title: Alcohol consumption and telomere length: observational and Mendelian randomization approaches

abstract: Alcohols impact on telomere length, a proposed marker of biological age, is unclear. We performed the largest observational study to date and compared findings with Mendelian randomization (MR) estimates. Two-sample MR used data from a recent genome-wide association study (GWAS) of telomere length. Genetic variants were selected on the basis of associations with alcohol consumption and alcohol use disorder (AUD). Non-linear MR employed UK Biobank individual data. MR analyses suggest a causal relationship between alcohol and telomere length: both genetically predicted alcohol traits were inversely associated with telomere length. 1 S.D. higher genetically-predicted log-transformed alcoholic drinks weekly had a -0.07 S.D. effect on telomere length (95% confidence interval [CI]:-0.14 to -0.01); genetically-predicted AUD - 0.06 S.D. effect (CI:-0.10 to -0.02). Results were consistent across methods and independent from smoking. Non-linear analyses indicated a potential threshold relationship between alcohol and telomere length. Our findings have implications for potential aging-related disease prevention strategies.

category: addiction medicine


title: Examining Health Service Rates Among Residents of Retirement Homes and Other Older Adult Populations in Ontario, Canada: A Population-Based Cohort Study

abstract:
BackgroundThere are no standardized reporting systems or assessments specific to residents of retirement homes in North America. As such, little is known about these older adults as a distinct population. We created a new population-level cohort of residents of retirement homes and examined their health service rates relative to other older adult populations.

MethodsWe conducted a population-based retrospective cohort study in Ontario, Canada in 2018. The postal codes of all licensed retirement homes (n = 757) were classified and linked to individual-level health system administrative data to derive a cohort of residents of retirement homes. A generalized linear model with a gamma distribution and log link function was used to model rates of emergency department visits, hospitalizations, alternate levels of care (ALC) days, primary care visits, and specialist physician visits.

ResultsResidents of retirement homes comprised two percent of the older adult population in Ontario (n = 54,773; 2.3%). After adjustment for relevant characteristics, residents of retirement homes had 10 times the rate of emergency department visits (Relative Rate [RR] 10.02, 95% Confidence Interval [CI] 9.83 to 10.21), 20 times the rate of hospitalizations (RR 20.43, 95% CI 20.08 to 20.78), and 44 times the rate ALC days (RR 43.91, 95% CI 43.28 to 44.54) compared to community-dwelling older adults.

InterpretationResidents of retirement homes are a distinct older adult population with high rates of hospital-based care. Our findings contribute to policy debates about the provision of health care in privately operated congregate care settings for older adults.

category: geriatric medicine


title: Optimized Post-Vaccination Strategies and Preventative Measures for SARS-CoV-2

abstract:
IntroductionSince March of 2020, over 210 million SARS-CoV-2 cases have been reported and roughly five billion doses of a SARS-CoV-2 vaccine have been delivered. The rise of the more infectious delta variant has recently indicated the value of reinstating previously relaxed non-pharmacological and test-driven preventative measures. These efforts have been met with resistance, due, in part, to a lack of site-specific quantitative evidence which can justify their value. As vaccination rates continue to increase, a gap in knowledge exists regarding appropriate thresholds for escalation and de-escalation of COVID-19 preventative measures.

MethodsWe conducted a series of simulation experiments, trialing the spread of SARS-CoV-2 virus in a hypothesized working environment that is subject to COVID-19 infections from the surrounding community. We established cohorts of individuals who would, in simulation, work together for a set period of time. With these cohorts, we tested the rates of workplace and community acquired infections based on applied isolation strategies, community infection rates (CIR), scales of testing, non-pharmaceutical interventions, variant predominances and testing strategies, vaccination coverages, and vaccination efficacies of the members included. Permuting through each combination of these variables, we estimated expected case counts for 33,462 unique workplace scenarios.

ResultsWhen the CIR is 5 new confirmed cases per 100,000 or fewer, and at 50% of the workforce is vaccinated with a 95% efficacious vaccine, then testing daily with an antigen-based or PCR based test in only unvaccinated workers will result in less than one infection through 4,800 person weeks. When the community infection rate per 100,000 persons is less than or equal to 60, and the vaccination coverage of the workforce is 100% with 95% vaccine efficacy then no masking or routine testing + isolation strategies are needed to prevent workplace acquired infections regardless of variant predominance. Identifying and isolating workers with antigen-based SARS-CoV-2 testing methods results in the same or fewer workplace acquired infections than testing with polymerase chain reaction (PCR) methods.

ConclusionsSpecific scenarios exist in which preventative measures taken to prevent SARS-CoV-2 spread, including masking, and testing plus isolation strategies can safely be relaxed. Further, efficacious testing with quarantine strategies exist for implementation in only unvaccinated cohorts in a workplace. Due to shorter turnaround time, antigen-based testing with lower sensitivity is more effective than PCR testing with higher sensitivities in comparable testing strategies. The general reference interactive heatmap we provide can be used for site specific, immediate, parameter-based case count predictions to inform appropriate institutional policy making.

category: health informatics


title: The Relationship of Vaccine Uptake and COVID-19 Infections among Nursing Home Staff and Residents in Missouri

abstract: Nursing homes (NH) continue to struggle with COVID-19 morbidity and mortality with older adult residents at greater risk of infection due to proximity to other residents, advanced aging-related chronic illnesses, and contact with staff. While many states have prioritized COVID-19 vaccinations among older adults, vaccinations among NH staff vary. The purpose of this study was to quantify the relationship between nursing home staff vaccination uptake and COVID-19 infections among residents. A zero-inflated Poisson regression model was constructed to predict the weekly number of COVID-19 cases among Missouri nursing home residents using data from the Centers for Medicaid and Medicare Services. A total of 1,124 COVID-19 infections were reported among 504 NH residents between January 1, 2021 and August 22, 2021. After adjusting for number of total residents, resident vaccine rate, staff quality rating, and respective county COVID-19 rate, for every percent increase in nursing home staff vaccine rate the risk of COVID-19 infections significantly decreased by 13% (IRR 0.87, 95% CI 0.81, 0.93). This study identified that NH staff, likely due to greater mobility, are important to prioritize in vaccination efforts to protect themselves and residents of their facilities from COVID-19 infections. Further, the CMS staff ratings were significant predictors of infection as well, which highlight the structural challenges that exist within and outside the context of a highly infectious and deadly pandemic. These results also provide insights to optimizing vaccination roll-out to best protect our communities most vulnerable residents.

category: infectious diseases


title: Long Term Physical, Mental and Social Health Effects of COVID-19 in the Pediatric Population: A Scoping Review

abstract:
BackgroundThe majority of COVID-19 symptom presentations in adults and children appear to run their course within a couple of weeks. However, a subgroup of adults has started to emerge with effects lasting several months or more after initial infection. However, little is known about long term physical, mental and social health effects of COVID-19 in the pediatric population. The purpose of this review was to determine these impacts well into the second year of the pandemic.

MethodsA search was conducted using PUBMED, Web of Science, Science Direct, and COCHRANE between 11/1/2019 and 9/1/2021. Search inclusion criteria were as follows: (1) COVID-19 illness and symptoms in children; (2) SARS-COv2 in children; (3) English language; and (4) human studies only.

ResultsThe few studies that have documented long-term physical symptoms in children show that fatigue, difficulty in concentrating (brain fog), sleep disturbances, and sensory problems are the most reported outcomes. Most studies examining the impact of COVID-19 in pediatric populations have focused on initial clinical presentation, and symptoms, which are similar to those in adult populations. Additionally, COVID-19 has had a moderate impact on children and adolescents social environment, which may exacerbate current and future physiological, psychological, behavioral, and academic outcomes.

ConclusionsThere are limited studies reporting long physical symptoms of COVID-19 in the pediatric population. However, pediatric COVID-19 cases are underreported due to low rates of testing and symptomatic infection, which calls for more longitudinal studies. Children who have experienced COVID-19 illness should be monitored for long physiological, psychological, behavioral, and academic outcomes.


title: Mortality Outcomes in Task-Sharing for Emergency Care: Impact of Emergency Physician Supervision on Non-Physician Emergency Care in Rural Uganda

abstract:
IntroductionEmergency care (EC) capacity is limited by physician shortages in low- and middle-income countries like Uganda. Task-sharing -- delegating tasks to more narrowly trained cadres -- including EC nonphysician clinicians (NPCs) is a proposed solution. However, little data exists to guide emergency medicine (EM) physician supervision of NPCs. This studys objective was to assess the mortality impact of decreasing EM physician supervision of EC NPCs.

MethodsRetrospective analysis of prospectively collected data from an EC NPC training program in rural Uganda included three cohorts: "Direct" (2009-2010): EM physicians supervised all NPC care; "Indirect" (2010-2015): NPCs consulted EM physicians on an ad hoc basis; "Independent" (2015-2019): NPC care without EM physician supervision. Multivariable logistic regression analysis of three-day mortality included demographics, vital signs, co-morbidities and supervision. Sensitivity analysis stratified patients by numbers of abnormal vital signs.

ResultsOverall, 38,344 ED visits met inclusion criteria. From the "Direct" to the "Unsupervised" period patients with [≥]3 abnormal vitals (25.2% to 10.2%, p<0.001) and overall mortality (3.8% to 2.7%, p<0.001) decreased significantly. "Indirect" and "Independent" supervision were independently associated with increased mortality compared to "Direct" supervision ("Indirect" Odds Ratio (OR)=1.49 [95%CI 1.07 - 2.09], "Independent" OR=1.76 [95%CI 1.09 - 2.86]). The 86.2% of patients with zero, one or two abnormal vitals had similar mortality across cohorts, but the 13.8% of patients with [≥]3 abnormal vitals had significantly reduced mortality with "Direct" supervision ("Indirect" OR=1.75 [95%CI 1.08 - 2.85], "Independent" (OR=2.14 [95%CI 1.05 - 4.34]).

Conclusion"Direct" EM physician supervision of NPC care significantly reduced overall mortality as the highest risk [~]10% of patients had nearly 50% reduction in mortality. However, for the other [~]90% of ED visits, independent EC NPC care had similar mortality outcomes as directly supervised care, suggesting a synergistic model could address current staffing shortages limiting EC access and quality.

SUMMARY BOXO_ST_ABSWhat is already known?C_ST_ABSO_LIPhysician shortages and lack of specialty training limit implementation of emergency care and associated reductions in mortality in low- and middle-income countries (LMIC) such as Uganda.
C_LIO_LITask-sharing, often to non-physician clinicians, is proposed as a solution however data to support safe, effective training and physician supervision protocols is limited.
C_LI

What are the new findings?O_LIThe highest risk 10% of emergency care patients have approximately a 50% reduction in mortality when non-physician clinicians are directly supervised by emergency medicine physicians.
C_LIO_LIFor most emergency care patients (the lowest risk 90%) independent emergency care by non-physician clinicians provides similar morality outcomes to direct supervision by an emergency medicine physician.
C_LI

What do the new findings imply?O_LITraining of both emergency care physicians and non-physician clinicians is essential, as physicians provide improved mortality outcomes, especially for the critically ill, and non-physician clinicians will help address lack of trained and available emergency care providers in a timely, cost-effective manner.
C_LIO_LIPhysician supervision of all emergency care is the penultimate goal, however non-physician clinicians can be trained to provide comparable morality outcomes for the vast majority of patients when practicing independently.
C_LIO_LITriage protocols are needed to identify high-risk emergency care patients, such as those with 3 or more abnormal vital signs, for early involvement of an emergency physician either directly, or through supervision of a non-physician clinician.
C_LI

category: public and global health


title: Dichotomy between the humoral and cellular responses elicited by mRNA and adenoviral vector vaccines against SARS-CoV-2.

abstract: Protection from severe disease and hospitalization by SARS-CoV-2 vaccination has been amply demonstrated by real-world data. However, the rapidly evolving pandemic raises new concerns. One pertains efficacy of adenoviral vector-based vaccines, particularly the single-dose Ad26.COV2.S, relative to mRNA vaccines. We investigated the immunogenicity of Ad26.COV2.S and mRNA vaccines in 33 subjects vaccinated with either vaccine class five months earlier on average. After controlling for time since vaccination, Spike-binding antibody and neutralizing antibody levels were higher in the mRNA-vaccinated subjects, while no significant differences in antigen-specific B cell and T cell responses were observed between the two groups. Thus, a dichotomy exists between humoral and cellular responses elicited by the two vaccine classes. Our results have implications for the need of booster doses in vaccinated subjects and might explain the dichotomy reported between the waning protection from symptomatic infection by SARS-CoV-2 vaccination and its persisting efficacy in preventing hospitalization and death.


title: Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a sixteen-week interval between doses

abstract: While the standard regimen of the BNT162b2 mRNA vaccine includes two doses administered three weeks apart, some public health authorities decided to space them, raising concerns about vaccine efficacy. Here, we analyzed longitudinal humoral responses including antibody binding, Fc-mediated effector functions and neutralizing activity against the D614G strain but also variants of concern and SARS-CoV-1 in a cohort of SARS-CoV-2 naive and previously infected individuals, with an interval of sixteen weeks between the two doses. While the administration of a second dose to previously infected individuals did not significantly improve humoral responses, we observed a significant increase of humoral responses in naive individuals after the 16-weeks delayed second shot, achieving similar levels as in previously infected individuals. We compared these responses to those elicited in individuals receiving a short (4-weeks) dose interval. For the naive donors, these responses were superior to those elicited by the short dose interval.


title: Estimates of presumed population immunity to SARS-CoV-2 by state in the United States, August 2021

abstract:
BackgroundInformation is needed to monitor progress toward a level of population immunity to SARS-CoV-2 sufficient to disrupt viral transmission. We estimated the percentage of the United States (US) population with presumed immunity to SARS-CoV-2 due to vaccination, natural infection, or both as of August 26, 2021.

MethodsPublicly available data as of August 26, 2021, from the Centers for Disease Control and Prevention (CDC) were used to calculate presumed population immunity by state. Seroprevalence data were used to estimate the percentage of the population previously infected with SARS-CoV-2, with adjustments for underreporting. Vaccination coverage data for both fully and partially vaccinated persons were used to calculate presumed immunity from vaccination. Finally, we estimated the percentage of the total population in each state with presumed immunity to SARS-CoV-2, with a sensitivity analysis to account for waning immunity, and compared these estimates to a range of population immunity thresholds.

ResultsPresumed population immunity varied among states (43.1% to 70.6%), with 19 states with 60% or less of their population having been infected or vaccinated. Four states have presumed immunity greater than thresholds estimated to be sufficient to disrupt transmission of less infectious variants (67%), and none were greater than the threshold estimated for more infectious variants (78% or higher).

ConclusionsThe US remains a distance below the threshold sufficient to disrupt viral transmission, with some states remarkably low. As more infectious variants emerge, it is critical that vaccination efforts intensify across all states and ages for which the vaccines are approved.

SummaryAs of August 26, 2021, no state has reached a population level of immunity thought to be sufficient to disrupt transmission. (78% or higher), with some states having remarkably low presumed immunity.


title: Decreased door-to-balloon time in patients with ST-segment elevation myocardial infarction during the early COVID-19 pandemic in South Korea - an observational study

abstract:
BackgroundThe coronavirus disease 2019 (COVID-19) resulted in a marked decrease in the number of patient visits for acute myocardial infarction (AMI) and delayed patient response and intervention in several countries. This study evaluated the effect of the COVID-19 pandemic on the number of patients, patient response time (pain-to-door), and intervention time (door-to-balloon) for patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI).

MethodsPatients with STEMI or NSTEMI visiting a hospital in South Korea who underwent primary coronary intervention during the COVID-19 pandemic (January 29, 2020, to December 31, 2020) were compared with those in the equivalent period in 2018 to 2019. Patient response and intervention times were compared for the COVID-19 pandemic window (2020) and the equivalent period in 2018 to 2019.

ResultsWe observed no decrease in the number of patients with STEMI (P=0.50) and NSTEMI (P=0.94) during the COVID-19 pandemic compared to that in the previous years. Patient response times (STEMI: P=0.34; NSTEMI: P=0.89) during the overall COVID-19 pandemic period did not differ significantly. However, we identified a significant decrease in time to intervention among patients with STEMI (14%; p<0.01) during the early COVID-19 pandemic.

ConclusionsWe found that the number of patient with STEMI and NSTEMI was consistent during the COVID-19 pandemic and that no time delays in patient response and intervention occurred. However, the door-to-balloon time among patients with STEMI significantly reduced during the early COVID-19 pandemic, which could be attributed to reduced emergency care utilization during the early pandemic.

category: cardiovascular medicine


title: Absence of Excess Mortality in a Highly Vaccinated Population During the Initial Covid-19 Delta Period.

abstract:
BackgroundAll-cause excess mortality (the number of deaths that exceed projections in any period) has been widely reported during the Covid-19 pandemic. Whether excess mortality has occurred during the Delta wave is less well understood.

MethodsWe performed an observational study using data from the Massachusetts Department of Health. Five years of US Census population data and CDC mortality statistics were applied to a seasonal autoregressive integrated moving average (sARIMA) model to project the number of expected deaths for each week of the pandemic period, including the Delta period (starting in June 2021, extending through August 28th 2021, for which mortality data are >99% complete). Weekly Covid-19 cases, Covid-19-attributed deaths, and all-cause deaths are reported. County-level excess mortality during the vaccine campaign are also reported, with weekly rates of vaccination in each county that reported 100 or more all-cause deaths during any week included in the study period.

ResultsAll-cause mortality was not observed after March 2021, by which time over 75% of persons over 65 years of age in Massachusetts had received a vaccination. Fewer deaths than expected (which we term  deficit mortality) occurred both during the summer of 2020, the spring of 2021 and during the Delta wave (beginning June 13, 2021 when Delta isolates represented >10% of sequenced cases). After the initial wave in the spring of 2020, more Covid-19-attributed deaths were recorded that all-cause excess deaths, implying that Covid-19 was misattributed as the underlying cause, rather than a contributing cause of death in some cases.

ConclusionIn a state with high vaccination rates, excess mortality has not been recorded during the Delta period. Deficit mortality has been recorded during this period.

category: epidemiology


title: Equivalency of Protection from Natural Immunity in COVID-19 Recovered Versus Fully Vaccinated Persons: A Systematic Review and Pooled Analysis

abstract:
BACKGROUNDWe present a systematic review and pooled analysis of clinical studies to date, that (1) specifically compare the protection of natural immunity in the COVID-recovered versus the efficacy of full vaccination in the COVID-naive, and (2) the added benefit of vaccination in the COVID-recovered, for prevention of subsequent SARS-CoV-2 infection.

METHODSUsing the PRISMA 2020 guidance, we first conducted a systematic review of available literature on PubMed, MedRxIV and FDA briefings to identify clinical studies either comparing COVID vaccination to natural immunity or delineating the benefit of vaccination in recovered individuals. After assessing for eligibility, studies were qualitatively appraised and formally graded using the NOS system for observational, case-control and RCTs. Incidence rates were tabulated for the following groups: never infected (NI) and unvaccinated (UV), NI and vaccinated (V), previously infected (PI) and UV, PI and UV. Pooling was performed by grouping the RCTs and observational studies separately, and then all studies in total. Risk ratios and risk differences are reported for individual studies and pooled groups, in 1) NPI/V vs. PI/UV and 2) PI/UV vs. PI/V analysis. In addition, number needed to treat (NNT) analysis was performed for vaccination in naive and previously infected cohorts.

RESULTSNine clinical studies were identified including three randomized controlled studies, four retrospective observational cohorts, one prospective observational cohort, and a case-control study. The NOS quality appraisals of these articles ranged from four to nine (out of nine stars). All of the included studies found at least statistical equivalence between the protection of full vaccination and natural immunity; and, three studies found superiority of natural immunity. Four observational studies found a statistically significant incremental benefit to vaccination in the COVID-recovered individuals. In total pooled analysis, incidence in NPI/V trended higher than PI/UV groups (RR=1.86 [95%CI 0.77-4.51], P=0.17). Vaccination in COVID-recovered individuals provided modest protection from reinfection (RR=1.82 [95%CI 1.21-2.73], P=0.004), but the absolute risk difference was extremely small (AR= 0.004 person-years [95% CI 0.001-0.007], P=0.02). The NNT to prevent one annual case of infection in COVID-recovered patients was 218, compared to 6.5 in COVID-naive patients, representing a 33.5-fold difference in benefit between the two populations.

CONCLUSIONSWhile vaccinations are highly effective at protecting against infection and severe COVID-19 disease, our review demonstrates that natural immunity in COVID-recovered individuals is, at least, equivalent to the protection afforded by full vaccination of COVID-naive populations. There is a modest and incremental relative benefit to vaccination in COVID-recovered individuals; however, the net benefit is marginal on an absolute basis. COVID-recovered individuals represent a distinctly different benefit-risk calculus. Therefore, vaccination of COVID-recovered individuals should be subject to clinical equipoise and individual preference.


title: An Analysis of SARS-CoV-2 Vaccine Breakthrough Infections and Associated Clinical Outcomes

abstract: Understanding the rate and clinical features associated with vaccine breakthrough infections (VBT) is of critical public health importance. Recent evidence on VBT in Barnstable County, Massachusetts, has prompted guidance on masking for vaccinated individuals in areas of high community-level transmission.1 Additional data is needed to better understand the prevalence and rate of VBT infections. Using detailed disease investigation data from Washoe County, Nevada we sought to assess the rate of symptomatic infection and serious illness among VBT cases compared to non-vaccinated individuals with COVID-19. From February 12 - July 29, 2021, the Washoe County Health District identified and traced 6,128 out of 6,399 reported cases across the sample period. 338 (5.5%) of all cases were identified as breakthrough infections, and 289 (86%) vaccinated individuals had symptomatic infections. Severe clinical outcomes were infrequent with 17 hospitalizations (5% of VBT) and no deaths. Cycle threshold values were not statistically different between vaccinated and unvaccinated individuals.


title: Characteristics and outcomes of an international cohort of 400,000 hospitalised patients with Covid-19

abstract:
BackgroundPolicymakers need robust data to respond to the COVID-19 pandemic. We describe demographic features, treatments and clinical outcomes in the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) COVID-19 cohort, the worlds largest international, standardised cohort of hospitalised patients.

MethodsThe dataset analysed includes COVID-19 patients hospitalised between January 2020 and May 2021. We investigated how symptoms on admission, comorbidities, risk factors, and treatments varied by age, sex, and other characteristics. We used Cox proportional hazards models to investigate associations between demographics, symptoms, comorbidities, and other factors with risk of death, admission to intensive care unit (ICU), and invasive mechanical ventilation (IMV).

Findings439,922 patients with laboratory-confirmed (91.7%) or clinically-diagnosed (8.3%) SARS-CoV-2 infection from 49 countries were enrolled. Age (adjusted hazard ratio [HR] per 10 years 1.49 [95% CI 1.49-1.50]) and male sex (1.26 [1.24-1.28]) were associated with a higher risk of death. Rates of admission to ICU and use of IMV increased with age up to age 60, then dropped. Symptoms, comorbidities, and treatments varied by age and had varied associations with clinical outcomes. Tuberculosis was associated with an 86% higher risk of death, and HIV with an 87% higher risk of death. Case fatality ratio varied by country partly due to differences in the clinical characteristics of recruited patients.

InterpretationThe size of our international database and the standardized data collection method makes this study a reliable and comprehensive international description of COVID-19 clinical features. This is a viable model to be applied to future epidemics.

FundingUK Foreign, Commonwealth and Development Office, the Bill & Melinda Gates Foundation and Wellcome. See acknowledgements section for funders of sites that contributed data.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo identify large, international analyses of hospitalised COVID-19 patients that used standardised data collection, we conducted a systematic review of the literature from 1 Jan 2020 to 28 Apr 2020. We identified 78 studies, with data from 77,443 people (1) predominantly from China. We could not find any studies including data from low and middle-income countries. We repeated our search on 18 Aug 2021 but could not identify any further studies that met our inclusion criteria.

Added value of this studyOur study uses standardised clinical data collection to collect data from a vast number of patients across the world, including patients from low-, middle-, and high-income countries. The size of our database gives us great confidence in the accuracy of our descriptions of the global impact of COVID-19. We can confirm findings reported by smaller, country-specific studies and compare clinical data between countries. We have demonstrated that it is possible to collect large volumes of standardised clinical data during a pandemic of a novel acute respiratory infection. The results provide a valuable resource for present policymakers and future global health researchers.

Implications of all the available evidencePresenting symptoms of SARS-CoV-2 infection in patients requiring hospitalisation are now well-described globally, with the most common being fever, cough, and shortness of breath. Other symptoms also commonly occur, including altered consciousness in older adults and gastrointestinal symptoms in younger patients, and age can influence the likelihood of a patient having symptoms that match one or more case definitions. There are geographic and temporal variations in the case fatality rate (CFR), but overall, CFR was 20.6% in this large international cohort of hospitalised patients with a median age of 60 years (IQR: 45 to 74 years).


title: A Deep Learning Method to Detect Opioid Prescription and Opioid Use Disorder from Electronic Health Records

abstract:
ObjectiveAs the opioid epidemic continues across the United States, methods are needed to accurately and quickly identify patients at risk for opioid use disorder (OUD). The purpose of this study is to develop two predictive algorithms: one to predict opioid prescription and one to predict OUD.

Materials and MethodsWe developed an informatics algorithm that trains two deep learning models over patient EHRs using the MIMIC-III database. We utilize both the structured and unstructured parts of the EHR and show that it is possible to predict both of these challenging outcomes.

ResultsOur deep learning models incorporate both structured and unstructured data elements from the EHRs to predict opioid prescription with an F1-score of 0.88 {+/-} 0.003 and an AUC-ROC of 0.93 {+/-} 0.002. We also constructed a model to predict OUD diagnosis achieving an F1-score of 0.82 {+/-} 0.05 and AUC-ROC of 0.94 {+/-} 0.008.

DiscussionOur model for OUD prediction outperformed prior algorithms for specificity, F1 score and AUC-ROC while achieving equivalent sensitivity. This demonstrates the importance of a.) deep learning approaches in predicting OUD and b.) incorporating both structured and unstructured data for this prediction task. No prediction models for opioid prescription as an outcome were found in the literature and therefore this represents an important contribution of our work as opioid prescriptions are more common than OUDs.

ConclusionAlgorithms such as those described in this paper will become increasingly important to understand the drivers underlying this national epidemic.


title: COVID-19 epidemics monitored through the logarithmic growth rate and SIR model

abstract:
BackgroundThe SIR model is often used to analyse and forecast the expansion of an epidemic. In this model, the number of patients exponentially increases and decreases, resulting in two phases. Therefore, in these phases, the logarithm of infectious patients changes at a constant rate, the logarithmic growth rate K. However, in the case of the coronavirus disease 2019 (COVID19) epidemic, K never remains constant but increases and decreases linearly; therefore, the SIR model does not fit that seen in reality. We would like to clarify the cause of this phenomenon and predict the occurrence of COVID19 epidemics.

MethodsWe simulated a situation in which smaller epidemics were repeated with short time intervals. The results were compared with the epidemic data from 279 countries and regions.

ResultsIn the simulations, the K values increased and decreased linearly, similar to the real data. Because the previous peak covered the initial increase in the epidemic, K did not increase as much as expected; rather, the difference in the basic reproduction number R0 appeared in the slope of increasing K. Additionally, the mean infectious time{tau} appeared in the negative peaks of K. By using the R0 and{tau} estimated from the changes in K, changes in the number of patients could be approximated using the SIR model. This supports the appropriateness of the model for evaluating COVID-19 epidemics. By using the model, the distributions of the parameters were identified. On average, an epidemic started every eleven days in a country. The worldwide mean R0 was 2.9; however, this value showed an exponential character and could thus increase explosively. In addition, the average{tau} was 12 days; this is not the native value but represents a shortened period because of the isolation of patients. As{tau} represents the half-life, the infectious time varies among patients; hence, prior testing should be performed before isolation is lifted. The changes in K represented the state of epidemics and were several weeks to a month ahead of the changes in the number of confirmed cases. In the actual data, when K was positive on consecutive days, the number of patients increased a few weeks later. In addition, if the negative peaks of K could not be reduced to as small as 0.1, the number of patients remained high. Thus, the number of K-positive days and mean infectious time had a clear correlation with the total number of patients. In such cases, mortality, which was lognormally distributed, with a mean of 1.7%, increased. To control the epidemic, it is important to observe K daily, not to allow K to remain positive continuously, and to terminate a peak with a series of K-negative days. To do this, it was necessary to shorten{tau} by finding and isolating a patient earlier. The effectiveness of the countermeasures is apparent in{tau} . The effect of vaccination, in terms of controlling the epidemic, was limited.


title: Convergent antibody responses associated with broad neutralization of hepatitis C virus and clearance of infection

abstract: Early development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, much remains to be learned at a molecular level about protective E2-reactive antibodies, since HCV infection persists in some individuals despite early development of broadly neutralizing plasma. To examine B cell repertoire features associated with broad neutralization and viral clearance, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of people with cleared or persistent HCV, including subjects with high or low plasma neutralizing breadth in both clearance and persistence groups. We identified many E2-reactive public BCR clonotypes, which are antibody clones with the same V and J-genes and identical CDR3 sequences, shared among subjects grouped by either clearance or neutralization status. The majority (89) of these public clonotypes were shared by two subjects with broad plasma neutralizing activity and cleared infection, but not found in subjects with high plasma neutralizing breadth and persistent infection. We cloned a potent, cross-reactive neutralizing monoclonal antibody (mAb) by pairing the most abundant public heavy and light chains from these two subjects, providing evidence that broadly E2-reactive public clonotypes arise in a subset of individuals with broadly neutralizing plasma and spontaneous clearance of infection. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development.


title: Clinical Results with a B Cell Activating Anti-CD73 Antibody for the Immunotherapy of COVID-19

abstract: Robust polyclonal humoral immune responses have the potential to generate a diverse set of antibodies to neutralize and eliminate viruses such as SARS-CoV-2 and protect against transmission, re-infection and the evolution of variants that evade immunity. CD73 is present on subsets of human B and T cells where it plays a role in lymphocyte activation and migration. CD73 also functions as an ectoenzyme that converts AMP into immunosuppressive adenosine. We have developed a humanized anti-CD73 antibody, mupadolimab (CPI-006), that blocks CD73 enzymatic activity and activates CD73POS B cells, thereby inducing differentiation into plasmablasts, immunoglobulin class switching, and antibody secretion independent of the adenosine modulatory activity. These effects suggest mupadolimab may enhance the magnitude, diversity, and duration of anti-viral responses in patients with COVID-19. This hypothesis was tested in a dose escalation phase 1 trial in 29 hospitalized patients with COVID-19. Single doses of 0.3 mg/kg - 5 mg/kg mupadolimab were well tolerated with no drug related adverse events. Doses greater than 0.3 mg/kg resulted in rapid generation of IgG and IgM to SARS-CoV-2 significantly above titers measured in convalescent controls, with elevated IgG titers sustained for more than 6 months beyond presentation of symptoms. Based on these findings, a randomized double-blind, placebo-controlled Phase 3 study in hospitalized patients was initiated. The primary endpoint was proportion of patients alive and free from respiratory failure within 28 days. This trial was discontinued early during the period of waning COVID-19 incidence after enrolling 40 patients. Although underpowered, results from this trial suggest improvement in the primary and key secondary endpoints in patients treated with single doses of 2 mg/kg and 1 mg/kg compared to placebo. The presumed mechanism of action, stimulation of B cells, may represent a novel approach to immunotherapy of COVID-19 and other viral infections.


title: Quantitative interpretation of Sedia LAg Assay test results after HIV diagnosis.

abstract:
BackgroundTesting for  recent HIV infection is common in surveillance, where only population-level estimates (of incidence) are reported. Typically,  recent infection is a category, obtained by applying a threshold on an underlying continuous biomarker from some laboratory assay(s). Somehow interpreting the biomarker values obtained for individual subjects, for example interpreting them as estimates of the date of infection, has obvious potential applications in the context of studies of early infection, and has also for some years attracted significant interest as an extra component of post-test counselling and treatment initiation. The applicable analyses have typically run aground on the complexity of the full biomarker growth model, which is in principle a non-linear mixed-effects model of unknown structure, the fitting of which seems infeasible from realistically obtainable data.

MethodsIt is known that to estimate Mean Duration of Recent Infection (MDRI) at a given value of the recent/non-recent -infection discrimination threshold, one may compress the full biomarker growth model into a relation capturing the probability of a recent test result as a function of time since infection. Noting that the time-derivative (gradient) of this curve (for a value of threshold - h) is identical to the formal likelihood relevant to Bayesian inference of the infection date, for a subject yielding an assay result * h * on the date of their first positive HIV test. This observation bypasses the need for fitting a complex detailed biomarker growth model. Using publicly available data from the CEPHIA collaboration, we calculated curves for a range of thresholds for the Sedia Lag assay and performed Bayesian inference of infection data, given a uniform prior implied by a last negative and first positive test.

ResultsWe demonstrate the generation of posteriors for infection date, for patients with various delays between their last negative and first positive HIV test, and a range of LAg assay results (ODn) hypothetically obtained on the date of the first positive result.

ConclusionDepending on the last-negative / first-positive interval, there is a range of ODn values that yields posteriors significantly different from the uniform prior one would be left with based merely on interval censoring. Hence, a LAg ODn obtained on the date of, or soon after, diagnosis contains potentially significant information about infection dating. It seems worth analysing other assays with meaningful dynamic range, especially tests already routinely used in primary HIV diagnosis (for example chemiluminescent assays and reader/cartridge lateral flow tests which admit objective variable line intensity readings) which have a sufficient dynamic range that corresponds to a clinically meaningful range of times-since-infection that are worth distinguishing from each other.


title: A method to reduce ELISA serial dilution assay workload applied to SARS-CoV-2 and seasonal HCoVs

abstract:
ObjectivesAssays using ELISA measurements on serially diluted serum samples have been heavily used to measure serum reactivity to SARS-CoV-2 antigens and are widely used in virology and elsewhere in biology. We test a method to reduce the workload of these assays, and measure reactivity of SARS-CoV-2 and HCoV antigens to human serum samples collected before and during the COVID-19 pandemic.

MethodsWe apply Bayesian hierarchical modelling to ELISA measurements of human serum samples against SARS-CoV-2 and HCoV antigens.

ResultsInflection titers for SARS-CoV-2 full-length spike protein (S1S2), spike protein receptor-binding domain (RBD), and nucleoprotein (N) inferred from three spread-out dilutions correlated with those inferred from eight consecutive dilutions with an R2 value of 0.97 or higher. We confirm existing findings showing a small proportion of pre-pandemic human serum samples contain cross-reactive antibodies to SARS-CoV-2 S1S2 and N, and that SARS-CoV-2 infection increases serum reactivity to the beta-HCoVs OC43 and HKU1 S1S2.

ConclusionsIn serial dilution assays, large savings in resources and/or increases in throughput can be achieved by reducing the number of dilutions measured and using Bayesian hierarchical modelling to infer inflection or endpoint titers. We have released software for conducting these types of analysis.


title: Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK

abstract:
BackgroundCOVID-19 vaccines have been used for 9 months in the UK. Real world data have demonstrated the vaccines to be highly effective against COVID-19, severe disease and death. Here, we estimate vaccine effectiveness over time since the second dose of Comirnaty, Vaxzevria and Spikevax in England.

MethodsWe used a test-negative case-control design to estimate vaccine effectiveness against symptomatic disease, hospitalisation and mortality by age, comorbidity status and over time after the second dose to investigate waning separately for Alpha and Delta variants.

ResultsVaccine effectiveness against symptomatic disease peaked in the early weeks after the second dose and then fell to 47.3 (95% CI 45 to 49.6) and 69.7 (95% CI 68.7 to 70.5) by 20+ weeks against the Delta variant for Vaxzevria and Comirnaty, respectively. Waning of vaccine effectiveness was greater for 65+ year-olds compared to 40-64 year-olds. Vaccine effectiveness fell less against hospitalisations to 77.0 (70.3 to 82.3) and 92.7 (90.3 to 94.6) beyond 20 weeks post-vaccination and 78.7 (95% CI 52.7 to 90.4) and 90.4 (95% CI 85.1 to 93.8) against death for Vaxzevria and Comirnaty, respectively. Greater waning was observed among 65+ year-olds in a clinically extremely vulnerable group and 40-64-year olds with underlying medical conditions compared to healthy adults.

ConclusionsWe observed limited waning in vaccine effectiveness against hospitalisation and death more than 20 weeks post-vaccination with Vaxzevria or Comirnaty. Waning was greater in older adults and those in a clinical risk group, suggesting that these individuals should be prioritised for booster doses.


title: Modeling the levels, trends, and connectivity of malaria transmission using genomic data from a health facility in Thies, Senegal

abstract: Molecular data and analysis outputs are being integrated into malaria surveillance efforts to provide valuable programmatic insights for national malaria control programs (NMCPs). A plethora of studies from diverse geographies have demonstrated that malaria parasite genetic data can be an important tool for drug resistance monitoring, species identification, outbreak analysis, and transmission characterization. Despite many successful research efforts, there are still important knowledge gaps hindering practical translation of each of these use cases for NMCPs. Here, we leverage epidemiological modeling and time-series data of 2035 genetic sequences collected in Thies, Senegal from 2006-2018 to provide a quantitative and setting-specific assessment of the levels, trends, and connectivity of malaria transmission. We also identify the genetic features that are the most informative for inferring transmission in Thies, such as the fraction of the population with multiple infections and the persistence of parasite lineages across multiple transmission seasons. The model fitting and uncertainty quantification framework also reveals a significant decrease in the level of malaria transmission around 2013. This difference coincides with a large-scale drought and bed net campaign by the NMCP and USAID and is independently corroborated by geo-spatial models of incidence in Thies. We find that genetically identical samples are more likely to be geographically clustered even at the neighborhood scale; and moreover, these lineages propagate non-randomly around the city. Our approach and results provide quantitative guidance for the interpretation of malaria parasite genetic data from Thies, Senegal and indicates the value of increased malaria genomic surveillance for NMCPs.


title: Concurrent validity and reliability of suicide risk assessment instruments: A meta analysis of 20 instruments across 27 international cohorts

abstract:
ObjectiveA major limitation of current suicide research is the lack of power to identify robust correlates of suicidal thoughts or behaviour. Variation in suicide risk assessment instruments used across cohorts may represent a limitation to pooling data in international consortia.

MethodHere, we examine this issue through two approaches: (i) an extensive literature search on the reliability and concurrent validity of the most commonly used instruments; and (ii) by pooling data (N[~]6,000 participants) from cohorts from the ENIGMA-Major Depressive Disorder (ENIGMA-MDD) and ENIGMA-Suicidal Thoughts and Behaviour (ENIGMA-STB) working groups, to assess the concurrent validity of instruments currently used for assessing suicidal thoughts or behaviour.

ResultsOur results suggested a pattern of moderate-to-high correlations between instruments, consistent with the wide range of correlations, r=0.22-0.97, reported in the literature. Two common complex instruments, the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Scale for Suicidal Ideation (SSI), were highly correlated with each other (r=0.83), as were suicidal ideation items from common depression severity questionnaires.

ConclusionsOur findings suggest that multi-item instruments provide valuable information on different aspects of suicidal thoughts or behaviour, but share a core factor with single suicidal ideation items found in depression severity questionnaires. Multi-site collaborations including cohorts that used distinct instruments for suicide risk assessment should be feasible provided that they harmonise across instruments or focus on specific constructs of suicidal thoughts or behaviours.

Key pointsO_LIQuestion: To inform future suicide research in multi-site international consortia, it is important to examine how different suicide measures relate to each other and whether they can be used interchangeably.
C_LIO_LIFindings: Findings suggest detailed instruments (such as the Columbia Suicide Severity Rating Scale and Beck Scale for Suicidal Ideation) provide valuable information on suicidal thoughts and behaviour, and share a core factor with items on suicidal ideation from depression severity rating scale (such as the Hamilton Depression Rating Scale or the Beck Depression Inventory).
C_LIO_LIImportance: Results from international collaborations can mitigate biases by harmonising distinct suicide risk assessment instruments.
C_LIO_LINext steps: Pooling data within international suicide research consortia may reveal novel clinical, biological and cognitive correlates of suicidal thoughts and/or behaviour.
C_LI

category: psychiatry and clinical psychology


title: Inflammation and nitro-oxidative stress in current suicidal attempts and current suicidal ideation: a systematic review and meta-analysis.

abstract: A meta-analysis showed a significant association between activated immune-inflammatory and nitro-oxidative (IO&NS) pathways and suicide attempts (SA). There is no data on whether suicidal ideation (SI) is accompanied by activated IO&NS pathways and whether there are differences between SA and SI. The current study searched PubMed, Google Scholar, and Web of Science, for articles published from inception until May 10, 2021, and systematically reviewed and meta-analyzed the association between recent SA/SI (< 3 months) and IO&NS biomarkers. We included studies which compared psychiatric patients with and without SA and SI and controls (either healthy controls or patients without SA or SI) and used meta-analysis (random-effect model with restricted maximum-likelihood) to delineate effect sizes with 95% confidence intervals (CI). Our search included 59 studies comprising 4.034 SA/SI cases and 12.377 controls. Patients with SA/SI showed activated IO&NS pathways (SMD: 0.299; CI: 0.200; 0.397) when compared to controls. The immune profiles were more strongly associated with SA than with SI, particularly when compared to healthy controls, as evidenced by activated IO&NS (SMD: 0.796; CI: 0.503; 1.089), immune (SMD: 1.409; CI: 0.637; 1.462), inflammatory (SMD: 1.200; CI: 0.584; 1.816), and neurotoxic (SMD: 0.904; CI: 0.431; 1.378) pathways. The effects sizes of the IO&NS, immune and inflammatory profiles were significantly greater in SA than in SI. In conclusion: increased neurotoxicity due to inflammation and nitro-oxidative stress and lowered neuroprotection explains at least in part why psychiatric patients show increased SA and SI. The IO&NS pathways are more pronounced in recent SA than in SI.


title: Computational systematics of nutritional support of vaccination against viral and bacterial pathogens as prolegomena to vaccinations against COVID-19

abstract: A total of 6,628 PUBMED-registered publications on the relationships between the effects of vaccination and the provision of micronutrients have been studied by methods of topological analysis of text data. In case of insufficient intake of certain micronutrients, the functioning of the acquired immunity is disrupted resulting in an imbalance of populations of T-cells CD4+/CD8+ and of B-lymphocytes. Nutritional supplements of folate, vitamins A, D and B12, which are recognized regulators of cell division, support a wide range of lymphocyte populations. Trace elements zinc, iron, selenium, manganese and omega-3 polyunsaturated fatty acids are also important for supporting the mechanisms of acquired immunity. The data presented show that a course intake of these micronutrients by patients planning vaccination can significantly improve its effectiveness. In particular, these micronutrients can increase the titers of antibodies to pathogens, and to reduce the percentage of patients who still contract infection after vaccination. Supplements of these micronutrients can also contribute to the safety of vaccination: to prevent malaise and, in the unfortunate case of contracting infection despite the vaccine, to reduce the severity of the course and the mortality from the corresponding infection.

category: respiratory medicine


title: Public perception of organ donation and transplantation policies in Southern Spain

abstract:
BackgroundThis research explores how public awareness and attitudes towards donation and transplantation policies may contribute to Spains success in cadaveric organ donation.

Materials and MethodsA representative sample of 813 people residing in Andalusia (Southern Spain) were surveyed by telephone or via Internet between October and December 2018.

ResultsMost participants trust Spains donation and transplantation system (93%) and wish to donate their organs after death (76%). Among donors, a majority have expressed their consent (59%), while few non-donors have expressed their refusal (14%). Only a minority is aware of the presumed consent system in force (28%) and feel sufficiently informed regarding the requirements needed to be an organ donor (16%). Participants mainly consider that relatives should represent the deceaseds preferences and be consulted when the deceaseds wishes are unknown, as is the case in Spain.

ConclusionsPublic trust in the transplant system may contribute to Spains high performance in organ donation. High levels of societal support towards organ donation and transplantation do not correspond in Spain with similar levels of public awareness of donation and transplantation policies.

category: transplantation


title: Age-specific effects of childhood BMI on multiple sclerosis risk: a Mendelian Randomisation study

abstract:
ObjectiveHigher Body Mass Index (BMI) during early life is thought to be a causal risk factor for Multiple Sclerosis (MS). We used longitudinal mendelian randomisation (MR) to determine whether there is a critical window during which BMI influences MS risk.

MethodsSummary statistics for childhood BMI and for MS susceptibility were obtained from recent large GWAS. We generated exposure instruments for BMI during four non-overlapping epochs (< 3 months, 3 months-1.5 years, 2-5 years, and 7-8 years) and performed MR using the inverse-variance weighted method with standard sensitivity analyses. Multivariable MR was used to account for effects mediated via later-life BMI.

ResultsFor all time epochs other than birth, genetically determined higher BMI was associated with an increased liability to MS: Birth (OR 0.81, 95% CI 0.50-1.31, NSNPs=7, p=0.39), Infancy (OR 1.18, 95%CI 1.04-1.33, NSNPs=18, p=0.01), Early childhood (OR 1.31, 95%CI 1.03-1.66, NSNPs=4, p=0.03), Later childhood (OR 1.34, 95% CI 1.08-1.66, NSNPs=4, p=0.01). Multivariable MR suggested that these effects may be mediated by effects on adult BMI.

ConclusionWe provide evidence using MR that genetically-determined higher BMI during early life is associated with increased MS risk. This effect may be driven by shared genetic architecture with later-life BMI.

category: neurology


title: Real-world serologic responses to Extended-interval and Heterologous COVID-19 mRNA vaccination in Frail Elderly - Interim report from a prospective observational cohort study

abstract:
BackgroundThe Coronavirus disease 2019 (Covid-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted accelerated vaccines development. Their use was prioritized to protect the most vulnerable, notably, the elderly. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been employed. The effectiveness of these strategies in the frail elderly are unknown.

MethodsIn this real-world vaccination study, under a government-decreed rationing strategy, elderly adults residing in long-term care facilities, with or without previously-documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. Clinical data and blood were serially collected during and after this interval period. Sera were tested for SARS-CoV-2-specific IgG antibodies (to trimeric S; RBD; nucleocapsid) by automated chemiluminescent ELISA.

FindingsAfter a significant increase 4 weeks post-prime dose, there was a significant decline in anti-RBD and anti-S IgG levels until the boost dose, followed by an increase 4 weeks later. Previously uninfected individuals exhibited lower antibody responses up to 16 weeks post-prime dose, but achieved comparable levels to previously infected counterparts by 4 weeks post-second dose. Individuals primed with BNT162b2 exhibited larger decrease in anti-RBD and anti-S IgG levels with 16-week interval between doses, compared to those who received mRNA-1273. No differences in antibody levels 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations.

InterpretationsThese interim results of this ongoing longitudinal study show that, among frail elderly, neither age, sex, nor comorbidity affect antigenicity of mRNA-based COVID vaccines, but previous SARS-CoV-2 infection and type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. Homologous/heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following second dose, supporting their interchangeability.

FundingThis project was supported by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference group and the COVID-19 Immunity Task Force (CITF).


title: Multiplex PCR Assay to Detect High Risk Lineages of Salmonella Typhi and Paratyphi A

abstract:
Enteric fever infections remain a significant public health issue, with up to 20 million infections per year. Increasing rates of antibiotic resistant strains have rendered many first-line antibiotics potentially ineffective. Genotype 4.3.1 (H58) is the main circulating lineage of S. Typhi in many South Asian countries and is associated with high levels of antibiotic resistance. The emergence and spread of extensively drug resistant (XDR) typhoid strains has increased the need for a rapid molecular test to identify and track these high-risk lineages for surveillance and vaccine prioritisation. Current methods require samples to be cultured for several days, followed by DNA extraction and sequencing to determine the specific lineage. We designed and evaluated the performance of a new multiplex PCR assay, targeting S. Paratyphi A as well as the H58 and XDR lineages of S. Typhi on a collection of bacterial strains. Our assay was 100% specific for the identification of lineage specific S. Typhi and S. Paratyphi A, when tested with a mix of non-Typhi Salmonella and non-Salmonella strains. With additional testing on clinical and environmental samples, this assay will allow rapid lineage level detection of typhoid of clinical significance, at a significantly lower cost to whole-genome sequencing. To our knowledge, this is the first report of a SNP-based multiplex PCR assay for the detection of lineage specific serovars of Salmonella Typhi.

Data StatementAll supporting data, code and protocols have been provided within the article or through supplementary data files.


title: Prior Covid-19 and high RBD-IgG levels correlate with protection against VOC-delta SARS-CoV-2 infection in vaccinated Nursing Home Residents

abstract:
BackgroundNursing Home (NH) residents are at high risk of serious illness and death from coronavirus disease 2019 (Covid-19), especially with the SARS-CoV-2 variants of concerns (VOC). It is unknown as to whether a history of Covid-19 prior to the vaccine and post-vaccine RBD-IgG levels are predictors of BNT162b2 vaccine effectiveness against VOC-{delta} in nursing home residents.

MethodsWe analyzed the data from two NHs that faced a VOC-{delta} outbreak in July-August 2021. These NHs had suffered prior Covid-19 outbreaks in 2020 and 2021. In many of the residents, RBD-IgG levels were measured 6 weeks after the second vaccine dose, i.e. 3 to 5 months before the VOC-{delta} outbreak onset, and again during the outbreak (SARS-CoV-2 IgG II Quant assay, Abbott Diagnostics). We compared residents with vs without prior Covid-19 for (i) VOC-{delta} incidence, (ii) the correlation between post-vaccine RBD-IgG levels and VOC-{delta} incidence, and (iii) the time-related change in RBD-IgG levels.

ResultsAmong the 140 analyzed residents (58 to 101 years; 94 females, 46 men, mean age: 84.6 yr {+/-} 9.5 yr), one resident among the 44 with prior Covid-19 before vaccination developed a VOC-{delta} infection during the outbreak (1.3%) vs 55 of the 96 without Covid-19 prior to vaccination (57.3 %)(p<0.0001). The median value for RBD-IgG 6 weeks after the vaccine and during the outbreak was higher in residents with prior Covid-19 (31,553 AU/mL and 22,880 AU/mL) than in those without (1,050 AU/mL and 260 AU/mL)(p<0.0001). In residents without Covid-19 prior to vaccination, post-vaccination RDB-IgG levels did not predict protection against VOC-{delta} infection.

ConclusionsIn contrary to residents with prior SARS-CoV-2 infection, those without a history of Covid-19 before two BNT162b2 doses are not protected against VOC-{delta} infection and their RBD-Ig-G levels are low 3 to 5 months after vaccination. This suggests that a booster vaccine dose should be considered in this group of residents for a better protection against VOC-{delta} infection.


title: Effectiveness of vaccination in preventing severe SARS CoV-2 infection in South India-a hospital based cross sectional study

abstract:
Background & objectivesEstablishing concrete evidence on the effect of vaccination on the severity of SARS CoV-2 infections in real-world situations is the need of the hour. This study aims to estimate the effectiveness of Covid 19 vaccines in preventing the new and severe SARS CoV-2 infections.

DesignCross-sectional study

Setting& ParticipantsWe did this cross-sectional study among the 4565 patients consecutive adult inpatients admitted in the Covid 19 wards of a tertiary care hospital from May 7, 2021, to October 7, 2021, during the second wave of the Covid 19 pandemic. Information on basic demographic variables, RT PCR status, vaccination status, outcome and clinical severity of illness were obtained from the electronic hospital patient records.

ResultsOnly 4% of the study participants had prior vaccination. The type of vaccine and number of doses didnt have any protective effect against the new SARS CoV-2 infection and breakthrough infection. Fully vaccinated RTPCR positive patients had an 82% reduction in the need for ICU admission (OR 0.09; AOR 0.18, CI (0.04 to 0.8), P <0.05) and a non-significant 79% in mortality (OR 0.19; AOR 0.21, CI (0.04 to 1.1) P>0.05).

ConclusionVaccination doesnt protect against new SARS Cov-2 infection and breakthrough infection however significant protection was documented against severe SARS Cov-2 infection. The protective effect shown by the vaccines in preventing the severe form of SARS Cov-2 infection among fully vaccinated patients was 82%. Vaccination coverage should be increased urgently to halt the impending wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.


title: PREVALENCE AND DISTRIBUTION OF ANTIMICROBIAL RESIDUES IN TISSUES OF BROILERS SOLD AT A LOCAL MARKET IN ENUGU STATE, NIGERIA USING THE EUROPEAN FOUR PLATE TEST

abstract:
BackgroundConsumption of animal tissues treated with antimicrobial agents may be deleterious if they contain violative levels of the residues. This study determined antimicrobial residues prevalence in broilers sold at Ikpa market, Nsukka, Nigeria.

MethodsTissues from muscle, liver and kidney of 60 commercial broilers (180 samples) were tested for antimicrobial residues using the conventional Four Plate Test.

ResultPrevalence of 80.0% (48/60) and 51.7% (93/180) was recorded in the birds and samples {muscle 40.0%(24/60); liver 55.0%(33/60) and kidney 60.0%(36/60)} respectively. There was no significant association between residue occurrence and tissue type ({chi}2 (2) = 5.206; p = 0.074). Possible antimicrobial classes detected were: macrolid (50.0%) at pH 8.0 with Micrococcus luteus; {beta}-lactams and tetracyclines (64.4%) with Bacillus subtillis at pH 6.0; sulphonamides (53.3%) at pH 7.2 with Bacillus subtillis, and aminoglycosides (46.8%) at pH 8.0 with Bacillus subtillis. Twenty-four tissue samples were positive at all four pH levels indicating use of more than one class of antimicrobials during each treatment.

ConclusionAntimicrobial residues were detected in commercial broilers (muscles, liver and kidney) sampled at Ikpa Market, Nsukka. This is of public health importance given that antimicrobial residues are not monitored in poultry consumed in Nigeria.


title: COVID-19 Acceleration and Vaccine Status in France - August 2021

abstract:
ObjectivesThis note provides an assessment of COVID-19 acceleration among groups with different vaccine status in France.

MethodsWe assess viral acceleration using a novel indicator introduced in Baunez et al. (2021). The acceleration index relates the percentage change of tests that have been performed on a given day to the percentage change in the associated positive cases that same day. We compare viral acceleration among vaccinated and unvaccinated individuals in France over the period May 31st - August 29, 2021.

ResultsOnce the state of the epidemic within each groups is accounted for, it turns out that viral acceleration has since mid-July converged to similar levels among vaccinated and unvaccinated individuals in France, even though viral speed is larger for the latter group compared to the former.

ConclusionOur results call for an increasing testing effort for both vaccinated and unvaccinated individuals, in view of the fact that viral circulation is currently accelerating at similar levels for both groups in France.

category: health policy


title: COVID-19 Acceleration and Vaccine Status in France - Summer 2021


title: Covid-19 in the Phase 3 Trial of mRNA-1273 During the Delta-variant Surge

abstract:
BackgroundFollowing emergency use authorization in December 2020, the Coronavirus Efficacy (COVE) trial was amended to an open-label phase, where participants were unblinded and those randomized to placebo were offered vaccination. Emergence of the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with increased incidences of coronavirus disease 2019 (Covid-19) among unvaccinated and vaccinated persons. This exploratory analysis evaluated the incidence and genetic sequences of Covid-19 cases in the ongoing COVE trial during the open-label phase, with a focus on July-August 2021, when delta-variants surged in the US.

MethodsCovid-19 cases were identified in participants initially randomized to mRNA-1273 (vaccinated from July-December 2020) and those initially randomized to the placebo (vaccinated December 2020-April 2021) who received at least one dose and were SARS-CoV-2-negative at baseline in the modified-intent-to-treat population were analyzed. Included were Covid-19 cases occurring after 26-Mar-2021 with positive RT-PCR results in nasopharyngeal samples (central lab test) and reported Covid-19 symptoms. Genetic sequencing of Covid-19 cases was also performed.

ResultsThere were 14,746 participants in the earlier mRNA-1273 (mRNA-1273e) group and 11,431 in the later placebo-mRNA1273 (mRNA-1273p) group. Covid-19 cases increased from the start of the open-label phase to July-August 2021. During July and August, 162 Covid-19 cases occurred in the mRNA-1273e group and 88 in the mRNA-1273p group. Of the cases sequenced, 144/149 [97%]) in the mRNA-1273 and 86/88 (99%) in the mRNA-1273p groups were attributed to delta. The incidence rate of Covid-19 was lower for the mRNA-1273p (49.0/1000 person-years) versus mRNA-1273e (77.1/1000 person-years) group [36.4% (95% CI 17.1%-51.5%) reduction]. There were fewer severe Covid-19 cases in the mRNA-1273p (6; 6.2/1000 person-years) than mRNA-1273e (13; 3.3/1000 person-years) [46.0% (95% CI -52.4%-83.2%) reduction]. Three Covid-19 related hospitalizations occurred with two resulting deaths in the mRNA-1273e group.

ConclusionIncidence rates of Covid-19 and severe Covid-19 were lower during the months when delta was the dominant variant (July/August 2021) among COVE participants vaccinated more recently. Analysis of COVID-19 cases from the open-label phase of the COVE study is ongoing.


title: Cardiovascular Risk Factors and Outcomes in COVID-19: Hospital-Based Prospective Study in India

abstract:
Background & ObjectivesPresence of cardiovascular (CV) risk factors enhance adverse outcomes in COVID-19. To determine association of risk factors with clinical outcomes in India we performed a study.

MethodsSuccessive virologically confirmed patients of COVID-19 at a government hospital were recruited at admission and in-hospital outcome and other details obtained. The cohort was classified according to age, sex, hypertension, diabetes and tobacco use. To compare intergroup outcomes we performed univariate and multivariate logistic regression.

ResultsFrom March-September 2020 we recruited 4645 (men 3386, women 1259) out of 5103 COVID-19 patients (91.0%). Mean age was 46{+/-}18y, hypertension was in 17.8%, diabetes in 16.6% and tobacco-use in 29.5%. Duration of hospital stay was 6.8{+/-}3.7 days, supplemental oxygen was in 18.4%, non-invasive ventilation in 7.1%, mechanical ventilation in 3.6% and 7.3% died. Unadjusted and age-sex adjusted odds ratio and 95% confidence intervals, respectively were, age [≥]50y (4.16, 3.22-5.37 and 4.15,3.21-5.35), men (1.88,1.41-2.51 and 1.26,0.91-1.48); hypertension (2.22,1.74-2.83 and 1.32,1.02-1.70), diabetes (1.88,1.46-2.43 and 1.16,0.89-1.52) and tobacco (1.29,1.02-1.63 and 1.28,1.00-1.63). Need for invasive ventilation was greater in age >50y (3.06,2.18-4.28 and 3.06,2.18-4.29) and diabetes (1.64,1.14-2.35 and 1.12,0.77-1.62). Non-invasive ventilation was more in age [≥]50y (2.27,1.80-2.86 and 2.26,1.79-2.85) and hypertension (1.82,1.41-2.35 and 1.29,0.99-1.69). Multivariate adjustment for presenting factors attenuated the significance.

ConclusionCardiovascular risk factors-age, male sex, hypertension, diabetes and tobacco-are associated with greater risk of death and adverse outcomes in COVID-19 patients in India.


title: Topological relationships between perivascular spaces and progression of white matter hyperintensities: a pilot study in a sample of the Lothian Birth Cohort 1936

abstract: Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesised to also have topological proximity. However, this, and the influence of their spatial proximity on WMH progression are unknown. We analysed longitudinal MRI data from 29/32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive ageing, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (Wave - 1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (Waves - 1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each if these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest deep WMH clusters preferentially form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.


title: Mobile monitoring of traffic-related air pollution for a prospective cohort study in the greater Seattle area

abstract:
Growing evidence links traffic-related air pollution (TRAP) to adverse health effects. We designed an innovative and extensive mobile monitoring campaign to characterize TRAP exposure levels for the Adult Changes in Thought (ACT) study, a Seattle-based cohort. The campaign measured particle number concentration (PNC) to capture ultrafine particles (UFP), black carbon (BC), nitrogen dioxide (NO2), fine particulate matter (PM2.5), and carbon dioxide (CO2) at 309 stop sites representative of the cohort. We collected about 29 two-minute visit measures at each site during all seasons, days of the week, and most times of day during a one-year period. Validation showed good agreement between our BC, NO2, and PM2.5 measurements and regulatory monitoring sites (R2 = 0.68-0.73). Universal kriging-partial least squares models of annual average pollutant concentrations had cross-validated mean square error-based R2 (and root mean square error) values of 0.77 (1,177 pt/cm3) for PNC, 0.60 (102 ng/m3) for BC, 0.77 (1.3 ppb) for NO2, 0.70 (0.3 {micro}g/m3) for PM2.5, and 0.50 (4.2 ppm) for CO2. Overall, we found that the design of this extensive campaign captured the spatial pollutant variations well and these were explained by sensible land use features, including those related to traffic.

SynopsisWe develop well-performing, long-term average pollutant exposure prediction models for epidemiologic application from an innovative and extensive short-term mobile monitoring campaign.

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org.highwire.dtl.DTLVardef@1ae2eforg.highwire.dtl.DTLVardef@128c12borg.highwire.dtl.DTLVardef@a219baorg.highwire.dtl.DTLVardef@4736fa_HPS_FORMAT_FIGEXP  M_FIG C_FIG


title: Characterization of annual average traffic-related air pollution levels (particle number, black carbon, nitrogen dioxide, PM2.5, carbon dioxide) in the greater Seattle area from a year-long mobile monitoring campaign


title: Readmissions in Patients with Cerebral Cavernous Malformations (CCMs): A National Readmission Database (NRD) Study

abstract:
BACKGROUNDCerebral cavernous malformations (CCMs) are microvascular CNS lesions prone to hemorrhage leading to neurological sequela such as stroke and seizure. A subset of CCM patients have aggressive disease leading to multiple bleeding events, likely resulting multiple hospitalizations. Hospital admission rates are an important metric that has direct financial impact on hospitals and an indicator of overall disease burden. Furthermore, analysis of hospital readmissions can lead to early identification of high-risk patients and provides insight into the pathogenesis of CCM lesions. The purpose of this study is to identify high risk CCM patients with increased all cause readmission and comorbidities associated with increased readmissions.

METHODSAll US hospital admissions due to CCMs were searched using the 2017 National Readmission Database (NRD). Patients with readmissions within 30 days of discharge from index hospitalization were identified and analyzed, relative to the remaining population.

RESULTSAmong all patients hospitalized for CCM, 14.9% (13.7-16.2%) required all cause readmission within 30 days. Multivariate logistical regression analysis showed that substance abuse (p=0.003), diabetes (p=0.018), gastrointestinal bleed (p=0.002), renal failure (p=0.027), and coronary artery disease (p=0.010) were predictive of all cause readmissions, while age group 65-74 (p=0.042), private insurance (p<0.001), and treatment at a metropolitan teaching institution (p=0.039) were protective. Approximately half of all readmissions are caused by neurological (33.9%) and infectious (14.6%) etiologies. The 30-day lesion bleeding rate after index hospitalization is 0.8% (0.5-1.2%).

CONCLUSIONSAll identified comorbidities associated with increased risks of readmission contribute to vascular stress, suggesting its role in lesion pathogenesis. This is the first and only study to analyze readmission metrics for CCMs in order to identify high risk patient factors to date.

category: primary care research


title: Identifying At-Risk Communities and Key Vulnerability Indicators in the COVID-19 Pandemic

abstract: Throughout the COVID-19 pandemic, certain communities have been disproportionately exposed to detrimental health outcomes and socioeconomic injuries. Quantifying community needs is crucial for identifying testing and service deserts, effectively allocating resources, and informing funding and decision making. We have constructed research-driven metrics measuring the public health and economic impacts of COVID-19 on vulnerable populations. In this work we further examine and validate these indices by training supervised models to predict proxy outcomes and analyzing the feature importances to identify gaps in our original metric design. The indices analyzed in this work are unique among COVID-19 risk assessments due to their robust integration of disparate data sources. Together, they enable more effective responses to COVID-19 driven health inequities.


title: Genomic analysis of SARS-CoV-2 breakthrough infections from Varanasi, India

abstract: Studies worldwide have shown that the available vaccines are highly effective against SARS-CoV-2. However, there are growing laboratory reports that the newer variants of concerns (VOCs e.g. Alpha, Beta, Delta etc) may evade vaccine induced defense. In addition to that, there are few ground reports on health workers having breakthrough infections. In order to understand VOC driven breakthrough infection we investigated 14 individuals who tested positive for SARS-CoV-2 after being administered a single or double dose of Covishield (ChAdOx1, Serum Institute of India) from the city of Varanasi, which is located in the Indian state of Uttar Pradesh. Genomic analysis revealed that 78.6% (11/14) of the patients were infected with the B.1.617.2 (Delta) variant. Notably, the frequency (37%) of this variant in the region was significantly lower (p<0.01), suggesting that the vaccinated people were asymmetrically infected with the Delta variant. Most of the patients tested displayed mild symptoms, indicating that even a single dose of the vaccine can help in reducing the severity of the disease. However, more comprehensive epidemiological studies are required to understand the effectiveness of vaccines against the newer VOCs.


title: Alterations in CD39/CD73 Axis of T cells associated with COVID-19 severity

abstract:
Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in COVID-19 patients. Lower plasma ATP and adenosine levels were identified in mild and severe COVID-19 patients associated with proinflammatory cytokine profiles compared to healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+CD25+CD39+ (activated/memory Treg) and CD4+CD25+CD39+CD73+ T cells, and increased frequencies of high differentiated (CD27-CD28-) CD8+T cells compared to health controls. Severe COVID-19 patients also showed higher frequencies of CD4+CD39+, CD4+CD25-CD39+ (memory T effector cell), high differentiated CD8+ T cells (CD27-CD28-) and diminished frequencies of CD4+CD73+, CD4+CD25+CD39+ mTreg, CD4+CD25+CD39+CD73+, CD8+CD73+ and low-differentiated CD8+ T cells (CD27+CD28+) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+Annexin-V+ and CD8+Annexin-V+ T cells, showing increased T cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of PBMC from severe COVID-19 patients with adenosine reduced the NF-kB activation in T cells and monocytes. Together, these data add new knowledge regarding the immunopathology of COVID-19 through purinergic regulation, especially concerning adenosine deficiency.

Brief CommentaryO_ST_ABSBackgroundC_ST_ABSHost factors modulates the type and the strength of the immune response during the viral infection, as well as the disease outcomes. However, to date, the role of purinergic signaling in SARS-CoV-2 infection remains unclear. We sought to evaluate alterations in extracellular adenine nucleotides and CD39/CD73 axis in T cells and their relationship with acute COVID-19 immunopathogenesis.

Translational SignificanceCOVID-19 patients present lower extracellular ATP and adenosine levels associated with altered CD39 and CD73 expression in CD4+ and CD8+ T cells. Purinergic signaling correlated with alterations in the differentiation status of CD8+ T cells, lymphocyte mitochondrial membrane polarization and T cell apoptosis. Our demonstration of the lower NF-{kappa}B activation in T cells and monocytes after in vitro adenosine treatment may indicate the regulatory effect of adenosine in the inflammation and cytokine storm of COVID-19. This study adds new knowledge regarding the immunopathology of COVID-19 through purinergic regulation.


title: Association of Initial Clinical Characteristics with the Need for the Intensive Care Unit and Hospitalization in Patients Presenting to the Emergency Department with Acute Symptomatic COVID-19

abstract:
ObjectiveTo evaluate the association of initial clinical symptoms with need for hospitalization, intensive care, or death in ED patients within 30 days after presenting with acute symptomatic COVID-19.

MethodsThis study is a retrospective case-series of patients presenting to a single ED with acute symptomatic COVID-19 from March 7-August 9, 2020. Symptomatic patients with laboratory-confirmed SARS-CoV-2 infection were eligible for this study. Patients who tested positive for COVID-19 due to screening tests but had no reasonably associated symptoms were excluded. Participants were analyzed by three categories representative of clinical severity: intensive care unit (ICU) care/death, general ward admission, and ED discharge/convalescence at home. Outcomes were ascertained 30 days after initial presentation to account for escalation in severity after the ED visit. We conducted univariate and multivariable logistic regression analyses to report odds ratios (OR) with 95% confidence intervals (CI) between hospital or ICU care/death versus convalescence at home and between ICU care/death versus general ward admission.

ResultsIn total, 994 patients were included in the study, of which, 551 (55.4%) patients convalesced at home, 314 (31.6%) patients required general ward admission, and 129 (13.0%) required ICU care or died. In the multivariable models, ED patients requiring hospital admission were more likely to be aged [≥] 65 years (adjusted OR [aOR] 7.4, 95% CI: 5.0, 10.8), Black/African American (aOR 3.0, 95% CI: 1.6, 5.8) or Asian/American Indian/Alaska Native/Other (aOR 2.2, 95% CI: 1.1, 4.3), and experience dyspnea (aOR 2.7, 95% CI: 2.0, 3.7) or diarrhea (aOR 1.6, 95% CI: 1.1, 2.2). However, they were less likely to experience sore throat (aOR 0.4, 95% CI: 0.2, 0.6), myalgia (aOR 0.5, 95% CI: 0.4, 0.7), headache (aOR 0.5, 95% CI: 0.4, 0.8), or olfactory/taste disturbance (aOR 0.5, 95% CI: 0.3, 0.8). ED patients who required ICU care or died were more likely to experience altered mental status (aOR 3.8, 95% CI: 2.1, 6.6), but were less likely to report history of fever (0.5, 95% CI: 0.3, 0.8).

ConclusionsCOVID-19 presents with a multitude of clinical symptoms and an understanding of the association of symptoms with clinical severity may be useful for predicting ultimate patient outcomes.

category: emergency medicine


title: The Delta Variant Had Negligible Impact on COVID-19 Vaccine Effectiveness in the USA

abstract:
The SARS-CoV-2 Delta variant (B.1.617.2) was initially identified in India in December 2020. Due to its high transmissibility, its prevalence in the U.S.A. grew from a near-zero baseline in early May 2021 to nearly 100% by late August 2021, according to CDC tracking. We accessed openly available data sources from the public health authorities of seven U.S. states, five U.S. counties, and the District of Columbia on RT-PCR COVID-19 tests split by the COVID-19 vaccination status of individuals tested during this period. Together, these time series enable estimation and tracking of COVID-19 vaccine effectiveness (VE*) (against RT-PCR diagnosed infection) concurrently with the growth of Delta variant prevalence in those locations. Our analyses reveal that in each locality the VE* for the combined set of all three US vaccines remained relatively stable and quite well-performing, despite the dramatic concurrent rise of Delta variant prevalence. We conclude that the Delta variant does not significantly evade vaccine-induced immunity. The variations in our measured VE* appear to be driven by demographic factors affecting the composition of the vaccinated cohorts, particularly as pertains to age distribution. We report that the measured VE*, aggregated across the collected sites, began at a value of about 0.9 in mid-May, declined to about 0.76 by mid-July, and recovered to about 0.9 by mid-September.

SummaryWe estimated local COVID-19 vaccine effectiveness using RT-PCR COVID-19 test data broken out by vaccination status from select localities in the U.S.A. between 15 May and 15 September 2021 while the SARS-CoV-2 Delta variant (B.1.617.2) was ascending from essentially zero prevalence to total dominance of the genome, and showed that the rise of the Delta variant had negligible effect on vaccine effectiveness.


title: Thrombotic adverse events reported for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines: comparison of occurrence and clinical outcomes in the EudraVigilance database

abstract:
BackgroundVaccination against COVID-19 is the cornerstone to control and mitigate the ongoing pandemic. Thrombotic adverse events linked to Moderna, Pfizer and the Oxford-AstraZeneca vaccine have been documented and described as extremely rare. While the Oxford-AstraZeneca vaccine has received much of the attention, the other vaccines should not go unchallenged. This study aimed to determine the frequency of reported thrombotic adverse events and clinical outcomes for these three COVID-19 vaccines, namely, Moderna, Pfizer and Oxford-AstraZeneca

MethodsA retrospective descriptive analysis was conducted of spontaneous reports for Moderna, Pfizer and Oxford-AstraZeneca COVID-19 vaccines submitted to the EudraVigilance database in the period from 17 February to 14 June 2021.

FindingsThere were 729,496 adverse events for the three vaccines, of which 3,420 were thrombotic, mainly Oxford-AstraZeneca (n=1,988, 58{middle dot}1%) followed by Pfizer (n=1,096, 32{middle dot}0%) and Moderna (n=336, 9{middle dot}8%). As serious adverse events, there were 705 reports of pulmonary embolism for the three vaccines, of which 130 reports (18{middle dot}4%) were for Moderna, 226 reports (32{middle dot}1%) for Pfizer and 349 (49{middle dot}5%) for Oxford-AstraZeneca vaccines. The occurrence of pulmonary embolism is significantly associated with a fatal outcome (P=<0{middle dot}001). Sixty-three fatalities were recorded (63/3420, 1.8%), of which Moderna (n=6), Pfizer (n=25) and Oxford-AstraZeneca (n=32).

InterpretationThrombotic adverse events reported for the three vaccines remains extremely rare with multiple causative factors reported elsewhere as precipitating these events. Practicing vigilance and proper clinical management for the affected vaccines, as well as continuing to report adverse events, are essential.

FundingNo funding was sought for this study.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSDuring the first quarter of 2021, several European countries suspended the use of the Oxford-AstraZeneca vaccine amid reports of blood clot events and the death of a vaccinated person. This was followed by several reports of fatalities related to pulmonary embolism and other thrombotic events including thrombocytopenia which has been referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). The European Medicines Agency on 18 March 2021 concluded that the Oxford- AstraZeneca vaccine was safe, effective and the benefits outweighed the risks.

Added value of this studyThis study investigated the occurrence of thrombotic adverse events and their clinical outcomes of the three approved and most used COVID-19 vaccines namely Moderna, Pfizer and Oxford-AstraZeneca, using one of the largest spontaneous adverse events databases, namely EudraVigilance. Out of 729,496 adverse events reported for the three vaccines in the study period, only 3420 (0.47%) potential thrombotic adverse events were reported, the majority associated with Oxford-AstraZeneca (n=1,988, 58.1%).

Implications of all the available evidenceMore than 4{middle dot}89 billion doses of different COVID-19 vaccines have been administered across the globe.

Despite thrombotic adverse events reported for the three vaccines in focus for this study - Moderna, Pfizer and Oxford-AstraZeneca - being extremely rare, so continuing to report adverse events is essential. On the basis of scientific evidence showing that benefit outweighs risk, people continue to be urged to accept the vaccination when offered.


title: An Integrated Molecular Atlas of Alzheimer's Disease

abstract:
INTRODUCTIONEmbedding single-omics disease associations into the wider context of multi-level molecular changes in Alzheimers disease (AD) remains one central challenge in AD research.

METHODSResults from numerous AD-specific omics studies from AMP-AD, NIAGADS, and other initiatives were integrated into a comprehensive network resource and complemented with molecular associations from large-scale population-based studies to provide a global view on AD.

RESULTSWe present the AD Atlas, an online resource (www.adatlas.org) integrating over 20 large studies providing disease-relevant information on 20,353 protein-coding genes, 8,615 proteins, 997 metabolites and 31 AD-related phenotypes. Multiple showcases demonstrate the utility of this resource for contextualization of AD research results and subsequent downstream analyses, such as drug repositioning approaches.

DISCUSSIONBy providing a global view on multi-omics results through a user-friendly interface, the AD Atlas enables the formulation of molecular hypotheses and retrieval of clinically relevant insights that can be validated in follow-up analyses or experiments.


title: Time-dependent prediction of mortality and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation using machine learning

abstract: Allogeneic hematopoietic cell transplantation (HCT) effectively treats high-risk hematologic diseases but can entail HCT-specific complications, which may be minimized by appropriate patient management, supported by accurate, individual risk estimation. However, almost all HCT risk scores are limited to a single risk assessment before HCT without incorporation of additional data. We developed machine learning models which integrate both baseline patient data and time-dependent laboratory measurements to individually predict mortality and cytomegalovirus (CMV) reactivation after HCT at multiple time points per patient. These gradient boosting machine models provide well-calibrated, time-dependent risk predictions and achieved areas under the receiver-operating characteristic of 0.92 and 0.83 and areas under the precision-recall curve of 0.58 and 0.62 for prediction of mortality and CMV reactivation, respectively, in a 21-day time window. Both models were successfully validated in a prospective, non-interventional study and performed on par with expert hematologists in a pilot comparison.


title: Investigating the impact of weakly supervised data on text mining models of publication transparency: a case study on randomized controlled trials

abstract: Lack of large quantities of annotated data is a major barrier in developing effective text mining models of biomedical literature. In this study, we explored weak supervision strategies to improve the accuracy of text classification models developed for assessing methodological transparency of randomized controlled trial (RCT) publications. Specifically, we used Snorkel, a framework to programmatically build training sets, and UMLS-EDA, a data augmentation method that leverages a small number of existing examples to generate new training instances, for weak supervision and assessed their effect on a BioBERT-based text classification model proposed for the task in previous work. Performance improvements due to weak supervision were limited and were surpassed by gains from hyperparameter tuning. Our analysis suggests that refinements to the weak supervision strategies to better deal with multi-label case could be beneficial.


title: Potential COVID-19 vaccination opportunities in primary care practices in the United States

abstract: Rapid, widespread COVID-19 vaccination is critical to pandemic mitigation and recovery. To help policymakers interested in further enhancing primary care delivery of COVID-19 vaccines, it is important to estimate the absolute number of vaccination opportunities, and identify how these opportunities may fall disproportionately among different communities given the unequal way that COVID-19 falls upon communities of color, low-income, and rural communities. To quantify the potential benefits of greater primary care engagement in vaccination efforts, we estimated the number of potential vaccination opportunities (PVOs) in primary care in the remaining calendar months of year 2021, and the possible uptake if we supplied enough vaccine to primary care practices to fulfill their opportunities. To estimate how many potential vaccination opportunities (PVOs) may occur in primary care, we used three sets of data, analyzing the latest available waves of the following: (i) the National Ambulatory Medical Care Survey (NAMCS, 2016, N = 677 providers); (ii) the National Health Interview Survey (NHIS, 2018, N = 29,839 individuals in 29,839 households); and (iii) the Medical Expenditure Panel Survey (MEPS, 2018, N = 40,025 individuals in 14,500 households). Per the NAMCS data, which provide a nationally-representative sample of ambulatory care visits, primary care physicians normally provide 40.2 million primary care visits per month. The majority of the primary care utilization is absorbed by those aged 16 to 64 years old who are not otherwise priority groups (i.e., not having chronic diseases as defined by ACIP) but the second large group of visits are those with a chronic disease (27.2% of all visits). As compared to the NAMCS data providing an estimate of care from the perspective of providers, the overall sample in NHIS provides a view of primary care access and utilization from a population perspective. Per NHIS, 34% of the civilian US population saw a generalist physician in the prior calendar year, or 109.8 million people. Overall, we would estimate that over the latter half of calendar year 2021, approximately 15 million potential vaccine opportunities per month would be available through US primary care practices.