title: Population Optimally Immunized after Accounting for Type-Specific COVID-19 Vaccine Waning Intervals: State-Level Prevalence and Trends

abstract:
BACKGROUNDCOVID-19 vaccines exhibit real-world waning effectiveness against SARS-CoV-2 infection within the first 3-6 months after a completed series. Consequently, the main metric tracked by the CDC (percent "fully vaccinated," with no adjustment for booster status) has become insufficiently informative.

METHODSWe analyzed CDC daily vaccination data to quantify COVID-19 immunization status for 4 mutually-exclusive groups: (1) not immunized; (2) partially immunized (people who received the 1st dose of a 2-dose series); (3) immunized with waning immunity (previously immunized people whose booster dose is overdue); and (4) optimally immunized (people who: (a) received the Janssen vaccine <2 months ago or completed an mRNA vaccine series <6 months ago, or (b) received the Janssen vaccine >2 months ago or completed an mRNA vaccine series >6 months ago and received a booster dose.)

RESULTSThe proportion of the total US population who were optimally immunized against COVID-19 fell from a high of 45.3% on July 17 to 29.4% on November 30. During November, the majority of states experienced a worsening trend in the percent of the total population who were overdue for a booster dose, including the 4 largest states, with percentage point increases of 3.5 in New York, 3.4 in California, 2.3 in Texas and 1.7 in Florida.

CONCLUSIONSOur proposed classification scheme accounts for type-specific vaccine waning intervals, provides an accurate assessment of progress toward national immunization goals, and reveals the urgent need for additional public health mitigation strategies to successfully combat the COVID-19 pandemic in the United States.


title: Omicron strain spreads with the doubling time of 3.2-3.6 days in South Africa province of Gauteng that achieved herd immunity to Delta variant

abstract: Omicron, the novel highly mutated SARS-CoV-2 Variant of Concern (VOC, Pango lineage B.1.1.529), was first collected in early November 2021 in South Africa. By the end of November 2021, it had spread and approached fixation in South Africa, and had been detected on all continents. We analyzed the exponential growth of Omicron over the four-week periods in two most populated South Africas provinces, Gauteng and KwaZulu-Natal, arriving at the doubling time estimates of respectively 3.3 days [95% CI: 3.2-3.4 days] and 2.7 days [95% CI: 2.3-3.3 days]. Similar or even shorter doubling times were observed in other locations: Australia (3.0 days), New York State (2.5 days), UK (2.4 days), and Denmark (2.0 days). Log- linear regression suggests that the spread began in Gauteng around October 11, 2021, however, due to presumable stochasticity in the initial spread, this estimate can be inaccurate. Phylogenetics-based analysis indicates that the Omicron strain started to diverge in between October 6 and October 29, 2021. We estimated that the weekly growth of the ratio of Omicron to Delta is in the range 7.2-10.2, considerably higher than the growth of the ratio of Delta to Alpha (estimated to be in in the range 2.5-4.2), and Alpha to pre-existing strains (estimated to be in the range of 1.8-2.7). High relative growth does not necessarily imply higher Omicron infectivity. A two-strain SEIR model suggests that the growth advantage of Omicron may stem from immune evasion, which permits this VOC to infect both the recovered and the fully vaccinated individuals. As we demonstrated within the model, immune evasion is more concerning than increased transmissibility, because it can facilitate larger epidemic outbreaks.

category: epidemiology


title: The spread of SARS-CoV-2 variant Omicron with the doubling time of 2.0-3.3 days can be explained by immune evasion


title: Dose-response relationship of extended-release methylphenidate for ADHD in adults: post-hoc analysis based on a systematic review

abstract:
ObjectiveTo assess potential dose-response relationships of extended-release methylphenidate for ADHD in adults on efficacy outcomes.

Study design and settingPost-hoc analysis based on a systematic review of extended-release methylphenidate (https://doi.org/10.1002/14651858.CD012857). Using data from clinical trials comparing multiple fixed-dose methylphenidate groups with placebo, we conducted subgroup meta-analyses for available efficacy outcomes.

Results and conclusionFive trials used a fixed-dose design with multiple methylphenidate groups receiving different doses. All trials were pivotal industry sponsored studies conducted to obtain marketing authorisation. We analysed four efficacy outcomes: Selfrated ADHD symptoms (5 trials, 1807 participants), investigator-rated ADHD symptoms (5 trials, 1904 participants), quality of life (4 trials, 1158 participants), and peer-rated ADHD symptoms (2 trials, 879 participants). There were no dose-response relationships for any outcome.

category: psychiatry and clinical psychology


title: Stranded abroad during the COVID-19 pandemic: examining the psychological and financial impact of border restrictions

abstract:
ObjectiveWith the easing of COVID-19-related international travel restrictions in late 2021 it is time to consider the direct and indirect social, emotional, and financial impacts that these border closures have had. The study aims to evaluate the psychological and financial distress reported by people stranded abroad due to international travel restrictions introduced in response to the COVID-19 pandemic.

MethodsBetween July and September 2021, we implemented a cross-sectional online survey targeting individuals stranded abroad due to international travel restrictions. The survey collected data about COVID-19 travel restriction-related travel impacts; personal stress, anxiety, and depression (using the validated DASS-21tool); as well as impacts on housing and financial security; and demographic data.

FindingsWe had 1054 participants complete the survey; most were trying to return to the Oceania region (75.4%), with 45% stranded in Europe. Overall, 64.2% reported financial distress while stranded abroad. 64.4% ([x] =9.43, SD=5.81) reported either a moderate or severe (based on the DASS-21 classification) level of depression, 41.7% for anxiety ([x] =5.46, SD=4.74), and 58.1% for stress ([x] =10.64, SD=5.26). Statistically significant factors associated with moderate to extremely severe depression, anxiety, and stress were financial stress, an employment change, being <30yrs, having a high perceived risk of contracting COVID-19 abroad and being stranded for >2 months.

ConclusionThe study is among the first to explore the psychological and financial distress-related impacts associated with being stranded abroad due to COVID-19 travel restrictions. It highlights a range of unintended consequences that arise from pandemic-related travel restriction, identifies the health and social needs for a particularly vulnerable population, and provides clues as to the types of support that may be adopted to best support them. This research will assist policymakers in identifying support packages for people stranded abroad due to global disaster.

category: public and global health


title: Trust in the research community predicts intent to comply with COVID-19 prevention measures: An analysis of a large-scale international survey dataset

abstract: In the present study, I explored the relationship between peoples trust in different agents related to prevention of spread of COVID-19 and their compliance with pharmaceutical and non-pharmaceutical preventive measures. The COVIDiSTRESSII Global Survey dataset, which was collected from international samples, was analysed to examine the aforementioned relationship across different countries. For data-driven exploration, network analysis and Bayesian generalized linear model (GLM) analysis were performed. The result from network analysis demonstrated that trust in the scientific research community was most central in the network of trust and compliance. In addition, the outcome from Bayesian GLM analysis indicated that the same factor, trust in the scientific research community, was most fundamental in predicting participants intent to comply with both pharmaceutical and non-pharmaceutical preventive measures. I briefly discussed the implications of the findings, the importance of trust in the scientific research community in explaining peoples compliance with measure to prevent spread of COVID-19.


title: Trust in the scientific research community predicts intent to comply with COVID-19 prevention measures: An analysis of a large-scale international survey dataset


title: Vaccine hesitancy for COVID-19 explored in a phenomic study of 259 socio-cognitive-behavioural measures in the UK-REACH study of 12,431 UK healthcare workers

abstract:
BackgroundVaccination is key to successful prevention of COVID-19 particularly nosocomial acquired infection in health care workers (HCWs).  Vaccine hesitancy is common in the population and in HCWs, and like COVID-19 itself, hesitancy is more frequent in ethnic minority groups. UK-REACH (United Kingdom Research study into Ethnicity and COVID-19 outcomes) is a large-scale study of COVID-19 in UK HCWs from diverse ethnic backgrounds, which includes measures of vaccine hesitancy. The present study explores predictors of vaccine hesitancy using a  phenomic approach, considering several hundred questionnaire-based measures.

MethodsUK-REACH includes a questionnaire study encompassing 12,431 HCWs who were recruited from December 2020 to March 2021 and completed a lengthy online questionnaire (785 raw items; 392 derived measures; 260 final measures). Ethnicity was classified using the Office for National Statistics five (ONS5) and eighteen (ONS18) categories. Missing data were handled by multiple imputation. Variable selection used the islasso package in R, which provides standard errors so that results from imputations could be combined using Rubins rules. The data were modelled using path analysis, so that predictors, and predictors of predictors could be assessed. Significance testing used the Bayesian approach of Kass and Raftery, a  very strong Bayes Factor of 150, N=12,431, and a Bonferroni correction giving a criterion of p<4.02 x 10-8 for the main regression, and p<3.11 x 10-10 for variables in the path analysis.

ResultsAt the first step of the phenomic analysis, six variables were direct predictors of greater vaccine hesitancy: Lower pro-vaccination attitudes; no flu vaccination in 2019-20; pregnancy; higher COVID-19 conspiracy beliefs; younger age; and lower optimism the roll-out of population vaccination. Overall 44 lower variables in total were direct or indirect predictors of hesitancy, with the remaining 215 variables in the phenomic analysis not independently predicting vaccine hesitancy. Key variables for predicting hesitancy were belief in conspiracy theories of COVID-19 infection, and a low belief in vaccines in general. Conspiracy beliefs had two main sets of influences:

O_LIHigher Fatalism, which was influenced a) by high external and chance locus of control and higher need for closure, which in turn were associated with neuroticism, conscientiousness, extraversion and agreeableness; and b) by religion being important in everyday life, and being Muslim.
C_LIO_LIreceiving information via social media, not having higher education, and perceiving greater risks to self, the latter being influenced by higher concerns about spreading COVID, greater exposure to COVID-19, and financial concerns.
C_LI

There were indirect effects of ethnicity, mediated by religion. Religion was more important for Pakistani and African HCWs, and less important for White and Chinese groups. Lower age had a direct effect on hesitancy, and age and female sex also had several indirect effects on hesitancy.

ConclusionsThe phenomic approach, coupled with a path analysis revealed a complex network of social, cognitive, and behavioural influences on SARS-Cov-2 vaccine hesitancy from 44 measures, 6 direct and 38 indirect, with the remaining 215 measures not having direct or indirect effects on hesitancy. It is likely that issues of trust underpin many associations with hesitancy. Understanding such a network of influences may help in tailoring interventions to address vaccine concerns and facilitate uptake in more hesistant groups.

FundingUKMRI-MRC and NIHR


title: Deep learning-driven risk-based subtyping of cognitively impaired individuals

abstract: Quantifying heterogeneity in Alzheimers disease (AD) risk is critical for individualized care and management. Recent attempts to assess AD heterogeneity have used structural (magnetic resonance imaging (MRI)-based) or functional (A{beta} or tau) imaging, which focused on generating quartets of atrophy patterns and protein spreading, respectively. Here we present a computational framework that facilitated the identification of subtypes based on their risk of progression to AD. We used cerebrospinal fluid (CSF) measures of A{beta} from the Alzheimers Disease Neuroimaging Initiative (ADNI) (n=544, discovery cohort) as well as the National Alzheimers Coordinating Center (NACC) (n=508, validation cohort), and risk-stratified individuals with mild cognitive impairment (MCI) into quartiles (high-risk (H), intermediate-high risk (IH), intermediate-low risk (IL), and low-risk (L)). Patients were divided into subgroups utilizing patterns of brain atrophy found in each of these risk-stratified quartiles. We found H subjects to have a greater risk of AD progression compared to the other subtypes at 2- and 4-years in both the discovery and validation cohorts (ADNI: H subtype versus all others, p < 0.05 at 2 and 4 years; NACC: H vs. IL and LR at 2 years, p < 0.05, and a trend toward higher risk vs. IH, and p < 0.05 vs. IH, and L risk groups at 48 months with a trend toward lower survival vs. IL). Using MRI-based neural models that fused various deep neural networks with survival analysis, we then predicted MCI to AD conversion. We used these models to identify subtype-specific regions that demonstrate the largest levels of atrophy-related importance, which had minimal overlap (Average pairwise Jaccard Similarity in regions between the top 5 subtypes, 0.25{+/-}0.05 ({+/-} std)). Neuropathologic changes characteristic of AD were present across all subtypes in comparable proportions (Chi-square test, p>0.05 for differences in ADNC, n=31). Our risk-based approach to subtyping individuals provides an objective means to intervene and tailor care management strategies at early stages of cognitive decline.

category: neurology


title: An oligogenic risk model for Gilles de la Tourette syndrome based on whole-genome sequencing data

abstract: Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder from the spectrum of tic disorders (TDs). GTS and other TDs have a substantial genetic component with the heritability estimated at between 60 and 80%. Here we propose an oligogenic risk model of GTS and other TDs using whole-genome sequencing (WGS) data from a group of Polish GTS patients and their families (n=185). The model is based on the overrepresentation of putatively pathogenic coding and non-coding genetic variants in genes selected from a set of 86 genes previously suggested to be associated with GTS. Based on the variant overrepresentation (SKAT test results) between unrelated GTS patients and controls based on gnomAD database allele frequencies five genes (HDC, CHADL, MAOA, NAA11, and PCDH10) were selected for the risk model. Putatively pathogenic variants (n = 98) with the median allele frequency of [~]0.04 in and near these genes were used to build an additive classifier which was then validated on the GTS patients and their families. This risk model successfully assigned individuals from 22 families to either healthy or GTS groups (AUC-ROC = 0.6, p < 0.00001). These results were additionally validated using the GTS GWAS data from the Psychiatric Genomic Consortium. To investigate the GTS genetics further we identified 32 genes from the list of 86 genes as candidate genes in 14 multiplex families, including NEGR1 and NRXN with variants overrepresented in multiple families. WGS data allowed the construction of an oligogenic risk model of GTS based on possibly pathogenic variants likely contributing to the risk of GTS and TDs. The model includes putatively deleterious rare and non-coding variants in and near GTS candidate genes that may cooperatively contribute to GTS etiology and provides a novel approach to the analysis of clinical WGS data.

category: genetic and genomic medicine


title: Vaccinating Children Against COVID-19 is Essential Prior to the Removal of Non-Pharmaceutical Interventions

abstract:
Objectives(s)To evaluate the joint impact of childhood vaccination rates and masking policies, in schools and workplaces, on community transmission and severe outcomes due to COVID-19.

Study designWe utilized a stochastic, agent-based simulation of North Carolina, to evaluate the impact of 24 health policy decisions on overall incidence of disease, COVID-19 related hospitalization, and mortality from July 1, 2021-July 1, 2023.

ResultsUniversal mask removal in schools in January 2022 could lead to a 38.1-47%, 27.6-36.2%, and 15.9-19.7% increase in cumulative infections for ages 5-9, 10-19, and the total population, respectively, depending on the rate of vaccination of children relative to the adult population. Additionally, without increased vaccination uptake in the adult population, a 25% increase in child vaccination uptake from 50% to 75% uptake and from 75% to 100% uptake relative to the adult population, leads to a 22% and 18% or 28% and 33% decrease in peak hospitalizations in 2022 across scenarios when masks are removed either January 1st or March 8th 2022, respectively. Increasing vaccination uptake for the entire eligible population can reduce peak hospitalizations in 2022 by an average of 89% and 92% across all masking scenarios compared to the scenarios where no children are vaccinated.

Conclusion(s)High vaccination uptake among both children and adults is necessary to mitigate the increase in infections from mask removal in schools and workplaces.

category: health policy


title: Safety and Immunogenicity of SARS-CoV-2 S-2P Protein Vaccine MVC-COV1901 in People Living with HIV

abstract:
ObjectivesTo provide data on the immune response to COVID-19 vaccines in people living with HIV (PWH), MVC-COV1901, a recombinant protein vaccine containing S-2P protein adjuvanted with CpG 1018 and aluminium hydroxide, was assessed.

MethodsA total of 57 PWH of [≥] 20 years of age who are on stable antiretroviral therapy and with CD4+ T cell [≥] 350 cells/mm3 and HIV viral load < 103 copies/ml were compared with 882 HIV-negative participants. Participants received 2 doses of MVC-COV1901 28 days apart. Safety and the immunogenicity were evaluated.

ResultsNo vaccine-related serious adverse events (SAEs) were recorded. Seroconversion rates (SCRs) of 100% and 99.8% were achieved in people living with HIV (PWH) and comparators, respectively, 28 days after second dose. The geometric mean titers (GMTs) (95% confidence interval [CI]) against wild type SARS-CoV-2 virus were 136.62 IU/mL (WHO Standardized International Unit) (95% CI 114.3-163.3) and 440.41 IU/mL (95% CI 421.3-460.4), for PWH and control groups, respectively, after adjusting for sex, age, BMI category, and comorbidity, and the adjusted GMT ratio of comparator/PWH was 3.22 (95% CI 2.6-4.1). A higher CD4/CD8 ratio was associated with a higher GMT (R=0.27, p=0.039).

ConclusionsMVC-COV1901 has shown robust safety but weaker immunogenicity responses in PWH. As a result, a third dose or booster doses of MVC-COV1901 may be appropriate for PWH.

category: hiv aids


title: Measurement of SARS-CoV-2 antigens in plasma of pediatric patients with acute COVID-19 or MIS-C using an ultrasensitive and quantitative immunoassay

abstract:
BackgroundDetection of SARS-CoV-2 antigens in blood has high sensitivity in adults with acute COVID-19, but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery).

MethodsPlasma was collected from inpatients (<21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n=36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n=53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n=67) or within 24h of negative RT-PCR (n=43).

ResultsSpecificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity, respectively; sensitivity in patients with concurrent nasopharyngeal swab cycle threshold (Ct) [≤] 35 were 93%/63%. Antigen concentrations ranged from 1.28-3,844 pg/mL (N) and 1.65-1,071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw.

ConclusionsUltrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

Key pointsIn a U.S. pediatric cohort tested with ultrasensitive immunoassays, SARS-CoV-2 nucleocapsid antigens were detectable in most patients with acute COVID-19, and spike antigens were commonly detectable. Both antigens were undetectable in almost all MIS-C patients.

category: infectious diseases


title: Single cell gene expression profiling of nasal ciliated cells reveals distinctive biological processes related to epigenetic mechanisms in patients with severe COVID-19

abstract:
ObjectiveTo explore the molecular processes associated with cellular regulatory programs in patients with COVID-19, including gene activation or repression mediated by epigenetic mechanisms. We hypothesized that a comprehensive gene expression profiling of nasopharyngeal epithelial cells might expand understanding of the pathogenic mechanisms of severe COVID-19.

MethodsWe used single-cell RNA sequencing (scRNAseq) profiling of ciliated cells (n = 12725) from healthy controls (SARS-CoV-2 negative n =13) and patients with mild/moderate (n =13) and severe (n =14) COVID-19. ScRNAseq data at the patient level were used to perform gene set and pathway enrichment analyses. We prioritized candidate miRNA-target interactions and epigenetic mechanisms.

ResultsPathways linked to mitochondrial function, misfolded proteins, and membrane permeability were upregulated in patients with mild/moderate disease compared to healthy controls. Besides, we noted that compared to mild/moderate disease, cells derived from severe COVID-19 patients had downregulation of sub-networks associated with epigenetic mechanisms, including DNA and histone H3K4 methylation and chromatin remodeling regulation. We found 11-ranked miRNAs that may explain miRNA-dependent regulation of histone methylation, some of which share seed sequences with SARS-CoV-2 miRNAs.

ConclusionOur results may provide novel insights into the epigenetic mechanisms mediating the clinical course of SARS-CoV-2 infection.


title: Modeling COVID-19 Aerosol Transmission in Primary Schools

abstract: Schools must balance public health, education, and social risks associated with returning to in-person learning. These risks are compounded by the ongoing uncertainty about vaccine availability and uptake for children under 12 years of age. In this paper, we show how the risk of infections that result directly from in-class aerosol transmission within an elementary school population can be estimated in order to compare the effects of different countermeasures. We compare the effectiveness of these countermeasures in reducing transmission including required masking at three levels of mask effectiveness, improving room airflow exchange rates, weekly testing of the students, and lunch partitioning. Our results show that multiple layers of interventions are necessary to keep in-class infections relatively low. These results can inform school administrators about how these interventions can help manage COVID-19 spread within their own elementary school populations.


title: Pulmonary Embolism Readmission Trend Over the Years: A National Readmission Database Study

abstract:
IntroductionAcute pulmonary embolism (PE) is known to be associated with significant short-term and long-term complications. However, with the evolution of PE management, the outcomes of PE-related complications and the need for readmission have not been well studied. The aim of this study is to see the trend in readmissions in PE patients from the years 2010 to 2018.

MethodsWe utilized the National Readmission Database from 2010 to 2018 to identify hospitalized patients with a principal diagnosis of acute pulmonary embolism. Identified the total number of readmissions for acute PE from 2010 to 2018. A multivariate cox regression model was used to identify independent predictors of readmission.

ResultsThe number of patients with 30-day readmissions has gradually increased from 14,508 in 2010 to 19,703 in 2018. The proportion of females admitted was higher than males in all years. The 30-day all-cause readmission after principal admission for PE decreased from 11.2% to 9.7% from 2010 to 2014 but increased to 11.8% in 2018 (p<0.001). Risk-adjusted readmission specific for PE showed a decrease from 1.2 to 1% (p=0.023) from 2010 to 2018. When adjusted to age and gender, an increase in the proportion of readmissions with intracranial bleeding was seen among both the 30-day (0.7% in 2010 to 1.2% in 2018, aOR 1.06, p<0.001) and 90-day (0.7% in 2010 to 1.2% in 2018, aOR 1.06, p-trend 0.003) cohorts. Similarly, an increasing trend of readmissions for UGI bleed was seen among both 30-day (0.9% vs 4.3%, aOR=1.26, p-trend <0.001) and 90-day readmissions (0.7% vs 3.8%, aOR=1.27, p-trend <0.001). The units of blood transfusion required per readmission reduced in both cohorts during the study period.

ConclusionOur study suggests that there is a statistically significant decrease in PE-specific readmission from 2010 to 2018, but an increase in all-cause readmissions. We also report an increase in non-major bleeding during readmissions, including ICH and UGI bleed. These findings warrant further studies to elucidate the mechanism for decreasing PE-specific readmission but possible causes for the increase in all-cause readmission in the hope of optimizing management and continuing improving outcomes.

category: cardiovascular medicine


title: Access to healthcare as an important moderating variable for understanding geography of immunity levels for COVID-19 - preliminary insights from Poland

abstract:
BackgroundBiases in COVID-19 burden and uncertainty in estimation of the corresponding epidemiologic indexes is a known and common phenomenon in infectious diseases. We investigated to what extent healthcare access (HCA) related supply/demand interfered with registered data on COVID-19 in Poland.

Material and methodsWe run a multiple linear regression model with interactions to explain geographic variation in seroprevalence, hospitalizations (on voivodeship - NUTS-2 level) and current (beginning of the 4th wave - 15.09-21.11.2021) case notifications/crude mortality (on poviat - old NUTS-4 level). We took vaccination coverage and cumulative case notifications up to the so called 3rd wave as predictor variables and supply/demand (HCA) as moderating variables.

ResultsHCA with interacting terms (mainly demand) explained to the great extent the variance of current incidence and most variance of current mortality. HCA (mainly supply) is significantly moderating cumulative case notifications till the 3rd wave explaining the variance in seroprevalence and hospitalization.

ConclusionsSeeking causal relations between vaccination-or infection-gained immunity level and current infection dynamics could be misleading without understanding socio-epidemiologic context such as the moderating role of HCA (sensu lato). After quantification, HCA could be incorporated into epidemiologic models for improved prediction of real disease burden.


title: Changes in the trajectory of Long Covid symptoms following COVID-19 vaccination: community-based cohort study

abstract:
ObjectiveTo estimate associations between COVID-19 vaccination and Long Covid symptoms in adults who were infected with SARS-CoV-2 prior to vaccination.

DesignObservational cohort study using individual-level interrupted time series analysis.

SettingRandom sample from the community population of the UK.

Participants28,356 COVID-19 Infection Survey participants (mean age 46 years, 56% female, 89% white) aged 18 to 69 years who received at least their first vaccination after test-confirmed infection.

Main outcome measuresPresence of long Covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021.

ResultsMedian follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (84% of participants). First vaccination was associated with an initial 12.8% decrease (95% confidence interval: -18.6% to -6.6%) in the odds of Long Covid, but increasing by 0.3% (-0.6% to +1.2%) per week after the first dose. Second vaccination was associated with an 8.8% decrease (-14.1% to -3.1%) in the odds of Long Covid, with the odds subsequently decreasing by 0.8% (-1.2% to -0.4%) per week. There was no statistical evidence of heterogeneity in associations between vaccination and Long Covid by socio-demographic characteristics, health status, whether hospitalised with acute COVID-19, vaccine type (adenovirus vector or mRNA), or duration from infection to vaccination.

ConclusionsThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose. Vaccination may contribute to a reduction in the population health burden of Long Covid, though longer follow-up time is needed.

Summary boxWhat is already known on this topic

O_LICOVID-19 vaccines are effective at reducing rates of SARS-CoV-2 infection, transmission, hospitalisation, and death
C_LIO_LIThe incidence of Long Covid may be reduced if infected after vaccination, but the relationship between vaccination and pre-existing long COVID symptoms is unclear, as published studies are generally small and with self-selected participants
C_LI

What this study adds

O_LIThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose
C_LIO_LIThere was no evidence of differences in this relationship by socio-demographic characteristics, health-related factors, vaccine type, or duration from infection to vaccination
C_LIO_LIAlthough causality cannot be inferred from this observational evidence, vaccination may contribute to a reduction in the population health burden of Long Covid; further research is needed to understand the biological mechanisms that may ultimately contribute to the development of therapeutics for Long Covid
C_LI


title: Superspreading of SARS-CoV-2 infections: A Systematic Review and Meta-analysis

abstract: Superspreading in transmission is a feature of SARS-CoV-2 transmission. We conducted a systematic review and meta-analysis on globally reported dispersion parameters of SARS-CoV-2. The pooled estimate was 0.55 (95% CI: 0.30, 0.79). The study location and method were found to be important drivers for its diversity.


title: Surveillance of COVID-19 vaccine effectiveness - a real-time case-control study in southern Sweden

abstract: The extensive register infrastructure available for COVID-19 surveillance in Scania county, Sweden, makes it possible to classify cases with respect to hospitalization and disease severity, stratify on time since last dose and demographic factors, account for prior infection, and extract data for population controls automatically. Estimated vaccine effectiveness 0-3 months after the last dose remained stable during the study period but waned markedly 6 months after the last dose in older persons.


title: Risk of hospitalization and mortality after breakthrough SARS-CoV-2 infection by vaccine type and previous SARS-CoV-2 infection utilizing medical claims data

abstract:
We compare the risks of hospitalization (n=1121) and mortality (n=138) in a cohort of 17,881 breakthrough SARS-CoV-2 infections for the Pfizer, Moderna and Janssen vaccines for those with and without SARS-CoV-2 infections prior to vaccination. Cox regression analysis results in a lower hazard ratio for breakthroughs receiving the Moderna vaccine, but a significantly higher hazard ratio for breakthroughs receiving the Janssen vaccine, as compared to breakthroughs who got the Pfizer vaccine. Further, the risk of hospitalization (P<0.001) and death (P<0.05) were lower among breakthroughs who had a SARS-CoV-2 infection prior to vaccination, independent of age, sex, comorbidities, and vaccine type.

NoteWe do not study the role of natural immunity in SARS-CoV-2 infections, as our cohort does not contain unvaccinated individuals.


title: Estimating Active Cases of COVID-19

abstract: Having accurate and timely data on active COVID-19 cases is challenging, since it depends on the availability of an appropriate infrastructure to perform tests and aggregate their results. In this paper, we consider a case to be active if it is infectious, and we propose methods to estimate the number of active infectious cases of COVID-19 from the official data (of confirmed cases and fatalities) and from public survey data. We show that the latter is a viable option in countries with reduced testing capacity or infrastructures.

category: health informatics


title: Predicted Symptomatic Effectiveness of Pfizer-BioNTech BNT162b2 Vaccine Against Omicron Variant of SARS-CoV-2

abstract: This paper presents predictions of the symptomatic effectiveness of the Pfizer-BioNTech BNT162b2 (Comirnaty) vaccine against Omicron B.1.1.529, the latest SARS-CoV-2 variant of concern. They were obtained assuming fold decreases in Omicron neutralisation by vaccine-induced antibodies versus neutralisation of the virus Wild Type. A 25-fold decrease was assumed based on Omicron pseudovirus neutralisation study by Pfizer and BioNTech; a 94-fold, based on live-Omicron neutralisation study in South Africa; and 40, 80 and 120 folds, hypothesised based on genetic information. The effectiveness of two vaccine doses was predicted as 66% (42, 86), 48% (25, 72) and 42% (20, 66) for up to five months starting 2-4 weeks after the second dose, for the 25, 80 and 120 folds, respectively. The effectiveness of booster vaccination was predicted under a highly conservative assumption that the third dose would increase neutralisation by only 3.3 folds compared to the second dose. The predictions of effectiveness for up to five months, starting 2-4 weeks after the third dose, were 81% (59, 95), 67% (43, 87) and 61% (37, 82) for the 25, 80 and 120 folds, respectively. Despite the large fold decreases considered, the vaccine could still provide substantial protection, particularly after a booster and against severe disease. The paper is accompanied by free software which can be used to predict the symptomatic effectiveness of Comirnaty against Omicron under different neutralisation folds, including those obtained experimentally.


title: ShaPRS: Leveraging shared genetic effects across traits or ancestries improves accuracy of polygenic scores

abstract: We present shaPRS, a novel method that leverages widespread pleiotropy between traits, or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant evidence of heterogeneity, the genetic effect from the disease or population closest to the target population is maintained. We show via simulation and a series of real-world examples that shaPRS substantially enhances the accuracy of PRS for complex diseases and greatly improves PRS performance across ancestries. shaPRS is a PRS pre-processing method that is agnostic to the actual PRS generation method and, as a result, it can be integrated into existing PRS generation pipelines and continue to be applied as more performant PRS methods are developed over time.


title: Vitamin D Supplementation is Associated with Slower Epigenetic Aging

abstract:
Adverse effects of low vitamin D level on mortality and morbidity are controversially discussed. Especially older people are at risk for vitamin D deficiency and therefore exposed to its potentially harmful influence on the aging process. A way of measuring differences in the biological age is through DNA methylation age (DNAm age) and its deviation from chronological age, DNAm age acceleration (DNAmAA). We previously reported on an association between vitamin D deficiency and higher 7-CpG DNAmAA in participants of the Berlin Aging Study II (BASE-II).

In this study, we employ a quasi-interventional study design to assess the relationship between DNAmAA of five epigenetic clocks and vitamin D supplementation. Longitudinal data were available for 1,036 participants of BASE-II that were reexamined on average 7.4 years later in the GendAge study (mean age at follow-up: 75.6 years, SD = 3.8 years, age range: 64.9 - 94.1 years, 51.9 % female). DNAmAA was estimated with the 7-CpG clock, Horvaths clock, Hannums clock, PhenoAge and GrimAge. Methylation data were obtained through methylation-sensitive single nucleotide primer extension (MS-SNuPE) or Illuminas Infinium "MethylationEPIC" array.

Vitamin D deficient participants who chose to start vitamin D supplementation after baseline examination showed a 2.6 year lower 7-CpG DNAmAA (p=0.011) and 1.3-year lower Horvath DNAmAA (p=0.042) compared to untreated and vitamin D deficient participants. DNAmAA did not statistically differ between participants with successfully treated vitamin D deficiency and healthy controls (p>0.16).

Therefore, we conclude that intake of vitamin D supplement is associated with lower DNAmAA in participants with vitamin D deficiency. Additionally, our findings suggest that sufficient vitamin D supplementation can compensate and potentially reverse the increase in 7-CpG DNAmAA that we found in in vitamin D deficient participants.

category: geriatric medicine


title: Optimal duration of antibiotic treatment for community-acquired pneumonia in adults: a systematic review and duration-effect meta-analysis

abstract:
ImportanceCommunity-acquired pneumonia (CAP) is a leading cause of morbidity and mortality globally. The optimal duration of antimicrobial therapy remains unclear and controversial.

ObjectiveTo find the optimal treatment duration with antibiotics for CAP in adults.

Data SourcesMEDLINE, Embase and CENTRAL from inception to present (25 August, 2021).

Study SelectionAll randomized controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. We included any antibiotics, administered orally or intravenously. We included both outpatients and inpatients but not those admitted to intensive care unit.

Data Extraction and SynthesisTwo review authors independently screened and extracted data. We conducted random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the pre-specified non-inferiority margin of 10% examined against 10 days using intention-to-treat dataset.

Main Outcomes and MeasuresThe primary outcome was clinical improvement at day 15 (range 7-45 days). Secondary outcomes were all-cause mortality, serious adverse events, and clinical improvement at day 30 (15-60 days). We calculated odds ratios.

ResultsWe included 9 trials (2399 patients with a mean [SD] age of 61.2 [22.1]; 39% women). The duration-effect curve was monotonic with longer duration leading to lower probability of improvement, and the lower 95%CI curve was constantly above the prespecified non-inferiority margin throughout the examined duration. Harmful outcome curves indicated no association. The average percentage of clinical improvement rate at day 15 in the 10-day treatment arms was 68%. Using that average, we computed the absolute clinical improvement rates at the following durations: a 3-day treatment 75% (95%CI: 68 to 81%), 5-day treatment 72% (66 to 78%), and 7-day treatment 69% (61 to 76%).

Conclusions and RelevanceShorter treatment duration probably achieves the optimal balance between efficacy and treatment burden for treating CAP in adults. However, the small number of included studies and the overall moderate to high risk of bias may compromise the certainty of the results. Further research focusing on the shorter duration range is required.

RegistrationPROSPERO (CRD 42021273357).

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat is the optimal treatment duration of antibiotics for community-acquired pneumonia (CAP) in adults.?

FindingsThis systematic review and duration-effect meta-analysis of 9 trials with 2399 patients found that the shorter treatment duration (3-9 days) was likely to be non-inferior to the standard treatment duration (10 days) for CAP in adults if they achieved clinical stability.

MeaningShorter antibiotic treatment duration probably achieves the optimal balance between efficacy and treatment burden for CAP in adults.


title: Analytical evaluation of thirty-two SARS-CoV-2 lateral flow antigen tests demonstrates sensitivity remains with the SARS-CoV-2 Gamma lineage.

abstract: The limit of detection (LOD) of thirty-two antigen lateral flow tests (Ag-RDT) were evaluated with the SARS-CoV-2 Gamma variant. Twenty-eight of thirty-two Ag-RDTs exceeded the World Health Organization criteria of an LOD of 1.0x106 genome copy numbers/ml and performance was equivalent as with the 2020 B.1 lineage and Alpha variant.


title: Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction

abstract: The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.


title: Functional brain network changes after major surgery and delirium

abstract:
BackgroundDelirium is a frequent complication of elective surgery in elderly patients, associated with an increased risk of long-term cognitive impairment and dementia. Disturbances in the functional brain network were previously reported during delirium. We hypothesized persisting alterations in functional brain networks three months after elective surgery in patients with postoperative delirium, and hypothesized that postoperative brain connectivity changes (irrespective of delirium) are related to cognitive decline.

MethodsElderly patients (N=554) undergoing elective surgery underwent clinical assessments (including Trail Making Test B (TMT-B) and resting-state functional magnetic resonance imaging (rs-fMRI) before and three months after surgery. Delirium was assessed on the first seven postoperative days. After strict motion correction, rs-fMRI connectivity strength and network characteristics were calculated in 246 patients (130 patients underwent scans at both timepoints), of whom 38 (16%) developed postoperative delirium.

ResultsRs-fMRI functional connectivity strength increased after surgery in the total study population ({beta}=0.006, 95%CI=0.000-0.012, p=0.021), but decreased after postoperative delirium ({beta}=-0.014, 95%CI=0.000-0.012, p=0.026). No difference in TMT-B scores was found at follow-up between patients with and without postoperative delirium. Patients who decreased in functional connectivity strength declined in TMT-B scores compared to the group that did not ({beta}=11.04, 95%CI=0.85-21.2, p=0.034).

ConclusionsDelirium was associated with decreased functional connectivity strength three months after the syndrome was clinically resolved, which implies that delirium has lasting impact on brain networks. Decreased connectivity strength was associated with statistically significant (but not necessarily clinically relevant) cognitive deterioration after major surgery, which was not specifically related to delirium.

Summary statementDelirium was associated with decreased resting-state fMRI functional connectivity strength three months after the syndrome was clinically resolved. Irrespective of delirium, decreased connectivity strength after major surgery was associated with a statistically significant cognitive deterioration.

category: anesthesia


title: Emergence of the Delta Variant and risk of SARS-CoV-2 infection in secondary school students and staff: prospective surveillance in 18 schools, England

abstract:
BackgroundThe role of educational settings on SARS-CoV-2 infection and transmission remains controversial. We investigated SARS-CoV-2 infection, seroprevalence and seroconversions rates in secondary schools during the 2020/21 academic year, which included the emergence of the more transmissible Alpha and Delta variants, in England.

MethodsThe UK Health Security Agency (UKHSA) initiated prospective surveillance in 18 urban English secondary schools. Participants had nasal swabs for SARS-CoV-2 RT-PCR and blood sampling for SARS-CoV-2 Nucleoprotein and Spike protein antibodies at the start (Round 1: September-October 2020) and end (Round 2: December 2021) of the autumn term, when schools reopened after national lockdown was imposed in January 2021 (Round 3: March-April) and end of the academic year (Round 4: May-July).

FindingsWe enrolled 2,314 participants (1277 students, 1037 staff). In-school testing identified 31 PCR-positive participants (20 students, 11 staff). Another 247 confirmed cases (112 students, 135 staff) were identified after linkage with national surveillance data, giving an overall positivity rate of 12.0% (278/2313; staff [14.1%, 146/1037] vs students [10.3%, 132/1276; p=0.006). Nucleoprotein-antibody seroprevalence increased for students and staff between Rounds 1-3 but changed little in Round 4, when the Delta variant was the dominant circulating strain. Overall, Nucleoprotein-antibody seroconversion was 18.4% (137/744) in staff and 18.8% (146/778) in students, while Spike-antibody seroconversion was higher in staff (72.8% (525/721) than students (21.3%, 163/764) because of vaccination.

InterpretationSARS-CoV-2 infection and transmission in secondary schools remained low when community infection rates were low because of national lockdown, even after the emergence of the Delta variant

FundingDHSC


title: Increased risk of fungal infection detection in women using using menstrual cups vs. tampons

abstract:
ObjectiveTo determine if the use of menstrual cups rather than tampons is associated with more or less health risk.

DesignAnalysing biological, demographic, and behavioural data in a cohort of women who reported using mostly tampons (n = 81) or menstrual cups (n = 22).

SettingA cross-sectional analysis using the inclusion data of a single centre longitudinal study.

Population149 women from 18 to 25 years old living in the area of Montpellier (France) who reported having at least one new sexual partner over the last year.

MethodsStatistical modelling (mainly binomial regression models and factor analyses of mixed data).

Main Outcome MeasuresSelf-reported data from questionnaires (fungal infection, urinary tract infection, stress level) and biological data (HPV screening, vaginal microbiota profiling, circulating antibodies titration, and local cytokine concentrations).

ResultsWe identify an increased risk of reporting fungal infections for women using menstrual cups over tampons. We do not detect significant differences in terms of vaginal microbiota composition or local cytokines expression profile but find that women fall into two different clusters in a factor analysis of mixed data depending on the type of menstrual product they use more (cups or tampons).

ConclusionsThese results point to potential health risks in the use of menstrual cups and differences in local vaginal environments. In-depth studies are needed to better understand potential associations between menstrual product use and womens health.

FundingEuropean Research Council (EVOLPROOF, grant 648963)

EthicsThe PAPCLEAR study ClinicalTrials.gov identifier is NCT02946346.

Tweetable abstractA cross-sectional study finds a significant association between menstrual cup use and fungal infection risk.


title: Increased risk of fungal infection detection in women using menstrual cups vs. tampons: a cross-sectional study


title: Reduced Odds of SARS-CoV-2 Reinfection after Vaccination among New York City Adults, June-August 2021

abstract:
BackgroundBelief in immunity from prior infection and concern that vaccines might not protect against new variants are contributors to vaccine hesitancy. We assessed effectiveness of full and partial COVID-19 vaccination against reinfection when Delta was the predominant variant in New York City.

MethodsWe conducted a case-control study in which case-patients with reinfection during June 15- August 31, 2021 and control subjects with no reinfection were matched (1:3) on age, sex, timing of initial positive test in 2020, and neighborhood poverty level. Conditional logistic regression was used to calculate matched odds ratios (mOR) and 95% confidence intervals (CI).

ResultsOf 349,598 adult residents who tested positive for SARS-CoV-2 infection in 2020, did not test positive again >90 days after initial positive test through June 15, 2021, and did not die before June 15, 2021, 1,067 were reinfected during June 15-August 31, 2021. Of 1,048 with complete matching criteria data, 499 (47.6%) were known to be symptomatic for COVID-19-like-illness, and 75 (7.2%) were hospitalized. Unvaccinated individuals, compared with fully vaccinated individuals, had elevated odds of reinfection (mOR, 2.23; 95% CI, 1.90, 2.61), of symptomatic reinfection (mOR, 2.17; 95% CI, 1.72, 2.74), and of reinfection with hospitalization (mOR, 2.59; 95% CI, 1.43, 4.69). Partially versus fully vaccinated individuals had 1.58 (95% CI: 1.22, 2.06) times the odds of reinfection. All three vaccines authorized or approved for use in the U.S. were similarly effective.

ConclusionAmong adults with previous SARS-CoV-2 infection, vaccination reduced odds of reinfections when the Delta variant predominated.


title: A large, curated, open-source stroke neuroimaging dataset to improve lesion segmentation algorithms

abstract: Accurate lesion segmentation is critical in stroke rehabilitation research for the quantification of lesion burden and accurate image processing. Current automated lesion segmentation methods for T1-weighted (T1w) MRIs, commonly used in rehabilitation research, lack accuracy and reliability. Manual segmentation remains the gold standard, but it is time-consuming, subjective, and requires significant neuroanatomical expertise. We previously released a large, open-source dataset of stroke T1w MRIs and manually segmented lesion masks (ATLAS v1.2, N=304) to encourage the development of better algorithms. However, many methods developed with ATLAS v1.2 report low accuracy, are not publicly accessible or are improperly validated, limiting their utility to the field. Here we present ATLAS v2.0 (N=955), a larger dataset of T1w stroke MRIs and manually segmented lesion masks that includes both training (public) and test (hidden) data. Algorithm development using this larger sample should lead to more robust solutions, and the hidden test data allows for unbiased performance evaluation via segmentation challenges. We anticipate that ATLAS v2.0 will lead to improved algorithms, facilitating large-scale stroke rehabilitation research.


title: Butyrate-producing gut bacteria are associated with protection from allergic symptoms after Hurricane Harvey

abstract: Hurricane Harvey caused record-breaking, catastrophic flooding across the city of Houston. After floodwaters receded, several health concerns arose, including the potential adverse impact of exposure to mold in flooded homes. We rapidly launched the Houston Hurricane Harvey Health Study to evaluate if microbiome sampling in the wake of a disaster could inform flood-associated environmental exposures and adverse health outcomes. We enrolled a total of 347 subjects at 1-month and 12-months post-Harvey, collecting human (stool, nasal, saliva) and environmental (house swab) samples to profile the bacterial and fungal microbiota. Here we show reported exposure to mold was associated with increased risk of allergic symptoms for up to one year post-disaster, and that butyrate-producing bacteria in the gut were linked to protection from allergic symptoms in mold-exposed individuals. Together, these data provide new insights into how microbiome:environment interactions may influence health in the setting of a flood-related disaster.

category: occupational and environmental health


title: Registration and medical certification of deaths in the Indian States: A comparative analysis of data of CRS and MCCD reports (2010-2019)

abstract:
BackgroundThe medical certification of cause of death (MCCD) under Civil Registration System (CRS) has been implemented in the States/UTs in a phased manner to provide data on cause of death but due to incomplete coverage and inadequate quality of civil registration data and medically certified data system, use of this data has been compromised. The completeness of registration of death (CoRD) and completeness of medically certified deaths were assessed from 2010 to 2019 at state level to understand their current status and trend over time and also to identify gaps in data to improve data quality.

MethodsCoRD and CoMeRD for each year for each state was calculated from the CRS reports and MCCD reports respectively for the period 2010-2019. Data were analyzed nationally as per geographical region and individual state. Union Territories excluding Delhi and Telangana have not been considered in this analysis.

ResultsThe CoRD in India have increased in the CRS from 66.9% in 2010 to 92 percent in 2019, a significant increase of 37.7% over 9 years (P<0.001) whereas India has not witnessed a substantial increase in the CoMeRD in MCCD which has increased from 17.1% in 2010 to only 20.6% in 2019. Among the 29 States, 18 (62%) had CoRD >95 percent in 2019, with 15 states recording 100 percent of CoRD however just 3 states (10.3%) have CoMeRD more than 50% namely Goa (100%), Manipur (67.3%) and Delhi (61.7%).

Interpretation & conclusionsDespite the significant progress made in CoRD in India, importance of medical certification cannot be undermined; critical differences between the States within the CRS and MCCD remain a cause of concern. Concentrated efforts to assess the strengths and weaknesses at the State level of the MCCD and CRS processes, quality of data and plausibility of information generated are needed in India.

category: health systems and quality improvement


title: Neutralizing Antibody Activity Against SARS-CoV-2 Variants in Gestational Age-Matched Mother-Infant Dyads

abstract:
Pregnancy confers unique immune responses to infection and vaccination across gestation. To date, there is limited data comparing vaccine versus infection-induced nAb to COVID-19 variants in mothers during pregnancy. We analyzed paired maternal and cord plasma samples from 60 pregnant individuals. Thirty women vaccinated with mRNA vaccines were matched with 30 naturally infected women by gestational age of exposure. Neutralization activity against the five SARS-CoV-2 Spike sequences was measured by a SARS-CoV-2 pseudotyped Spike virion assay. Effective nAbs against SARS-CoV-2 were present in maternal and cord plasma after both infection and vaccination. Compared to wild type or Alpha variant Spike, these nAbs were less effective against the Kappa, Delta, and Mu Spike variants. Vaccination during the third trimester induced higher nAb levels at delivery than infection during the third trimester. In contrast, vaccine-induced nAb levels were lower at the time of delivery compared to infection during the first trimester. The transfer ratio (cord nAb level/maternal nAb level) was greatest in mothers vaccinated in the second trimester. SARS-CoV-2 vaccination or infection in pregnancy elicit effective nAbs with differing neutralization kinetics that is impacted by gestational time of exposure. Vaccine induced neutralizing activity was reduced against the Delta, Mu, and Kappa variants.

Graphic abstract

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title: Accuracy and usability of saliva and nasal rapid antigen self-testing for detection of SARS-CoV-2 infection in the general population: a head-to-head comparison

abstract:
BackgroundSARS-CoV-2 self-tests may lower the threshold of testing and produce a result quickly. This could support the early detection of infectious cases and reduce further community transmission. However, the diagnostic accuracy of (unsupervised) self-testing with rapid antigen diagnostic tests (Ag-RDTs) is mostly unknown. We therefore conducted a large-scale head-to-head comparison of the diagnostic accuracy of a self-performed SARS-CoV-2 saliva and nasal Ag-RDT, each compared to a molecular reference test, in the general population in the Netherlands.

MethodsIn this cross-sectional study we consecutively included individuals aged 16 years and older presenting for SARS-CoV-2 testing at three Dutch public health service test sites irrespective of their indication for testing, vaccination status, and symptomatology. Participants were sampled for molecular testing at the test site and received two self-tests (the Hangzhou AllTest saliva self-test and the SD Biosensor nasal self-test by Roche Diagnostics) to perform at home within a few hours without knowledge of their molecular test result. Information on presence and type of symptoms, user experiences, and results of both self-tests were collected via an online questionnaire. For each self-test, sensitivity, specificity, positive and negative predictive values were determined with molecular testing as reference standard.

FindingsThe SARS-CoV-2 molecular reference test positivity rate was 6.5% in the 2,819 participants. Overall sensitivities with 95% confidence intervals were 46.7% (85/182; 39.3%-54.2%) for the saliva Ag-RDT, and 68.9% (124/180; 61.6%-75.6%) for the nasal Ag-RDT. With a viral load cut-off ([≥]5.2 log10 SARS-CoV-2 E-gene copies/mL) as a proxy of infectiousness, sensitivities increased to 54.9% (78/142; 46.4%-63.3%) for the saliva Ag-RDT and 83.9% (120/143; 76.9%-89.5%) for the nasal Ag-RDT.

For the nasal Ag-RDT, sensitivities were 78.5% [71.1%-84.8%] and 22.6% [9.6%-41.1%] in those with and without symptoms at the time of sampling, which increased to 90.4% (113/125; 83.8%-94.9%) and 38.9% (7/18; 17.3%-64.3%) after applying the viral load cut-off. In those with and without prior confirmed SARS-CoV-2, sensitivities were 36.8% [19/372; 16.3%-61.6%] and 72.7% [161/2437; 65.1%-79.4%] for the nasal Ag-RDT, which increased to 100% (7/7; 59.0%-100%) and 83.1% (113/126; 75.7%-89.0%) after applying the viral load cut-off.

The diagnostic accuracy of the nasal Ag-RDT did not differ by COVID-19 vaccination status, sex, and age. Specificities were >99%, positive predictive values >70% and negative predictive values >95%, for the saliva Ag-RDT, and >99%, >90%, and >95% for the nasal Ag-RDT, respectively, in most analyses.

Interpreting the results was considered (very) easy for both self-tests.

InterpretationThe Hangzhou AllTest self-performed saliva Ag-RDT is not reliable for SARS-CoV-2 infection detection overall nor in the studied subgroups. The SD Biosensor self-performed nasal Ag-RDT had high sensitivity in individuals with symptoms and in those without a prior SARS-CoV-2 infection. The overall accuracy in individuals with symptoms was comparable to that found in previous studies with professional sampling for this Ag-RDT. The extremely low sensitivity of the nasal Ag-RDT in asymptomatic individuals and in individuals who had had a prior SARS-CoV-2 infection is an important finding and warrants further investigation.

FundingDutch Ministry of Health, Welfare, and Sport.


title: Food for thought: Eating before saliva collection and interference with SARS-CoV-2 detection

abstract:
BackgroundSaliva is an optimal specimen for detection of viruses that cause upper respiratory infections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its cost-effectiveness and non-invasive collection. However, together with intrinsic enzymes and oral microbiota, childrens unique dietary habits may introduce substances that interfere with diagnostic testing.

MethodsTo determine whether childrens dietary choices impact SARS-CoV-2 detection in saliva, we performed a diagnostic study that simulates testing of real-life specimens provided from healthy children (n=5) who self-collected saliva at home before and at 0, 20, and 60 minutes after eating from 20 foods they selected. Each of seventy-two specimens was split into two volumes and spiked with SARS-CoV-2-negative or -positive standards prior to side-by-side testing by reverse-transcription polymerase chain reaction matrix-assisted laser desorption ionization time-of-flight (RT-PCR/MALDI-TOF) assay.

ResultsDetection of internal extraction control and SARS-CoV-2 nucleic acids was reduced in replicates of saliva collected at 0 minutes after eating 11 of 20 foods. Interference resolved at 20 and 60 minutes after eating all foods except hot dog in one participant. This represented a significant improvement in detection of nucleic acids compared to saliva collected at 0 minutes after eating (P=0.0005).

ConclusionsWe demonstrate successful detection of viral nucleic acids in saliva self-collected by children before and after eating a variety of foods. Fasting is not required before saliva collection for SARS-CoV-2 testing by RT-PCR/MALDI-TOF, but waiting 20 minutes after eating is sufficient for accurate testing. These findings should be considered for SARS-CoV-2 testing and broader viral diagnostics in saliva specimens.


title: Racial/ethnic disparities in antibiotic use and healthcare utilization, 2016/2018

abstract: White Americans make more office-based and emergency department visits per capita than other races/ethnicities, but the proportion of visits during which antibiotics are administered or prescribed is similar across races/ethnicities. Racial/ethnic disparities in antibiotic use may be due more to disparities in healthcare access and utilization than to prescriber behavior.


title: Effects of racial/ethnic disparities in healthcare utilization on antibiotic use, 2016/2018


title: SARS-CoV-2 B.1.1.529 variant (Omicron) evades neutralization by sera from vaccinated and convalescent individuals

abstract:
Recently, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant B.1.1.529 (Omicron) has been described.

Here, we analyze titers of neutralizing antibodies of sera from convalescent or vaccinated individuals against the new B.1.1.529 variant and compared them with titers against other Variants of Concern (B.1.1.7, B.1.351, B.1617.2) using replication competent SARS-CoV-2 variants.

We found that sera from vaccinated individuals neutralized the B.1.1.529 variant to a much lesser extent than any other variant analyzed. Neutralization capacity against B.1.1.529 was maintained best against sera from super immune individuals (infected and vaccinated or vaccinated and infected).


title: Reduced neutralisation of SARS-COV-2 Omicron-B.1.1.529 variant by post-immunisation serum

abstract: In this report, we present live neutralisation titres against SARS-CoV-2 Omicron variant, compared with neutralisation against Victoria, Beta and Delta variants. Sera from day-28 post second-dose were obtained from participants in the Com-COV2 study who had received a two-dose COVID-19 vaccination schedule with either AstraZeneca (AZD1222) or Pfizer (BNT162b2) vaccines. There was a substantial fall in neutralisation titres in recipients of both AZD1222 and BNT16b2 primary courses, with evidence of some recipients failing to neutralise at all. This will likely lead to increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection, although there is currently no evidence of increased potential to cause severe disease, hospitalization or death.


title: Incidence rates and symptomatology of community infections with SARS-CoV-2 in children and parents: The CoKids longitudinal household study

abstract:
AIMThe CoKids study aimed to estimate the community incidence of symptomatic and asymptomatic SARS-CoV-2 in children and parents and to assess the symptomatology of SARS-COV-2 infections relative to SARS-CoV-2 negative respiratory episodes.

METHODSIn this prospective study, households with at least one child <18 years were recruited from three existing Dutch cohorts. Participation included SARS-CoV-2 screening at 4-6 weeks intervals for all household members during 23 weeks of follow-up and active reporting of new onset respiratory symptoms until July 1st 2021. Follow-up was temporarily intensified following new onset respiratory symptoms in a household member or a SARS-CoV-2 positive screening test and included daily symptom recording, repeated PCR testing (nose-throat, saliva and fecal samples) and SARS-CoV-2 antibody measurement (paired dried blood spots) in all household members. Age-stratified incidence rates for SARS-CoV-2 positive and negative episodes were calculated. Symptomatology and disease burden of respiratory episodes were compared by SARS-CoV-2 status and age.

RESULTSIn total 307 households were enrolled including 1209 subjects. We detected 64 SARS-CoV-2 positive and 118 SARS-CoV-2 negative respiratory outbreaks. The highest incidence rate was found in children <12 years for SARS-CoV-2 negative episodes (0.93/ person-year (PY); 95%CI: 0.88-0.96). The SARS-CoV-2 incidence in this age-group was 0.21/PY for confirmed only, and 0.41/PY if probable cases were included. SARS-CoV-2 incidence did not differ by age group (p>0.27). Nasal congestion/runny nose, with or without cough and fatigue were the three most prevalent symptom clusters for both SARS-CoV-2 positive and negative respiratory episodes. Among children, no differences were observed in the symptomatology and severity of SARS-CoV-2 positive versus negative respiratory episodes, whereas among adults, SARS-CoV-2 positive episodes had a higher number and severity of symptoms and with a longer duration p<0.001).

CONCLUSIONUsing active, longitudinal household follow up, we detected a high incidence rate of SARS-CoV-2 infections in children that was similar to adults. The findings suggest that after 20 months of COVID-19 pandemic, up to 2/3 of Dutch children < 12 years have been infected with SARS-CoV-2. Symptomatology and disease severity of SARS-CoV-2 in children is similar to respiratory illness from other causes. In adults, SARS-COV-2 positive episodes are characterized by more and prolonged symptoms, and higher severity. These findings may assist decisions on COVID-19 policies targeting children.


title: Burden of influenza hospitalization among high-risk groups in the United States

abstract:
BackgroundSeasonal influenza poses a substantial clinical and economic burden in the United States and vulnerable populations, including the elderly and those with comorbidities, are at elevated risk for influenza-related medical complications.

MethodsWe conducted a retrospective cohort study using the IQVIA PharMetrics(R) Plus claims database in two stages. In Stage 1, we identified patients with evidence of medically-attended influenza during influenza seasons from October 1, 2014 to May 31, 2018 (latest available data for Stage 1) and used a multivariable logistic regression model to identify patient characteristics that predicted 30-day influenza-related hospitalization. Findings from Stage 1 informed high-risk subgroups of interest for Stage 2, where we selected cohorts of influenza patients during influenza seasons from October 1, 2014 to March 1, 2019 and used 1:1 propensity score matching to patient without influenza with similar high-risk characteristics to compare influenza-attributable rates of all-cause hospital and emergency department visits during follow-up (30-day and in index influenza season).

ResultsIn Stage 1, more than 1.6 million influenza cases were identified, of which 18,509 (1.2%) had a hospitalization. Elderly age was associated with 9 times the odds of hospitalization ([≥]65 years vs. 5-17 years; OR=9.4, 95% CI 8.8-10.1) and select comorbidities were associated with 2-3 times the odds of hospitalization. In Stage 2, elderly influenza patients with comorbidities had 3 to 7 times higher 30-day hospitalization rates compared to matched patients without influenza, including patients with congestive heart failure (41.0% vs.7.9%), chronic obstructive pulmonary disease (34.6% vs. 6.1%), coronary artery disease (22.8% vs. 3.8%), and late-stage chronic kidney disease (44.1% vs. 13.1%; all p<0.05).

ConclusionsThe risk of influenza-related complications is elevated in the elderly, especially those with certain underlying comorbidities, leading to excess healthcare resource utilization. Continued efforts, beyond currently available vaccines, are needed to reduce influenza burden in high-risk populations.


title: Surgical Planning and Optimization of Patient-Specific Fontan Grafts With Uncertain Post-Operative Boundary Conditions and Anastomosis Displacement

abstract:
ObjectiveFontan surgical planning involves designing grafts to perform optimized hemodynamic performance for the patients long-term health benefit. The uncertainty of post-operative boundary conditions (BC) and graft anastomisis displacements may significantly affect the optimized graft designs and lead to undesired outcomes, especially for hepatic flow distribution (HFD). We aim to develop a computation framework to automatically optimize patient-specific Fontan grafts with the maximized possibility of keeping the post-operative results within clinical acceptable thresholds.

MethodsThe uncertainties of BC and anastomosis displacements were modeled by using Gaussian distributions according to prior research studies. By parameterizing the Fontan grafts, we built surrogate models of hemodynamic parameters by taking the design parameters and BC as inputs. A two-phased reliability-based robust optimization (RBRO) strategy was developed by combining deterministic optimization (DO) and optimization under uncertainty (OUU) to reduce the computation cost.

ResultsWe evaluated the performance of the RBRO framework by comparing it with the DO method on four Fontan patient cases. The results showed that the surgical plans computed from the proposed method yield up to 79.2% improvement on the reliability of HFD than those from the DO method (p < 0.0001). The mean values of iPL and %WSS satisfied the clinically acceptable thresholds.

ConclusionThis study demonstrated the effectiveness of our RBRO framework to address uncertainties of BC and anastomosis displacements for Fontan surgical planning.

SignificanceThe technique developed in this paper demonstrates a significant improvement in the reliability of predicted post-operative outcomes for Fontan surgical planning. This planning technique is immediately applicable as a building block to enable technology for optimal long-term outcomes for pediatric Fontan patients and can also be used to other pediatric and adult cardiac surgeries.


title: Exploring selection bias in COVID-19 research: Simulations and prospective analyses of two UK cohort studies

abstract:
BackgroundNon-random selection into analytic subsamples could introduce selection bias in observational studies of SARS-CoV-2 infection and COVID-19 severity (e.g. including only those have had a COVID-19 PCR test). We explored the potential presence and impact of selection in such studies using data from self-report questionnaires and national registries.

MethodsUsing pre-pandemic data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (mean age=27.6 (standard deviation [SD]=0.5); 49% female) and UK Biobank (UKB) (mean age=56 (SD=8.1); 55% female) with data on SARS-CoV-2 infection and death-with-COVID-19 (UKB only), we investigated predictors of selection into COVID-19 analytic subsamples. We then conducted empirical analyses and simulations to explore the potential presence, direction, and magnitude of bias due to selection when estimating the association of body mass index (BMI) with SARS-CoV-2 infection and death-with-COVID-19.

ResultsIn both ALSPAC and UKB a broad range of characteristics related to selection, sometimes in opposite directions. For example, more educated participants were more likely to have data on SARS-CoV-2 infection in ALSPAC, but less likely in UKB. We found bias in many simulated scenarios. For example, in one scenario based on UKB, we observed an expected odds ratio of 2.56 compared to a simulated true odds ratio of 3, per standard deviation higher BMI.

ConclusionAnalyses using COVID-19 self-reported or national registry data may be biased due to selection. The magnitude and direction of this bias depends on the outcome definition, the true effect of the risk factor, and the assumed selection mechanism.

Key messagesO_LIObservational studies assessing the association of risk factors with SARS-CoV-2 infection and COVID-19 severity may be biased due to non-random selection into the analytic sample.
C_LIO_LIResearchers should carefully consider the extent that their results may be biased due to selection, and conduct sensitivity analyses and simulations to explore the robustness of their results. We provide code for these analyses that is applicable beyond COVID-19 research.
C_LI


title: Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

abstract:
The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s. RAS allows the rapid initiation of life-saving antimalarial treatment, before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed to-date: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact.

From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in Nigeria, Uganda and the Democratic Republic of the Congo (DRC). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. In order to achieve this, a number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed to track cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS.

Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and cost-effectiveness of the RAS intervention.


title: Coronavirus (COVID-19) Spike in Georgia: An Epidemiologic Study of Data, Modelling, and Policy Implications to Understand the Gender-and Race-Specific Variations

abstract:
ObjectiveThe purpose of this study was to investigate the gender-and race-specific predictive variations in COVID-19 cases and deaths in Georgia, USA.

MethodsThe data were extracted from the Georgia Department of Public Health (GDPH). Statistical methods, such as descriptive statistics, Artificial neural networks (ANN), and Bayesian approach, were utilized to analyze the data.

ResultsMore Whites died from COVID-19 than African-Americans/Blacks in Cobb, Hall, Gwinnett, and non-Georgia residents; however, more Blacks died in Dekalb and Fulton counties. The highest posterior mean for female deaths was obtained in Gwinnett County (77.17; 95% CI, 74.23-80.07) and for male deaths in Fulton County (73.48; 95% CI, 72.18-74.49). For overall race/ethnicity, Whites had the highest posterior mean for deaths (183.18; 95% CI, 128.29-238.27) compared with Blacks (162.48; 95% CI, 127.15- 197.42). Assessing the classification of the chronic medical conditions using ANN, Cobb and Hall Counties showed the highest mean AUC-ROC of the models (78% and 79%, respectively).

ConclusionsThe predictive models of COVID-19 transmission will help public health practitioners and researchers to better understand the course of the COVID-19 pandemic. The study findings are generalizable to populations with geographic and racial/ethnic similarities and may be used to determine gender/race-specific future virus models for effective interventions or policy modifications.

Human SubjectsNo personal identifiable information was obtained.


title: Scoping review of online postal sexually transmitted infection services: access, usage and clinical outcomes

abstract:
BackgroundThere has been considerable expansion in online postal self-sampling STI services in many parts of the UK, driven by increasing demand on sexual health services and developments in diagnostics and digital health provision. This shift in service delivery has occurred against a backdrop of reduced funding and service fragmentation and the impact is unknown. We explored characteristics of people accessing and using online postal self-sampling (OPSS) services for STIs in the UK, the acceptability of these services, and their impact on sexual health inequalities.

MethodsA scoping review was conducted of studies published in English-language based on pre-agreed inclusion/exclusion criteria, between 01/01/2010 to 07/07/2021. Nine databases were searched, and 23 studies that met the eligibility criteria were included. Studies were appraised using the Mixed Methods Appraisal Tool.

ResultsStudy designs were heterogenous, including quantitative, qualitative and mixed method analyses. The majority were either evaluating a single site/self-sampling provider, exploratory or observational and of variable quality. Few studies collected comprehensive user demographic data. Individuals accessing OPSS tended to be asymptomatic, of White ethnicity, women, over 20 years, and from less deprived areas. OPSS tended to increase overall STI testing demand and access, although return rates for blood samples was low, as was test positivity. There were varied results on whether services reduced time to treatment. OPSS services were acceptable to the majority of users. Qualitative studies showed the importance of trust, confidentiality, discretion, reliability, convenience and improved patient choice.

ConclusionOPSS services appear highly acceptable to users. However, uptake appears to be socially patterned and some groups that bear a disproportionate burden of poor sexual health in the UK are under-represented among users. Current provision of online self-sampling could widen health inequalities, particularly where other options for testing are limited. Work is needed to fully evaluate the impact and cost-effectiveness of OPSS services.

O_TEXTBOXKey messages

O_LIAn increasing proportion of STI testing in the UK is occurring via online postal self-sampling services
C_LIO_LIService users tend to be asymptomatic, white, women, over 20s, and from less deprived areas
C_LIO_LIOPSS services are acceptable to users and can improve choice
C_LIO_LIThere is a need for a wide-ranging evaluation of OPSS services to determine their impact on sexual health inequalities, access, clinical outcomes and service delivery
C_LI

C_TEXTBOX

category: sexual and reproductive health


title: Neural networks for classification and image generation of aging in genetic syndromes

abstract: In medical genetics, one application of neural networks is the diagnosis of genetic diseases based on images of patient faces. While these applications have been validated in the literature with primarily pediatric subjects, it is not known whether these applications can accurately diagnose patients across a lifespan. We aimed to extend previous works to determine whether age plays a factor in facial diagnosis, as well as to explore other factors that may contribute to the overall diagnosis accuracy. To investigate this, we chose two relatively common conditions, Williams syndrome and 22q11.2 deletion syndrome. We built a neural network classifier trained on images of affected and unaffected individuals of different ages. Our classifier outperformed clinical geneticists at recognizing face images of these two conditions within each of the age groups (the performance varied between the age groups): (1) under 2 years old, (2) 2-9 years old, (3) 10-19 years old, (4) 20-34 years old, and (5) [≥]35 years old. The overall accuracy improvement by our classifier over the clinical geneticists was 15.5% and 22.7% for Williams syndrome and 22q11.2 deletion syndrome, respectively. Additionally, comparison of saliency maps revealed that key facial features learned by the neural network differed slightly with respect to age. Finally, joint training real images with multiple different types of fake images created by a generative adversarial network showed up to 3.25% accuracy gain in classification accuracy.


title: SUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification

abstract: Genes with moderate to low expression heritability may explain a large proportion of complex trait heritability, but these genes are insufficiently captured in transcriptome-wide association studies (TWAS) partly due to the relatively small available reference datasets for developing expression genetic prediction models to capture the moderate to low genetically regulated components of gene expression. Here, we introduce a new method, Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction model accuracy and the power of TWAS by using a large expression quantitative trait loci (eQTL) summary-level dataset. We applied SUMMIT to the eQTL summary-level data provided by the eQTLGen consortium, which involve 31,684 blood samples from 37 cohorts. Through simulation studies and analyses of GWAS summary statistics for 24 complex traits, we show that SUMMIT substantially improves the accuracy of expression prediction in blood, successfully builds expression prediction models for genes with low expression heritability, and achieves higher statistical power than several benchmark methods. In the end, we conducted a case study of COVID-19 severity with SUMMIT and identified 11 likely causal genes associated with COVID-19 severity.


title: Adverse event reviews in healthcare: What matters to patients and their family? A qualitative study exploring the perspective of patients and family.

abstract:
ObjectivesExplore what  good patient and family involvement in healthcare adverse event reviews may involve.

DesignData was collected using semi-structured telephone interviews. Interview transcripts were analysed using an inductive thematic approach.

SettingNHS Scotland.

Participants19 interviews were conducted with patients who had experienced an adverse event during the provision of their healthcare, or their family member.

ResultsFour key themes were derived from these interviews: trauma, communication, learning and litigation.

ConclusionsFindings suggest there are many advantages of actively involving patients and their families in adverse event reviews. An open, collaborative, person-centred approach which listens to, and involves, patients and their families is perceived to lead to improved outcomes for all. For the patient and their family, it can help with reconciliation following a traumatic event and help restore their faith in the healthcare system. For the health service, listening and involving people will likely enhance learning with subsequent improvements in healthcare provision with reduction in risk of similar events occurring for other patients. Communicating in a compassionate manner could also decrease litigation claims following an adverse event. Overall, having personalised conversations and a streamlined review process, with open engagement to enhance learning, was important to most participants in this study.


title: Estimates of reduced vaccine effectiveness against hospitalization, infection, transmission and symptomatic disease of a new SARS-CoV-2 variant, Omicron (B.1.1.529), using neutralizing antibody titers

abstract:
The emergence of the Omicron variant (B.1.1.529) of SARS-CoV-2 has raised concerns about how mutations in the spike protein might influence immune escape and vaccine protection against infection and disease, COVID-19. Initial estimates of immune escape measure neutralizing antibody titers, which have been shown to be a correlate of protection for COVID-19, but vary among studies. However, no studies have examined variation in vaccine effectiveness (VE) using estimated reductions in neutralizing antibody titers across virus variants. We quantified consistency in relative neutralizing antibody titers across studies. We then examined relationships between variant-specific reductions in neutralizing antibodies and protection against documented infection, symptomatic disease, and hospitalizations across variants and vaccines. We found considerable variation in variant-specific neutralizing antibody titers between studies, but within-study comparisons across variants were far more robust. There was insufficient data to estimate VE for a single vaccine across variants, especially for higher levels of immune evasion (>7-fold reductions in neutralizing antibody titers) observed with the Omicron variant (40-fold). Instead, we leveraged variation among both vaccines and virus variants to estimate VE -neutralizing antibody titer relationships across a 30 to 100-fold range of neutralizing antibody titers reduction. Omicron increased the risk of hospitalization four to five-fold and increased the risk of symptomatic disease seven to ten-fold for mRNA vaccinees, with similar relative effects for recently vaccinated, or individuals with waned antibody titers. Third doses restored titers and protection to levels similar to waned immunity against Delta. Overall, these analyses indicate that vaccine effectiveness against severe disease is significantly diminished for waned individuals, and protection against infection, symptomatic disease and transmission is nearly eliminated. However, third doses significantly ameliorate these reductions but only restore protection to levels equivalent to waned protection against the Delta variant. The invasion of Omicron is likely to result in widespread infection, and substantial hospitalizations unless widespread boosting of immunity occurs.

FundingCalifornia Department of Health, National Science Foundation


title: A standardized approach for case selection and genomic data analysis of maternal exomes for the diagnosis of oocyte maturation and early embryonic developmental arrest in IVF

abstract:
OBJECTIVETo develop a methodology for case selection and whole-exome sequencing (WES) analysis in infertile women due to recurrent oocyte maturation defects(OOMD) and/or preimplantation embryo lethality (PREMBL).

DESIGNRetrospective cohort study.

SETTINGIVF patients attending the Istanbul Memorial Hospital (2015-2021). WES and bioinformatics were performed at Igenomix and National Research Council, Italy.

PATIENTSA statistical methodology for identification of infertile endophenotypes (recurrent low oocyte maturation rate, LMR, low fertilization rate, LFR, and preimplantation developmental arrest, PDA, was developed using a large IVF dataset (11,221 couples). 28 OOMD/PREMBL infertile women were subsequently enrolled for WES.

INTERVENTION30X-WES was performed on womens gDNA. Pathogenic variants were prioritized using a custom-made bioinformatic pipeline set to minimize false positive discoveries through resampling in control cohorts (i.e., HGDP and 1,343 WES from oocyte donors). Individual scRNAseq data from 18 human MII oocytes and antral granulosa cells(AGC) was used for genome-wide validation.

MAIN OUTCOME MEASUREIdentification of High-impact variants causative of OOMD/PREMBL endophenotypes.

RESULTSVariant prioritization analysis identified 265 unique variants in 248 genes (average per sample 22.4). 87.8% of genes harbouring high-impact variants are expressed by MII oocytes and/or AGC, significantly higher compared to a random sample of controls. Seven of the 28 women (25%) are homozygous carriers of missense pathogenic variants in known candidate genes for OOMD/PREMBL, including PATL2, NLRP5 (N=2), TLE6,PADI6, TUBB8 and TRIP13. Furthermore, novel gene-disease associations were identified. One LMR woman was a homozygous carrier of high impact variants in ELSA, an essential gene for phopase I meiotic transition in mice, whereas three women carried biallelic pathogenic variants in CEP128 gene, participating in the formation of the spindle in mitosis and ciliogenesis.

CONCLUSIONSThis analytical framework revealed known and new genes associated with isolated recurrent OOMD/PREMBL, providing essential indications for scaling this strategy to larger studies.


title: Delta Variant SARS-CoV-2 infections in pediatric cases during the second wave in India

abstract: The aim of this study was to identify the SARS-CoV-2 lineages circulating in the pediatric population of India during the second wave of the pandemic. Clinical and demographic details linked with the nasopharyngeal/oropharyngeal swabs (NPS/OPS) collected from SARS-CoV-2 cases (n=583) aged 0-18 year and tested positive by real-time RT-PCR were retrieved from March to June 2021.Symptoms were reported among 37.2% of patients and 14.8% reported to be hospitalized. The E gene CT value had significant statistical difference at the point of sample collection when compared to that observed in the sequencing laboratory. Out of these 512 sequences 372 were VOCs, 51 were VOIs. Most common lineages observed were Delta, followed by Kappa, Alpha and B.1.36, seen in 65.82%, 9.96%, 6.83% and 4.68%, respectively in the study population. Overall, it was observed that Delta strain was the leading cause of SARS-CoV-2 infection in Indian children during the second wave of the pandemic. We emphasize on the need of continuous genomic surveillance in SARS-CoV-2 infection even amongst children.


title: Cardiac and aortic size measures in adult echocardiography should be indexed by body surface area regardless of body mass index

abstract:
Abstract and keywordsO_ST_ABSAimsC_ST_ABSBody surface area (BSA) is the most commonly used metric for body size indexation of echocardiographic measures, but its use in patients who are underweight or obese is questioned (body mass index (BMI) <18.5 kg/m2 or [≥]30 kg/m2, respectively). We aim to use survival analysis to identify an optimal body size indexation metric for echocardiographic measures that would be a better predictor of survival than BSA regardless of BMI.

Methods and ResultsAdult patients with no prior valve replacement were selected from the National Echo Database Australia. Survival analysis was performed for echocardiographic measures both unindexed and indexed to different body size metrics, with 5-year cardiovascular mortality as the primary endpoint. Indexation of echocardiographic measures (left ventricular end-diastolic diameter [n=337,481] and mass [n=330,959], left atrial area [n=136,989], aortic sinus diameter [n=125,130], right atrial area [n=81,699], right ventricular diameter [n=3,575], right ventricular outflow tract diameter [n=2,841]) by BSA had better prognostic performance vs unindexed measures (healthy/overweight: C-statistic 0.656 vs 0.618, average change in Akaike Information Criteria ({Delta}AIC) 800; underweight: C-statistic 0.669 vs 0.654, {Delta}AIC 15; obese: C-statistic 0.630 vs 0.612, {Delta}AIC 113). Indexation by other body size metrics (lean body mass or height and/or weight raised to various powers) did not improve prognostic performance versus BSA by a clinically relevant magnitude (average C-statistic increase [≤]0.01), with smaller differences in higher BMI subgroups.

ConclusionIndexing measures of cardiac and aortic size by BSA improves prognostic performance regardless of BMI, and no other body size metric has a clinically meaningful better performance.


title: Prognostic association supports indexing size measures in echocardiography by body surface area


title: SARS-CoV-2 variant dynamics across US states show consistent differences in effective reproduction numbers

abstract: Accurately estimating relative transmission rates of SARS-CoV-2 Variant of Concern and Variant of Interest viruses remains a scientific and public health priority. Recent studies have used the sample proportions of different variants from sequence data to describe variant frequency dynamics and relative transmission rates, but frequencies alone cannot capture the rich epidemiological behavior of SARS-CoV-2. Here, we extend methods for inferring the effective reproduction number of an epidemic using confirmed case data to jointly estimate variant-specific effective reproduction numbers and frequencies of co-circulating variants using case data and genetic sequences across states in the US from January to October 2021. Our method can be used to infer structured relationships between effective reproduction numbers across time series allowing us to estimate fixed variant-specific growth advantages. We use this model to estimate the effective reproduction number of SARS-CoV-2 Variants of Concern and Variants of Interest in the United States and estimate consistent growth advantages of particular variants across different locations.


title: Patients with benign breast disease and breast cancer need more COVID-19 vaccines

abstract: Albeit the efficacy of COVID-19 vaccines in immunocompromised patients is undermined, it is still found beneficial. Patients with cancer have a much lower COVID-19 vaccination rate globally, and the vaccination coverage in breast cancer patients in China remains elusive. A total of 23029 patients with benign breast diseases and breast cancers were included in the study, and the vaccination rates of patients with benign breast tumors and other benign breast diseases, nonmetastatic and metastatic breast cancer were 44.0%, 54.7%, 19.2% and 9.6%, respectively. Breast cancer in situ patients had a similar vaccination rate with patients with benign breast tumors (45.9% vs 44.0%) while those with invasive breast cancer had much lower vaccination rates. The overall vaccination rate remains meager in breast cancer patients, and gap was found in patients with lower clinical stage. Hence vaccination should be further promoted among patients with benign breast diseases and breast cancer.