title: Sensitive detection of Plasmodium vivax malaria by the rotating-crystal magneto-optical method in Thailand

abstract: The rotating-crystal magneto-optical detection (RMOD) method has been developed for the rapid and quantitative diagnosis of malaria and tested systematically on various malaria infection models. Very recently, an extended field trial in a high-transmission region of Papua New Guinea demonstrated its great potential for detecting malaria infections, in particular Plasmodium vivax. In the present small-scale field test, carried out in a low-transmission area of Thailand, RMOD confirmed malaria in all samples found to be infected with Plasmodium vivax by microscopy, our reference method. Moreover, the magneto-optical signal for this sample set was typically 1-3 orders of magnitude higher than the cut-off value of RMOD determined on uninfected samples. Based on the serial dilution of the original patient samples, we expect that the method can detect Plasmodium vivax malaria in blood samples with parasite densities as low as [~] 5 - 10 parasites per microliter, a limit around the pyrogenic threshold of the infection. In addition, by investigating the correlation between the magnitude of the magneto-optical signal, the parasite density and the erythrocytic stage distribution, we estimate the relative hemozoin production rates of the ring and the trophozoite stages of in vivo Plasmodium vivax infections.


title: Patient Characteristics in Cases of Reinfection or Prolonged viral shedding in SARS-CoV-2

abstract:
ImportanceAs testing options increase for COVID-19, their interpretability is challenged by the increasing variety of clinical contexts in which results are obtained. In particular, positive COVID-19 diagnostic (RT-PCR) tests that occur after a patient has seroconverted may be indicative of reinfection. However, in the absence of SARS-CoV-2 sequence data, the possibility of prolonged viral shedding may not be excluded. We highlight a testing pattern that identifies such cases and study its statistical power in identifying potential reinfection. We also study the medical records of patients that matched the pattern.

ObjectiveTo describe the frequency and demographic information of people with a testing pattern indicative of SARS-CoV-2 reinfection.

DesignWe examined 4.2 million test results from a large national health insurer in the United States. Specifically, we identified the pattern of a positive RT-PCR test followed by a positive IgG test, again followed by a positive RT-PCR.

SettingData from outpatient laboratories across the United States was joined with claims data from a single large commercial insurers administrative claims database.

ParticipantsStudy participants are those whose insurance, either commercial or Medicare, is provided by a single US based insurer.

ExposuresPeople who received at least two positive diagnostic tests via RT-PCR for SARS-Cov-2 separated by 42 or more days with at least one serological test (IgG) indicating the presence of antibodies between diagnostic tests.

Main Outcomes and MeasuresCount and characteristics of people with the timeline of three tests as described in Exposures.

ResultsWe identified 79 patients who had two positive RT-PCR tests separated by more than six weeks, with a positive IgG test in between. These patients tended to be older than those COVID-19 patients without this pattern (median age 56 vs. 42), and they exhibited comorbidities typically attributed to a compromised immune system and heart disease.

Conclusions and RelevanceWhile the testing pattern alone was not sufficient to distinguish potential reinfection from prolonged viral shedding, we were able to identify common traits of the patients identified through the pattern.

category: infectious diseases


title: SPARSEMODr: Rapid simulations of spatially explicit and stochastic models of infectious disease

abstract:
O_LISimulating the dynamics of realistically complex models of infectious disease is conceptually challenging and computationally expensive. This results in a heavy reliance on customized software and, correspondingly, lower reproducibility across disease modeling studies.
C_LIO_LISPARSEMOD stands for SPAtial Resolution-SEnsitive Models of Outbreak Dynamics. The goal of our project, encapsulated by the SPARSEMODr package for R package, is to offer a framework for rapidly simulating the dynamics of stochastic and spatially-explicit models of infectious disease for use in pedagogical and applied contexts.
C_LIO_LIWe outline the universal functions of our package that allow for user-customization while demonstrating the common work flow.
C_LIO_LISPARSEMODr offers an extendable framework that should allow the open-source community of disease modelers to add new model types and functionalities in future releases.
C_LI

category: epidemiology


title: Long-term symptoms after SARS-CoV-2 infection in school children: population-based cohort with 6-months follow-up. Short Report

abstract: Although long COVID in children exists, it is still unclear to what extent children are affected. The Ciao Corona study is a longitudinal cohort investigating SARS-CoV-2 seroprevalence and clustering of cases among around 2500 children and adolescents (hereafter referred to as children) from 55 randomly selected primary and secondary schools in the canton of Zurich in Switzerland. Between June 2020 and April 2021, we completed three testing phases where we collected venous blood for serological analysis and asked about symptoms with online questionnaires. We compared children who tested positive for SARS-CoV-2 antibodies in October/November 2020 with those who tested negative. Children who were seronegative in October/November 2020 and seroconverted or were not retested in March/April 2021 were excluded from the analysis (n=256). In March-May 2021 we assessed the presence of symptoms occurring since October 2020, lasting for at least 4 weeks, and persisting for either >4 weeks or >12 weeks. Overall, 1355 of 2503 children with a serology result in October/November 2020 and follow up questionnaire in March-May 2021 were included. Among seropositive and seronegative 6-to 16-year-old children, 9% versus 10% reported at least one symptom beyond 4 weeks, and 4% versus 2% at least one symptom beyond 12 weeks. None of the seropositive children reported hospitalization after October 2020. This study suggests a low prevalence of symptoms compatible with long COVID in a randomly selected population-based cohort of children followed over 6 months after serological testing.


title: Symptom profiles and accuracy of clinical definitions for COVID-19 in the community. Results of the Virus Watch community cohort.

abstract:
BackgroundUnderstanding the symptomatology and accuracy of clinical case definitions for COVID-19 in the community is important for the initiation of Test, Trace and Isolate (TTI) and may, in future, be important for early prescription of antivirals.

MethodsVirus Watch is a large community cohort with prospective daily recording of a wide range of symptoms and self-reporting of swab results (mainly undertaken through the UK TTI system). We compared frequency, severity, timing, and duration of symptoms in test positive and test negative cases. We compared the test performance of the current UK case definition used by TTI (any one of: new continuous cough, high temperature, or loss of or altered sense of smell or taste) with a wider definition that also included muscle aches, chills, headache, or loss of appetite.

FindingsWe included results from 8213 swabbed illnesses, 944 of which tested positive for SARS-CoV-2. All symptoms were more common in test positive than test negative illnesses and symptoms were also more severe and of longer duration. Common symptoms such as cough, headache, fatigue, muscle aches, and loss of appetite occurred early in the course of illness but were also very common in test-negative illnesses. In contrast, high temperature and loss of or altered sense of smell or taste were less frequently identified in swab positive illnesses but were markedly more common than in swab negative illnesses. The current UK definition had a sensitivity and specificity of 81% and 47% respectively for symptomatic COVID-19 compared to 93% and 26% for the broader definition. On average, cases met the broader case definition 0.3 days earlier than the current definition. 1.7-fold more illnesses met the broader definition than the current case definition.

InterpretationCOVID-19 is difficult to distinguish from other respiratory infections and common ailments on the basis of symptoms. Broadening the list of symptoms used to encourage engagement with TTI could moderately increase the number of infections identified and shorten delays to isolation, but with a large increase in the number of tests needed and the number of unwell individuals and contacts who are advised to self-isolate whilst awaiting results, and subsequently test negative for SARS-CoV-2.


title: Effectiveness of BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on mortality following COVID-19

abstract: We estimated risk of death in vaccinated compared to unvaccinated COVID-19 cases. Cases vaccinated with 1 dose of BNT162b2 had 44% reduced risk of death, 55% with 1 dose of ChAdOx1, and 69% with 2 doses of BNT162b2. This is on top of the protection provided against becoming a case.


title: Rapidly emerging SARS-CoV-2 B.1.1.7 sub-lineage in the United States of America with spike protein D178H and membrane protein V70L mutations

abstract: The SARS-CoV-2 B.1.1.7 lineage is highly infectious and as of April 2021 accounted for 92% of COVID-19 cases in Europe and 59% of COVID-19 cases in the U.S. It is defined by the N501Y mutation in the receptor binding domain (RBD) of the Spike (S) protein, and a few other mutations. These include two mutations in the N terminal domain (NTD) of the S protein, HV69-70del and Y144del (also known as Y145del due to the presence of tyrosine at both positions). We recently identified several emerging SARS-CoV-2 variants of concerns, characterized by Membrane (M) protein mutations, including I82T and V70L. We now identify a sub-lineage of B.1.1.7 that emerged through sequential acquisitions of M:V70L in November 2020 followed by a novel S:D178H mutation first observed in early February 2021. The percentage of B.1.1.7 isolates in the U.S. that belong to this sub-lineage increased from 0.15% in February 2021 to 1.8% in April 2021. To date this sub-lineage appears to be U.S.-specific with reported cases in 31 states, including Hawaii. As of April 2021 it constituted 36.8% of all B.1.1.7 isolates in Washington. Phylogenetic analysis and transmission inference with Nextstrain suggests this sub-lineage likely originated in either California or Washington. Structural analysis revealed that the S:D178H mutation is in the NTD of the S protein and close to two other signature mutations of B.1.1.7, HV69-70del and Y144del. It is surface exposed and may alter NTD tertiary configuration or accessibility, and thus has the potential to affect neutralization by NTD directed antibodies.


title: Mitigating the psychological impacts of COVID-19 restrictions: The Behavioural Activation in Social Isolation (BASIL) pilot randomised controlled trial to prevent depression and loneliness among older people with long term conditions

abstract:
BackgroundOlder adults with long-term conditions have become more socially isolated (often due to advice to  shield to protect them from COVID-19) and are thus at particular risk of depression and loneliness. There is a need for brief scalable psychosocial interventions to mitigate the psychological impacts of social isolation. Behavioural Activation is a plausible intervention, but a trial is needed.

MethodsWe undertook an external randomised pilot trial (ISRCTN94091479) designed to test recruitment, retention and engagement with, and the acceptability and preliminary effects of the intervention. Participants aged [≥] 65 years with two or more long-term conditions were recruited between June and October 2020. Behavioural Activation was offered to intervention participants (n=47), and control participants received usual care (n=49).

FindingsRemote recruitment was possible and 45/47 (95.7%) randomised to the intervention completed one or more sessions (median 6 sessions). 90 (93.8%) completed the one month follow-up, and 86 (89.6%) completed the three month follow-up. The between-group comparison for the primary clinical outcome at one month was an adjusted between group mean difference of -0.50 PHQ-9 points (95% CI -2.01 to 1.01), but only a small number of participants had completed the intervention at this point. At three months, the PHQ-9 adjusted mean difference was 0.19 (95% CI -1.36 to 1.75). When we examined loneliness, the between-group difference in the De Jong Gierveld Loneliness scale at one month was 0.28 (95% CI -0.51 to 1.06), and there was statistically significant between group difference at three months (-0.87; 95% CI -1.56 to -0.18). Participants who withdrew had minimal depressive symptoms at entry.

InterpretationBehavioural Activation is a plausible intervention to mitigate the psychological impacts of COVID-19 isolation for older adults. The intervention can be delivered remotely and at scale, but should be reserved for older adults with evidence of depressive symptoms. The significant reduction in loneliness is unlikely to be a chance finding, and this will now be confirmed in a fully powered RCT.

FundingThis study was funded by National Institute for Health Research (NIHR) Programme Grants for Applied Research (PGfAR) RP-PG-0217-20006

category: psychiatry and clinical psychology


title: Central inhibition of pain is augmented in women with self-injurious behavior

abstract: Individuals who engage in nonsuicidal self-injury (NSSI) have demonstrated higher pain thresholds and tolerance compared with individuals without NSSI. The objective of the study was to assess which aspects of the pain regulatory system that account for this augmented pain perception. In a cross-sectional design, 81 women, aged 18-35 (mean [SD] age, 23.4 [3.9]), were included (41 with NSSI and 40 healthy controls). A quantitative sensory testing protocol, including heat pain thresholds, heat pain tolerance, pressure pain thresholds, conditioned pain modulation (assessing central down-regulation of pain), and temporal summation (assessing facilitation of pain signals) was used. Thermal pain stimuli were assessed during fMRI scanning and NSSI behaviors and clinical symptoms were self-assessed. NSSI participants demonstrated higher pain thresholds during heat and pressure pain compared to controls. During conditioned pain modulation, NSSI participants showed a more effective central down-regulation of pain for NSSI participants. Temporal summation did not differ between the groups. There were no correlations between pain outcomes and NSSI behaviors or clinical characteristics. The fMRI analyses revealed increased activity in the primary and secondary somatosensory cortex in NSSI participants, compared to healthy controls, which are brain regions implicated in sensory aspects of pain processing. The findings suggest segregated inhibitory mechanisms for pain and emotion in NSSI, as pain insensitivity was linked to enhanced inhibitory control of pain in spite of significant impairments in emotion regulation. This may represent an endophenotype associated with a greater risk for developing self-injurious behavior.


title: THE US MIDLIFE MORTALITY CRISIS CONTINUES: INCREASED DEATH RATES FROM CAUSES OTHER THAN COVID-19 DURING 2020

abstract: COVID-19 prematurely ended many lives, particularly among the oldest Americans, but the pandemic also had an indirect effect on health and non-COVID mortality among the working-age population, who suffered the brunt of the economic consequences. This analysis investigates whether monthly excess mortality in the US during 2020 varied by age and cause of death. Based on national-level death counts and population estimates for 1999-2020, negative binomial regression models--fit separately by sex-- were used to estimate monthly cause-specific excess mortality by age group during 2020. Among males, 71% non-COVID excess deaths occurred at working ages (25-64), but those ages accounted for only 36% of non-COVID excess deaths in females. The results revealed substantial numbers of excess deaths from external causes (particularly among males), heart disease, diabetes, Alzheimers disease (particularly among women), and cerebrovascular disease. For males, the largest share of non-COVID excess deaths resulted from external causes, nearly 80% of which occurred at working ages. Although incorrectly classified COVID-19 deaths may explain some excess non-COVID mortality, misclassification is unlikely to explain the increase in external causes of mortality. Auxiliary analyses suggested that drug-related mortality may be driving the rise in external mortality, but drug overdoses were already increasing for a full year prior to the pandemic. The oldest Americans bore the brunt of COVID-19 mortality, but working-age Americans, particularly men, suffered substantial numbers of excess non-COVID deaths, most commonly from external causes and heart disease.

category: public and global health


title: THE US MIDLIFE MORTALITY CRISIS CONTINUES: INCREASED EXCESS CAUSE-SPECIFIC MORTALITY DURING 2020


title: Impact of non-pharmaceutical interventions on SARS-CoV-2 outbreaks in English care homes: a modelling study

abstract:
BackgroundCOVID-19 outbreaks are still occurring in English care homes despite the non-pharmaceutical interventions (NPIs) in place.

MethodsWe developed a stochastic compartmental model to simulate the spread of SARS-CoV-2 within an English care home. We quantified the outbreak risk under the NPIs already in place, the role of community prevalence in driving outbreaks, and the relative contribution of all importation routes into the care home. We also considered the potential impact of additional control measures, namely: increasing staff and resident testing frequency, using lateral flow antigen testing (LFD) tests instead of PCR, enhancing infection prevention and control (IPC), increasing the proportion of residents isolated, shortening the delay to isolation, improving the effectiveness of isolation, restricting visitors and limiting staff to working in one care home.

FindingsThe model suggests that importation of SARS-CoV-2 by staff, from the community, is the main driver of outbreaks, that importation by visitors or from hospitals is rare, and that the past testing strategy (monthly testing of residents and daily testing of staff by PCR) likely provides negligible benefit in preventing outbreaks. Daily staff testing by LFD was 39% (95% 18-55%) effective in preventing outbreaks at 30 days compared to no testing.

InterpretationIncreasing the frequency of testing in staff and enhancing IPC are important to preventing importations to the care home. Further work is needed to understand the impact of vaccination in this population, which is likely to be very effective in preventing outbreaks.

FundingThe National Institute for Health Research, European Union Horizon 2020, Canadian Institutes of Health Research, French National Research Agency, UK Medical Research Council. The World Health Organisation funded the development of the COS-LTCF Shiny application.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSCare homes have been identified as being at increased risk of COVID-19 outbreaks, and a number of modelling studies have considered the transmission dynamics of SARS-CoV-2 in this setting. We searched the PubMed database and bioRxiv and medRxivs COVID-19 SARS-CoV-2 preprints for English-language articles on the 11th May 2021, with the search terms ("COVID-19" OR "SARS-CoV-2" OR "coronavirus") AND ("care home" OR "LTCF" OR "long term care facility" OR "nursing home") AND ("model"). In addition to these searches, we identified articles relevant to this work through informal networks. These searches returned 87 studies, of which 12 explicitly modelled SARS-CoV-2 transmission within care homes and explored the effectiveness of non-pharmaceutical interventions in these settings. These studies employed a number of modelling approaches (agent-based and compartmental models) and considered various strategies for mitigating epidemic spread within care homes. Only one of these studies modelled care homes in England, but didnt consider individual care homes as separate entities (transmission between residents in separate facilities was equally likely as within one facility) and only modelled one intervention within the care home: the effect of restricting visitors. Another study modelled a different type of long-term care facility, a rehabilitation facility in France. Other studies modelled care homes in Canada, Scotland, and the US. These modelled care homes were larger than the average English care home. Only one study included importation of SARS-CoV-2 to care homes from hospitals through resident hospitalisation.

Added value of this studyWe developed a stochastic compartmental model describing the transmission dynamics of SARS-CoV-2 within English care homes. This study is the first to assess the relative importance of all SARS-CoV-2 importation routes to care homes (including resident hospitalisation) and to quantify the impact of a range of non-pharmaceutical interventions against SARS-CoV-2 particularly for English care homes. We found that community prevalence, through staff importations, was the main driver of outbreaks in care homes at 30 days, not importation from hospital visits nor by visitors. In line with this, we found daily testing of staff to be the most effective testing strategy in preventing outbreaks. We show the previous testing strategy (PCR testing residents once every 28 days and staff once a week) to be ineffective in preventing outbreaks and suggest that more frequent testing of staff is required. Restricting visitors bore little effect on the probability of an outbreak occurring by day 30. Interventions focusing on decreasing the transmission of SARS-CoV-2 in the care home were the most effective in reducing the frequency of outbreaks. We provide a Shiny application for users to explore alternative care home characteristics, outbreak characteristics and interventions.

Implications of all the available evidencePreventing the importation of SARS-CoV-2 to care homes from the community through staff is key to preventing outbreaks. Infection prevention and control (IPC) measures targeting transmission within the care home and frequent testing of staff, ideally daily, are the most effective strategies considered. Many care homes in England are currently unable to meet the additional workload daily testing would entail, therefore additional support should be considered to enable these measures. Allowing visitors should be considered given their general positive contribution to residents physical and mental health and likely negligible contribution to outbreaks.


title: Longitudinal changes in home-based arts engagement during and following the first national lockdown due to the COVID-19 pandemic in the United Kingdom

abstract:
AimsThis study aimed to examine potential heterogeneity in longitudinal changes in home-based arts engagement during the first national lockdown and following gradual easing of restrictions in the UK. Further, it sought to explore factors that were associated with patterns of longitudinal changes in home-based arts engagement.

MethodsData were from the UCL COVID-19 Social Study. The analytical sample consisted of 29,147 adults in the UK who were followed up for 22 weeks from 21st March to 21st August 2020. Data were analysed using growth mixture models.

ResultsOur analyses identified five classes of growth trajectories. There were two stable classes showing little change in arts engagement over time (64.4% in total), two classes showing initial increases in arts engagement followed by declines as restrictions were eased (29.8%), and one class showing slight declines during strict lockdown followed by an increase in arts engagement after the easing of restrictions (5.9%). A range of factors were found to be associated with class membership of these arts engagement trajectories, such as age, gender, education, income, employment status, and health.

ConclusionsThere is substantial heterogeneity in longitudinal changes in home-based arts engagement. For participants whose engagement changed over time, growth trajectories of arts engagement were related to changes in lockdown measures. These findings suggest that some individuals may have drawn on the arts when they needed them the most, such as during the strict lockdown period, even if they usually had lower levels of arts engagement before the pandemic. Overall, our results indicate the importance of promoting arts engagement during pandemics and periods of lockdown as part of public health campaigns.


title: Caesarean birth in public maternities in Argentina: a formative research study on the views of obstetricians, midwives, and trainees.

abstract:
ObjectivesTo explore obstetricians, midwives, and trainees perceptions of CS determinants in the context of public obstetric care services provision in Argentina. Our hypothesis is that known determinants of CS use may differ in settings with limited access to essential obstetric services.

SettingWe conducted a formative research study in nineteen public maternity hospitals in Argentina. An institutional survey assessed the availability of essential obstetric services. Subsequently, we conducted online surveys and semi-structured interviews to assess the opinions of providers on known CS determinants.

ResultsObstetric services showed an adequate provision of emergency obstetric care but limited services to support women during birth. Midwives, with some exceptions, are not involved during labour. We received 680 surveys from obstetricians, residents, and midwives (response rate of 63%) and interviewed 26 key informants. Six out of ten providers (411, 61%) indicated that the use of CS is associated with the complexities of our caseload. Limited pain management access was deemed a potential contributing factor for CS in adolescents and first-time mothers. Providers have conflicting views on the adequacy of training to deal with complex or prolonged labour Obstetricians with more than ten years of clinical experience indicated that fear of litigation was also associated with CS. Overall, there is consensus on the need to implement interventions to reduce unnecessary CS.

ConclusionsPublic Maternity Hospitals in Argentina have made significant improvements in the provision of emergency services. The environment of service provision does not seem to facilitate the physiological process of vaginal birth. Providers acknowledged some of those challenges.

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis study is one of the few studies exploring the perceptions of providers working in low-resourced settings in middle-income countries on the determinants of increasing trends of CS.
C_LIO_LILarge sample and representation of all professionals and obstetric tasks working in low-resourced settings.
C_LIO_LICluster analysis allowed to describe the response variability across professional groups in relation to specific CS determinants.
C_LIO_LIThe use of Formative Research is a valuable tool to inform the design and implementation of future interventions.
C_LIO_LIEven though the response rate is good (63%) those who did not respond may have different views on the determinants of CS.
C_LIO_LISome participant hospitals had lower response rate.
C_LI

category: obstetrics and gynecology


title: Two-phase sample selection strategies for design and analysis in post-genome wide association fine-mapping studies

abstract: Post-GWAS analysis, in many cases, focuses on fine-mapping targeted genetic regions discovered at GWAS-stage; that is, the aim is to pinpoint potential causal variants and susceptibility genes for complex traits and disease outcomes using next-generation sequencing (NGS) technologies. Large-scale GWAS cohorts are necessary to identify target regions given the typically modest genetic effect sizes. In this context, two-phase sampling design and analysis is a cost-reduction technique that utilizes data collected during phase 1 GWAS to select an informative subsample for phase 2 sequencing. The main goal is to make inference for genetic variants measured via NGS by efficiently combining data from phases 1 and 2. We propose two approaches for selecting a phase 2 design under a budget constraint. The first method identifies sampling fractions that select a phase 2 design yielding an asymptotic variance covariance matrix with certain optimal characteristics, e.g. smallest trace, via Lagrange multipliers (LM). The second relies on a genetic algorithm (GA) with a defined fitness function to identify exactly a phase 2 subsample. We perform comprehensive simulation studies to evaluate the empirical properties of the proposed designs for a genetic association study of a quantitative trait. We compare our methods against two ranked designs: residual-dependent sampling and a recently identified optimal design. Our findings demonstrate that the proposed designs, GA in particular, can render competitive power in combined phase 1 and 2 analysis compared to alternative designs while preserving type 1 error control. These results are especially apparent under the more practical scenario where design values need to be defined a priori and are subject to mispecification. We illustrate the proposed methods in a study of triglyceride levels in the North Finland Birth Cohort of 1966. R code to reproduce our results is available at github.com/egosv/TwoPhase_postGWAS.

category: genetic and genomic medicine


title: The effect of smaller classes on infection-related school absence: Evidence from the Project STAR randomized controlled trial

abstract:
In an effort to reduce viral transmission, many schools are planning to reduce class size if they have not reduced it already. Yet the effect of class size on transmission is unknown. To determine whether smaller classes reduce school absence, especially when community disease prevalence is high, we merge data from the Project STAR randomized class size trial with influenza and pneumonia data from the 122 Cities Mortality Reporting System on deaths from pneumonia and influenza.

Project STAR was a block-randomized trial that followed 10,816 Tennessee schoolchildren from kindergarten in 1985-86 through third grade in 1988-89. Children were assigned at random to small classes (13 to 17 students), regular-sized classes (22 to 26 students), and regular-sized class with a teachers aide.

Mixed effects regression showed that small classes reduced absence, but not necessarily by reducing infection. In particular, small classes reduced absence by 0.43 days/year (95% CI -0.06 to -0.80, p<0.05), but had no significant interaction with pneumonia and influenza mortality (95% CI -0.27 to +0.30, p>0.90). Small classes, by themselves, may not suffice to reduce the spread of viruses.

category: health policy


title: Drug Repositioning by Merging Active Subnetworks Validated in Cancer and COVID-19

abstract: Computational Drug Repositioning aims at ranking and selecting existing drugs for use in novel diseases or existing diseases for which these drugs were not originally designed. Using vast amounts of available omic data in digital form within an in silico screening has the potential for speeding up considerably the shortlisting of promising candidates in response to outbreaks of diseases such as COVID-19 for which no satisfactory cure has yet been found. We describe DrugMerge as a methodology for preclinical computational drug repositioning based on merging multiple drug rankings obtained with an ensemble of Disease Active Subnetwork construction algorithms. DrugMerge uses differential transcriptomic data from cell lines/tissues of patients affected by the disease and differential transcriptomic data from drug perturbation assays, in the context of a large gene co-expression network. Experiments with four benchmark diseases (Asthma, Rheumatoid Arthritis, Prostate Cancer, and Colorectal Cancer) demonstrate that our method detects in first position drugs in clinical use for the specified disease, in all four cases. Our method is competitive with the state-of-the-art tools such as CMAP (Connectivity Map). Application of DrugMerge to COVID-19 data found rankings with many drugs currently in clinical trials for COVID-19 in top positions, thus showing that DrugMerge is able to mimic human expert judgment.


title: Performance evaluation of the BD SARS-CoV-2 reagents for the BD MAX™ system

abstract:
BackgroundThe RT-qPCR assay for detecting SARS-CoV-2 virus is the favorable approach to test suspected COVID-19 cases. However, discordant results can occur when two or more assays are compared. Variability in analytical sensitivities between assays, among other factors, may account for these differences in reporting.

MethodsThe limits of detection (LOD) for the BD SARS-CoV-2 Reagents for BD MAX System ("MAX SARS-CoV-2 assay"), the Biomerieux BioFire(R) Respiratory Panel 2.1 ("BioFire SARS-CoV-2 assay"), the Roche cobas SARS-CoV-2 assay ("cobas SARS-CoV-2 assay"), and the Hologic Aptima(R) SARS-CoV-2 assay Panther(R) ("Aptima SARS-CoV-2 assay") RT-qPCR systems were determined using a total of 84 contrived nasopharyngeal specimens with seven target levels for each comparator. The positive and negative percent agreement (PPA and NPA, respectively) for the MAX SARS-CoV-2 assay were compared to the Aptima SARS-CoV-2 assay in a post-market clinical study utilizing 708 paired nasopharyngeal specimens collected from suspected COVID-19 cases. Discordant results were further tested by the cobas and BioFire SARS-CoV-2 assays.

ResultsThe measured LOD for the MAX SARS-CoV-2 assay (251 copies/mL) was comparable to the cobas SARS-CoV-2 assay (298 copies/mL) and the BioFire SARS-CoV-2 assay (302 copies/mL); the Aptima SARS-CoV-2 assay had a LOD of 612 copies/mL. The MAX SARS-CoV-2 assay had a PPA of 100% (95%CI: [97.3%-100.0%]) and a NPA of 96.7% (95%CI: [94.9%-97.9%]) when compared to the Aptima SARS-CoV-2 assay.

ConclusionsThe MAX SARS-CoV-2 assay exhibited a high analytical sensitivity and specificity for SARS-CoV-2 detection. The clinical performance of the MAX SARS-CoV-2 assay agreed with another sensitive EUA cleared assay.


title: Epidemiological characteristics and incubation period of SARS-CoV-2 during the 2020-2021 winter pandemic wave in north China: an observational study

abstract: As the emergence of new variants of SARS-CoV-2 persists across the world, it is of importance to understand the distributional behavior of incubation period of the variants for both medical research and public health policy-making. We collected the published individual level data of 941 patients of the 2020-2021 winter pandemic wave in Hebei province, north China. We computed some epidemiological characteristics of the wave and estimated the distribution of the incubation period. We further assessed the covariate effects of sex, age and living with a case with respect to incubation period by a model. The infection-fatality rate was only 0.1%. The estimated median incubation period was at least 22 days, significantly extended from the estimates (ranging from 4 to 8.5 days) of the previous wave in mainland China and those ever reported elsewhere around the world. The proportion of asymptomatic patients was 90.6%. No significant covariate effect was found. The distribution of incubation period of the new variants showed a clear extension from their early generations.


title: Measurement of Respiratory Rate using Wearable Devices and Applications to COVID-19 Detection

abstract: We show that heart rate enabled wearable devices can be used to measure respiratory rate. Respiration modulates the heart rate creating excess power in the heart rate variability at a frequency equal to the respiratory rate, a phenomenon known as respiratory sinus arrhythmia. We isolate this component from the power spectral density of the heart beat interval time series, and show that the respiratory rate thus estimated is in good agreement with a validation dataset acquired from sleep studies (root mean squared error = 0.648 min-1, mean absolute percentage error = 3%). Using the same respiratory rate algorithm, we investigate population level characteristics by computing the respiratory rate from 10,000 individuals over a 14 day period, with equal number of males and females ranging in age from 20 - 69 years. 90% of respiratory rate values for healthy adults fall within the range 11.8 min-1 19.2 min-1 with a mean value of 15.4 min-1. Respiratory rate is shown to increase with nocturnal heart rate. It also varies with BMI, reaching a minimum at 25 kg/m2, and increasing for lower and higher BMI. The respiratory rate decreases slightly with age and is higher in females compared to males for age < 50 years, with no difference between females and males thereafter. The 90% range for the coefficient of variation in a 14 day period for females (males) varies from 2.3%-9.2% (2.3%-9.5%) for ages 20-24 yr, to 2.5%-16.8% (2.7%-21.7%) for ages 65-69 yr. We show that respiratory rate is often elevated in subjects diagnosed with COVID-19. In a 7 day window centered on the date when symptoms present (or the test date for asymptomatic cases), we find that 33% (18%) of symptomatic (asymptomatic) individuals had at least one measurement of respiratory rate 3 min-1 higher than the regular rate.


title: Reduction in COPD exacerbations during COVID-19: a systematic review and meta-analysis

abstract:
BackgroundReports have suggested a reduction in exacerbations of chronic obstructive pulmonary disease (COPD) during the coronavirus (COVID-19) pandemic, particularly hospital admissions for severe exacerbations. However, the magnitude of this reduction varies between studies.

MethodElectronic databases were searched from January 2020 to May 2021. Two independent reviewers screened titles and abstracts and, when necessary, full text to determine if studies met inclusion criteria. A modified version of the Newcastle-Ottawa Scale was used to assess study quality. A narrative summary of eligible studies was synthesised, and meta-analysis was conducted using a random effect model to pool the rate ratio and 95% confidence intervals (95% CI) for hospital admissions. Exacerbation reduction was compared against the COVID-19 Containment and Health Index.

ResultsA total of 13 of 745 studies met the inclusion criteria and were included in this review, with data from nine countries. Seven studies could be included in the meta-analysis. The pooled rate ratio of hospital admissions for COPD exacerbations during the pandemic period was 0.50 (95% CI 0.42-0.58). Findings on the rate of community-treated exacerbations were inconclusive. Three studies reported a significant decrease in the incidence of respiratory viral infections compared with the pre-pandemic period. There was not a significant relationship between exacerbation reduction and the COVID-19 Containment and Health Index.

ConclusionThere was a 50% reduction in admissions for COPD exacerbations during the COVID-19 pandemic period, associated with a reduction in respiratory viral infections that trigger exacerbations. We provide pooled evidence supporting the potential effectiveness of COVID-19 preventive interventions in reducing the risk of admissions for COPD exacerbations.

category: respiratory medicine


title: Regional distribution of anoxic brain injury after cardiac arrest: clinical and electrographic correlates

abstract:
IntroductionDisorders of consciousness, EEG background suppression and epileptic seizures are associated with poor outcome after cardiac arrest. The underlying patterns of anoxic brain injury associated with each remain unknown. Our objective was to identify the distribution of anoxic brain injury after cardiac arrest, as measured with diffusion MRI, and to define the regional correlates of disorders of consciousness, EEG background suppression, and seizures.

MethodsWe analyzed patients from a prospectively-maintained, single-center database of unresponsive patients who underwent diffusion-weighted MRI following cardiac arrest (n = 204). We classified each patient based on recovery of consciousness (command-following) before discharge, the most continuous EEG background (burst suppression versus continuous), and the presence or absence of seizures. Anoxic brain injury was measured using the apparent diffusion coefficient (ADC) signal. We identified abnormalities in ADC relative to control subjects without cardiac arrest (n = 48) and used voxel lesion symptom mapping to identify regional associations with disorders of consciousness, EEG background suppression, and seizures. We then used a bootstrapped lasso regression procedure to identify robust, multivariate regional associations with each clinical and EEG variable. Finally, using area under receiver operating characteristic curves, we then compared the classification ability of the strongest regional associations to that of brain-wide summary measures.

ResultsCompared to control subjects, cardiac arrest patients demonstrated a reduction in the ADC signal that was most significant in the occipital lobes. Disorders of consciousness were associated with reduced ADC most prominently in the occipital lobes, but also in the basal ganglia, medial thalamus and cerebellar nuclei. Regional injury more accurately classified patients with disorders of consciousness than whole-brain injury. Background suppression mapped to a similar set of brain regions, but regional injury could no better classify patients than whole-brain measures. Seizures were less common in patients with more severe anoxic injury, particularly in those with injury to the lateral temporal white matter.

DiscussionAnoxic brain injury was most prevalent in posterior cerebral regions, and this regional pattern of injury was a better predictor of disorders of consciousness than whole-brain injury measures. EEG background suppression lacked a specific regional association, but patients with injury to the temporal lobe were less likely to have seizures. Collectively, our results suggest that the regional pattern of anoxic brain injury is relevant to the clinical and electrographic sequelae of cardiac arrest and may hold importance for prognosis.

category: neurology


title: Predisposing factors associated with the severity of the illness in adults with Covid-19 in Nepal.

abstract:
ObjectiveWe aimed to determine the prevalence of the severity of COVID-19 illness and its associated predisposing factors in Nepal.

DesignCross-sectional, observational study

SettingSingle-centered hospital-based study, conducted at Nepal armed police force (APF) hospital, Kathmandu, Nepal.

ParticipantsAll individuals aged [≥]18 years with laboratory-confirmed SARS-Cov-2 (the SARS-CoV-2 specific real-time-RT-PCR result positive), regardless the severity of their disease.

MeasurementsDisease severity was evaluated as a primary outcome and age, sex, BMI, smoking history, alcohol history, Hypertension, diabetes mellitus were evaluated as predictors in the analysis.

ResultsMean ages of the patients were 40.79{+/-}16.04 years, and about two-thirds of the patients were male 146 (73.7%). More than half 57.1% (95%CI: 52.42-61.51) of the population had a mild infection, whereas 16.7% (95%CI: 7.4-24.6%) had severe/critical illness. In univariate analysis, each 1-year increase in age (OR: 1.05; 95% CI:1.030-1.081; P<0.001), each 1 unit increase in BMI (OR:1.12; 95% CI:1.02-1.25; P=0.033), comorbid illness (OR: 5.79; 95%CI: 2.51-13.33; P<0.001), hypertension (OR:5.95; 95%CI:2.66-13.30: P<0.001), diabetes mellitus (OR:3.26; 95%CI:1.30-8.15: P<0.005), and fever (OR:34.64; 95% CI:7.98-150.38; P<0.001) were independently associated with severity of the disease, whereas age (OR: 1.049; 95% CI: 1.019-1.080; P=0.02), hypertension (OR: 4.77; 95%CI: 1.62-14.04; P=0.004), and fever (OR: 51.02; 95%CI: 9.56-272.51; P<0.001) remained a significant predictive factors in multivariate analysis.

ConclusionThe majority of the patients with COVID-19 had a mild illness, with 16.7% severe illness. Age, BMI, hypertension, diabetes mellitus, comorbidity, and temperature were associated the severity of the illness. Age, hypertension, and fever emerged as an independent predictive factors in multivariate analysis, and thus, these vulnerable groups should be given special protection to the infection and proactive intervention should be initiated at an early stage of the infection to diminish the severity of the illness and improve the clinical outcome of the disease.

Strengths and limitations of the studyO_LIMuch of the studies on COVID-19 in Nepal focus on the describing epidemiology and clinical profile of the disease, however, risk factors that contribute to the severity of the illness are overlooked.
C_LIO_LIThis study may help estimate the burden of the disease and identify the vulnerable group with poor prognosis, which is vital for clinicians and the public health approach to deal with the disease.
C_LIO_LIAlthough limiting the study to a single-center with a relatively small sample size, it, however, allows evaluation of the importance of the demographic and geographical variation.
C_LIO_LISocio-economic factors, lifestyle, and availability of quality medical care may have contributed to the severity of the COVID-19, which needs to be addressed in a further large-scale study.
C_LI


title: Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor

abstract:
BackgroundIn a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure.

MethodsIn the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints.

ResultsAnakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.010). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (hazard ratio: 0.45; P: 0.045). Hospital stay was shorter.

ConclusionsEarly start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia.

(Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)


title: Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

abstract:
BackgroundColchicine has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory actions.

MethodsIn this randomised, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).

FindingsBetween 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalisation (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47).

InterpretationIn adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.

FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.


title: Sepsis prediction via the clinical data integration system in the ICU

abstract:
BackgroundSepsis is vital in critical care medicine, and early detection and intervention are key to survival. We aimed to establish an early warning system for sepsis based on a data integration system that can be implemented in the intensive care unit (ICU).

MethodsWe trained the LightGBM and multilayer perceptron on the open-source database Medical Information Mart for Intensive Care for sepsis prediction. An ensemble sepsis prediction model was established based on the transfer learning and ensemble learning technique on the private dataset of Ruijin Hospital. The Shapley Additive Explanations analysis was applied to present feature importance on the prediction inference. With the development of data-integrating hub to collect and transmit data from different brands of ICU medical devices, the data integration system was established to receive, integrate, standardize, and store the real-time clinical data. In this way, the sepsis prediction model developed in the ICU of the Ruijin Hospital for the real-world study of sepsis early warning on ICU management. The trial was registered with ClinicalTrials.gov (NCT05088850).

FindingsOur best early warning model achieved an area under the receiver operating characteristic curve (AUC) of 0{middle dot}9833 in the task of detecting sepsis in 4-h preceding on the open-source database, while our ensemble model achieved an AUC of 0{middle dot}9065-0{middle dot}9436 in the retrospective research from 1-5-h preceding on the private database, and 0{middle dot}8636-0{middle dot}8992 in real-time real-world studies using the data integration system in the ICU of the Ruijin Hospital. In the continuous early warning process of patients admitted to the ICU, 22 patients who met the diagnostic criteria for sepsis during hospitalization were predicted as positive cases; 29 patients without sepsis were predicted as negative cases. Additionally, 17 patients were predicted as false-positive cases; in six patients with sepsis during ICU stay, the predicted probabilities at different time nodes were all less than the warning threshold 0{middle dot}7 and predicted as false-negative cases.

InterpretationMachine learning models could allow accurate and real-time inference to detect sepsis onset within 5-h preceding at most with the help of the data integration system. We identified the features such as age, antibiotics, ventilation, and net balance to be important for the sepsis prediction inference. We argue that this system has promising potential to improve ICU management by helping medical practitioners identify at-sepsis-risk patients and prepare for timely diagnosis and intervention.

FundingShanghai Municipal Science and Technology Major Project, the ZHANGJIANG LAB, and the Science and Technology Commission of Shanghai Municipality.

category: intensive care and critical care medicine


title: SEPRES: Sepsis prediction via a clinical data integration system and real-world studies in the intensive care unit


title: Microsimulation of SARS-CoV-2 Transmission in Society

abstract: The outbreak of the pandemic disease, COVID-19, has shown that the approaches by different countries has resulted in a range of infection rates through their societies. This has arisen from the varying personal behaviour and tactical use of lockdown strategies within each country. We report the use of microsimulation of a simulated community in Australia, using a discrete infection model within a community of residences, places of work and recreation to demonstrate the applicability of this method to both the current pandemic and to infection more generally. Simulations without any societal intervention on infection spread provided base simulations that could be compared with social and societal controls in the future and which were compared with the initial doubling times of country outbreaks across the world. Different population sizes were represented in some simulations and in other simulations the effects of either social distancing or the use of facial masks as personal behaviours was investigated within the community. Good agreement is found between the initial doubling times for several countries and the simulations that suggests that modelling infection as a collection of individual infections provides an alternative to current epidemiological models. The variation of the basic reproductive number, R0, with time and population size, suggests that one of the fundamentals assumptions in SIR type models is wrong, but varies according to the properties of the population being modelled. Investigation of the infection spread shows that the number of super-spreaders varies with the size of the population and occurs through contacts in clubs, supermarkets, schools and theatres where the source of infection is an employee and where there are high numbers of contacts. The simulations of individual control show that the benefits of social distancing or wearing masks is only fully realised where there is considerable compliance within society to these measures.


title: Indian Interventional trials for COVID-19 drugs: Insights and Learnings

abstract: Since the COVID-19 pandemic began, India has substantially contributed to drug development and clinical research. Task Force on Repurposing of Drugs (TFORD) for COVID19 has tried to look at the overall position of India in terms of interventional clinical trials and highlight learnings which can prepare us to fight future pandemics in a better way. Trials registered on CTRI from March 2020 to December 2020 were considered for this purpose. From a total 409 trials registered, 108 focused on modern drugs. From 108 trials studied, 92 were randomized trials, 34 trials were sponsored by Indian Pharmaceutical industry, 23 were self-sponsored and 20 were sponsored by Research institutes and hospitals. Only 83 trials studied the repurposed drugs. An unfortunate revelation was that out of 108 trials, 79 showed as not yet recruiting. This highlights the urgent need for Government, Research institutions and Indian Pharmaceutical industries to break down silos and work together towards this common cause.


title: SPEEDS: A Portable Serological Testing Platform for Rapid Electrochemical Detection of SARS-CoV-2 Antibodies

abstract: The COVID-19 pandemic has resulted in a worldwide health crisis. Rapid diagnosis, new therapeutics and effective vaccines will all be required to stop the spread of COVID-19. Quantitative evaluation of serum antibody levels against the SARS-CoV-2 virus provides a means of monitoring a patients immune response to a natural viral infection or vaccination, as well as evidence of a prior infection. In this paper, a portable and low-cost electrochemical immunosensor is developed for the rapid and accurate quantification of SARS-CoV-2 serum antibodies. The immunosensor is capable of quantifying the concentrations of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against the SARS-CoV-2 spike protein in human serum. For IgG and IgM, it provides measurements in the range of 10.1 ng/mL - 60 {micro}g/mL and 1.64 ng/mL - 50 {micro}g/mL, respectively, and both antibodies can be assayed in 13 min. We also developed device stabilization and storage strategies to achieve stable performance of the immunosensor within 24-week storage at room temperature. We evaluated the performance of the immunosensor using COVID-19 patient serum samples collected at different time points after symptom onset. The rapid and sensitive detection of IgG and IgM provided by our immunosensor fulfills the need of rapid COVID-19 serology testing for both point-of-care diagnosis and population immunity screening.


title: Maliqua: A study within Malakit, a project on malaria and gold miners in French Guiana

abstract: Malaria is endemic in French Guiana, especially within the gold mining community working illegally. Gold miners travel to remote camps in the forest to carry out their activities, exposing themselves to the presumed contamination area. This paper presents the results of a qualitative case study of the Malakit project, a free distribution of self-diagnosis and self-treatment kits, along with appropriate training/information from health facilitators, at resting sites in Brazil and Suriname on the borders with French Guiana. This study documents how Malakit is part of the care trajectory of gold miners. The data was collected using three methods: 1) on-site observation; 2) semi-structured individual interviews (n=26); 3) semi-structured group interviews (n=2). The results inform us that Malakit responds to the need for treatment and facilitates access to care. Gold miners say they trust the facilitators and receive accurate explanations. The majority of participants find the kit easy to use and to carry and explanations given were sufficient, although some people needed to be reminded how to use it once in the forest. Results remind us that malaria among illegal gold miners in French Guiana is a question of social inequalities in health, where the interaction of the health, social, economic and political contexts of Brazil and French Guiana influence exposure to numerous risk factors. Thus, malaria intervention practices such as Malakit cannot be carried out without considering the complexity generated by social inequalities in health.


title: Application of BRACE Method to Address Treatment Selection Bias in Observational Data

abstract:
BackgroundCancer treatments can paradoxically appear to reduce the risk of non-cancer mortality in observational studies, due to residual confounding from treatment selection bias. Here we apply a novel method, Bias Reduction through Analysis of Competing Events (BRACE), to reduce bias in the presence of residual confounding.

MethodsWe studied 36630 prostate cancer patients, 4069 lung cancer patients, and 7117 head/neck cancer patients, using the Veterans Affairs Informatics and Computing Infrastructure database. We estimated effects of intensive treatment (prostate: prostatectomy vs. radiotherapy; lung: lobectomy vs. sublobar resection or radiotherapy; head/neck: radiotherapy with concurrent cisplatin and/or multiagent induction vs. radiotherapy with or without alternative systemic therapy) on cancer-specific mortality, non-cancer mortality, and overall survival (OS), using both multivariable Cox (MVA) and propensity score (inverse probability treatment weighting (IPTW)) models. Next, we applied the BRACE method to adjust for residual confounding, based on the observed treatment effect on competing event and relative event hazards.

ResultsFor each cohort, intensive treatment was associated with significantly reduced hazards for cancer-specific mortality, non-cancer mortality, and OS. Compared to the results for MVA and IPTW models, hazard ratios (95% confidence intervals) for the effect of intensive treatment on OS were attenuated in each cohort after applying BRACE: (prostate-MVA: 0.75 (0.71, 0.80), IPTW: 0.73 (0.66, 0.75), BRACE: 0.98 (0.95, 1.00); lung-0.79 (0.68, 0.91), 0.79 (0.66, 0.89), BRACE: 0.81 (0.65, 0.94); head/neck-0.71 (0.66, 0.76), 0.70 (0.66, 0.76), BRACE: 0.81 (0.76, 0.86)). BRACE estimates were similar to findings from meta-analyses and randomized trials.

ConclusionsWe found evidence of residual confounding in several observational cohorts after applying standard methods, which were mitigated after applying BRACE. Application of this method could provide more reliable estimates and inferences when residual confounding is identified and represents a novel approach to improving the validity of outcomes research.


title: Effect of COVID-19 on inequalities in premature mortality in England: an analysis of excess mortality by deprivation and ethnicity

abstract:
ObjectivesTo examine the impact of the Covid-19 pandemic on inequalities in premature mortality in England by deprivation and ethnicity.

DesignA statistical model to estimate increased mortality in population sub-groups during the Covid-19 pandemic by comparing observed with expected mortality in each group based on trends over the previous five years.

SettingInformation on deaths registered in England since 2015 was used, including age, sex, area of residence, and cause of death. Ethnicity was obtained from Hospital Episode Statistics (HES) records linked to death registration data.

ParticipantsPopulation study of England, including all 569,824 deaths from all causes registered between 21 March 2020 and 26 February 2021.

Main outcome measuresExcess mortality in each sub-group over and above the number expected based on trends in mortality in that group over the previous five years.

ResultsThe gradient in excess mortality by deprivation was greater in the under 75s (most deprived had 1.25 times as many deaths as expected, least deprived 1.14) than in all ages (most deprived had 1.24 times as many deaths as expected, least deprived 1.20). Among the Black and Asian groups, all deprivation quintiles had significantly larger excesses than the most deprived White group and there were no clear gradients across quintiles. Among the White group, only the most deprived had more excess deaths than deaths directly involving Covid-19. Among the Black group all deprivation quintiles experienced more excess deaths than deaths directly involving Covid-19.

ConclusionThe Covid-19 pandemic has widened inequalities in premature mortality by deprivation. Among those under 75, the direct and indirect effects of the pandemic on deaths have disproportionately impacted ethnic minority groups irrespective of deprivation, and the most deprived White group. Statistics limited to deaths directly involving Covid-19 understate the pandemics impact on inequalities by deprivation and ethnic group at younger ages.

Key Messages

What is already known on this topicO_LIEstimates of excess mortality for all ages combined for the period March 2020 to February 2021 show a small difference in the relative impact of Covid-19 on excess mortality between the most deprived and the least deprived
C_LIO_LIThroughout the pandemic estimates of excess mortality have been greater for ethnic minority groups compared with the white group.
C_LI

What this study addsO_LIAmong the under 75s the gradient of excess mortality across the deprivation spectrum indicates a stark increase in already established inequalities in premature mortality
C_LIO_LIIndependent of deprivation, excess mortality in Black and Asian ethnic groups is much higher than that of the white group, indicating that ethnicity is a determinant of excess mortality, regardless of level of area-based deprivation.
C_LI


title: Phylogenomics and population genomics of SARS-CoV-2 in Mexico reveals variants of interest (VOI) and a mutation in the Nucleocapsid protein associated with symptomatic versus asymptomatic carriers

abstract:
Understanding the evolution of SARS-CoV-2 virus in various regions of the world during the Covid19 pandemic is essential to help mitigate the effects of this devastating disease. We describe the phylogenomic and population genetic patterns of the virus in Mexico during the pre-vaccination stage, including asymptomatic carriers. A RT-qPCR screening and phylogenomics reconstructions directed a sequence/structure analysis of the Spike glycoprotein, revealing mutation of concern E484K in genomes from central Mexico, in addition to the nationwide prevalence of the imported variant 20C/S:452R (B.1.427/9). Overall, the detected variants in Mexico show Spike protein mutations in the N-terminal domain (i.e., R190M), in the receptor-binding motif (i.e., T478K, E484K), within the S1-S2 subdomains (i.e., P681R/H, T732A), and at the basis of the protein, V1176F, raising concerns about the lack of phenotypic and clinical data available for the variants of interest (VOI) we postulate: 20B/478K.V1 (B.1.1.222 or B.1.1.519) and 20B/P.4 (B.1.1.28.4). Moreover, the population patterns of Single Nucleotide Variants (SNVs) from symptomatic and asymptomatic carriers obtained with a self-sampling scheme confirmed the presence of several fixed variants, and differences in allelic frequencies among localities. We identified the mutation N:S194L of the Nucleocapsid protein associated with symptomatic patients. Phylogenetically, this mutation is frequent in Mexican sub-clades, so we propose an additional VOI, 20A/N:194L.V2 (B.1.243). Our results highlight the dual and complementary role of Spike and Nucleocapsid proteins in adaptive evolution of SARS-CoV-2 to their hosts and provide a baseline for specific follow-up of mutations of concern during the vaccination stage.

IMPACT STATEMENTFollowing self-sampling, screening of mutations of concern, and a combined phylogenomic and population genetics pipeline, we reveal the appearance of three VOI with mutations in the Spike protein, P.4 (B.1.1.28.4) and 20B/478K.V1 (B.1.1.222, leading to B.1.1.519), and in the Nucleocapsid protein, 20A/N:194L.V2 (B.1.243), in Mexico during the pre-vaccination stage. The mutation S194L in the Nucleocapsid was found to associate with symptomatic patients versus asymptomatic carriers in the population investigated. Our research can aid epidemiological genomics efforts during the vaccination stage in Mexico by contributing with a combined analytical platform and information about variants within different genetic lineages with the potential to evolve into variants of concern (VOC).


title: SARS-CoV-2 Vaccine-Induced Antibody Response and Reinfection in Persons with Past Natural Infection

abstract:
Several studies have shown that subjects with a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection had significantly higher antibody titers than previously uninfected vaccinees after vaccination with mRNA vaccine. Yet no information is available for other vaccines.

In the current observational cohort study, 105 health care workers who had received Covishield an Adeno associated viral vector-based DNA vaccine were enrolled at Sarojini Nadu Medical College Agra, India. The study included 40 (23 men and 17 women) subjects with a previous history of SARS-CoV-2 infection and 65 participants (39 men and 26 women) who were not infected previously. Both the groups received the adenovirus vector vaccine ChAdOx1-S recombinant vaccines (Covishield, Astra Zeneca). The levels of SARS-CoV-2-anti-spike-IgG-antibodies titer were measured using Electrochemiluminescence immunoassay on Roche platform as arbitrary units per milliliter (AU/ml).

After 28 days of the second dose, subjects with no previous SARSCoV-2 infection showed a significantly lower level of circulating anti-spike-IgG-antibody titers compared to previously infected participants. After the second dose, we also observed a significant increase in SARS-CoV-2 infection in subjects with no prior history of SARS-CoV-2 infection compared to subjects with a previous history of natural infection.

The most important observation of the study is a low percentage of infection in previously infected subjects. The finding of the study also indicates the presence of robust humoral memory response in previously infected patients.


title: Evaluation of High Flow Local Extraction on control of the aerosol plume in an operating theatre

abstract:
BackgroundEngineering controls are a necessity for minimising aerosol transmission of SARS-CoV-2, yet so far, little attention has been given to such interventions. High flow local extraction (HFLE) is a standard in other industries that deal with airborne contaminants.

ObjectiveThis study aims to provide a quantitative evaluation of an HFLE concept feasible to implement in most real clinical settings.

DesignA unique combined experimental model of Laser sheet illumination videography paired with continuous nanoparticle counts was used to quantitatively assess the impact of HFLE in an operating theatre. Propylene Glycol was aerosolised via a customised physiological lung simulator and dispersion was measured in 3 dimensions. Cumulative probability heat maps were generated to describe aerosol behaviour. Continuous particle counts were made at 15 locations throughout the room to validate laser assessments.

ResultsHigh flow local extraction reduced dispersion of simulated exhaled aerosols to undetectable levels. With the HFLE in operation and optimally positioned, the aerosol plume was tightly controlled. Particle counts remained at baseline when HFLE was active. HFLE becomes less effective when positioned at increasing distance from the mouth.

Aerosol plume behaviour in the absence of HFLE was highly variable and unpredictable.

ConclusionsThis analysis demonstrates great potential for HFLE to have a significant impact in reducing aerosol transmission. Simple HFLE devices can be easily engineered and could be widely deployed without impacting on the safe delivery of care.


title: Platelet expression and reactivity after BNT162b2 vaccine administration

abstract:
SARS-CoV-2 infection induces a coagulopathy characterized by platelet activation and a hypercoagulable state with an increased incidence of cardiovascular events. The viral spike protein S has been reported to enhance thrombosis formation, stimulate platelets to release pro-coagulant factors and promote the formation of platelet-leukocyte aggregates even in absence of the virus. Although SARS-CoV-2 vaccines induce spike protein overexpression to trigger SARS-CoV-2-specific immune protection, thrombocyte activity has not been investigated in this context. Here, we provide the first phenotypic platelet characterization of healthy human subjects undergoing BNT162b2 vaccination.

Using mass cytometry, we analyzed the expression of constitutive transmembrane receptors, adhesion proteins and platelet activation markers in 12 healthy donors before and at five different timepoints within four weeks after the first BNT162b2 administration. We measured platelet reactivity by stimulating thrombocyte activation with thrombin receptor-activating peptide (TRAP). Activation marker expression (P-Selectin, LAMP-3, LAMP-1, CD40L and PAC-1) did not change after vaccination. All investigated constitutive transmembrane proteins showed similar expressions over time. Platelet reactivity was not altered after BNT162b2 administration. Activation marker expression was significantly lower compared to an independent cohort of mild symptomatic COVID-19 patients analyzed with the same platform.

This study reveals that BNT162b2 administration does not alter platelet protein expression and reactivity.

category: cardiovascular medicine


title: A Cross-Sectional Analysis of Oral Health Spending Over the Lifespan in Commercial and Medicaid Insured Populations

abstract:
BackgroundLife course theory creates a better framework to understand how oral health needs and challenges align with specific phases of the lifespan, care models, social programs, and changes in policy.

MethodsData are from the 2018 IBM Watson Multi-State Medicaid Marketscan Database (31 million claims) and the 2018 IBM Watson Dental Commercial and Medicare Supplemental Claims Database (45 million claims). Analysis compares per enrollee spending fee-for-service dental claims and medical spending on dental care from ages 0 to 89.

ResultsDental utilization and spending are lower during the first 4 years of life and in young adulthood than in other periods of life. Stark differences in the timing, impact, and severity of caries, periodontal disease, and oral cancer are seen between those enrolled in Medicaid and commercial dental plans. Early childhood caries and oral cancer occur more frequently and at younger ages in Medicaid populations.

ConclusionsThis unique lifespan analysis of the U.S. multi-payer dental care system demonstrates the complexities of the current dental service environment and a lack of equitable access to oral healthcare.

Practical ImplicationsHealth policies should be focused on optimizing care delivery to provide effective preventive care at specific stages of the lifespan.

category: dentistry and oral medicine


title: Will there be a third COVID-19 wave? A SVEIRD model based study of Indian situation.

abstract:
Since first patient detected in India in late February, 2020, SARS-CoV-II virus is playing havoc on India. After the first wave, India is now riding the 2nd wave. As was in the case of European countries like Italy and UK, the 2nd wave is more contagious and at the time of writing this paper, the per day infection is as high as 400,000. The alarming thing is it is not uncommon that people is getting infected multiple time. On the other hand, mass vaccination has started step by step. There is also growing danger of potential 3rd wave is unavoidable, which can even infect kids and minors.

In this situation, an estimation of the dynamics of SARS-CoV-2 is absolutely necessary to combat the pandemic. We have used a modified SEIRD model, that includes vaccination and repeat infection as well. We have studied India and 8 Indian states with varying SARS-CoV-2 infection. We have shown that, Covid-19 wave will be repeated time to time, but the intensity will slow down with time. In most possible situation, our calculation shows COVID-19 will remain as endemic for foreseeable future, unless we are able to increase our vaccination rate manifold.


title: Evaluation on the Effectiveness on the Implementation of WHO-CST Programme in Hong Kong: A RCT Protocol

abstract: Developmental delays/disorders in young children are identified as a public health priority. WHO and Autism Speaks co-designed a training programme titled "WHO-Caregiver Skills Training" (WHO-CST) which aims at providing training for caregivers whose children are with possible symptoms of Autism spectrum disorder (ASD) symptoms and pervasive developmental disorders (PDD), so that they can learn better strategies on managing the daily lives of their children and foster better communication between the parent-children dyad. The WHO-CST programme is currently implemented in more than 30 regions worldwide and it started in Hong Kong from 2018. As the programme is newly developed, only a few studies tried to evaluate the effectiveness of the programme in qualitative approaches, or in quantitative approach with relatively small sample (e.g. n < 10). In the present study, our team, who is responsible for the implementation and evaluation of the WHO-CST programme in Hong Kong, attempt to assess the effectiveness of the training in WHO-CST under a randomized controlled trial (RCT) design with about 120 eligible caregivers who will be randomly assigned in experimental and control groups. Our measurement will include the Joint Engagement Rating Inventory (JERI) developed by experts in WHO to gauge how parents engage their children in a 10-minute video recording their dyadic interaction and behaviors in a defined play setting. A set of other measurements on the caregivers experience of using intervention skills and their enhancement of knowledges will also be measured. We hypothesize that caregivers in treatment group will have better growth in scores of both JERI and measurements of other outcome than the wait-list control groups after the 12-week WHO-CST training, and also persistence of skill and knowledge level should also be found after a 30-day follow-up test.


title: Public attitudes to COVID-19 vaccines: A qualitative study

abstract:
OBJECTIVETo explore public attitudes to COVID-19 vaccines in the UK, focused on intentions and decisions around taking vaccines, views on  vaccine passports, and experiences and perspectives on post-vaccination behavior.

DESIGNQualitative study consisting of 6 online focus groups conducted between 15th March - 22nd April 2021.

SETTINGOnline video conferencing

PARTICIPANTS29 adult UK-based participants

RESULTSThree main groups regarding participants decision or intention to receive a COVID-19 vaccine were identified: (1) Accepters, (2) Delayers and (3) Refusers. Two reasons for vaccine delay were identified: delay due to a perceived need more information and delay until vaccine was "required" in the future. Three main facilitators (Vaccination as a social norm; Vaccination as a necessity; Trust in science) and six barriers (Preference for "natural immunity"; Concerns over possible side effects; Distrust in government; Perceived lack of information; Conspiracy theories; "Covid echo chambers") to vaccine uptake were identified. For some delayers, vaccine passports were perceived to be a reason why they would get vaccinated in the future. However, vaccine passports were controversial, and were framed in three main ways: as "a necessary evil"; as "Orwellian"; and as a "human rights problem". Participants generally felt that receiving a vaccine was not changing the extent to which people were adhering to COVID-19 measures.

CONCLUSIONSOverall, positive sentiment toward vaccines was high. However, there remains a number of potential barriers which might be leading to vaccine delay in some.  Vaccine delay might be a more useful and precise construct than vaccine hesitancy in explaining why some may initially ignore or be uncertain about vaccination invitations. Vaccine passports may increase or  nudge uptake in some delayers but remain controversial. Earlier concerns that vaccination might reduce adherence to social distancing measures are not borne out in our data, with most people reporting ongoing adherence and caution.


title: Screening of renal function among a group of physicians working in a hospital who are often self neglected

abstract:
BackgroundPrevalence of chronic kidney disease (CKD) has been increasing rapidly worldwide and early screening to detect kidney disease, particularly at its early stages is pivotal to stop its further deterioration. Population based study on detection at early stage of kidney disease and its prevalence are scanty in our country, especially among the medical professional personnel. Hence taking advantage of the observance of World Kidney Day 2020, we conducted a screening program for kidney disease organized at the Chattogram Maa O Shishu Hospital (CMOSH) premises among a group of physicians of the hospital.

MethodsThis was a cross sectional observational study among 67 physicians of different ranks (medical officer to professor), working at our hospital in different discipline. Age, body weight, height, Body Mass Index (BMI), blood pressure were documented, and urinary protein and serum creatinine were measured at a single sitting. Kidney function was estimated by calculating the glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula. Kidney function was classified according to estimated GFR (eGFR) and Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines.

ResultsA total of 67 working physicians of the hospital were studied. Among them majority subjects (30) were in the age group of 20 to 29 years. Among all 11.9% participants had proteinuria (trace to 1 plus). The distribution of eGFR was symmetrical, with the majority (70.10%) of subjects in the 60 to 89 ml/min category; 11.90% had 30 to 59 ml/min category and only 17.90% of the study population had eGFR > 90 ml/min. An inverse relation between eGFR and age, and a direct relation between eGFR and BMI were observed.

ConclusionProteinuria, low eGFR levels might be related with future decline in renal function among the studied subjects and so regular health check-up is important to abate the potential epidemic of kidney disease among the health professionals.

category: nephrology


title: The New Therapeutics in Alzheimer's Disease Longitudinal Cohort study (NTAD): study protocol

abstract:
IntroductionWith the pressing need to develop treatments that slow or stop the progression of Alzheimers disease, new tools are needed to reduce clinical trial duration and validate new targets for human therapeutics. Such tools could be derived from neurophysiological measurements of disease.

Methods and AnalysisThe New Therapeutics in Alzheimers disease study (NTAD) aims to identify a biomarker set from magneto/electro-encephalographic that is sensitive to disease and progression over one year. The study will recruit 100 people with amyloid-positive mild cognitive impairment or early-stage Alzheimers disease and 30 healthy controls aged between 50 and 85 years. Repeat measurements of the clinical, cognitive and imaging data (magnetoencephalography, electroencephalography and magnetic resonance imaging) of participants with Alzheimers disease or mild cognitive impairment will be taken at baseline and at one year. To assess reliability of magneto/electro-encephalographic changes, a subset of 30 participants with mild cognitive impairment or early-stage Alzheimers disease will undergo repeat magneto/electro-encephalographic two weeks after baseline. Clinical and cognitive assessment will be repeated at 2 years. Linear mixed models of baseline and longitudinal change in neurophysiology are the primary analyses of interest, supported by Bayesian inference. Additional outputs will include relative effect sizes for physiological markers, atrophy and cognitive change and the respective numbers needed to treat each arm of simulated clinical trials of a future disease modifying therapy.

Ethics and disseminationThe study has received a favourable opinion from the East of England Cambridge Central Research Ethics Committee (REC reference 18/EE/0042). Results will be disseminated through internal reports, peer-reviewed scientific journals, conference presentations, website publication, submission to regulatory authorities and other publications. Data will be made available via the Dementias Platform UK Data Portal on completion of initial analyses by the NTAD study group.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_ST_ABSStrengthsC_ST_ABSO_LINTAD is a longitudinal, multicentre study of magneto/electro-encephalographic measures of Alzheimers disease progression
C_LIO_LINTAD assesses the test-retest reliability of magneto/electro-encephalographic parameters
C_LIO_LIAll participants with early-stage Alzheimers disease or mild cognitive impairment will be amyloid-positive
C_LI

LimitationsO_LIAttrition during follow up may limit inferences
C_LIO_LIRecruitment is from volunteer panels and clinical services that may not reflect national diversity of people affected by Alzheimers disease
C_LI


title: Amplitude setting and dopamine response of finger tapping and gait are related in Parkinson's disease

abstract:
ObjectiveMovement amplitude setting is affected early in Parkinsons disease (PD), clinically manifesting as bradykinesia. Our objective was to determine if amplitude setting of upper limb bimanual movements and bipedal gait are similarly modulated in PD.

Methods27 PD and 24 control participants were enrolled. Participants performed a bimanual anti-phase finger tapping task wearing gloves with joint angular sensors, and an instrumented gait assessment. Motor load was varied by asking participants to perform movements at a normal and fast pace. PD participants were evaluated OFF (PD-OFF) and ON (PD-ON) levodopa.

ResultsPD-OFF participants had shorter tap interval, smaller tap amplitude, and greater tap amplitude variability than controls in the more affected hands (all p<0.05). Tap amplitude and stride length (p=0.030), and tap frequency and gait cadence (p=0.011) were correlated in PD-OFF. Tap frequency and amplitude were also correlated with motor UPDRS (p<0.005) and bradykinesia motor (p<0.05) and ADL (p<0.005) UPDRS subscales. Levodopa improved mean tap amplitude and stride length during fast tapping in PD participants.

ConclusionIn PD-OFF, mean finger tapping amplitude and gait stride length were correlated and showed similar dopaminergic response.

SignificanceFuture studies manipulating upper limb amplitude could help provide greater understanding of the networks responsible for amplitude setting in PD.


title: Trait mindfulness is associated with less amyloid, tau, and cognitive decline in individuals at risk for Alzheimer's disease

abstract:
BACKGROUND AND OBJECTIVESMindfulness, defined as non-judgmental awareness of the present moment, has been associated with an array of mental and physical health benefits, including improved cognitive functioning and changes to brain structure and function. Mindfulness may also represent a protective factor for Alzheimers disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia.

METHODSTwo hundred sixty-one nondemented older adults with a family history of AD dementia were included from the PREVENT-AD observational cohort study, including 124 with A{beta}- and tau-positron emission tomography (PET) scans. All participants completed measures of trait mindfulness and longitudinal cognitive assessments. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and (1) cognitive decline, (2) A{beta}, and (3) tau.

RESULTSHigher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less A{beta}-PET signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau-PET signal in bilateral temporal regions, namely entorhinal cortex, amygdala, and parahippocampal, fusiform, and inferior temporal gyri. These relationships remained significant when additional demographic (age, sex, education and APOE status) and psychological (personality traits and neuropsychiatric symptoms) were included in analyses. When mindfulness, personality traits, and neuropsychiatric symptoms were entered into the same model, mindful nonjudgment showed the strongest association with cognitive decline and A{beta}.

DISCUSSIONTrait mindfulness is associated with less cognitive decline and less A{beta} and tau in the brain in older adults at risk for AD dementia. In addition to its other health benefits, trait mindfulness may also represent a psychological protective factor for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies with cognition and pathology as outcome variables, will be important for further clarifying the potential protective benefits of mindfulness on AD risk.


title: Interval timing and midfrontal delta oscillations are impaired in Parkinson's disease patients with freezing of gait

abstract: Gait abnormalities and cognitive dysfunction are common in patients with Parkinsons disease (PD) and get worst with disease progression. Recent evidence has suggested a strong relationship between gait abnormalities and cognitive dysfunction in PD patients and impaired cognitive control could be one of the causes for abnormal gait patterns. However, the pathophysiological mechanisms of cognitive dysfunction in PD patients with gait problems are unclear. Here, we collected scalp electroencephalography (EEG) signals during a 7-second interval timing task to investigate the cortical mechanisms of cognitive dysfunction in PD patients with (PDFOG+, n=34) and without (PDFOG-, n=37) freezing of gait, as well as control subjects (n=37). Results showed that the PDFOG+ group exhibited the lowest maximum response density at around 7 seconds compared to PDFOG- and control groups, and this response density peak correlated with gait abnormalities as measured by FOG scores. EEG data demonstrated that PDFOG+ had decreased midfrontal delta-band power at the onset of the target cue, which was also correlated with maximum response density and FOG scores. In addition, our classifier performed better at discriminating PDFOG+ from PDFOG- and controls with an area under the curve of 0.93 when midfrontal delta power was chosen as a feature. These findings suggest that abnormal midfrontal activity in PDFOG+ is related to cognitive dysfunction and describe the mechanistic relationship between cognitive and gait functions in PDFOG+. Overall, these results could advance the development of novel biosignatures and brain stimulation approaches for PDFOG+.


title: Pregnancy and birth outcomes after SARS-CoV-2 vaccination in pregnancy

abstract:
BackgroundSARS-CoV-2 infection during pregnancy is associated with significant maternal morbidity and increased rates of preterm birth. For this reason, COVID-19 vaccine administration in pregnancy has been endorsed by multiple professional societies including ACOG and SMFM despite exclusion of pregnant women from initial clinical trials of vaccine safety and efficacy. However, to date little data exists regarding outcomes after COVID-19 vaccination of pregnant patients.

Study DesignA comprehensive vaccine registry was combined with a delivery database for an integrated healthcare system to create a delivery cohort including vaccinated patients. Maternal sociodemographic data were examined univariately for factors associated with COVID-19 vaccination. Pregnancy and birth outcomes were analyzed, including a composite measure of maternal and neonatal pregnancy complications, the Adverse Outcome Index.

ResultsOf 2002 patients in the delivery cohort, 140 (7.0%) received a COVID-19 vaccination during pregnancy and 212 (10.6%) experienced a COVID-19 infection during pregnancy. The median gestational age at first vaccination was 32 weeks (range 13 6/7-40 4/7), and patients vaccinated during pregnancy were less likely than unvaccinated patients to experience COVID-19 infection prior to delivery (1.4% (2/140) vs. 11.3% (210/1862)) P<0.001No maternal COVID-19 infections occurred after vaccination during pregnancy.

Factors significantly associated with increased likelihood of vaccination included older age, higher level of maternal education, lower pre-pregnancy BMI, and use of infertility treatment for the current pregnancy. Tobacco or other substance use, Hispanic ethnicity, and higher gravidity were associated with a lower likelihood of vaccination. No significant difference in the composite adverse outcome (5.0% (7/140) vs. 4.9% (91/1862) P=0.95) or other maternal or neonatal complications, including thromboembolic events and preterm birth, was observed in vaccinated mothers compared to unvaccinated patients.

ConclusionsVaccinated pregnant women in this birth cohort were less likely to experience COVID-19 infection compared to unvaccinated pregnant patients, and COVID-19 vaccination during pregnancy was not associated with increased pregnancy or delivery complications. Significant sociodemographic disparities in vaccine uptake and/or access were observed among pregnant patients, and future efforts should focus on outreach to low-uptake populations.


title: Frailty is a predictor of medication-related harm requiring healthcare utilisation: a multicentre prospective cohort study

abstract:
ObjectivesTo determine the association between frailty and medication-related harm requiring healthcare utilisation.

DesignProspective observational cohort study.

Setting6 primary and 5 secondary care sites across South East England, September 2013 - November 2015.

Participants1280 participants, 65 years old or over, who were due for discharge from general medicine and older persons wards following an acute episode of care. Exclusion criteria were limited life expectancy, transfer to another hospital and consent not gained.

Main outcome measuresMedication-related harm requiring healthcare utilisation, including adverse drug reactions, non-adherence and medication error determined via triangulation of: patient/carer reports gathered through a structured telephone interview; primary care medical record review; and prospective consultant-led review of re-admission to recruiting hospital. Frailty was measured using a Frailty Index, developed using a standardised approach. Marginal estimates were obtained from logistic regression models to examine how probabilities of healthcare service use due to medication-related harm were associated with increasing polypharmacy and frailty.

ResultsHealthcare utilisation due to medication-related harm was significantly associated with frailty (OR = 10.06, 95% CI 2.06 to 49.26, p = 0.004), independent of age, gender, and polypharmacy. With increasing polypharmacy, the need for healthcare use as a result of MRH increases from a probability of around 0.2 to 0.4. This is also the case for frailty.

ConclusionsFrailty is as important as polypharmacy in its association with MRH. Reducing the burden of frailty through an integrated health and social care approach, alongside strategies to reduce inappropriate polypharmacy, may reduce MRH related healthcare utilisation.

Trial registrationApproved by the National Research Ethics Service, East of England (REC Reference 13/EE/0075)

category: geriatric medicine


title: A validation study of the identification of haemophagocytic lymphohistiocytosis in England using population-based health data

abstract:
We assessed the validity of coded health care data to identify cases of haemophagocytic lymphohistiocytosis (HLH). Hospital Episode Statistics (HES) identified 127 cases within five hospital Trusts 2013-2018 using ICD-10 codes D76.1, D76.2 and D76.3. Hospital records were reviewed to validate diagnoses. 73/74 patients with confirmed/probable HLH were coded D76.1 or D76.2 (positive predictive value 89.0% [95% CI 80.2-94.9%]). For cases considered not HLH, 44/53 were coded D76.3 (negative predictive value 97.8% [95% CI 88.2%-99.9%]). D76.1 or D76.2 had 68% sensitivity in detecting HLH compared to an established active case finding HLH register in Sheffield. Office for National Statistics (ONS) mortality data (2003-2018) identified 698 patients coded D76.1, D76.2 and D76.3 on death certificates. 541 were coded D76.1 or D76.2 of whom 524(96.9%) had HLH in the free text cause of death. Of 157 coded D76.3, 66(42.0%) had HLH in free text.

D76.1 and D76.2 codes reliably identify HLH cases, and provide a lower bound on incidence. Non-concordance between D76.3 and HLH excludes D76.3 as an ascertainment source from HES. Our results suggest electronic health care data in England can enable population wide registration and analysis of HLH for future research.

category: hematology


title: Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines

abstract: The durability of circulating neutralizing antibody (nAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their boosting by vaccination remains to be defined. We show that outpatient and hospitalized SARS-CoV-2 seropositive individuals mount a robust neutralizing antibody (nAb) response that peaks at days 23 and 27 post-symptom onset, respectively. Although nAb titers remained higher in hospitalized patients, both study groups showed long-lasting nAb responses that can persist for up to 12 months after natural infection. These nAb responses in previously seropositive individuals can be significantly boosted through immunization with two doses of the CoronaVac (Sinovac) or one dose of the BNT162b2 (BioNTech/Pfizer) vaccines, suggesting a substantial induction of B cell memory responses. Noteworthy, three obese previously seropositive individuals failed to mount a booster response upon vaccination, warranting further studies in this population. Immunization of naive individuals with two doses of the CoronaVac vaccine or one dose of the BNT162b2 vaccine elicited similar levels of nAbs compared to seropositive individuals 4.2 to 13.3 months post-infection with SARS-CoV-2. Thus, this preliminary evidence suggests that both, seropositive and naive individuals, require two doses of CoronaVac to ensure the induction of robust nAb titers.