated and mRNA vaccines significantly reduced the rate of moderate cases, while the vaccine related shortening of viral RNA shedding were only observed in moderate patients. Correlation analysis showed that 10 significant laboratory variables were shared by the unvaccinated mild patients and mild patients inoculated with an inactivated vaccine, but not by the mild patients inoculated with an mRNA vaccine. Moreover, we demonstrated that a multivariate regression model established based on the variables correlating with viral persistence in unvaccinated mild patients could predict the duration of viral shedding for all groups of patients.
CONCLUSIONSVaccination contributed limitedly to the clearance viral RNA in COVID-19 patients. While, laboratory variables in early infection could predict the persistence of viral RNA. | infectious diseases |
10.1101/2022.04.13.22273829 | Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralizing antibodies in vaccinated solid organ transplant recipients | The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). Although a 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, its effectiveness was still largely unknown. We analyzed 113 vaccinated SOTRs, and 30 healthy controls (HCs), some of whom had recovered from COVID, for their immune responses against the original vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant. Here, we report that 3 doses of the mRNA vaccine had only a modest effect in eliciting anti-viral responses against all viral strains in the fully vaccinated SOTRs who did not contract the virus. Only 34.0% (16/47) of this group of patients demonstrated both detectable anti-RBD IgG and neutralization activities against alpha, beta, and delta variants, and only 8.5% (4/47) of them showed additional omicron-neutralizing capacities. In contrast, 79.5% (35/44) of the vaccinated recovered-SOTRs demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. These findings illustrate a significant impact of previous infection on the development of anti-COVID immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population. | infectious diseases |
10.1101/2022.04.18.22273944 | Baseline profile of intrinsic cytokines predicting prognosis of chronic hepatitis B patients responding to HBV therapeutic vaccinations | ObjectiveTo explore relevant biomarkers in chronic HBV (CHB) infected individuals, and whether their presence can be related to the prognosis of CHB (i.e., used as a prediction tool) and used as inclusion and exclusion criteria in clinical trials.
MethodsThirty-four (34) cytokines and chemokines were analyzed in the baseline plasma of 130 chronic HBV infected patients and were matched with the clinical outcomes of these patients regarding to their responses to anti-HBV treatment by a mathematic model based on the Boolean method. A retrospective analysis was implemented to establish the prediction model, and a perspective analysis was performed to verify the prediction efficacy.
ResultsThrough analyzing 34 cytokines and chemokines in the baseline plasma of 130 chronic HBV infected patients by Boolean methods, we generated a predicting model successfully capable of screening out therapy non-responded patients. In this prediction model, six cytokines, including IL-8, IL-10, IL-17, IL-1RA, IFN-, IL-18, defined as expressed or not-expressed, contributed to 21 possibilities, every of which predicts a clinical outcome. The model was verified in a separate chronic HBV infected population database, which included 76 patients, with 100% responders and 50% who are not responded to the immunotherapy identified.
ConclusionsThe prediction model can be used to screen CHB patients as the inclusion incorporated into HBV clinical design and practice. By screening out inappropriate participants in clinical trials, therapy response rate may rise and lead to a more homogeneous responding population. For Boolean method which requires continuous iteration, more accurate prediction models will be established with more homogeneous data. This is very helpful for revealing the reason why certain CHB individuals can be functionally cured and others were not. The method may also have great potential and possible applications for other immunotherapies in the future.
Significance of this studyO_ST_ABSWhat is already known about the subject?C_ST_ABSO_LIChronic hepatitis B virus (CHB) infection can be controlled while rarely cured, or functionally cured. The exact reason why certain CHB individuals can be functionally cured and others were not, regarding to different treatment strategies, remains unclear.
C_LIO_LILack of relevant immunological biomarkers are often to blame clinical failures in immunotherapeutic treatments, particularly for the hepatitis B virus (HBV) therapeutic vaccination, since such trials use virological parameters as inclusion and exclusion criteria of patients, but seldom more relevant immunological biomarkers.
C_LI
What are the new findings?O_LIUsing patterns of cytokines, instead of single cytokines, to present CHB individuals immune status can help discovering the prognosis of their responses or not response to HBV therapeutic vaccination.
C_LIO_LIBy utilizing the model, we predicted 10 patients out of 10 who were sensitive to the anti-HBV immunotherapy and 33 out of 66 who were not, in a distinct CHB population, and verified the predicting efficacy.
C_LI
How might it impact on clinical practice in the foreseeable future?O_LIImmune status, presented by different patterns of cytokines/chemokines, might be used as an in/exclusion criteria in clinical trials to select a more appropriate treatment for CHB individuals.
C_LIO_LIBy screening out inappropriate participants in clinical trials, therapy response rate may rise and lead to a more homogeneous responding population. For Boolean method which requires continuous iteration, more accurate prediction models will be established with such more homogeneous data. This is very helpful for revealing the reason why certain CHB individuals can be responsive to the treatments and toward the functionally cured and others could not.
C_LI | infectious diseases |
10.1101/2022.04.14.22273491 | Comprehensive validation of fasting- and oral glucose tolerance test-based indices of insulin secretion against gold-standard measures | Background and aimsWith prediabetes and diabetes increasingly recognized as heterogenous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on OGTT- and fasting-measurements in comparison with gold standard methods.
Materials and methodsThe hyperglycaemic clamp extended with GLP-1 infusion and IVGTT, as well as OGTT, was performed in two well-phenotyped cohorts. The gold-standard-derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearsons and Spearmans correlation coefficients. The insulin- and C-peptide-based indices were analysed separately in different groups of glucose tolerance and the entire cohorts.
ResultsThe highest correlation coefficients were found for AUC (I0-30)/AUC (G0-30), first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycaemic clamp. AUC (I0-30)/AUC (G0-30), first-phase Stumvoll, AUC (I0-120)/AUC (G0-120) and BIGTT-AIR0-60-120 demonstrated the strongest association with incretin-stimulated insulin response.
ConclusionWe have identified glucose- and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold-standard measures and could be potentially used in future researches and clinical practice. | endocrinology |
10.1101/2022.04.13.22273731 | High-resolution characterization of recent tuberculosis transmission in Botswana using geospatial and genomic data - the Kopanyo Study | IntroductionCombining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis (Mtb) transmission in high tuberculosis burden settings.
MethodsWe performed whole genome sequencing (WGS) on Mtb DNA extracted from sputum cultures from a population-based tuberculosis study conducted in 2012-2016 in Gaborone, Botswana. We used kernel density estimation, spatial K-functions, and created spatial distributions of phylogenetic trees. WGS-based clusters of isolates [≤]5 single nucleotide polymorphisms were considered recent transmission, and large WGS-based clusters ([≥]10 members) were considered outbreaks.
ResultsWe analyzed data from 1449 participants with culture-confirmed TB. Among these, 946 (65%) participants had both molecular and geospatial data. A total of 62 belonged to five large outbreaks (10-19 participants each). Geospatial clustering was detected in two of the five large outbreaks, suggesting heterogeneous spatial patterns within the community.
ConclusionsIntegration of genomic and geospatial data identified distinct patterns of tuberculosis transmission in a high-tuberculosis burden setting. Targeted interventions in these smaller geographies may interrupt on-going transmission. | epidemiology |
10.1101/2022.04.15.22273907 | Multi-faceted analysis of COVID-19 epidemic in the Republic of Korea considering Omicron variant: Mathematical modeling-based study | BackgroundThe most recent variant of concern, Omicron (B.1.1.529), has caused numerous cases worldwide including the Republic of Korea due to its fast transmission and reduced vaccine effectiveness.
MethodsA mathematical model considering age-structure, vaccine, antiviral treatment, and influx of the Omicron variant was developed. We estimated transmission rates among age groups using maximum likelihood estimation for the age-structured model. The impact of nonpharmaceutical interventions (in community and border), quantified by a parameter in the force of infection, and vaccination were examined through a multi-faceted analysis. A theory-based endemic equilibrium study was performed to find the manageable number of cases according to Omicron-and healthcare-related factors.
ResultsBy fitting the model to the available data, the estimated values of ranged from 0.31 to 0.73, representing the intensity of nonpharmaceutical interventions such as social distancing level. If < 0.55 and 300,000 booster shots were administered daily from February 3, 2022, the number of severe cases was forecasted to exceed the severe bed capacity. Moreover, the number of daily cases is reduced as the timing of screening measures is delayed. If screening measure was intensified as early as November 24, 2021 and the number of overseas entrant cases was contained to 1 case per 10 days, simulations showed that the daily incidence by February 3, 2022 could have been reduced by 87%. Furthermore, we found that the incidence number in mid-December 2021 exceeded the theory-driven manageable number of daily cases.
ConclusionNonpharmaceutical interventions, vaccination, and antiviral therapy influence the spread of Omicron and number of severe cases in the Republic of Korea. Intensive and early screening measures during the emergence of a new variant is key in controlling the epidemic size. Using the endemic equilibrium of the model, a formula for the manageable daily cases depending on the severity rate and average length of hospital stay was derived so that the number of severe cases does not surpass the severe bed capacity. | epidemiology |
10.1101/2022.04.15.22273911 | Causal effects of maternal circulating amino acids on offspring birthweight: a Mendelian randomisation study | Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomization and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms (SNPs) robustly associated with 19 amino acids (p < 4.9 x 10-10) were used as genetic instrumental variables. Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per SD increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. Our findings strengthen evidence for key roles of maternal circulating amino acids in healthy fetal growth. | epidemiology |
10.1101/2022.04.18.22273970 | A comparative analysis of pediatric mental health-related emergency department utilization in Montreal, Canada before and during the COVID-19 pandemic | BackgroundReports on longitudinal trends in mental health-related (MHR) emergency department (ED) utilization spanning the pre- and post-pandemic periods are lacking, along with evidence comparing healthcare services utilization by sociodemographic subgroups. The aim of this study was to evaluate COVID-19-associated changes in MHR ED utilization among youth overall and by age, sex, and socioeconomic status (SES).
MethodsThis retrospective cross-sectional study analyzed MHR ED utilization before and during the COVID-19 pandemic at a large urban pediatric tertiary care hospital in Montreal, Canada. All ED visits for children (5-11 years) and adolescents (12-17 years) between April 1, 2016 and November 30, 2021 were included. The main outcome was the monthly count of MHR ED visits. Pre-pandemic and pandemic periods were compared using an interrupted time series design. The effect of seasonality (in months), age (in years), sex (male or female), and SES (low, average, high) were compared using a generalized additive model.
ResultsThere were a total of 437,147 ED visits (204,215 unique patients) during the five-year study period of which 9,748 (5.8%) were MHR visits (7,686 unique patients). We observed an increase of 69% (95% CI, +53% to +85%; p = .001) in the mean monthly count of MHR ED visits during the pandemic period, which remained significant after adjusting for seasonality (44% increase, 95% CI, +38% to +51%; p = .001). The chance of presenting for a MHR ED visit increased non-linearly with age. There were increased odds of presenting for a MHR ED visit among girls between the pre-pandemic and pandemic periods (OR 1.42, 95% CI 1.29-1.56). No difference by SES group during and before the COVID-19 pandemic was found (OR 1.01, 95% CI 0.89-1.15 [low]; OR 1.09, 95% CI 0.96-1.25 [high]).
ConclusionsOur study shows important increases in MHR ED utilization among youth, and especially among girls, during the first 20 months of the COVID-19 pandemic, highlighting the need for sustained, targeted and scalable mental health resources to support youth mental health during the current and future crises. | psychiatry and clinical psychology |
10.1101/2022.04.14.22273868 | Effectiveness of Four Vaccines in Preventing SARS-CoV-2 Infection in Kazakhstan | BACKGROUNDIn February 2021 Kazakhstan began offering COVID-19 vaccines to adults. Breakthrough SARS-CoV-2 infections raised concerns about real-world vaccine effectiveness. We aimed to evaluate effectiveness of four vaccines against SARS-CoV-2 infection.
METHODSWe conducted a retrospective cohort analysis among adults in Almaty using aggregated vaccination data and individual-level breakthrough COVID-19 cases ([≥]14 days from 2nd dose) using national surveillance data. We ran time-adjusted Cox-proportional-hazards model with sensitivity analysis accounting for varying entry into vaccinated cohort to assess vaccine effectiveness for each vaccine (measured as 1-adjusted hazard ratios) using the unvaccinated population as reference (N=565,390). We separately calculated daily cumulative hazards for COVID-19 breakthrough among vaccinated persons by age and vaccine month.
RESULTSFrom February 22 to Sept 1, 2021 in Almaty, 747,558 (57%) adults were fully vaccinated (received 2 doses) and 108,324 COVID-19 cases (11,472 breakthrough) were registered. Vaccine effectiveness against infection was 78% (sensitivity estimates: 74-82%) for QazVac, 77% (72- 81%) for Sputnik V, 71% (69-72%) for Hayat-Vax, and 69% (64-72%) for CoronaVac. Among vaccinated persons, the 90-day follow-up cumulative hazard for breakthrough infection was 2.2%. Cumulative hazard was 2.9% among people aged [≥]60 years versus 1.9% among persons aged 18-39 years (p<0.001), and 1.2% for people vaccinated in February-May versus 3.3% in June-August (p<0.001).
CONCLUSIONOur analysis demonstrates high effectiveness of COVID-19 vaccines against infection in Almaty similar to other observational studies. Higher cumulative hazard of breakthrough among people >60 years of age and during variant surges warrants targeted booster vaccination campaigns.
What is already known on this topicO_LIPlenty of data are published on effectiveness of mRNA vaccines; however, these vaccines were not widely available in many low- and middle-income countries in 2021.
C_LIO_LIThere are no real-world effectiveness studies on several vaccines available in the Central Asia region, including QazVac vaccine, an inactivated vaccine developed by Kazakhstan.
C_LIO_LIUnderstanding how these vaccines are performing outside of clinical trials is critical for the COVID-19 response and lack of published data can contribute to vaccine hesitancy.
C_LI
What this study addsO_LIOur study demonstrated that at the population-level the four vaccines against COVID-19 used in Kazakhstan were effective at preventing SARS-CoV-2 infection.
C_LIO_LIVaccination reduced the risk of infection by 76% and prevented over 100,000 cases of SARS-CoV-2 infection in Almaty, the countrys most populous city.
C_LIO_LIThis is also the first study that demonstrated high vaccine effectiveness in real-world conditions of QazVac, developed in Kazakhstan.
C_LI
How this study might affect research, practice or policyO_LIPolicy makers in Kazakhstan and the Central Asia region need data on vaccines provided in the region to update evidence-based vaccine guidelines for different populations.
C_LI | public and global health |
10.1101/2022.04.13.22273837 | How did the COVID-19 Pandemic impact self-reported cancer screening rates in 12 Midwestern states? | ObjectiveIn the early months of the COVID-19 pandemic, the U.S. healthcare system reallocated resources to emergency response and mitigation. This reallocation impacted essential healthcare services, including cancer screenings.
MethodsTo examine how the pandemic impacted cancer screenings at the population-level, this study analyzes 2018 and 2020 Behavioral Risk Factor Surveillance System (BRFSS) data to estimate the change in the proportion of eligible adults reporting a recent cancer screen (mammogram, pap smear, colon/sigmoidoscopy, blood stool test). All analyses accounted for response rates and sampling weights, and explored differences by gender and region across 12 Midwestern states.
ResultsWe found that the proportion of adult women completing a mammogram declined across all states (-0.9% to -18.1%). The change in colon/sigmoidoscopies, pap smears, and blood stool tests were mixed, ranging from a 9.7% decline in pap smears to a 7.1% increase in blood stool tests. Declines varied considerably between states and within states by gender or metro/urban/rural status.
ConclusionsThe COVID-19 pandemic led to delayed breast, cervical, and colorectal cancer detection services. Policymakers should aim to advance cancer control efforts by implementing targeted screening initiatives. | public and global health |
10.1101/2022.04.14.22273877 | Genome-wide association analysis and Mendelian randomization proteomics identify novel protein biomarkers and drug targets for primary prevention of heart failure | We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomization (MR) and colocalization analyses on human proteins to provide causal evidence for the role of druggable proteins in the genesis of HF. We identified 39 genome-wide significant HF risk variants, of which 18 are previously unreported. Using a combination of MR proteomics and genetic cis-only colocalization analyses, we identified 10 additional putatively causal genes for HF. Findings from GWAS and MR-proteomics identified seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of HF. | genetic and genomic medicine |
10.1101/2022.04.14.22273877 | Genome-wide association analysis and Mendelian randomization proteomics identify novel protein biomarkers and drug targets for primary prevention of heart failure | We conducted a large-scale meta-analysis of heart failure (HF) genome-wide association studies (GWAS) consisting of over 90,000 HF cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for HF. Using the GWAS results and blood protein quantitative loci (pQTLs), we performed Mendelian randomization (MR) and colocalization analyses on human proteins to provide causal evidence for the role of druggable proteins in the genesis of HF. We identified 39 genome-wide significant HF risk variants, of which 18 are previously unreported. Using a combination of MR proteomics and genetic cis-only colocalization analyses, we identified 10 additional putatively causal genes for HF. Findings from GWAS and MR-proteomics identified seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of HF. | genetic and genomic medicine |
10.1101/2022.04.18.22273967 | A boost with SARS-CoV-2 BNT162b2 mRNA vaccine elicits strong humoral responses independently of the interval between the first two doses | Due to the recrudescence of SARS-CoV-2 infections worldwide, mainly caused by Omicron BA.1 and BA.2 variants of concern, several jurisdictions are administering a mRNA vaccine boost. Here, we analyzed humoral responses induced after the second and third doses of mRNA vaccine in naive and previously-infected donors who received their second dose with an extended 16-week interval. We observed that the extended interval elicited robust humoral responses against VOCs, but this response was significantly diminished 4 months after the second dose. Administering a boost to these individuals brought back the humoral responses to the same levels obtained after the extended second dose. Interestingly, we observed that administering a boost to individuals that initially received a short 3-4 weeks regimen elicited humoral responses similar to those elicited in the long interval regimen. Nevertheless, humoral responses elicited by the boost in naive individuals did not reach those present in previously-infected vaccinated individuals. | infectious diseases |
10.1101/2022.04.14.22273898 | Effectiveness and waning of protection with different SARS-CoV-2 primary and booster vaccines during the Delta pandemic wave in 2021 in Hungary (HUN-VE 3 study) | BackgroundIn late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered starting from August 2021.
MethodsThe nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations on SARS-CoV-2-related infection, hospitalization and mortality during the Delta wave.
ResultsThe study population included 8,087,988 individuals aged 18-100 years at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14-120 days after primary immunization in the 16-64 and 65-100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%-95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%-75.3% and 72.9%-100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14-120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed moderate decline over time, while booster vaccines restored effectiveness up to almost 100%, except for the Sinopharm booster.
ConclusionsThe HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines. This is the first study to provide comparable effectiveness results for six different booster types during the Delta pandemic wave. | infectious diseases |
10.1101/2022.04.12.22273675 | SARS-CoV-2 evolution and immune escape in immunocompromised patients treated with exogenous antibodies | BackgroundSARS-CoV-2 mutations conferring escape from neutralizing antibodies can arise in immunocompromised patients with prolonged infection, but the conditions that facilitate immune escape are still not fully understood.
MethodsWe characterized endogenous immune responses, within-host SARS-CoV-2 evolution, and autologous neutralization of the viral variants that arose in five immunocompromised patients with prolonged infection and B cell deficiencies.
ResultsIn two patients treated with the monoclonal antibody bamlanivimab, viral resistance to autologous serum arose early and persisted for several months, accompanied by ongoing evolution in the spike protein. These patients exhibited deficiencies in both T and B cell arms, and one patient succumbed to disease. In contrast, we did not observe spike mutations in immunologically important regions in patients who did not receive exogenous antibodies or who received convalescent plasma and had intact T cell responses to SARS-CoV-2.
ConclusionsOur results underscore the potential importance of multiple factors - the absence of an effective endogenous immune response, persistent virus replication, and selective pressure such as single-agent bamlanivimab - in promoting the emergence of SARS-CoV-2 mutations associated with immune evasion. These findings highlight the need for larger clinical studies in immunocompromised populations to better understand the ramifications of different therapies. Our results also confirm that patients with B cell deficiencies can elicit effector T cells and may suggest an important role for T cells in controlling infection, which is relevant to vaccines and therapeutics. | intensive care and critical care medicine |
10.1101/2022.04.16.22273937 | Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: First systematic review and meta-analysis | Background and aimsConcerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines.
MethodsFrom inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose.
ResultsEight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms.
ConclusionTakotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered. | cardiovascular medicine |
10.1101/2022.04.16.22273937 | Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: a systematic review and meta-analysis | Background and aimsConcerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines.
MethodsFrom inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose.
ResultsEight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms.
ConclusionTakotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered. | cardiovascular medicine |
10.1101/2022.04.13.22272869 | Estimating the risk of hospitalisation and death in England's remaining unvaccinated population | The roll-out of COVID-19 vaccines in the England has generally been very good - with over 80% of over 12s having received two doses of vaccine by the start of February 2022, and 67% having received a further booster dose. Despite this, there is a small section of the population who remain unvaccinated, either due to lack of access, hesitancy or resistant to vaccination. In this report we estimate that, during 2021, there were approximately 3,500 deaths in unvaccinated people, who could otherwise have reasonably been expected to receive a vaccination. Further, we show that if all of the remaining unvaccinated population in England were to become infected (or reinfected) with the Omicron variant of COVID-19, we would expect to see approximately 11,700 further deaths and 29,600 hospitalisations. These number could fall to 5,300 and 19,600 respectively, if all but the most vaccine resistant individuals become fully vaccinated. | public and global health |
10.1101/2022.04.14.22273870 | Methadone overdoses increased 48% during the COVID-19 epidemic | BackgroundThe United States (US) is in the middle of an opioid overdose epidemic that has spanned over two decades and continues to escalate. Methadone is long-acting full opioid agonist which has been approved to treat opioid use disorder (OUD). Methadone can cause respiratory depression that may result in mortality. The restrictions on methadone availability including take-home dosing were loosened during the COVID-19 pandemic although there have been concerns about the high street value of diverted methadone. This report examined how fatal overdoses involving methadone have changed over the past two-decades including during the pandemic.
MethodsThe Center for Disease Control and Preventions Wide-ranging Online Data for Epidemiologic Research (WONDER) database, which draws data from death certificates, was used to find the unintentional methadone related overdose death rate from 1999-2020. Unintentional methadone deaths were defined using the International Statistical Classification of Diseases (ICD), 10th revision codes: X40-44 with only data which was coded for methadone (T40.3). Data from the Automation of Reports and Consolidated Orders System (ARCOS) on methadone overall use, narcotic treatment programs use, and pain management use was gathered for all states, including the District of Columbia, for 2020 and corrected for population.
ResultsThere have been dynamic changes over the past two-decades in overdoses involving methadone. Overdoses increased from 1999 (0.9/million) to 2007 (15.9) and declined until 2019 (6.5). Overdoses in 2020 (9.6) were 48.1% higher than in 2019 (t(50) = 3.05, p < .005).
The correlations between overall methadone use (r(49) = +0.75, p < 0.001), and narcotic treatment program use (r(49) = +0.77, p < 0.001) were positive, strong, and statistically significant. However, methadone use for pain treatment was not associated with overdoses (r(49) = -.08, p = .57).
ConclusionsOverdoses involving methadone significantly increased by 48.1% in 2020 relative to 2019. This mortality increase is much larger than the 5.3% elevation in calls involving methadone reported to poison control centers in the year following the March 16, 2020 loosening of methadone take-home regulations. Policy changes that were implemented following the COVID-19 pandemic involving methadone may warrant reconsideration. | toxicology |
10.1101/2022.04.18.22273968 | Coding Long COVID: Characterizing a new disease through an ICD-10 lens | Naming a newly discovered disease is always challenging; in the context of the COVID-19 pandemic and the existence of post-acute sequelae of SARS-CoV-2 infection (PASC), which includes Long COVID, it has proven especially challenging. Disease definitions and assignment of a diagnosis code are often asynchronous and iterative. The clinical definition and our understanding of the underlying mechanisms of Long COVID are still in flux. The deployment of an ICD-10-CM code for Long COVID in the US took nearly two years after patients had begun to describe their condition. Here we leverage the largest publicly available HIPAA-limited dataset about patients with COVID-19 in the US to examine the heterogeneity of adoption and use of U09.9, the ICD-10-CM code for "Post COVID-19 condition, unspecified."
Our results include a characterization of common diagnostics, treatment-oriented procedures, and medications associated with U09.9-coded patients, which give us insight into current practice patterns around Long COVID. We also established the diagnoses most commonly co-occurring with U09.9, and algorithmically clustered them into three major categories: cardiopulmonary, neurological, and metabolic. We aim to apply the patterns gleaned from this analysis to flag probable Long COVID cases occurring prior to the existence of U09.9, thus establishing a mechanism to ensure patients with earlier cases of Long-COVID are no less ascertainable for current and future research and treatment opportunities. | infectious diseases |
10.1101/2022.04.19.22273587 | The gut microbiome and early-life growth in a population with high prevalence of stunting | Stunting affects one-in-five children globally and is associated with greater infectious morbidity, mortality and neurodevelopmental deficits. Recent evidence suggests that the early-life gut microbiome affects child growth through immune, metabolic and endocrine pathways, and microbiome perturbations may contribute to undernutrition. We examined early-life fecal microbiome composition and function in 875 stool samples collected longitudinally in 335 children from 1-18 months of age in rural Zimbabwe, from a cluster-randomized trial of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF). Using whole metagenome shotgun sequencing, we examined the effect of the interventions, in addition to environmental or host factors including maternal HIV infection, on the succession of the early-life gut microbiome, and employed extreme gradient boosting machines (XGBoost) to model microbiome maturation and to predict child growth. WASH and IYCF interventions had little impact on the fecal microbiome, however children who were HIV-exposed but uninfected exhibited over-diversification and over-maturity of the early-life gut microbiome in addition to reduced abundance of Bifidobacteria species. Taxonomic microbiome features were poorly predictive of linear and ponderal growth, however functional metagenomic features, particularly B-vitamin and nucleotide biosynthesis pathways, moderately predicted both attained linear and ponderal growth and growth velocity. We find that the succession of the gut microbiome in a population at risk of stunting is unresponsive to WASH and IYCF interventions, but is strongly associated with maternal HIV infection, which may contribute to deficits in growth. New approaches targeting the gut microbiome in early childhood may complement efforts to combat child undernutrition.
One sentence summaryThe gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is comprehensively modified by maternal HIV infection and can moderately predict linear growth. | nutrition |
10.1101/2022.04.18.22273955 | Impact of OSA Treatment Success on Changes in Hypertension and Obesity: A Retrospective Cohort Study | ObjectivePediatric obstructive sleep apnea (OSA) has been shown to lead to the development of chronic cardiometabolic conditions, including obesity and cardiovascular disease. We sought to describe the impact of the success of continuous positive airway pressure (CPAP) and surgery, common treatment options for pediatric OSA, on cardiometabolic conditions.
MethodsA retrospective review of patients ([≤]18 years) diagnosed with OSA based on a polysomnogram at a tertiary care pediatric otolaryngology practice from 2015 to 2019 was conducted. Clinical data, including the systolic blood pressure (SBP) values, body mass index (BMI), overall apnea/hypopnea index (AHI) values, and CPAP compliance, were collected. Linear mixed-effects models were developed to observe the relationship between the clinical measurements of each comorbidity and OSA treatment modalities.
Results507 patients were included. BMI and SBP measures were collected for 230 and 277 patients respectively. The difference-in-difference estimate for the SBP z-score percentile after successful treatment was -5.3 {+/-} 2.0 percentile units per 100 days. The difference-in-difference estimate for SBP z-score percentile after successful CPAP treatment was -14.4 {+/-} 4.9 percentile units per 100 days while the estimate after successful surgical treatment was -4.6 {+/-} 2.3 percentile units per 100 days. No significant differences were found between clinical measures for obese patients in any treatment cohort.
ConclusionsThe success of OSA management was shown to have a positive impact on SBP in hypertensive patients and no impact on BMI in obese patients. In hypertensive patients, CPAP success tripled improvements in SBP z-score percentile compared to surgical treatment success. | otolaryngology |
10.1101/2022.04.18.22273999 | Examining the experiences of Indigenous families seeking health information for their sick or injured child: a scoping review protocol | IntroductionThe Truth and Reconciliation Commission drew attention to the inequalities and systemic harms experienced by Indigenous peoples in Canada and called on the Canadian government and healthcare professionals to close the gap related to Indigenous communities access to appropriate healthcare services. The Manitoba Metis Federation (self-governing organization representing Red River Metis) identified a need for Red River Metis families to have meaningful resources when seeking emergency care for their children. A better understanding of Metis families experiences in seeking child health information is needed to develop culturally relevant pediatric resources. To date, the literature on Indigenous families experiences seeking child health information has not been synthesized. A scoping review will map the literature on Indigenous families experiences seeking health information to care for a sick or injured child; and identify the barriers and facilitators to accessing this information.
Methods and analysisJoanna Briggs Institute methodology was used to develop the research question, What is the extent and nature of the literature available on the experiences of Indigenous families seeking health information for their sick or injured child? The search strategy, developed with a research librarian with extensive experience in Indigenous Peoples health, includes searching MEDLINE, EMBASE PsycINFO, CINAHL, and Scopus databases; grey literature, by searching the internet and consulting reference lists of key publications; examining key Indigenous research journal articles not indexed in the major biomedical databases; and snowball sampling. Two independent reviewers will screen titles and abstracts against the inclusion criteria, then screen the full texts of selected citations. Data will be extracted, collated and charted to summarize the types of studies, healthcare contexts, health information accessed, how health information was accessed, barriers and facilitators to accessing information and related measures.
Ethics and DisseminationA consultation exercise with a community advisory committee will review results and inform future research. Results will be integrated with findings from other project stages to inform the adaptation of a child health resource for Red River Metis families. | pediatrics |
10.1101/2022.04.15.22273479 | A retrospective cross-sectional analysis of community perceptions of flu and COVID-19 vaccines at Turtle Creek Primary Care Center | BackgroundInfluenza (flu) and COVID-19 vaccination rates are subpar across the US, especially in racial and/or socioeconomic minority groups who are understudied in public health literature.
ObjectiveThe objective of this study was to elucidate the attitudes of Turtle Creek patients towards flu and COVID-19 vaccines, with the goal of establishing targetable vaccine education gaps and ultimately increasing vaccine uptake in the community.
Design/PatientsThis study was conducted as a retrospective cross-sectional analysis. Authors completed 123 patient phone surveys of patients cared for at the Turtle Creek Primary Care Center inquiring about flu and COVID-19 infection status and vaccination uptake (August 26 - October 10, 2021).
Approach/Key ResultsOur data revealed a significant association between COVID-19 and flu vaccine acceptance. Additionally, we found a strong association between vaccine acceptance and age, with older patients being more likely to be vaccinated against COVID-19. Using multivariable logistic regression models, we assessed how flu and COVID-19 vaccine acceptance was affected by informational sources participants trusted most. In the COVID-19 models, those who cited "trusting medical professionals" had higher odds of vaccine acceptance while participants who cited "trusting social media" had significantly decreased odds of vaccine acceptance.
ConclusionOur study revealed significant trends for flu and COVID-19 vaccine acceptance by sociodemographic factors and trust in the medical system. Using these data, we can create future interventions to overcome vaccine hesitancy. | public and global health |
10.1101/2022.04.19.22273818 | Predictors of COVID-19 vaccine uptake: An online longitudinal study of US Veterans and non-Veterans | BackgroundTo effectively promote vaccine uptake, it is important to understand which people are most and least inclined to be vaccinated and why.
PurposeTo identify predictors of COVID-19 vaccine uptake and reasons for non-vaccination.
DesignA longitudinal English-language survey study.
SettingOnline in December-2020, January-2021, and March-2021. Participants. 930 US respondents (63% Veterans).
MeasurementsSurveys included questions about respondents behaviors, well-being, healthcare experiences, and attitudes regarding the pandemic.
ResultsThe proportion of respondents who received [≥]1-dose of a COVID-19 vaccine increased from 18% in January to 67% in March. Older age predicted vaccine uptake in January (OR=2.02[95%CI=1.14-3.78], p<.001) and March (10.92[6.76-18.05], p<.001). In January, additional predictors of vaccine uptake were higher numeracy (1.48[1.20-1.86], p<.001), COVID-19 risk perceptions (1.35[1.03-1.78], p=.029), and believing it is important that adults get the COVID-19 vaccine (1.66[1.05-2.66], p=.033). In March, additional predictors of vaccine uptake were believing it is important that adults get the COVID-19 vaccine (1.63[1.15- 2.34], p=.006), previous (January) COVID-19 vaccine intentions (1.37[1.10-1.72], p=.006), and belief in science (0.84[0.72-0.99], p=.041). Concerns about side effects and the vaccine development process were the most common reasons for non-vaccination. Unvaccinated respondents with no interest in getting a COVID-19 vaccine were younger (0.27[0.09-0.77], p=.016), held negative views about COVID-19 vaccines for adults (0.15[0.08-0.26], p<.001), had lower trust in healthcare (0.59[0.36-0.95], p=.032), and preferred to watch and wait in clinically ambiguous medical situations (0.66[0.48-0.89], p=.007).
LimitationsReliance on the accuracy and consistency of self-reported data.
ConclusionThese findings offer important insights regarding key predictors of vaccine uptake during the early stages of the COVID-19 vaccine rollout in the US, which can help guide health communications and public outreach. Evidence that attitudes and intentions towards COVID-19 vaccines are important predictors of uptake provides validation for studies which have used these measures and reinforces the need to develop effective strategies for addressing concerns about vaccine safety and development which continue to be at the forefront of vaccine hesitancy.
RegistrationThe pre-registration document associated with this manuscript is available at: https://aspredicted.org/MKS_HRZ. | public and global health |
10.1101/2022.04.14.22273888 | On the hip abduction moment required to balance on one leg: an experimental study | 1.Although the time a patient can stand on one leg is a common clinical test of balance in those prone to fall, a surprising knowledge gap is how much hip abduction muscle strength is required. This is important because hip abduction strength has been shown to be important for compensating for impairments in diabetic neuropathy, for example. As a start we tested the hypothesis that maximum hip abduction muscle endurance time at 50% effort would be longer than the time that 18 young and 17 older healthy adults can stand on one leg. First, maximum hip abduction endurance time at 50% effort as well as maximum abduction strength were measured in the gravity-free plane. Then subjects were asked to balance on their left foot for as long as they could while body segment kinematics and ground reaction data were measured. The results showed that the mean intensity of the hip abduction moment required to stand on one leg exceeded 50% of the maximum hip abduction strength for all four groups (young women and men 53% and 55%, and older women and men 94% and 72% respectively). However, unipedal stance times were not limited by hip abduction 50% effort endurance time (p = 0.9). Therefore a significant portion of the hip abduction moment required to stand on one leg must be carried by passive tissues. The underlying mechanism remains to be explained. | rehabilitation medicine and physical therapy |
10.1101/2022.04.19.22274012 | System Integrated Digital Empowerment and Rehabilitation to promote patient Activation and well-Being (SIDERA^B): Protocol for a Randomized Crossover Trial on Effectiveness and Implementation. | CONTEXTthe current increasing demand for rehabilitation among people with Non-Communicable Diseases (NCDs) requires the identification of home-based digital solutions alternative to conventional in-clinic interventions.
OBJECTIVEthis protocol proposes to test the effectiveness of an individualized telerehabilitation platform (SIDERA^B), with respect to the traditional face-to-face rehabilitation, in ensuring the continuity of care in patients with NCDs.
DESIGN, SETTING, AND SUBJECTSthis randomized, single-blind, controlled two-period crossover trial will involve about 150 outpatients with NCDs (N=40 with Chronic Heart Failure - CHF, N=60 with Chronic Obstructive Pulmonary Disease - COPD, and N=50 with Parkinsons Disease - PD) from the rehabilitation units of IRCCS Fondazione Don Carlo Gnocchi of Milan. Each participant will experience, consequently, two different types of interventions: rehabilitation with the SIDERA^B system (SIDERA^B - S), which allow for both tele-rehabilitation activities and tele-monitoring of vital parameters, and rehabilitation as usual (Usual Care - U) including a manual of rehabilitative exercises and self-monitoring of vital parameters.
INTERVENTIONSsubjects will be randomly assigned to one of the two specified sequences of interventions: U/S/U (the USU group), and S/U (the SU group). Both groups will be assessed at the baseline (T1), after the first intervention (T2), and after the second intervention (T3), with a follow-up evaluation (T4) scheduled only for the USU group.
MAIN OUTCOME MEASURESa multifaceted evaluation including quality of life and clinical/functional measures will be conducted at each time-point of assessment. The primary outcome measures will be 1) change in activation of patients measured by the Patient Activation Measure scale, and 2) change in subjects level of activity and participation measured by the WHO Disability Assessment Schedule 2.0.
CONCLUSIONSIDERA^B could represent a promising innovative digital solution able to support the ongoing migration of rehabilitation care from the clinic to the patients home, for the optimal long-term management of NCDs.
Trial registrationThe SIDERA^B trial was registered in the clinicaltrials.gov database (identifier NCT04041193) on August 1, 2019. | rehabilitation medicine and physical therapy |
10.1101/2022.04.18.22272912 | Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment | BackgroundThe last few years have seen major advances in blood biomarkers for Alzheimers Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias.
MethodsWe evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. 366 plasma samples from the Massachusetts Alzheimers Disease Research Centers longitudinal cohort study were examined to differentiate definite AD, other neurodegenerative diseases (OND), and cognitively normal (CN) individuals. A subset of samples were selected to have longitudinal follow up to also determine the utility of this plasma biomarker panel in predicting 4-year risk for cognitive decline in individuals with different levels of cognitive impairment.
ResultspTau181, tTau and GFAP were higher in AD compared to CN and OND, while NfL was elevated in AD and further increased in OND. pTau181 performed the best (AD vs CN: AUC=0.88, 2-fold increase; AD vs OND: AUC=0.78, 1.5-fold increase) but tTau also showed excellent discrimination (AD vs CN: AUC=0.79, 1.5-fold increase; AD vs OND: AUC=0.72, 1.3-fold increase). Participants with MCI who progressed to AD dementia had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors with the best discrimination for pTau181 (AUC=0.82, 1.7-fold increase) and GFAP (AUC=0.81, 1.6-fold increase).
ConclusionsThese new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP detect CNS disease with high specificity and accuracy. Moreover, the absolute baseline plasma levels of pTau and GFAP reflect clinical disease aggressiveness over the next 4 years, providing diagnostic and prognostic information that may have utility in both clinical and clinical trial populations.
Classification of EvidenceThis study provides Class II evidence that plasma levels of pTau181, tTau, NfL, and GFAP are associated with AD and that pTau181 and GFAP are associated with progression from MCI to AD dementia. | neurology |
10.1101/2022.04.18.22274003 | Genetically proxied PCSK9 inhibition provides indication of lower prostate cancer risk: a Mendelian randomization study | BackgroundProstate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomization (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c lowering drug targets on risk of PrCa.
Methods and FindingsSingle-nucleotide polymorphisms (SNPs) in and around HMGCR, NPC1L1 and PCSK9 genes associated with LDL-c (P<5x10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N=173,082) were used to proxy the therapeutic inhibition of these targets. Association estimates for the risk of total, advanced and early-onset PrCa were obtained from the PRACTICAL consortium. Replication was performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N=201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI) and testosterone).
Applying MR using the inverse-variance weighted approach accounting for genetic correlations between instruments provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR)=0.84, 95% confidence interval (CI)=0.74 to 0.96, P=7.86x10-3) and early-onset PrCa OR=0.70, 95% CI=0.52 to 0.95, P=0.021. Analyses using male-stratified instruments provided consistent results. In contrast, there was little evidence of an association of genetically proxied HMGCR (OR=0.83, 95% CI=0.67 to 1.03, P=0.093) or NPC1L1 (OR=1.27, 95% CI=0.87 to 1.87, P=0.218) inhibition on PrCa risk.
Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR=0.90, 95% CI=0.86 to 0.95, P=5.50x10-5) and circulating plasma levels of PCSK9 (OR=0.93 per SD reduction in PCSK9, 95% CI=0.87 to 0.997, P=0.04) on PrCa risk. Colocalization using eCAVIAR identified evidence (colocalization posterior probability=0.103) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk. Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta= -0.07, 95% CI= -0.10 to -0.03, P=1.44x10-4), but not BMI or testosterone, indicating a putative mediatory role of Lp(a).
ConclusionsOur study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a). | oncology |
10.1101/2022.04.15.22273871 | More efficient and inclusive time-to-event trials with covariate adjustment: a simulation study | Adjustment for prognostic covariates increases the statistical power of randomized trials. The factors influencing increase of power are well-known for trials with continuous outcomes. Here, we study which factors influence power and sample size requirements in time-to-event trials. We consider both parametric simulations and simulations derived from the TCGA cohort of hepatocellular carcinoma (HCC) patients to assess how sample size requirements are reduced with covariate adjustment. Simulations demonstrate that the benefit of covariate adjustment increases with the prognostic performance of the adjustment covariate (C-index) and with the cumulative incidence of the event in the trial. For a covariate that has an intermediate prognostic performance (C-index=0.65), the reduction of sample size varies from 1.7% when cumulative incidence is of 10% to 26.5% when cumulative incidence is of 90%. Broadening eligibility criteria usually reduces statistical power while our simulations show that it can be maintained with adequate covariate adjustment. In a simulation of HCC trials, we find that the number of patients screened for eligibility can be divided by 2.7 when broadening eligibility criteria. Last, we find that the Cox-Snell [Formula] is a good approximation of the reduction in sample size requirements provided by covariate adjustment. This metric can be used in the design of time-to-event trials to determine sample size. Overall, more systematic adjustment for prognostic covariates leads to more efficient and inclusive clinical trials especially when cumulative incidence is large as in metastatic and advanced cancers.
Key messagesO_LICovariate adjustment is a statistical technique that leverages prognostic scores within the statistical analysis of a trial. We study its benefits for time-to-event trials.
C_LIO_LIPower gain achieved with covariate adjustment is determined by the prognostic performance of the covariate and by the cumulative incidence of events at the end of the follow-up period.
C_LIO_LITrials in indications with large cumulative incidence such as metastatic cancers can benefit from covariate adjustment to improve their statistical power.
C_LIO_LICovariate adjustment maintains statistical power in trials when eligibility criteria are broadened.
C_LI | oncology |
10.1101/2022.04.18.22273978 | Effectiveness of BBIBP-CorV, BNT162b2 and mRNA-1273 vaccines against hospitalisations among children and adolescents during the Omicron outbreak in Argentina | BackgroundAlthough paediatric clinical presentations of COVID-19 are usually less severe than in adults, serious illness and death have occurred. Many countries started the vaccination rollout of children in 2021; still, information about effectiveness in the real-world setting is scarce. The aim of our study was to evaluate vaccine effectiveness (VE) against COVID-19-associated-hospitalisations in the 3-17-year population during the Omicron outbreak.
MethodsWe conducted a retrospective cohort study including individuals aged 3-17 registered in the online vaccination system of the Buenos Aires Province, Argentina. mRNA-1273 and BNT162b2 were administered to 12-17-year subjects; and BBIBP-CorV to 3-11- year subjects. Vaccinated group had received a two-dose scheme by 12/1/2021. Unvaccinated group did not receive any COVID-19 vaccine between 12/14/2021-3/9/2022, which was the entire monitoring period. Vaccine effectiveness (VE) against COVID-19-associated hospitalisations was calculated as (1-OR) x100.
FindingsBy 12/1/2021, 1,536,435 individuals aged 3-17 who had received zero or two doses of SARS-CoV-2 vaccines were included in this study. Of the latter, 1,440,389 were vaccinated and 96,046 not vaccinated. VE were 78{middle dot}0% [68{middle dot}7-84{middle dot}2], 76{middle dot}4%[62{middle dot}9-84{middle dot}5] and 80{middle dot}0%[64{middle dot}3-88{middle dot}0] for the entire cohort, 3-11 subgroup and 12-17 subgroup, respectively. VE for the entire population was 82{middle dot}7% during the period of Delta and Omicron overlapping circulation and decreased to 67{middle dot}7% when Omicron was the only variant present.
InterpretationThis report provides evidence of high vaccine protection against associated-hospitalisations in the paediatric population during the Omicron outbreak but suggests a decrease of protection when Omicron became predominant. Application of a booster dose in children aged 3-11 warrants further consideration.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThere is limited evidence on the effectiveness of vaccines in the pediatric population, particularly in children aged 3-11 years after the SARS-CoV-2 B.1.1.529 (Omicron) variants emergence.
We searched preprint and peer-reviewed published articles in PubMed, medRxiv, and SSRN for observational studies, with no language restrictions, using the term "COVID-19 OR SARS-CoV-2" AND "vaccine effectiveness" OR "vaccine impact" AND "children" OR "pediatric" AND "Omicron" published between December 1, 2021, and April 1, 2022. We found 4 studies that included subjects in the 3-17-year population who received a two-dose-scheme of any of the available vaccines-according to each countrys authorisation. Three studies were from the US; two were test-negative-case-control studies and one was a retrospective non-peer-reviewed cohort study. The reported vaccine effectiveness (VE) for 2-doses of BNT162b2-mRNA (Pfizer-BioNTech) in preventing hospitalisations during Omicron predominance was 48-78%; and it was 40-92% for 5-11 and 12-17-year subgroups, respectively. The fourth was a cohort study still in preprint form conducted in Chile and utilized an inactivated vaccine, CoronaVac (SinoVac), widely used in Latin-America. VE for two doses of CoronaVac in the 3-5-year subgroup against hospitalisations was 64% and 69% against ICU admissions.
Added value of this studyUp to date, there are no published studies about the effectiveness of the BBIBP-CorV vaccine against hospitalisation in the pediatric population. Additionally, there are no real-world studies from low and middle-income countries about VE in the 12-17 aged population during the Omicron outbreak.
This study shows that VE after 14 days or more from two-dose-scheme was 78{middle dot}0% [68{middle dot}7-84{middle dot}2], 76{middle dot}4% [62{middle dot}9-84{middle dot}5] and 80{middle dot}0% [64{middle dot}3-88{middle dot}0] for the 3-17-year entire group, and for 3-11-year (BBIBP-CorV) and 12-17-year (mRNA vaccines) subgroups, respectively. VE for the 3-17-year entire group was 82{middle dot}7% during the period of Delta and Omicron overlapping circulation and decreased to 67{middle dot}7% when Omicron was the only variant present. These effects were consistent across all subgroups.
Implications of all the available evidenceOur results provide evidence of high vaccine protection against COVID-19 associated-hospitalisations in the pediatric population during the Omicron outbreak, but suggest a decrease of protection when Omicron became predominant. Application of a booster dose in children aged 3-11 warrants further consideration. | infectious diseases |
10.1101/2022.04.18.22271936 | Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial | ImportanceThe performance of immunoassays for determining past SARS-CoV-2 infection, which were developed in unvaccinated individuals, has not been assessed in vaccinated individuals.
ObjectiveTo evaluate anti-nucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 vaccine efficacy trial participants after SARS-CoV-2 infection during the trials blinded phase.
DesignNested analysis in a Phase 3 randomized, placebo-controlled vaccine efficacy trial. Nasopharyngeal swabs for SARS-CoV-2 PCR testing were taken from all participants on Day 1 and Day 29 (vaccination days), and during symptom-prompted illness visits. Serum samples from Days 1, 29, 57, and the Participant Decision Visit (PDV, when participants were informed of treatment assignment, median day 149) were tested for anti-N Abs.
SettingMulticenter, randomized, double-blind, placebo-controlled trial at 99 sites in the US.
ParticipantsTrial participants were [≥] 18 years old with no known history of SARS-CoV-2 infection and at appreciable risk of SARS-CoV-2 infection and/or high risk of severe Covid-19. Nested sub-study consists of participants with SARS-CoV-2 infection during the blinded phase of the trial.
InterventionTwo mRNA-1273 (Moderna) or Placebo injections, 28 days apart.
Main Outcome and MeasureDetection of serum anti-N Abs by the Elecsys (Roche) immunoassay in samples taken at the PDV from participants with SARS-CoV-2 infection during the blinded phase. The hypothesis tested was that mRNA-1273 recipients have different anti-N Ab seroconversion and/or seroreversion profiles after SARS-CoV-2 infection, compared to placebo recipients. The hypothesis was formed during data collection; all main analyses were pre-specified before being conducted.
ResultsWe analyzed data from 1,789 participants (1,298 placebo recipients and 491 vaccine recipients) with SARS-CoV-2 infection during the blinded phase (through March 2021). Among participants with PCR-confirmed Covid-19 illness, seroconversion to anti-N Abs at a median follow up of 53 days post diagnosis occurred in 21/52 (40%) of the mRNA-1273 vaccine recipients vs. 605/648 (93%) of the placebo recipients (p < 0.001). Higher SARS-CoV-2 viral copies at diagnosis was associated with a higher likelihood of anti-N Ab seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28).
Conclusions and RelevanceAs a marker of recent infection, anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected. Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing
Trial RegistrationClinicalTrials.gov NCT04470427
Key PointsO_ST_ABSQuestionC_ST_ABSDoes prior mRNA-1273 vaccination influence anti-nucleocapsid antibody seroconversion and/or seroreversion after SARS-CoV-2 infection?
FindingsAmong participants in the mRNA-1273 vaccine efficacy trial with PCR-confirmed Covid-19, anti-nucleocapsid antibody seroconversion at the time of study unblinding (median 53 days post diagnosis and 149 days post enrollment) occurred in 40% of the mRNA-1273 vaccine recipients vs. 93% of the placebo recipients, a significant difference. Higher SARS-CoV-2 viral copy number upon diagnosis was associated with a greater chance of anti-nucleocapsid antibody seropositivity (odds ratio 1.90 per 1-log increase; 95% confidence interval 1.59, 2.28). All infections analyzed occurred prior to the circulation of delta and omicron viral variants.
MeaningConclusions about the prevalence and incidence of SARS-CoV-2 infection in vaccinated persons based on anti-nucleocapsid antibody assays need to be weighed in the context of these results. | infectious diseases |
10.1101/2022.04.18.22273989 | Validation of Reduced S-gene Target Performance and Failure for Rapid Surveillance of SARS-CoV-2 Variants | SARS-CoV-2, the virus that causes COVID-19, has many variants capable of rapid transmission causing serious illness. Timely surveillance of new variants is essential for an effective public health response. Ensuring availability and access to diagnostic and molecular testing is key to this type of surveillance. This study utilized reverse transcription polymerase chain reaction (RT-PCR) and whole genome sequencing results from COVID-19-positive patient samples obtained through a collaboration between Aegis Sciences Corporation and Walgreens Pharmacy that has conducted more than 8.5 million COVID-19 tests at [~]5,200 locations across the United States and Puerto Rico.
Viral evolution of SARS-CoV-2 can lead to mutations in the S-gene that cause reduced or failed S-gene amplification in diagnostic PCR tests. These anomalies, labeled reduced S-gene target performance (rSGTP) and S-gene target failure (SGTF), are characteristic of Alpha and Omicron (B.1.1.529, BA.1, and BA.1.1) lineages. This observation has been validated by whole genome sequencing and can provide presumptive lineage data following completion of diagnostic PCR testing in 24-48 hours from collection. Active surveillance of trends in PCR and sequencing results is key to the identification of changes in viral transmission and emerging variants. This study shows that rSGTP and SGTF can be utilized for near real-time tracking and surveillance of SARS-CoV-2 variants. | infectious diseases |
10.1101/2022.04.18.22273989 | Validation of Reduced S-gene Target Performance and Failure for Rapid Surveillance of SARS-CoV-2 Variants | SARS-CoV-2, the virus that causes COVID-19, has many variants capable of rapid transmission causing serious illness. Timely surveillance of new variants is essential for an effective public health response. Ensuring availability and access to diagnostic and molecular testing is key to this type of surveillance. This study utilized reverse transcription polymerase chain reaction (RT-PCR) and whole genome sequencing results from COVID-19-positive patient samples obtained through a collaboration between Aegis Sciences Corporation and Walgreens Pharmacy that has conducted more than 8.5 million COVID-19 tests at [~]5,200 locations across the United States and Puerto Rico.
Viral evolution of SARS-CoV-2 can lead to mutations in the S-gene that cause reduced or failed S-gene amplification in diagnostic PCR tests. These anomalies, labeled reduced S-gene target performance (rSGTP) and S-gene target failure (SGTF), are characteristic of Alpha and Omicron (B.1.1.529, BA.1, and BA.1.1) lineages. This observation has been validated by whole genome sequencing and can provide presumptive lineage data following completion of diagnostic PCR testing in 24-48 hours from collection. Active surveillance of trends in PCR and sequencing results is key to the identification of changes in viral transmission and emerging variants. This study shows that rSGTP and SGTF can be utilized for near real-time tracking and surveillance of SARS-CoV-2 variants. | infectious diseases |
10.1101/2022.04.18.22273950 | Quantifying spatial heterogeneity of malaria in the endemic Papua region of Indonesia: analysis of epidemiological surveillance data | BackgroundAs control efforts progress towards elimination, malaria is likely to become more spatially concentrated in few local areas. The purpose of this study was to quantify and characterise spatial heterogeneity in malaria transmission-intensity across highly endemic Indonesian Papua.
MethodsWe analysed individual-level malaria surveillance data for nearly half a million cases (2019-2020) reported in the Papua and West Papua provinces and adapted the Gini index approach to quantify spatial heterogeneity at the district and health-unit levels. We showed malaria incidence trends and the spatial and temporal distribution of sociodemographic characteristics and aetiological parasites among cases.
FindingsWhile Papua province accounted for the majority of malaria cases reported in the region and had seen a rise in transmission since 2015, West Papua province had maintained a comparatively low incidence. We observed that Gini index estimates were high, particularly when the lower spatial scale of health units was evaluated. The Gini index appears to be inversely associated to annual parasite-incidence, as well as the proportions of vivax malaria, male sex, and adults.
InterpretationThis study suggests that areas with varying levels of transmission-intensities exhibited distinct characteristics. Malaria was distributed in a markedly disproportionate manner throughout the region, emphasising the need for spatially targeted interventions. Periodic quantification and characterisation of risk heterogeneity at various spatial levels using routine malaria surveillance data may aid in tracking progress towards elimination and guiding evidence-informed prioritisation of resource allocation.
FundingStrengthening Preparedness in the Asia-Pacific Region through Knowledge (SPARK) project.
Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to and including November 19, 2021, for relevant articles on the spatial distribution of malaria in the Papua region of Indonesia, using the terms ("malaria") AND ("distribution" OR "variation" OR "heterogeneity" OR "cluster" OR "aggregation") AND ("Papua") AND ("Indonesia"). Despite the regions mostly stable transmission areas, there has been considerable variation in transmission intensity across the region. According to community surveys conducted up to 2010, estimates of parasite prevalence of Plasmodium falciparum and Plasmodium vivax were highly variable, ranging from 0% to at least 40% and from 0% to at least 7%, respectively, across the region. Similarly, when the Papuan subset of the 2007 National Basic Health Research data was used, the degree of spatial heterogeneity in malaria risk among Papuan districts remained apparent even after sociodemographic were adjusted. Current evidence that is more representative of the current situation, including an easily interpretable and comparable measure of spatial heterogeneity across space and time, is limited.
Added value of this studyOur analysis of large-scale and routinely collected malaria surveillance data from January 2019 to December 2020 revealed significant spatial heterogeneity across the Papua region, as measured by the Gini index. Complementing conventional approaches using geospatial maps and risk tables, the Gini index can be used to provide a single, and sensitive numerical indicator summarising the degree of transmission heterogeneity at a specified spatial level of interest. Along with the previously recognised high spatial heterogeneity among districts, this study revealed a greater degree of intra-district heterogeneity at the health-unit level. That is, within the districts, there were also few health centres and hospitals with a disproportionately higher malaria burden. We observed distinct characteristics of individuals who contracted malaria in districts with varying levels of incidence. The higher transmission magnitude was associated with a lower Gini index, as well as with lower proportions of vivax malaria, male sex, and adults among the cases.
Implications of all the available evidenceThis study provides contemporary empirical evidence for the spatial heterogeneity of malaria distribution across the Papua region of Indonesia, particularly at the lower spatial resolution of health units. Evaluating spatial heterogeneity at a lower spatial scale is likely essential to refine and update local malaria control strategic planning. The combination of comprehensive, routine malaria surveillance data and the Gini index may enable policymakers to assess the magnitude and characteristics of spatial heterogeneity with increased frequency, interpretability, and comparability, allowing for the rapid identification of transmission foci and the deployment of public health measures. Effective control of parasite reservoirs associated with intense transmission may further shrink the risk of infection in adjacent areas with a lower degree of malaria exposure. | infectious diseases |
10.1101/2022.04.19.22274005 | Similar viral loads in Omicron infections regardless of vaccination status | BackgroundAlthough SARS-CoV-2 booster vaccinations are underway, breakthrough infections with Omicron variants are occurring. This study analyzed associations between Omicron sublineage (BA.1.1 and BA.2) viral load and vaccination history.
MethodsViral loads in nasopharyngeal swabs were evaluated by quantitative real-time PCR, and the virus strain was evaluated by whole-genome analysis or TaqMan assay.
ResultsA total of 611 patients positive for an Omicron SARS-CoV-2 variant were included; 199 were unvaccinated, 370 had received two vaccine doses, and 42 had received three doses. Similar viral loads and Ct values of BA.1.1 and BA.2 were detected regardless of vaccination history. No correlations between age and BA.1.1 and BA.2 viral load were observed.
ConclusionOmicron-infected patients who had received a third vaccine dose had viral loads similar to patients with two doses or who were unvaccinated. | infectious diseases |
10.1101/2022.04.14.22273819 | An optimized flow cytometry protocol for simultaneous detection of T cell activation induced markers and intracellular cytokines: application to SARS-Cov-2 vaccinated individuals | Antigen (ag)-specific T cell analysis is an important step for investigation of cellular immunity in many settings, such as infectious diseases, cancer and vaccines. Multiparameter flow cytometry has advantages in studying both the rarity and heterogeneity of these cells. In the cellular immunologists toolbox, the expression of activation-induced markers (AIM) following antigen exposure has made possible the study and sorting of ag-specific T cells without using human leukocyte antigen (HLA)-multimers. In parallel, assessing the cytokine profile of responding T cells would support a more comprehensive description of the ongoing immune response. Here, a method and flow cytometry panel were optimized to combine the detection of activated CD4+ and CD8+ T cells in a TCR-dependent manner with the evaluation of cytokine production by intracellular staining, without affecting the positivity of activation markers. In particular, the expression of CD134 (OX40) and CD69 have been tested in conjunction with intracellular (ic) CD137 (4-1BB) to detect SARS-Cov-2 Spike protein-specific activated T cells. In our setting, assessing CD134 provided minimal contribution to detect the pool of AIM+ T cells, whereas a key role was described for ic-CD69, which was co-expressed with ic-CD137 in both CD4+ and CD8+ lymphocytes. Moreover, the analysis of TCR-triggered cytokine-producing T cells (IFN{gamma}, TNF and IL-2 were assessed) further confirmed the capacity of ic-CD69 to identify functionally responsive antigen-specific T cells, which were often largely negative or poorly positive for CD134 expression. In parallel, the use of CD45RA, CCR7 and CXCR5 allowed us to describe the T cell matuarion curve and detect T helper follicular CD4+ cells, including the antigen-specific activated subsets.
In conclusion, we optimized a method and flow cytometry panel combining assessment of activation induced markers and intracellular cytokines that will be useful for measuring TCR stimulation-dependent activation of CD4+ and CD8+ T cells. | allergy and immunology |
10.1101/2022.04.14.22273819 | An optimized flow cytometry protocol for simultaneous detection of T cell activation induced markers and intracellular cytokines: application to SARS-Cov-2 vaccinated individuals | Antigen (ag)-specific T cell analysis is an important step for investigation of cellular immunity in many settings, such as infectious diseases, cancer and vaccines. Multiparameter flow cytometry has advantages in studying both the rarity and heterogeneity of these cells. In the cellular immunologists toolbox, the expression of activation-induced markers (AIM) following antigen exposure has made possible the study and sorting of ag-specific T cells without using human leukocyte antigen (HLA)-multimers. In parallel, assessing the cytokine profile of responding T cells would support a more comprehensive description of the ongoing immune response. Here, a method and flow cytometry panel were optimized to combine the detection of activated CD4+ and CD8+ T cells in a TCR-dependent manner with the evaluation of cytokine production by intracellular staining, without affecting the positivity of activation markers. In particular, the expression of CD134 (OX40) and CD69 have been tested in conjunction with intracellular (ic) CD137 (4-1BB) to detect SARS-Cov-2 Spike protein-specific activated T cells. In our setting, assessing CD134 provided minimal contribution to detect the pool of AIM+ T cells, whereas a key role was described for ic-CD69, which was co-expressed with ic-CD137 in both CD4+ and CD8+ lymphocytes. Moreover, the analysis of TCR-triggered cytokine-producing T cells (IFN{gamma}, TNF and IL-2 were assessed) further confirmed the capacity of ic-CD69 to identify functionally responsive antigen-specific T cells, which were often largely negative or poorly positive for CD134 expression. In parallel, the use of CD45RA, CCR7 and CXCR5 allowed us to describe the T cell matuarion curve and detect T helper follicular CD4+ cells, including the antigen-specific activated subsets.
In conclusion, we optimized a method and flow cytometry panel combining assessment of activation induced markers and intracellular cytokines that will be useful for measuring TCR stimulation-dependent activation of CD4+ and CD8+ T cells. | allergy and immunology |
10.1101/2022.04.18.22274002 | Estimating spatial disease rates from health statistics without geographic identifiers | Effective analysis to support decision-making in public health requires adequate data that can be linked to the sociodemographic characteristics and distribution of communities that would be recipients of health programs. Although official statistics are an important source of data to support decisions on public health strategies, health statistics are of limited use if they do not include categorisations related to the spatial distribution of the population. This study introduces a method to use the frequency of disease reported by health care providers (HCP) to calculate disease rates in geographical areas in urban settings. Specifically, this study uses statistics on acute respiratory infections (ARI) to calculate the rate of these diseases at the census district level in Cucuta, a major city in Colombia. A Geographic Information System was used to establish the geographical area of influence (spatial scope) of each HCP, according to the distribution of the basic census geographical areas; the Urban Sections (USEC), in Cucuta. Three levels of increasing spatial aggregation were established considering the characteristics of the population receiving health care in primary, intermediate and tertiary public health services to establish the spatial scope of each HCP. The cases of ARI per USEC were calculated according to the proportion of the population of each USEC in each of the three levels. The spatial rate of ARI per USEC and the hotspots of higher risk of ARI were calculated using an Empirical Bayes method using a geostatistical software.
There were 97 HCP, of which, 31 provided health services in USEC in level 1; 20 provided health services in USEC in level 2; and 47 provided health services in USEC in level 3. A higher spatial rate of ARI was found in USEC in central south; central west; north and northwest; northeast; central east; and central regions, compared to the whole of Cucuta. Hotspots of higher risk were identified in two clusters of USEC in central south and west Cucuta and three isolated USEC in central and northwest Cucuta.
Health indicators at the census district geographical level could be calculated using basic statistics that do not include geographic identifiers by considering the characteristics of the HCP and the population receiving their services. The methodology of this study can be applied to other socioeconomic contexts where geographic identifiers are not attached to public health statistics to create better public health indicators and support potential health promotion and disease prevention strategies. | epidemiology |
10.1101/2022.04.18.22273996 | Air pollution exposure and mitochondrial DNA copy number in the UK Biobank | BackgroundLow levels of mitochondrial DNA copy number (mtDNA-CN) are a biomarker of mitochondrial dysfunction often induced by oxidative stress. Air pollution is a pervasive source of oxidative stress, but the association between air pollution exposure and mtDNA-CN is inconclusive.
ObjectiveWe evaluated the association between long-term exposure to PM [≤] 10 {micro}m diameter (PM10) and nitrogen dioxide (NO2) with mtDNA-CN in 195,196 adults in the UK Biobank study.
MethodsAnnual average PM10 and NO2 concentrations were estimated using separate land-use regression models for years 2007 and 2010. mtDNA-CN was measured in blood samples collected between 2007 and 2010 and was calculated as the ratio of mitochondrial coverage to the nuclear genome coverage derived from whole-genome sequencing in 195,196 UK Biobank participants. We used standardized values (Z-scores) after log-transformation as the mtDNA-CN metric.
ResultsThe median (interquartile range) annual average concentrations of PM10 and NO2 were 21.8 (20.3-23.6) and 28.9 (23.7-35.1) {micro}g/m3 in 2007, and 16.2 (15.5-17.1) and 27.8 (22.7-32.4) {micro}g/m3 in 2010. An increase of 10 {micro}g/m3 in annual average PM10 and NO2 exposure was associated with an adjusted difference in mtDNA-CN of -0.089 (95% confidence interval; -0.090, -0.087) and -0.018 (-0.018, -0.017), respectively. The associations persisted for lags of up to 3 years. PM2.5-10 was also inversely associated with mtDNA-CN.
ConclusionsIn this large-scale study, long-term exposure to PM10 and NO2 were inversely associated with mtDNA-CN. These findings suggest that oxidative stress-induced mitochondrial dysfunction, reflected by reduced mtDNA-CN, may be an additional mechanism mediating the health effects of air pollution. | epidemiology |
10.1101/2022.04.18.22273992 | An Evaluation of Prospective COVID-19 Modeling: From Data to Science Translation | BackgroundInfectious disease modeling can serve as a powerful tool for science-based management of outbreaks, providing situational awareness and decision support for policy makers. Predictive modeling of an emerging disease is challenging due to limited knowledge on its epidemiological characteristics. For COVID-19, the prediction difficulty was further compounded by continuously changing policies, varying behavioral responses, poor availability and quality of crucial datasets, and the variable influence of different factors as the pandemic progresses. Due to these challenges, predictive modeling for COVID-19 has earned a mixed track record.
MethodsWe provide a systematic review of prospective, data-driven modeling studies on population-level dynamics of COVID-19 in the US and conduct a quantitative assessment on crucial elements of modeling, with a focus on the aspects of modeling that are critical to make them useful for decision-makers. For each study, we documented the forecasting window, methodology, prediction target, datasets used, geographic resolution, whether they expressed quantitative uncertainty, the type of performance evaluation, and stated limitations. We present statistics for each category and discuss their distribution across the set of studies considered. We also address differences in these model features based on fields of study.
FindingsOur initial search yielded 2,420 papers, of which 119 published papers and 17 preprints were included after screening. The most common datasets relied upon for COVID-19 modeling were counts of cases (93%) and deaths (62%), followed by mobility (26%), demographics (25%), hospitalizations (12%), and policy (12%). Our set of papers contained a roughly equal number of short-term (46%) and long-term (60%) predictions (defined as a prediction horizon longer than 4 weeks) and statistical (43%) versus compartmental (47%) methodologies. The target variables used were predominantly cases (89%), deaths (52%), hospitalizations (10%), and Rt (9%). We found that half of the papers in our analysis did not express quantitative uncertainty (50%). Among short-term prediction models, which can be fairly evaluated against truth data, 25% did not conduct any performance evaluation, and most papers were not evaluated over a timespan that includes varying epidemiological dynamics. The main categories of limitations stated by authors were disregarded factors (39%), data quality (28%), unknowable factors (26%), limitations specific to the methods used (22%), data availability (16%), and limited generalizability (8%). 36% of papers did not list any limitations in their discussion or conclusion section.
InterpretationPublished COVID-19 models were found to be consistently lacking in some of the most important elements required for usability and translation, namely transparency, expressing uncertainty, performance evaluation, stating limitations, and communicating appropriate interpretations. Adopting the EPIFORGE 2020 guidelines would address these shortcomings and improve the consistency, reproducibility, comparability, and quality of epidemic forecasting reporting. We also discovered that most of the operational models that have been used in real-time to inform decision-making have not yet made it into the published literature, which highlights that the current publication system is not suited to the rapid information-sharing needs of outbreaks. Furthermore, data quality was identified to be one of the most important drivers of model performance, and a consistent limitation noted by the modeling community. The US public health infrastructure was not equipped to provide timely, high-quality COVID-19 data, which is required for effective modeling. Thus, a systematic infrastructure for improved data collection and sharing should be a major area of investment to support future pandemic preparedness. | epidemiology |
10.1101/2022.04.15.22272333 | Challenges of stakeholders' engagement for developing pragmatic, primary health care interventions for chronic respiratory diseases in low resource settings in India | Chronic respiratory diseases (CRDs) in low resource settings in India are often poorly diagnosed, leading to missed opportunities for early initiation of treatment and poor patient pathways. There is also a poor understanding in rural communities of the causes of CRDs; many symptoms are incorrectly attributed to asthma and treatment is inconsistent and often based on inaccurate diagnoses. There is a high prevalence of CRDs in rural regions of India. It is vital that interventions are developed to improve an understanding about CRD in low resource settings in India in order to reduce exposure to common risk factors and improve access to evidence based care. We piloted a frontline health care worker delivered educate, screen and treat intervention programme. We explored the role of stakeholders engagement towards the development of feasible community based interventions. The hypothesis was that without meaningful engagement with the key stakeholders, long term sustainability of the programme would be limited and potentially viewed as primarily for the organisations self-interest. A mixed method study combined a quantitative online survey of the sensitised health care providers and a qualitative assessment of the other stakeholders engagement activities. The methods of qualitative data collection included focus group discussions, feedback and individual interviews and data analysis used a thematic framework. We identified key stakeholders and investigated their knowledge, perceptions, beliefs, practices, educational needs and suggestions for improved care for CRD. Three main themes were 1) Community trust building 2) Mismatch between community awareness about CRD and access to evidence based care resources 3) Finding effective communication methods for low health literate and older age group population with CRD. First theme was built on two sub-themes: sensitised influential people in the community (community advisory committee); empowered, trained health workers in the community for patient screening and navigation. Second theme informed by three sub-themes: availability of sensitized health care providers and empowered health system; recognizing access to evidence based care for CRD in the region/district; recognizing the communitys change in behavior related to management of CRD with education. Third theme was informed by 2 sub-themes: communitys ability to understand the messages through different educational media and tools; challenges in engaging the low health literacy population. The findings of this study add to the literature on the numerous challenges faced by patients with CRD in low resource settings, indicating the need for identifying and educating key stakeholders, continuous support of patients, personalised education, and capacity building of health care providers. Given the significant challenges that the patients face, a feasible primary health care model needs to be developed incorporating strategies to deal with these challenges. | primary care research |
10.1101/2022.04.19.22273662 | Multimodal multi-center analysis of electroconvulsive therapy effects: brainwide gray matter increase without functional changes | BackgroundElectroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC).
MethodsWe analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with treatment-resistant depression before and within two weeks after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n=27).
ResultsWide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function.
ConclusionThese results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases. | psychiatry and clinical psychology |
10.1101/2022.04.19.22273034 | Pathogen- and type-specific changes in invasive bacterial disease epidemiology during the first year of the COVID-19 pandemic in the Netherlands | The COVID-19 control measures have resulted in a decline in invasive bacterial disease caused by Neisseria meningitidis (IMD), Streptococcus pneumoniae (IPD), and Haemophilus influenzae (Hi-D). The species comprise different serogroups and serotypes that impact transmissibility and virulence. We evaluated type- and pathogen-specific changes in invasive bacterial disease epidemiology in the Netherlands during the first year of the SARS-CoV-2 pandemic. Cases were based on nationwide surveillance for five bacterial species with either respiratory (IMD, IPD, Hi-D) or non-respiratory (controls) transmission routes and compared between the pre-COVID period (April 2015-March 2020) and the first COVID-19 year (April 2020-March 2021). IMD, IPD, and Hi-D cases decreased by 78%, 67%, and 35%, respectively, in the first COVID-19 year compared to the pre-COVID period although effects differed per age group. Serogroup B-IMD declined by 61%, while serogroup W and Y-IMD decreased >90%. IPD caused by serotypes 7F, 15A, 12F, 33F, and 8 showed the most pronounced decline ([≥]76%). In contrast to an overall decrease in Hi-D cases, vaccine-preventable serotype b (Hib) increased by 51%. COVID-19 control measures had pathogen- and type-specific effects related to invasive infections. Continued surveillance is critical to monitor potential rebound effects once restriction measures are lifted and transmission is resumed. | public and global health |
10.1101/2022.04.18.22274001 | Rasch Validation of the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) in Community-Dwelling Adults and in Adults with Stroke in the US | BackgroundWith the recent ongoing global COVID-19 pandemic and political divide in the United States (US), there is an urgent need to address the soaring mental well-being problems and to promote positive well-being. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) measures the positive aspects of mental health. Previous studies confirmed its construct validity, reliability, and unidimensionality with confirmatory factor analysis. Four studies have performed a Rasch analysis on the WEMWBS, but none of them tested adults in the US. The goals of our study are to use Rasch analysis to validate the WEMWBS in the general US population and in adults with stroke.
MethodsWe recruited community-dwelling adults and adults with chronic stroke with upper limb hemiplegia or hemiparesis. We used the Rasch Unidimensional Measurement Model (RUMM) 2030 software to evaluate item and person fit, targeting, person separation reliability (PSR), and differential item functioning (DIF) for sample sizes of at least 200 persons in each subgroup.
ResultsAfter deleting two items, the WEMBS analyzed in our 553 community-dwelling adults (average age 51.22{+/-}17.18 years; 358 women) showed an excellent PSR=0.91 as well as person and item fit, but the items are too easy for this population (person mean location=2.17{+/-}2.00). There was no DIF for sex, mental health, or practicing breathing exercises. In the 37 adults with chronic stroke (average age 58{+/-}13; 11 women) the WEMWBS had a good item and person fit, and PSR=0.92, but the items were too easy for this group as well (person mean location=3.13{+/-}2.00).
ConclusionsThe WEMWBS had good item and person fit but the targeting is off when used in community-dwelling adults and adults with stroke in the US. Adding more difficult items might improve the targeting and capture a broader range of positive mental wellbeing in both populations. Our pilot data in adults with stroke needs to be confirmed in a larger sample size. | rehabilitation medicine and physical therapy |
10.1101/2022.04.17.22273097 | Development of a Highly Sensitive Serum Neurofilament Light Chain Assay on an Automated Immunoassay Platform | BackgroundNeurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in cerebrospinal fluid (CSF) and blood. Numerous studies in MS have demonstrated that NfL correlates with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, widely accessible assay is needed. Our objective was to validate the analytical performance of the novel serum neurofilament light (sNfl) assay on the ADVIA Centaur(R) XP immunoassay system.
MethodsThe research assay was evaluated on the ADVIA Centaur XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), intra-assay variation, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types and transferred to Siemens CLIA laboratory, where it was analytically validated as a laboratory-developed test.
ResultsIn this study, a LLoQ of 1.85 pg/mL, intra-assay variation of <6%, and an assay range of up to 646 pg/mL were demonstrated. A cross-reactivity of <0.7% with neurofilament medium and heavy chains was observed, and the assay was not significantly affected by various interfering substances encountered in clinical specimens. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively.
ConclusionThe analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we believe the assay is acceptable for use in both research and clinical practice settings to determine elevated sNfL levels in patients. | neurology |
10.1101/2022.04.19.22274019 | Environmental Exposure to Respirable Particles and Estimated Risk of Sarcoidosis: A systematic Review and Meta-Analysis | IntroductionSarcoidosis is an inflammatory disease of unknown etiology that affects multiple organs in the body. In most cases, the affected organ is the lung. Sarcoidosis risk factors include environmental exposures, genetic predisposition, and immunological factors. The main objective of this review was to assess whether exposure to respirable particles is associated with increased risk of sarcoidosis.
MethodsA comprehensive search was conducted in scientific databases. Additional search of grey literature as well as handsearching of relevant records was performed. The search was restricted to studies published between January 1998 to October 2019. Meta-analysis was performed for studies that provided quantitative data.
ResultsAfter applying inclusion/exclusion criteria, nine articles were included in the systematic review and four in the meta-analysis. Quantitative analysis suggested that people exposed to respirable particles were approximately three times more likely to develop sarcoidosis compared to people who are unexposed.
Discussion and conclusionThis study collected and aggregated available evidence that assessed exposure to respirable particles and risk of developing sarcoidosis. Evidence of increased association between exposure to respirable particles and sarcoidosis was strongly suggested based on our qualitative review. More rigorous epidemiologic exposure studies are needed to generate data that would accurately determine the risk and causal pathways through which exposure to respirable particles could lead to the development of sarcoidosis. | occupational and environmental health |
10.1101/2022.04.15.22273900 | EHR Foundation Models Improve Robustness in the Presence of Temporal Distribution Shift | BackgroundTemporal distribution shift negatively impacts the performance of clinical prediction models over time. Pretraining foundation models using self-supervised learning on electronic health records (EHR) may be effective in acquiring informative global patterns that can improve the robustness of task-specific models.
ObjectiveTo evaluate the utility of EHR foundation models in improving the in-distribution (ID) and out-of-distribution (OOD) performance of clinical prediction models.
MethodsThe cohort consisted of adult inpatients admitted between 2009-2021. Gated recurrent unit (GRU)- and transformer (TRANS)-based foundation models were pretrained on EHR of patients admitted between 2009-2012 and were subsequently used to construct patient representations (CLMBR). These representations were used to learn logistic regression models (CLMBRGRU and CLMBRTRANS) to predict hospital mortality, long length of stay, 30-day readmission, and ICU admission. We compared CLMBRGRU and CLMBRTRANS with baseline logistic regression models learned on count-based representations (count-LR) and end-to-end (ETE) GRU and transformer models in ID (2009-2012) and OOD (2013-2021) year groups. Performance was measured using area-under-the-receiver-operating-characteristic curve, area- under-the-precision-recall curve, and absolute calibration error.
ResultsModels trained on CLMBR generally showed better discrimination relative to count-LR in both ID and OOD year groups. In addition, they often matched or were better than their ETE counterparts. Finally, foundation models performance in the self-supervised learning task tracked closely with the ID and OOD performance of the downstream models.
ConclusionsThese results suggest that pretraining foundation models on electronic health records is a useful approach for developing clinical prediction models that perform well in the presence of temporal distribution shift. | health informatics |
10.1101/2022.04.18.22273987 | Association of Socioeconomic Disparities and Predisposing Factors with Higher Prevalence of Hypertension related Left Ventricular Hypertrophy in Males: a Malaysian Community-Based Study | Left Ventricular Hypertrophy (LVH) is a risk for various cardiovascular events among those with hypertension (HT). However the prevalence of hypertension-related LVH (HT LVH+) in communities with lower socioeconomic status (SES) is not adequately reported. This study investigated the prevalence of HT LVH+ among the urban and rural males and the attributing factors. A total of 1,923 males who had echocardiographic examinations done were recruited. Their blood pressure was measured to diagnose those with or without hypertension. Left ventricular mass index was determined. Univariate analysis was performed to identify associated factors predisposing to LVH. A total of 992 males had HT, of which 264 had LVH, and were more prevalent in older age groups and Malays (p<0.001). Individuals from rural areas, with low income and low educational background were associated with higher LVH prevalence (p<0.001). Those with moderate aortic regurgitation was 3.17-fold higher in LVH. Ninety-nine normotensives had LVH, 71.7% came from rural. Total cholesterol and low density lipoprotein cholesterol levels were significantly higher in HT LVH+ from urban than the rural areas (p=0.029 and p=0.002, respectively). A quarter of the HT population in Malaysia develop LVH, majority of them were from rural, indicating that socioeconomic disparities contribute to the higher risk of HT LVH+. The rural populations may have attributed to different risk factors as opposed to those from urban, hence emphasize the need to deliver targeted strategies for prevention and management HT LVH+ by different SES. | cardiovascular medicine |
10.1101/2022.04.13.22273788 | The Dawn is Coming -- the Description and Prediction of Omicron SARS-CoV-2 Epidemic Outbreak in Shanghai by Mathematical Modeling | The COVID-19 Omicron outbreak in Shanghai has been going on for >1 month and 25 million population is subjected to strict lock-down quarantine. Until now, it is not clear how long this epidemic might end. Here, we present a time-delayed differentiation equation model to evaluate and forecast the spreading trend. Our model provides important parameters such as the average quarantine ratio, the detection interval from being infected to being tested positive, and the spreading coefficient to better understand the omicron progression. After data fitting, we concluded on 11 April that the maximum overall number infected in Shanghai would exceed 300,000 on 14 April and the turning point would be in the coming days around 13-15 April, 2022, which is perfectly in line with the real-life infection number. Furthermore, the quarantine ratio in Shanghai was found to be greater than 1, supportive of the effectiveness of the strict lockdown policy. Altogether, our mathematical model helps to define how COVID-19 epidemic progresses under the Shanghai lock-down unprecedented in human history and the Chinese zero tolerance policy. | epidemiology |
10.1101/2022.04.13.22273788 | The Dawn is Coming -- the Description and Prediction of Omicron SARS-CoV-2 Epidemic Outbreak in Shanghai by Mathematical Modeling | The COVID-19 Omicron outbreak in Shanghai has been going on for >1 month and 25 million population is subjected to strict lock-down quarantine. Until now, it is not clear how long this epidemic might end. Here, we present a time-delayed differentiation equation model to evaluate and forecast the spreading trend. Our model provides important parameters such as the average quarantine ratio, the detection interval from being infected to being tested positive, and the spreading coefficient to better understand the omicron progression. After data fitting, we concluded on 11 April that the maximum overall number infected in Shanghai would exceed 300,000 on 14 April and the turning point would be in the coming days around 13-15 April, 2022, which is perfectly in line with the real-life infection number. Furthermore, the quarantine ratio in Shanghai was found to be greater than 1, supportive of the effectiveness of the strict lockdown policy. Altogether, our mathematical model helps to define how COVID-19 epidemic progresses under the Shanghai lock-down unprecedented in human history and the Chinese zero tolerance policy. | epidemiology |
10.1101/2022.04.18.22273977 | Modelling the risk factors of malnutrition amongst children below five years of age in Uganda. A GSEM based analysis | This study aimed at establishing the causal mechanism through which the risk factors of malnutrition act to influence the undernutrition of under-fives in Uganda. A generalized structural equation model (GSEM) was estimated based on the multifaceted nature of the risk factors according to the UNICEF 1991 conceptual framework for child malnutrition. Uganda Demographic and Health Survey (UDHS-KR) dataset was used for the analysis. An index of malnutrition which was the overall response variable in the GSEM model was derived from the three anthropometric variables of stunting, underweight, and body wasting.
The findings indicate that sex of the child, age of the child, the perceived size of the child at birth, the weight of the child at birth, duration of breastfeeding, mothers education level, working status of the mother, wealth quintile of the household and mothers weight (BMI) were the factors that had a direct and significant influence on undernutrition. Further analysis of the causal mechanism reveals about five main paths of causal mechanism and these were; (i) the mothers level of education influences the mothers weight which influences the birth weight of the child and then this combination influences under-nutrition, (ii) mothers education levels also influence the household wealth status and as observed above, household wealth significantly influences under-nutrition, (iii) residence whether rural or urban setting influences under-nutrition through its influence on the household wealth, (iv) being in urban areas is also associated with employment opportunities which in turn influences the duration of breast feeding and then influences under-nutrition, (v) size at birth which is key in influencing under-nutrition is influenced by the working status of the mother which is dependent on the place of residence.
Based on the findings, the recommendation is that a multi-faceted approach that addresses all the factors at different levels be implemented in order to get a lasting solution to the silent killer of under-fives. | epidemiology |
10.1101/2022.04.18.22273981 | Prognostic significance of WT1 expression level thershold in acute myeloid leukemia patients receiving hematopoietic stem cell transplantation: Meta-Analysis | ObjectiveThe WT1 gene is considered as a poor prognostic factor for acute myeloid leukemia (AML) after Allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, the effect of the expression threshold of WT1 on the prognosisis controversial, which is evaluated in this meta-analysis.
MethodsRelevant studies about the expression threshold of WT1 on the prognosis of AML after Allo-HSCT were searched in online databases. Data were extracted from them and analyzed by Stata16.0 software.
ResultsFive studies involving 739 patients were screened out, including 433 cases experimental group and 306 cases control group. The experimental group and control group were compared for 1-year disease-free survival rate (DFS) [RR=1.19, 95%CI (1.03, 1.38), P =0.02] and 4-year DFS [RR= 1.18, 95%CI (0.98, 1.42), P =0.09]. The experimental group was lower than the control group in 1-year DFS, and there was no statistical significance in 4-year DFS. 1-year overall survival rate (OS) [RR=1.06, 95%CI (0.92, 1.23), P =0.40] and 4-year OS [RR= 1.16, 95%CI (1.03, 1.32), P =0.02], suggesting that the experimental group had a lower 4-year OS than the control group, and 1-year OS had no statistical significance.
ConclusionsHigh WT1 expression is unfavorable to the prognosis of AML patients undergoing Allo-HSCT. A threshold of 250 copies/104ABL of WT1 may be the best value for predicting the poor prognosis in these patients. | hematology |
10.1101/2022.04.15.22273742 | Online randomised trials with children: A scoping review protocol | IntroductionThis scoping review will determine how online, randomised trials with children are conducted. The objectives of the review are: (a) to determine what methods and tools have been used to create and conduct online trials with children and (b) to identify the gaps in the knowledge in this field.
Over the last decade, randomised trials employing online methods have gained momentum. Decentralised methods lend themselves to certain types of trials and can offer advantages over traditional trial methods, potentially increasing participant reach and diversity and decreasing research waste. However, decentralised trials that have all aspects of the trial exclusively online are not yet common, and those involving children even less so. This scoping review will describe and evaluate the methods used in these trials to understand how they may be effectively employed.
MethodsMethods are informed by guidance from the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. The search strategy was developed in consultation with an information specialist for the following databases: MEDLINE, CENTRAL, CINAHL, and Embase. Grey literature searches will be completed with the consultation of experts in decentralised trials and digital health using internet searches and suitable trial registries. Once identified, included full-text studies references will be manually searched for any trials that may have been missed. We will include randomised and quasi-randomised trials conducted exclusively online with participants under the age of 18 published in English. We will not limit by country of conduct or date of publication. Data will be collected using a data charting tool and presented in text, graphical, and tabular formats.
Ethics and DisseminationEthical approval is not needed since all data sources used are publicly available. The review will be available as a preprint before publication in an open-access, peer-reviewed journal. | public and global health |
10.1101/2022.04.18.22273974 | Confounder-adjusted MRI-based predictors of multiple sclerosis disability | IntroductionBoth aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as accelerated aging. Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects.
MethodsStandardized brain MRI and neurological examination were acquired prospectively in 649 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n=160). MS patients were randomly split into training (n=277) and validation (n=132) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales.
ResultsConfounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperforms published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort.
ConclusionGBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.
HighlightsO_LIRegressing out physiological confounders affecting volume of CNS structures in healthy volunteers, strengthened correlations between white matter volumes and disability outcomes in MS cohorts
C_LIO_LIAggregating volumetric features into generalized boosting machine (GBM) models outperformed correlations of individual MRI biomarkers with clinical outcomes in MS
C_LIO_LIDeveloped more sensitive and reliable models that predict MS-associated disability
C_LIO_LIIndependent validation cohorts show true model performances
C_LIO_LIDeveloped GBM models should be explored in future MS clinical trials
C_LI | neurology |
10.1101/2022.04.18.22273874 | Seroclearance of HBsAg in Chronic Hepatitis B Patients after a Tolerance Breaking Therapy: GM-CSF, followed by Human HBV Vaccine | ObjectiveSeroclearance of hepatitis B surface antigen (HBsAg) remains a challenge to the functional cure of HBV infection due to an HBV-specific immune tolerance that prevents virus eradication.
MethodsIn this clinical study, chronic hepatitis B patients treated with the standard nucleotide analog (NA) Adefovir Dipivoxil (ADV) or treated with ADV and IFN- were immunized with granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with Human HBV Vaccine.
ResultsThis THRIL-GM-Vac approach (THRee Injections of Low-dose GM-CSF followed by one dose of the HBV Vaccine) has achieved at least a 10-fold reduction of HBsAg level in 10 out of 23 (43.5%) patients tested. Moreover, two out of the ten patients eventually reached seroclearance. Thus THRIL-GM-Vac could break HBV-specific tolerance and boost HBsAg-specific cellular immunity. Consequently, the THRIL-GM-Vac approach could provide effective therapy for patients bearing medium-to-low levels of HBsAg.
ConclusionOur findings carry the clinical significance of showing a novel way to break immunotolerance that can tackle the persistent infection manifested as generated by chronic HBV burden in chronic hepatitis B (CHB) patients.
Significance of this studyO_ST_ABSWhat is already known about the subject?C_ST_ABSChronic hepatitis B virus (CHB) patients can be controlled with antiviral therapies while rarely cured or functionally cured. In addition to the standard anti-viral treatment, immunotherapeutic approaches may break the HBV established immunotolerance and, in turn, mount effective activation or reactivation of host anti-HBV immunity and can be achieved in HBV-related animal models. However, achieving such a functional cure in CHB patients has been challenging.
What are the new findings?O_LIWe demonstrated in this study that some levels of HBsAg seroclearance in CHB patients were treated with a 3-day treatment of GM-CSF followed by one HBV vaccine for six treatments within one year in addition to the standard of anti-viral treatment.
C_LIO_LINotably, dynamics of HBsAg declined in responders were correlated with dynamics of HBsAg-specific Treg cells and reciprocally associated with the dynamical changes of HBsAg-specific IFN-{gamma} +CD4+ (Th1) and IFN-{gamma} +CD8+(Tc1) T cells over the course.
C_LI
How might it impact on clinical practice in the foreseeable future?O_LIIt demonstrates in CHB patients that breaking Treg-immunotolerance can significantly be correlated with reducing the level of HBsAg in the responders by immunotherapy.
C_LIO_LISuch correlation can be used to predict outcomes of the efficacy of an immunotherapeutic treatment prior to completing its treatments.
C_LIO_LIThe evidence of HBsAg seroclearance in CHB patients by the presented immunotherapeutic approach will also shed light on improving such approach or similar strategies and further benefit those unmet medical needs.
C_LI | infectious diseases |
10.1101/2022.04.19.22274009 | Implementing an antibiogram profile to aid rational antimicrobial therapy and improving infection prevention in an urban hospital in The Gambia; strategies and lessons for low income and middle-income countries. | BackgroundDiagnostic microbiological capabilities remain a challenge in low- and middle-income countries resulting in major gaps. The global antimicrobial resistance burden has necessitated use of appropriate prescribing to curb the menace. This study highlights the process used to develop an antibiogram to monitor resistance at a secondary-level health facility to aid empirical clinical decision making.
MethodsThis retrospective cross-sectional descriptive study used 3 years of cumulative data at the Medical Research Council Unit The Gambia from January 2016 to December 2018. Phenotypic data was manually imputed into WHONET and the cumulative antibiogram constructed using standardised methodologies according to CLSI M39-A4 guidelines. Pathogens were identified by standard microbiological methods and antimicrobial susceptibility testing was performed using Kirby-Bauer disc diffusion method according to CLSI M100 guidelines.
ResultsA total of 14776 non-duplicate samples (blood cultures n=4382, urines n=4914, other miscellaneous swabs and aspirates n=2821 and n=390 respectively, sputa n=334, stools n=1463, CSF 353 and other samples n= 119) were processed of which 1163 (7.9%) were positive for clinically significant pathogens. Among the 1163 pathogens, E. coli (n= 315) S. aureus (n=232), and K. pneumoniae (n=96) were the leading cause of disease Overall, the susceptibility for E. coli and K. pneumoniae from all samples were: trimethoprim-sulfamethoxazole (17% and 28%), tetracycline (26% and 33%), gentamicin (72% and 46%), chloramphenicol (76 and 60%), and ciprofloxacin (69% and 59%), amoxicillin/clavulanic (77% and 54%) respectively. Extended spectrum beta-lactamase resistance was present in 23% (71/315) vs 35% (34/96) respectively. S. aureus susceptibility for methicillin was 99%.
ConclusionThis antibiogram has confirmed susceptibility to commonly used antimicrobials was higher for E. coli than K. pneumoniae with high ESBL resistance warranting surveillance. An alternative aminoglycoside with better sensitivity such as amikacin might be relevant although this was not tested and that cloxacillin remains a drug of choice for the Staphylococci. | infectious diseases |
10.1101/2022.04.18.22273982 | A Mixed Methods Study Evaluating Acceptability of a Daily COVID-19 Testing Regimen with a Mobile-App Connected, At-Home, Rapid Antigen Test: Implications for Current and Future Pandemics | BackgroundWidespread use of at-home rapid COVID-19 antigen tests has been proposed as an important public health intervention to interrupt chains of transmission. Antigen tests may be preferred over PCR because they provide on-demand results for relatively low cost and can identify people when they are most likely to be infectious, particularly when used daily. Yet the extent to which a frequent antigen testing intervention will result in a positive public health impact for COVID-19 will depend on high acceptability and high adherence to such regimens.
MethodsWe conducted a mixed-methods study assessing acceptability of and adherence to a daily at-home mobile-app connected rapid antigen testing regimen among employees of a US-based media company. Acceptability was assessed across seven domains of the Theoretical Framework of Acceptability.
ResultsAmong 31 study participants, acceptability of the daily testing intervention was generally high, with participants reporting high perceived effectiveness, intervention coherence, and self-efficacy; positive affective attitude; acceptable degree of burden and opportunity cost; and assessing the intervention as ethical. 71% reported a preference to test daily using an at-home antigen test than weekly employment-based PCR. Mean adherence to the 21-day testing regimen was 88% with 43% of participants achieving 100% adherence, 48% testing at least every other day, and 10% testing less than every other day.
ConclusionsDespite overall high acceptability and adherence, we identified three implementation challenges that must be addressed for frequent serial testing for COVID-19 to be implemented at scale and have a positive public health impact. First, users need guidance on how and when to adapt testing frequencies to different epidemiological conditions. Second, users and institutions need guidelines for how to safely store and share test results. Third, implementation of serial testing strategies must prioritize health equity and protect those most vulnerable to COVID-19. | infectious diseases |
10.1101/2022.04.18.22274004 | Potential drivers for schistosomiasis persistence: population genetic analyses from a cluster-randomized urogenital schistosomiasis elimination trial across the Zanzibar islands | The World Health Organization revised NTD Roadmap and its newly launched Guidelines target elimination of schistosomiasis as a public health problem in all endemic areas by 2030. Key to meeting this goal is elucidating how selective pressures imposed by interventions shape parasite populations. Our aim was to identify any differential impact of a unique cluster-randomized tri-armed elimination intervention (biannual mass drug administration (MDA) applied alone or in association with either mollusciciding (snail control) or behavioural change interventions) across two Zanzibarian islands (Pemba and Unguja) on the population genetic composition of Schistosoma haematobium over space and time. Fifteen microsatellite loci were used to analyse individual miracidia collected from infected individuals across islands and intervention arms at the start (2012 baseline: 1,529 miracidia from 181 children; 303 from 43 adults; age-range 6-75, mean 12.7 years) and at year 5 (2016: 1,500 miracidia from 147 children; 214 from 25 adults; age-range 9-46, mean 12.4 years). Measures of genetic diversity included allelic richness (Ar), inbreeding coefficient (FST), parentage analysis, estimated worm burden, worm fecundity, and genetic sub-structuring. There was little evidence of differential selective pressures on population genetic diversity, outbreeding or estimated worm burdens by treatment arm, with only the MDA+snail control arm within Unguja showing a (non-significant) trend towards reduced diversity over time. The greatest differences overall, most notably in terms of parasite fecundity (mean number of eggs per adult female worm) and genetic sub-structuring, were observed between the islands, consistent with Pembas persistently higher mean infection intensities compared to neighbouring Unguja, and within islands in terms of persistent infection hotspots (across three definitions). These findings highlight the important contribution of population genetic analyses to elucidate extensive genetic diversity and biological drivers, including potential gene-environmental factors, that may override short term selective pressures imposed by differential disease control strategies.
Author SummarySchistosomiasis is a parasitic disease caused by infection with blood flukes, which leads to acute and chronic pathology in millions of infected individuals, particularly those within the poorest tropical and subtropical regions. In 2012, the World Health Organization (WHO) set the ambitious goals to achieve Elimination of Schistosomiasis as a Public Health Problem (i.e., EPHP, prevalence of heavy infection intensity less than 1% in all sentinel sites) and complete Interruption of Transmission (i.e., IoT reduction of incidence of infection to zero) in selected African regions by 2025. More recently, the revised WHO Neglected Tropical Diseases (NTD)-Roadmap and Revised Schistosomiasis Control and Elimination Guidelines aim to achieve EPHP in all regions by 2030. Here we analysed population genetic data associated with a unique 5-year cluster-randomized trial across Zanzibar (Pemba and Unguja islands) which aimed to assess the impact of contrasting interventions to achieve urogenital schistosomiasis elimination. Whilst, consistent with the main trial study, no significant differential impact of interventions was detected in terms of infection epidemilogy, our data suggested that the greatest impact on genetic diversity was within the mass drug administration plus concurrent mollusciding arm. Moreover, our analyses revealed significant differences in both the genetic sub-structuring and notably the fecundity of parasites between Pemba and Unguja islands, and within Pemba island in relation to persistent hotspots, potentially indicative of genetic and biological factors driving persistence. These findings highlight the important contribution of population genetic analyses to reveal high levels of genetic diversity, biological drivers and potential gene-environmental interactions in determining infection dynamics and persistence, all of which present additional challenges for successful control. | epidemiology |
10.1101/2022.04.18.22273983 | Modeling the initial phase of COVID-19 epidemic: The role of age and disease severity in the Basque Country, Spain | Declared a pandemic by the World Health Organization (WHO), COVID-19 has spread rapidly around the globe. With eventually substantial global underestimation of infection, by the end of March 2022, more than 470 million cases were confirmed, counting more than 6.1 million deaths worldwide.
COVID-19 symptoms range from mild (or no) symptoms to severe illness, with disease severity and death occurring according to a hierarchy of risks, with age and pre-existing health conditions enhancing risks of disease severity. In order to understand the dynamics of disease severity during the initial phase of the pandemic, we propose a modeling framework stratifying the studied population into two groups, older and younger, assuming different risks for severe disease manifestation.
The deterministic and the stochastic models are parametrized using epidemiological data for the Basque Country population referring to confirmed cases, hospitalizations and deaths, from February to the end of March 2020. Using similar parameter values, both models were able to describe well the existing data. A detailed sensitivity analysis was performed to identify the key parameters influencing the transmission dynamics of COVID-19 in the population. We observed that the population younger than 60 years old of age would contribute more to the overall force of infection than the older population, as opposed to the already existing age-structured models, opening new ways to understand the effect of population age on disease severity during the COVID-19 pandemic.
With mild/asymptomatic cases significantly influencing the disease spreading and control, our findings support the vaccination strategy prioritising the most vulnerable individuals to reduce hospitalization and deaths, as well as the non-pharmaceutical intervention measures to reduce disease transmission. | epidemiology |
10.1101/2022.04.17.22273906 | The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance. | Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks.
One-Sentence SummaryExpanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic. | epidemiology |
10.1101/2022.04.18.22273880 | Changes of LipoxinA4 Levels Following Early Hospital Management of Patients with Non-Severe COVID-19: A Pilot Study | LipoxinA4 (LXA4) is an anti-inflammatory biomarker participating in the active process of inflammation resolution, which is suggested to be effective on infectious and inflammatory diseases like COVID-19. In this study, we hypothesized that LXA4 levels may increase following COVID-19 treatment and are even more accurate than commonly used inflammatory markers such as erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), and ferritin. To test this hypothesis, a pilot study was conducted with 31 adult hospitalized patients with non-severe COVID-19. LXA4 levels were measured at the baseline and 48-72 hours later. Accordingly, ESR and CRP levels were collected on the first day of hospitalization. Moreover, the maximum serum ferritin levels were collected during the five days. LXA4 levels significantly increased at 48-72 hours compared to the baseline. ESR, CRP, and ferritin levels were positively correlated with the increased LXA4. In contrast, aging was shown to negatively correlate with the increased LXA4 levels. LXA4 may be known as a valuable marker to assess the treatment response among non-elderly patients with non-severe COVID-19. Furthermore, LXA4 could be considered as a potential treatment option under inflammatory conditions. Further studies are necessary to clarify LXA4 role in COVID-19 pathogenesis, as well as the balance between such pro-resolving mediators and inflammatory parameters. | infectious diseases |
10.1101/2022.04.18.22273772 | High proportion of tuberculosis transmission among social contacts in rural China: a 12-year prospective population-based genomic epidemiological study | BackgroundTuberculosis (TB) is more prevalent in rural than urban areas in China, and delineating TB transmission patterns in rural populations could improve TB control.
MethodsWe conducted a prospective population-based study of culture-positive pulmonary TB patients diagnosed between July 1, 2009 and December 31, 2020 in two rural counties in China. Genomic clusters were defined with a threshold distance of 12-single-nucleotide-polymorphisms, based on whole-genome sequencing. Risk factors for clustering were identified by logistic regression. Transmission links were sought through epidemiological investigation of genomic-clustered patients.
FindingsOf 1517 and 751 culture-positive pulmonary TB patients in Wusheng and Wuchang counties, respectively, 1289 and 699 strains were sequenced. Overall, 624 (31{middle dot}4%, 624/1988) patients were grouped into 225 genomic clusters. Epidemiological links were confirmed in 41{middle dot}8% (196/469) of clustered isolates, including family (32{middle dot}7%, 64/196) and social contacts (67{middle dot}3%, 132/196). Social contacts were generally with relatives, within the community or in shared aggregated settings outside the community, but the proportion of clustered contacts in each category differed between the two sites. The time interval between diagnosis of student cases and contacts was significantly shorter than family and social contacts, probably due to enhanced student contact screening. Transmission of multidrug-resistant strains was likely responsible for 81{middle dot}4% (83/102) of MDR-TB cases, with minimal acquisition of additional resistance mutations.
InterpretationA large proportion of TB transmission in rural China occurred among social contacts, suggesting that active screening and aggressive contact tracing could benefit TB control, but contact screening should be tailored to local patterns of social interactions.
FundingNational Science and Technology Major Project of China, Natural Science Foundation of China, and Science and Technology Major Project of Shanghai
Evidence before this studyWe searched PubMed for genomic epidemiological studies of Mycobacterium tuberculosis published in English before April 2022 employing whole-genome sequencing, using the search terms "tuberculosis", "transmission", "population based", and "whole-genome sequencing". We identified only 11 studies in which whole-genome sequencing was used to investigate transmission of M tuberculosis at the population level. We also searched the China national knowledge infrastructure (CNKI) and WANFANG databases with the same search terms for papers published in Chinese, but did not identify any studies. The duration of most of the 11 studies we identified was less than 5 years. Seven studies conducted epidemiological investigations of genomic-clustered cases, but the proportion of cases with confirmed epidemiological links was very low. Therefore, no studies had sufficient evidence to identify populations and sites at high risk of TB transmission. Five studies were conducted in China but all were in urban areas and focused on MDR-TB patients and internal migrants. The pattern of TB transmission in rural China, where TB is more prevalent, had not been addressed.
Added value of this studyTo our knowledge, ours is the first population-based genomic epidemiological study to delineate TB transmission patterns in rural China. Close contacts have been shown to be a high-risk group for TB transmission in other countries. In China, however, the huge number of TB patients, limited resources for TB prevention and control and the stigma associated with tuberculosis all contribute to a failure to identify and screen many close contacts. As a consequence, close contacts have been calculated to contribute only about 2% of the total TB burden. In this study, through the investigation of genomic-clustered patients, we found at least 41{middle dot}8% of clustered patients were close contacts who comprised 9{middle dot}9% of the total TB patients in the study. Moreover, more than two-thirds of the close contacts were social contacts rather than members of the immediate family. The composition of social contacts differed between the two study sites due to differences in climate and lifestyle habits. The average time interval between the diagnosis of clustered student contacts was shorter than for family or community contacts. In addition, transmission of MDR strains was likely responsible for 81{middle dot}4% of MDR-TB cases, with minimal acquisition of additional resistance mutations. Our 12-year study identified patterns of TB transmission not identified by previous studies, demonstrating the value of long-term genomic epidemiological studies.
Implications of all the available evidenceOur study demonstrates that much of the transmission of TB in rural China was among close contacts, especially social contacts. Therefore, strengthening and improving proactive screening of close social contacts can identify more TB patients and shorten the time to patient detection. We believe that this type of vigorous active case-finding is essential for reducing TB transmission and the considerable TB burden in China. Long-term prospective genomic epidemiological studies provide a useful picture of TB transmission patterns that can help guide the design of strategies to improve TB prevention and control. | epidemiology |
10.1101/2022.04.19.22273815 | Implementation strategies to increase human papillomavirus vaccination uptake for adolescent girls in sub-Saharan Africa: A scoping review protocol | IntroductionThe human papillomavirus (HPV) is sexually transmitted and infects approximately 75% of sexually active people early in their sexual life. Persistent infection with oncogenic HPVtypes can lead to malignant conditions such as cervical cancer. In 2006, the World Health Organisation approved the use of efficacious HPV vaccine for girls aged 9 to 14 years to prevent HPV related conditions. Despite the HPV vaccine having been available for about 15 years, dose completion remains at 53% in sub-Saharan Africa for countries implementing the vaccination program. A fraught of barriers to implementation exist which prevent adequate coverage. Achieving success for HPV vaccination in real-world settings requires enacted implementation strategies to overcome implementation bottlenecks. Therefore, a better understanding and mapping of the implementation strategies used in sub-Saharan Africa to increase HPV vaccination uptake is critical. This review aims to identify implementation strategies to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa and provide a basis for policy and future research including systematic reviews to evaluate effective strategies as we accelerate the elimination of cervical cancer.
Materials and MethodsThis review will consider studies that pertain to implementation strategies used to increase HPV vaccination uptake for adolescent girls in sub-Saharan Africa. Studies targeted at different stakeholders to increase adolescent vaccine uptake will be included. Studies using interventions not fitting the definition of implementation strategies as defined by the refined compilation of implementation strategies from the Expert Recommendations for Implementing Change project will be excluded. MEDLINE (via PubMed), Embase, CINAHL (via EBSCO), Scopus and Google scholar will be searched. Two independent reviewers will screen titles and abstracts for studies that meet the reviews inclusion criteria, and the full text of eligible studies will be reviewed. Data will be extracted from eligible studies using data charting table developed by this team for inclusion by two independent reviewers and presented in table and graphical form with a narrative summary. | public and global health |
10.1101/2022.04.19.22274037 | The variability and performance of NHS Englands Reason to Reside criteria in predicting hospital discharge in acute hospitals in England. An observational study. | ObjectivesNHS England (NHSE) advocates using "reason to reside" (R2R) criteria to generate a binary outcome, which supports discharge related clinical decision making. The proportion of patients without R2R and their rate of discharge are reported daily, by acute hospitals in England. R2R is however, not based upon an inter-operable standardised data model (SDM), nor has its performance been validated against its purpose. We aimed to understand the degree of inter- and intra-centre variation in R2R related metrics reported to NHSE, define a SDM implemented within a single centre Electronic Health Record to generate an eR2R, and evaluate its performance in predicting subsequent discharge.
DesignRetrospective observational cohort study using routinely collected health data.
Setting122 NHS Trusts in England for national reporting and an adult acute hospital in England for local reporting.
Participants6,602,706 patient-days were analysed using 3 months national data and 1,039,592 patient-days, using 3 years single centre data.
Main outcome measuresVariability in R2R related metrics reported to NHSE. Performance of eR2R in predicting discharge within 24 hours.
ResultsThere were high levels of intra and inter-centre variability in R2R related metrics (p<0.0001), but not in eR2R. Informedness of eR2R for discharge within 24 hours was low (J-statistic 0.09 - 0.12 across three consecutive years). In those remaining in hospital without eR2R, 61.2% met eR2R criteria on subsequent days (76% within 24 hours), most commonly due to increased NEWS2 (21.9%) or intravenous therapy administration (32.8%).
ConclusionsR2R related performance metrics are highly variable between and within acute Trusts in England. Although case-mix or community care provision may account for some variability, the absence of a SDM is a major barrier to meaningful interpretation of these metrics. The performance of eR2R based on two alternative SDMs was poor, such that they could not meaningfully contribute to clinical decision making or evaluation of performance.
SummaryO_ST_ABSWhat is knownC_ST_ABSThere is considerable pressure on hospital bed capacity and significant variation in hospital discharges with concerns raised about delays in discharge planning across National Health Service Trusts. To address this, the UK Government developed a policy and criteria to identify in-patients in whom discharge home, or to a less acute setting, should be considered. The criteria, called "reasons to reside" (R2R) have been promoted as a tool to improve discharge planning and are a mandated metric for central reporting. The performance of R2R has not been assessed.
What this study addsThis study suggests a low performance of the R2R criteria as a clinical tool to identify patients suitable for discharge, and questions its usefulness as a reported metric in its current form. There is significant intra and inter-centre variability in both the reported proportion of patients not meeting R2R criteria, and the proportion of patients not meeting R2R criteria who were later discharged. The proportion of patients not meeting R2R criteria correlates poorly with their rate of discharge over the subsequent 24 hours and the performance of the R2R criteria as dichotomous test to identify patients suitable for discharge is low. Further, the R2R criteria are not a stable phenomenon, with more than half of those who remain in hospital without R2R, subsequently acquiring a R2R during the admission. | health policy |
10.1101/2022.04.19.22274055 | Clinical and haematological profile of dengue among adult patients at a tertiary care hospital in Pokhara | IntroductionDengue is an important infectious disease. This disease is prevalent in the terai belts of Nepal mainly. But in the last few years, the cases are in increasing trend in the hilly areas of Nepal also. Hence this study was done in an aim to study the clinical and haematological profile of the dengue cases.
MethodsThis was a retrospective cross-sectional quantitative study done at a tertiary teaching hospital of Pokhara, Nepal after obtaining ethical approval from the institutional ethical committee. The data of serologically confirmed dengue cases, during the period of August 2019 to December 2019, of age above 15 years, were collected and analysed using SPSS 20. Descriptive analysis in terms of mean, median, percentage as well as t-test for nominal and chi-square tests were used to compare different parameters. P-value[≤] 0.05 was considered statistically significant.
ResultsOut of 922 patients, approximately one-half (50.5%) cases were seen during the month of September. Most (82.8%) were the inhabitants of Kaski district. Median age of presentation was 29 years with slightly more cases of males (52.4%). Three hundred and forty seven patients were admitted. Fever (96.5%) and headache (40.6%) were the most common symptoms on presentation of admitted cases. Leukopenia (55.3%) was more common than thrombocytopenia (47.6%) in the admitted cases. On comparison between admitted patients with warning signs and those without signs, no significant variation was seen in terms of age, total leukocyte count and total platelet count.
ConclusionDengue is common in young population. Fever, headache and gastrointestinal symptoms are common among dengue patients. Leukopenia and thrombocytopenia are common laboratory features of dengue. | infectious diseases |
10.1101/2022.04.19.22274056 | Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Infection Caused by the SARS-CoV-2 Omicron Variant in People with a Prior SARS-CoV-2 Infection | BackgroundThe benefit of vaccination in people who experienced a prior SARS-CoV-2 infection remains unclear.
ObjectiveTo estimate the effectiveness of primary (two-dose) and booster (third dose) vaccination against Omicron infection among people with a prior documented infection.
DesignTest-negative case-control study.
SettingYale New Haven Health System facilities.
ParticipantsVaccine eligible people who received SARS-CoV-2 RT-PCR testing between November 1, 2021, and January 31, 2022.
MeasurementsWe conducted two analyses, each with an outcome of Omicron BA.1 infection (S-gene target failure defined) and each stratified by prior SARS-CoV-2 infection status. We estimated the effectiveness of primary and booster vaccination. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds among boosted and booster eligible people.
ResultsOverall, 10,676 cases and 119,397 controls were included (6.1% and 7.8% occurred following a prior infection, respectively). The effectiveness of primary vaccination 14-149 days after 2nd dose was 36.1% (CI, 7.1% to 56.1%) for people with and 28.5% (CI, 20.0% to 36.2%) without prior infection. The odds ratio comparing boosted and booster eligible people with prior infection was 0.83 (CI, 0.56 to 1.23), whereas the odds ratio comparing boosted and booster eligible people without prior infection was 0.51 (CI, 0.46 to 0.56).
LimitationsMisclassification, residual confounding, reliance on TaqPath assay analyzed samples.
ConclusionWhile primary vaccination provided protection against BA.1 infection among people with and without prior infection, booster vaccination was only associated with additional protection in people without prior infection. These findings support primary vaccination in people regardless of prior infection status but suggest that infection history should be considered when evaluating the need for booster vaccination.
Primary Funding SourceBeatrice Kleinberg Neuwirth and Sendas Family Funds, Merck and Co through their Merck Investigator Studies Program, and the Yale Schools of Public Health and Medicine. | infectious diseases |
10.1101/2022.04.19.22274056 | Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Infection Caused by the SARS-CoV-2 Omicron Variant in People with a Prior SARS-CoV-2 Infection | BackgroundThe benefit of vaccination in people who experienced a prior SARS-CoV-2 infection remains unclear.
ObjectiveTo estimate the effectiveness of primary (two-dose) and booster (third dose) vaccination against Omicron infection among people with a prior documented infection.
DesignTest-negative case-control study.
SettingYale New Haven Health System facilities.
ParticipantsVaccine eligible people who received SARS-CoV-2 RT-PCR testing between November 1, 2021, and January 31, 2022.
MeasurementsWe conducted two analyses, each with an outcome of Omicron BA.1 infection (S-gene target failure defined) and each stratified by prior SARS-CoV-2 infection status. We estimated the effectiveness of primary and booster vaccination. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds among boosted and booster eligible people.
ResultsOverall, 10,676 cases and 119,397 controls were included (6.1% and 7.8% occurred following a prior infection, respectively). The effectiveness of primary vaccination 14-149 days after 2nd dose was 36.1% (CI, 7.1% to 56.1%) for people with and 28.5% (CI, 20.0% to 36.2%) without prior infection. The odds ratio comparing boosted and booster eligible people with prior infection was 0.83 (CI, 0.56 to 1.23), whereas the odds ratio comparing boosted and booster eligible people without prior infection was 0.51 (CI, 0.46 to 0.56).
LimitationsMisclassification, residual confounding, reliance on TaqPath assay analyzed samples.
ConclusionWhile primary vaccination provided protection against BA.1 infection among people with and without prior infection, booster vaccination was only associated with additional protection in people without prior infection. These findings support primary vaccination in people regardless of prior infection status but suggest that infection history should be considered when evaluating the need for booster vaccination.
Primary Funding SourceBeatrice Kleinberg Neuwirth and Sendas Family Funds, Merck and Co through their Merck Investigator Studies Program, and the Yale Schools of Public Health and Medicine. | infectious diseases |
10.1101/2022.04.19.22274056 | Effectiveness of Primary and Booster COVID-19 mRNA Vaccination against Omicron Variant SARS-CoV-2 Infection in People with a Prior SARS-CoV-2 Infection | A Test Negative Case Control Study | BackgroundThe benefit of vaccination in people who experienced a prior SARS-CoV-2 infection remains unclear.
ObjectiveTo estimate the effectiveness of primary (two-dose) and booster (third dose) vaccination against Omicron infection among people with a prior documented infection.
DesignTest-negative case-control study.
SettingYale New Haven Health System facilities.
ParticipantsVaccine eligible people who received SARS-CoV-2 RT-PCR testing between November 1, 2021, and January 31, 2022.
MeasurementsWe conducted two analyses, each with an outcome of Omicron BA.1 infection (S-gene target failure defined) and each stratified by prior SARS-CoV-2 infection status. We estimated the effectiveness of primary and booster vaccination. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds among boosted and booster eligible people.
ResultsOverall, 10,676 cases and 119,397 controls were included (6.1% and 7.8% occurred following a prior infection, respectively). The effectiveness of primary vaccination 14-149 days after 2nd dose was 36.1% (CI, 7.1% to 56.1%) for people with and 28.5% (CI, 20.0% to 36.2%) without prior infection. The odds ratio comparing boosted and booster eligible people with prior infection was 0.83 (CI, 0.56 to 1.23), whereas the odds ratio comparing boosted and booster eligible people without prior infection was 0.51 (CI, 0.46 to 0.56).
LimitationsMisclassification, residual confounding, reliance on TaqPath assay analyzed samples.
ConclusionWhile primary vaccination provided protection against BA.1 infection among people with and without prior infection, booster vaccination was only associated with additional protection in people without prior infection. These findings support primary vaccination in people regardless of prior infection status but suggest that infection history should be considered when evaluating the need for booster vaccination.
Primary Funding SourceBeatrice Kleinberg Neuwirth and Sendas Family Funds, Merck and Co through their Merck Investigator Studies Program, and the Yale Schools of Public Health and Medicine. | infectious diseases |
10.1101/2022.04.19.22273940 | High neutralizing activity against Omicron BA.2 can be induced by COVID-19 mRNA booster vaccination | The VOC of SARS-CoV-2, Omicron (BA.1, BA.1.1, BA.2, or BA.3), is associated with an increased risk of reinfection. BA.2 has become the next dominant variant worldwide. Although BA.2 infection has been shown to be mild illness, its high transmissibility will result in high numbers of cases. In response to the surge of Omicron BA.1 cases, booster vaccination was initiated in many countries. But there is limited evidence regarding the effectiveness of a booster vaccination against BA.2. We collected blood samples from 84 physicians at Kobe University Hospital, Japan, in January 2022 [~]7 months after they had received two BNT162b2 vaccinations and [~]2 weeks after their booster vaccination. We performed a serum neutralizing assay against BA.2 using authentic virus.
Although most of the participants had no or a very low titer of neutralizing antibody against BA.2 at 7 months after two BNT162b2 vaccinations, the titer increased significantly at 2 weeks after the booster vaccination. | infectious diseases |
10.1101/2022.04.19.22272855 | Estimated effectiveness of vaccines and extended half-life monoclonal antibodies against respiratory syncytial virus (RSV) hospitalizations in young children | Several vaccines and extended half-life monoclonal antibodies (mAbs) against RSV infection have shown promising progress in clinical trials. Aiming to project the impact of various prevention strategies against RSV hospitalizations in young children, we applied age-structured transmission models to evaluate prevention strategies including maternal immunization, live-attenuated vaccines, and long-lasting mAbs. Our results suggest that maternal immunization and long-lasting mAbs are highly effective in preventing RSV hospitalizations in infants under 6 months of age, averting more than half of RSV hospitalizations in neonates. Live-attenuated vaccines could reduce RSV hospitalizations in vaccinated age groups and are also predicted to have a modest effect in unvaccinated age groups because of disruptions to transmission. A seasonal vaccination program at the country level at most provides a minor advantage regarding efficiency. Our findings highlight the substantial public health impact that upcoming RSV prevention strategies may provide. | public and global health |
10.1101/2022.04.19.22274052 | Wastewater to clinical case (WC) ratio of COVID-19 identifies insufficient clinical testing, onset of new variants of concern and population immunity in urban communities | Clinical testing has been the cornerstone of public health monitoring and infection control efforts in communities throughout the COVID-19 pandemic. With the extant and anticipated reduction of clinical testing as the disease moves into an endemic state, SARS-CoV-2 wastewater surveillance (WWS) is likely to have greater value as an important diagnostic tool to inform public health. As the widespread adoption of WWS is relatively new at the scale employed for COVID-19, interpretation of data, including the relationship to clinical cases, has yet to be standardized. An in-depth analysis of the metrics derived from WWS is required for public health units/agencies to interpret and utilize WWS-acquired data effectively and efficiently. In this study, the SARS-CoV-2 wastewater signal to clinical cases (WC) ratio was investigated across seven different cities in Canada over periods ranging from 8 to 21 months. Significant increases in the WC ratio occurred when clinical testing eligibility was modified to appointment-only testing, identifying a period of insufficient clinical testing in these communities. The WC ratio decreased significantly during the emergence of the Alpha variant of concern (VOC) in a relatively non-immunized communitys wastewater (40-60% allelic proportion), while a more muted decrease in the WC ratio signaled the emergence of the Delta VOC in a relatively well-immunized communitys wastewater (40-60% allelic proportion). Finally, a rapid and significant decrease in the WC ratio signaled the emergence of the Omicron VOC, likely because of the variants greater effectiveness at evading immunity, leading to a significant number of new reported clinical cases, even when vaccine-induced community immunity was high. The WC ratio, used as an additional monitoring metric, complements clinical case counts and wastewater signals as individual metrics in its ability to identify important epidemiological occurrences, adding value to WWS as a diagnostic technology during the COVID-19 pandemic and likely for future pandemics. | epidemiology |
10.1101/2022.04.20.22274078 | Early detection of acute kidney injury in critically ill children: Predictive value of renal arterial Doppler assessment | ObjectiveRenal resistive index (RRI) and renal pulsatility index (RPI) are Doppler-based variables proposed to assess renal perfusion at the bedside in critically ill patients. This study aimed to assess the accuracy of such variables to predict acute kidney injury (AKI) in mechanically ventilated children.
DesignProspective single-center observational study
SettingPediatric intensive care unit of a quaternary care teaching hospital.
Patients84 children under controlled ventilation (median age of 5.1 months and weight of 6.6 kg).
InterventionsConsecutive children underwent renal Doppler ultrasound examination within 24 hours of invasive mechanical ventilation. Renal resistive index (RRI) and renal pulsatility index (RPI) were measured. The primary outcome was severe AKI (KDIGO stage 2 or 3) on day 3. Secondary outcomes included the persistence of severe AKI on day 5.
ResultsOn day 3, 22 patients were classified as having AKI (any stage), of which 12 were severe. RRI could effectively predict severe AKI (area under the ROC curve [AUC] 0.94; 95% CI 0.86 - 0.98; p < 0.001) as well as RPI (AUC 0.86; 95% CI 0.76 - 0.92; p < 0.001). The AUC of the IRR was significantly greater than that obtained from the RPI (p = 0.023). The optimal cutoff for RRI was 0.85 (sensitivity, 91.7%; specificity, 84.7%; positive predictive value, 50.0%; and negative predictive value 98.4%). Similar results were obtained when the accuracy to predict AKI on day 5 was assessed. Significant correlations were observed between RRI and estimated glomerular filtration rate at enrollment ({rho} = -0.495, p<0.001) and on day 3 ({rho} = -0.467, p <0.001).
ConclusionsRenal Doppler ultrasound may be a promising tool to predict AKI in critically ill children under invasive mechanical ventilation. | pediatrics |
10.1101/2022.04.20.22274061 | Vaccine effectiveness against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron SARS-CoV-2 variants: a nationwide Danish cohort study | BackgroundThe continued occurrence of more contagious SARS-CoV-2 variants and waning immunity over time require ongoing re-evaluation of the vaccine effectiveness (VE). This study aimed to estimate the effectiveness in two age groups (12-59 and 60 years or above) of two and three vaccine doses (BNT162b2 mRNA or mRNA-1273 vaccine) by time since vaccination against SARS-CoV-2 infection and COVID-19-related hospitalization in an Alpha, Delta and Omicron dominated period.
MethodsA Danish nationwide cohort study design was used to estimate VE against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha, Delta and Omicron variants. Information was obtained from nationwide registries and linked using a unique personal identification number. The study included all residents in Denmark aged 12 years or above (18 years or above for the analysis of three doses) in the Alpha (February 20 to June 15, 2021), Delta (July 4 to November 20, 2021) and Omicron (December 21, 2021 to January 31, 2022) dominated periods. VE estimates including 95% confidence intervals (CIs) were calculated using Cox proportional hazard regression models with adjustments for age, sex and geographical region. Vaccination status was included as a time-varying exposure.
FindingsIn the oldest age group, VE against infection after two doses was 91.0% (95% CI: 88.5; 92.9) for the Alpha variant, 82.2% (95% CI: 75.3; 87.1) for the Delta variant and 39.9% (95% CI: 26.4; 50.9) for the Omicron variant 14-30 days since vaccination. The VE waned over time and was 71.5% (95% CI: 54.7; 82.8), 49.8% (95% CI: 46.5; 52.8) and 4.7% (95% CI: 0.2; 8.9) >120 days since vaccination against the three variants, respectively. Higher estimates were observed after the third dose with VE estimates against infection of 86.0% (Delta, 95% CI: 83.3; 88.3) and 57.6% (Omicron, 95% CI: 55.8; 59.4) 14-30 days since vaccination. Among both age groups, VE against COVID-19-related hospitalization 14-30 days since vaccination with two or three doses was 94.8% or above for the Alpha and Delta variants, whereas among the youngest age group, VE estimates against the Omicron variant after two and three doses were 62.4% (95% CI: 46.3; 73.6) and 89.8% (95% CI: 87.9; 91.3), respectively.
ConclusionsTwo vaccine doses provided high protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Alpha and Delta variants with protection waning over time. Two vaccine doses provided only limited protection against SARS-CoV-2 infection and COVID-19-related hospitalization with the Omicron variant. The third vaccine dose substantially increased the protection against Delta and Omicron. | public and global health |
10.1101/2022.04.20.22274064 | Pediatric Diarrhea Patients Living in Urban Areas Have Higher Incidence of Clostridioides difficile Infection | Clostridioides difficile infection (CDI) is a major cause of antibiotic-associated diarrhea and an unappreciated contributor to child mortality in low- and middle-income countries where diagnosis may be difficult. There is little information about the prevalence of CDI among infants, children, and adolescents in Africa. Seventy-six samples were collected from pediatric patients presenting with diarrhea, including infants ([≤] 2 years old), children (2-12 years) and adolescents (13 [≤]17 years) from three hospitals between January and December 2019. Demographic data, medical history and prior antibiotic use were recorded. Toxigenic culture and PCR were used to detect and validate the presence of C. difficile in the samples. A total of 29 (38.7%), 39 (52.0%) and 7 (9.3%) samples were from infants, children, and adolescents, respectively. Average age of the patients was 4.4 years. Of these samples, 31 (41%) were positive for C. difficile by culture and were verified by PCR amplification of C. difficile specific genes (tcdA and tcdB). Most positive cases were children (53.3%) and infants (40.0%) with the majority of them residing in the urban areas. Forty-nine (66.2%) of the patients had no known antibiotics exposure, whereas 29.0% and 29.7% reported use of over-the-counter antibiotics at 14 and 90 days, prior to the hospital visit, respectively. CDI is relatively common among children with diarrhea in Northern Nigeria. Therefore, for effective management and treatment, more attention should be given to testing for C. difficile as one of the causative agents of diarrhea. | infectious diseases |
10.1101/2022.04.14.22273903 | Effects of COVID-19 in Care Homes - A Mixed Methods Review | IntroductionThe report provides an up-to-date review of the global effects of the COVID-19 pandemic in care homes. We used a mixed methods approach to assess care home mortality by country, how the deaths compared with previous periods, and how excess deaths may be explained. We retrieved national datasets for 25 countries on mortality, 17 cohort studies assessing deaths compared to a previous period, and 16 cohort studies reporting interventions or factors associated with excess mortality.
The COVID-19 pandemic disproportionately impacted those living in care homes at the highest risk for severe outcomes. However, the pandemic only highlighted and exacerbated a long-running problem: underfunding, poor structural layout, undertraining, under-skilling, under-equipping, and finally, lack of humanity in dealing with the most vulnerable members of society.
The 17 cohort studies point to excess mortality worsening during the pandemic. Despite involving vast numbers of care homes around the globe, the quality of the evidence is not good. For example, the majority of the studies infer the cause of extra deaths from the observation window (mainly the spring of 2020) rather than through detailed investigations. This is why we do not draw any clear conclusions about the specific causes of death, apart from noting their significantly high numbers. In addition, we did not review all policy actions since 2020 but note there has been a scarcity of studies since then - an indicator that interest in this problem has waned and likely not been addressed.
Analysis of national datasets for 25 countries shows that care home deaths were, on average, 30% of the total COVID-19 deaths (range: 9-64%). The quality of the current evidence base is limited, short term, and lacks standardised methods to prevent robust countrywide comparisons. Residual excess deaths were also observed, with excess mortality being reported for both COVID-19 positive and negative patients.
Several reported interventions or factors suggest the potential to mitigate the risk in care homes substantially. Interventions that could reduce mortality include improving the care home quality, increasing staffing levels, reducing the number of beds in the facility, employing staff confinement strategies with residents, and improving clinical care such as implementing daily examinations. Some care home solutions like US Green House homes, which usually have fewer than 12 beds, may provide crucial insights into the care home problem compared with larger homes. Furthermore, care home residents faced barriers accessing emergency treatments during the pandemic waves. Finally, interventions targeting care homes should be subject to smaller trials given large effect sizes in some studies.
Approximately one per cent of the global population resides in care homes, while care home residents account for nearly one-third of deaths attributed to COVID-19 in the 25 countries studied. Reducing this ratio requires analysing current care home infrastructures, funding models, and incentives for providing high-quality care. The scale of the problem in care homes requires robust evaluation and coordinated strategies to improve outcomes for those most vulnerable to COVID-19. Failure to address these systemic problems could mean global care home populations will be similarly affected by future crises and pandemics. | public and global health |
10.1101/2022.04.19.22274044 | The statistical analysis of daily data associated with different parameters of the New Coronavirus COVID-19 pandemic in Georgia and their monthly interval prediction from January 1, 2022 to March 31, 2022 | In this work results of the next statistical analysis of the daily data associated with New Coronavirus COVID-19 infection of confirmed (C), recovered (R), deaths (D) and infection rate (I) cases of the population of Georgia in the period from January 01, 2022 to March 31, 2022 are presented. It also presents the results of the analysis of monthly forecasting of the values of C, D and I. As earlier, the information was regularly sent to the National Center for Disease Control & Public Health of Georgia and posted on the Facebook page https://www.facebook.com/Avtandil1948/.
The analysis of data is carried out with the use of the standard statistical analysis methods of random events and methods of mathematical statistics for the non-accidental time-series of observations. In particular, the following results were obtained.
Georgias ranking in the world for Covid-19 monthly mean values of infection and deaths cases in investigation period (per 1 million population) was determined. Among 157 countries with population [≥] 1 million inhabitants in February 2022 Georgia was in the 4 place on new infection cases, in the 2 place on death. Georgia took the best place in terms of confirmed cases of diseases (thirty fifth) and in mortality (tenth) - in March.
A comparison between the daily mortality from Covid-19 in Georgia from January 01, 2022 to March 31, 2022 with the average daily mortality rate in 2015-2019 shows, that the largest share value of D from mean death in 2015-2019 was 43.1 % (January 04, 2022), the smallest 2.12 % (March 23, 2022).
As in previous works [10-13] the statistical analysis of the daily and decade data associated with coronavirus COVID-19 pandemic of confirmed, recovered, deaths cases and infection rate of the population of Georgia are carried out. Maximum daily values of investigation parameters are following: C = 26320 (February 2, 2022), R = 48486 (February 12, 2022), D = 67 (January 4,2022), I = 41.58 % (February 14, 2022). Maximum mean decade values of investigation parameters are following: C = 22214 (1 Decade of February 2022), R = 23408 (2 Decade of February 2022), D = 45 (2 Decade of February 2022), I = 32.12% (1 Decade of February 2022).
It was found that as in spring, summer and from September to December 2021 [10,11,13], in investigation period of time the regression equations for the time variability of the daily values of C, R, D and I have the form of a tenth order polynomial.
Mean values of speed of change of confirmed - V(C), recovered - V(R), deaths - V(D) and infection rate V(I) coronavirus-related cases in different decades of months for the indicated period of time were determined. Maximum mean decade values of investigation parameters are following: V(C) = +1079 cases/day (3 Decade of January 2022), V(R) = +1139 cases/day (1 Decade of February 2022), V(D) = +0.8 cases/day (1 Decade of February 2022), V(I) = + 1.16 %/ day (3 decades of January 2022).
Cross-correlations analysis between confirmed COVID-19 cases with recovered and deaths cases shows, that from January 1, 2022 to March 31, 2022 the maximum effect of recovery is observed on 3-6 days after infection (CR=0.83-0.84), and deaths - after 2 and 4 days (CR=0.60). The impact of the omicron variant of the coronavirus on people (recovery, mortality) could be up to19 and 16 days respectively.
Comparison of daily real and calculated monthly predictions data of C, D and I in Georgia are carried out. It was found that in investigation period of time daily and mean monthly real values of C, D and I mainly fall into the 67% - 99.99% confidence interval of these predicted values. Exception - predicted values of I for January 2022 (alarming deterioration, violation of the stability of a time-series of observations).
Traditionally, the comparison of data about C and D in Georgia (GEO) with similar data in Armenia (ARM), Azerbaijan (AZE), Russia (RUS), Turkey (TUR) and in the World (WRL) is also carried out. | epidemiology |
10.1101/2022.04.20.22274087 | Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD | BackgroundWhite matter hyperintensities (WMHs) are pathological changes that develop with increased age and are associated with cognitive decline. Most research on WMHs has neglected to examine regional differences and instead focuses on using a whole-brain approach. This study examined regional WMH differences between normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimers disease (AD). Another goal was to examine whether WMH burden was associated with declines in different cognitive domains in each of the groups.
MethodsParticipants were selected from the Alzheimers Disease Neuroimaging Initiative and included if they had at least one WMH measurement and cognitive scores examining global cognition, executive functioning, and memory. MCI and AD participants were included only if they were amyloid positive. A total of 1573 participants with 7381 follow-ups met inclusion criteria. Linear mixed-effects models were completed to examine group differences in WMH burden and the association between WMH burden and cognition in aging, MCI, and AD.
ResultsPeople with MCI and AD had increased total and regional WMH burden compared to cognitively healthy older adults. An association between WMH and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions of interest. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region.
ConclusionThese results suggest WMH burden increases from aging to AD. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between WMH and memory and WMH and global cognition. These findings suggest that WMH burden is associated with changes in cognition in healthy aging and early cognitive decline, but other biological changes may have a stronger impact on cognition with AD. | geriatric medicine |
10.1101/2022.04.20.22274067 | POPULATION ANALYSIS OF MORTALITY RISK: PREDICTIVE MODELS USING MOTION SENSORS FOR * 100,000 PARTICIPANTS IN THE UK BIOBANK NATIONAL COHORT | We have developed novel technology for health monitoring, which inputs motion sensors to predictive models of health status. We have validated these models in clinical experiments with carried smartphones, using only their embedded accelerometers. Using smartphones as passive monitors for population measurement is critically important for health equity, since they are ubiquitous in high-income countries already and will become ubiquitous in low-income countries in the near future. Our study simulates smartphones by using accelerometers as sensor input.
We analyzed 100,000 participants in UK Biobank who wore activity monitors with motion sensors for 1 week. This national cohort is demographically representative of the UK population, and this dataset represents the largest such available sensor record. We performed population analysis using walking intensity, with participants whose motion during normal activities included daily living equivalent of timed walk tests. We extract continuous features from sensor data, for input to survival analysis for predictive models of mortality risk.
Simulating population monitoring, we validated predictive models using only sensors and demographics. This resulted in C-index of 0.76 for 1-year risk decreasing to 0.73 for 5-year. A minimum set of sensor features achieves similar C-index with 0.72 for 5-year risk, which is similar accuracy to previous studies using methods not achievable with phone sensors. The minimum model uses average acceleration, which has predictive value independent of demographics of age and sex, as does the physical measure of gait speed. Our digital health methods achieve the same accuracy as activity monitors measuring total activity, despite using only walking sessions as sensor input, orders of magnitude less than existing methods.
AUTHOR SUMMARYSupporting healthcare infrastructure requires screening national populations with passive monitors. That is, looking for health problems without intruding into daily living. Digital health offers potential solutions if sensor devices of adequate accuracy for predictive models are already widely deployed. The only such current devices are cheap phones, smartphone devices with embedded sensors. This limits the measures to motion sensors when the phones are carried during normal activities. So measuring walking intensity is possible, but total activity is not.
Our study simulates smartphone sensors to predict mortality risk in the largest national cohort with sensor records, the demographically representative UK Biobank. Death is the most definite outcome, accurate death records are available for 100,000 participants who wore sensor devices some five years ago. We analyzed this dataset to extract walking sessions during daily living, then used these to predict mortality risk. The accuracy achieved was similar to activity monitors measuring total activity and even to physical measures such as gait speed during observed walks. Our scalable methods offer a potential pathway towards national screening for health status. | health informatics |
10.1101/2022.04.20.22274106 | Effects of multiple-dose intranasal oxytocin treatment on social responsiveness in children with autism: A randomized, placebo-controlled trial | In the past decade, intranasal administration of the neuropeptide oxytocin is increasingly explored as a new treatment for reducing the core symptoms of autism spectrum disorder (ASD). The efficacy of continual oxytocin treatment in school-aged children with ASD is, however, not well established. Using a double-blind, randomized, placebo-controlled, parallel design, the current trial explored the effects of four weeks of intranasal oxytocin treatment (12 IU, twice daily) on social functioning in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). The double-blind phase was followed by a four-week single-blind extension phase during which all participants received intranasal oxytocin. In the double-blind phase, no treatment-specific effects were identified in the primary outcome assessing social functioning (parent-rated Social Responsiveness Scale), as well as on secondary outcomes assessing repetitive behaviors, anxiety, and attachment. Exploratory moderator analyses revealed that children who received the oxytocin treatment in combination with concomitant psychosocial treatment displayed a greater benefit than those who received psychosocial treatment or oxytocin alone. A modulating effect of parents beliefs about allocated treatment was also identified, indicating that parents who believed their child assigned to the active treatment reported greater benefit than those who believed their child received placebo, particularly in the actual oxytocin group. Finally, participants who were allocated to receive the placebo treatment during the double-blind phase of the trial and later crossed-over to receive the active treatment during the single-blind extension phase, displayed a significant within-group improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. While no overall treatment-specific improvements were identified, our results provide important indications that clinical efficacy can be augmented when oxytocin administration is paired with targeted psychosocial interventions that similarly stimulate socio-communicative behaviors. Future trials are urged to further elucidate the potential of embedding oxytocin treatment within a socially stimulating context. | psychiatry and clinical psychology |
10.1101/2022.04.18.22273840 | "Younger women had more access to COVID-19 information": An Intersectional Analysis of Factors Influencing Women and Girls' Access to COVID-19 Information in Rohingya and Host Communities in Bangladesh | IntroductionThe Rohingya and Bangladeshi host communities live at a heightened risk of COVID-19 impact due to their pre-existing vulnerabilities, religious beliefs, and strict socio-cultural and gender norms that render primarily women and girls vulnerable. However, the extent of this vulnerability varies within and across population groups in the host and Rohingya communities. The intersectionality lens helps identify, recognize, and understand these factors that create inequities within populations. This study explored the factors that influenced the women and girls access to information during the COVID-19 pandemic through an intersectional lens.
MethodologyThis paper presents partial findings from the exploratory qualitative part of mixed-method research conducted in ten Rohingya camps and four wards of the adjacent host communities in Coxs Bazar, Bangladesh. Data were extracted from 24 in-depth interviews (12 in each community) conducted from November 2020 to March 2021 with diverse participants, including adolescent girls, younger women, adult women, pregnant and lactating mothers, persons with disabilities, older adults, and single female-household heads. All participants provided verbal informed consent before the interviews. In the case of the adolescents, assent was taken from the participants, and verbal informed consent was taken from their parents/guardians. The ethical clearance of this study was sought from the institutional review board of BRAC James P Grant School of Public Health, BRAC University.
ResultWe find that the women and girls living in Rohingya communities exhibit a more profound structural interplay of factors within their socio-ecological ecosystem depending on their age, power, and position in the society, physical (dis)abilities, and pre-existing vulnerabilities stemming from their exodus, making them more vulnerable to COVID-19 impact by hindering their access to information. Unlike Rohingya, the host women and girls explain the impact of the COVID-19 pandemic on their access to information through the lens of intergenerational poverty and continuous strain on existing resources, thereby highlighting shrinking opportunities due to the influx, COVID-19 infodemic and misinformation, access to digital devices amongst the adolescents, and restricted mobility mainly due to transport, school closures, and distance-related issues. Moreover, the socio-cultural beliefs and the gender norms imposed on women and adolescent girls played an essential role in accessing information regarding the COVID-19 pandemic and consequently influenced their perception of and response to the disease and its safety protocols. Socio-cultural gender norms led to mobility restrictions, which compounded by lockdowns influenced their access to information resulting in dependency on secondary sources, usually from male members of their families, which can easily mislead/provide mis/partial information. The younger age groups had more access to primary sources of information and a broader support network. In comparison, the older age groups were more dependent on secondary sources, and their social networks were limited to their family members due to their movement difficulty because of age/aging-related physical conditions.
ConclusionThis study explored and analyzed the intersectional factors that influenced the women and girls access to information during the COVID-19 pandemic from two contexts with varying degrees of pre-existing vulnerability and its extent. These include gender, age, state of vulnerability, power and privilege, socio-economic status, and physical (dis)ability. It is imperative that services geared towards the most vulnerable are contextualized and consider the intersectional factors that determine the communities access to information. | public and global health |
10.1101/2022.04.20.22274071 | Specific gait changes in prodromal hereditary spastic paraplegia type 4 - The preSPG4 study | BackgroundIn hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested.
ObjectivesIdentification of specific movement abnormalities before manifestation of gait impairment and quantification of disease progression in the prodromal phase.
Methods70 subjects participated in gait assessment, including 30 prodromal SPAST mutation carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy controls. Gait was assessed by an infrared-camera-based motion capture system to analyze features like range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale (SPRS) and neurofilament light chain (NfL) as a fluid biomarker indicating neurodegeneration.
ResultsCompared to healthy controls, we found an altered gait pattern in prodromal mutation carriers during the swing phase in segmental angles of the lower leg (p<0.05) and foot (p<0.01), and in heel ground clearance (p<0.01). Furthermore, ranges of motion of segmental angles were reduced for foot (p<0.001) and lower leg (p<0.01). These changes occurred in prodromal mutation carriers without quantified leg spasticity in clinical examination. Gait features correlated with NfL levels and SPRS score.
ConclusionGait analysis can quantify changes in prodromal and mild-to-moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages. | neurology |
10.1101/2022.04.19.22274039 | School Feeding Programmes and Physical Nutrition Outcomes of Primary School Children in Developing Countries | ContextSchool feeding programmes have been widely implemented and particularly in developing countries with the aim to improve school enrolment and attendance especially of girls and to reduce short term hunger to improve childrens performance in school.
Beyond the first 1000 days of the lives of children, school feeding programmes remain one of the critical interventions that have used schools as a platform to contribute to the fulfilment of their nutritional needs though the evidence to this effect is little and mixed.
ObjectiveThis review focused on assessing the impact of school feeding programmes on reduction in underweight, thinness, and stunting among primary school children in developing countries.
Data sourcesElectronic searches were carried out in PUBMED, SCORPUS and Cochrane library. The WHO clinical trials registry as well as reference lists of relevant articles were also hand searched.
Data ExtractionData was extracted from included studies which have been published in the past 10 years (2010 - August 2021) from original research where the main intervention was the provision of school based meals.
Data analysisMeta-analysis was conducted to determine changes in height-for-age (HAZ), weight-for-age (WAZ) and BMI-for-age (BAZ) z scores. A random effects model was applied to determine the mean difference in all outcomes of interest which were evaluated as continuous variables.
ResultsChildren aged 3 - 16 years were enrolled in the included studies and the number of participants ranged between 321 and 2,869 across studies. Of the included studies, the feeding intervention provided for a minimum of 30% RDA for the age group with the intervention lasting up to a maximum of 34 weeks. The impact of school feeding intervention on HAZ, BAZ and WAZ showed statistically non-significant (p>0.05) mean differences of 0.02 (95% CI, -0.06 to 0.10), 0.11 (95% CI, -0.01 to 0.23) and 0.06 (95% CI, -0.04 to 0.16) respectively
ConclusionSchool feeding interventions have not shown any significant positive effect on the physical nutrition outcomes of primary school children. Short duration of intervention of studies, poor compliance to feeding and substitution of school meals could have accounted for the weak effect sizes. | nutrition |
10.1101/2022.04.18.22273850 | Incorporating Genetic Determinants of Prostate-Specific Antigen Levels Improves Prostate Cancer Screening | Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. We evaluated the potential of genetic determinants of PSA levels to improve screening utility by accounting for variation in PSA not due to cancer. A multi-ancestry genome-wide meta-analysis of 95,768 men without prostate cancer discovered 128 PSA-associated index variants (P<5x10-8), including 82 novel signals. The resulting 128-variant polygenic score for PSA (PGSPSA) explained 7.3-8.8% of PSA variation in external validation cohorts. Adjusting PSA values using PGSPSA enabled more accurate diagnostic decisions, such as avoiding 17-20% of negative prostate biopsies. Genetically adjusted PSA was more predictive of aggressive prostate cancer (odds ratio (OR)=3.04, P=3.3x10-7; AUC=0.716) than unadjusted PSA (OR=2.80, P=3.2x10-6; AUC=0.684) and improved detection of aggressive disease when combined with a prostate cancer PGS (AUC: 0.732 vs. 0.645, P=3.3x10-4). We further showed that PSA-related selection bias distorts genetic associations with prostate cancer and hampers PGS performance. Our findings provide a roadmap towards personalizing cancer biomarkers and screening. | genetic and genomic medicine |