title: Combination of single cell sequencing data and GWAS summary statistics reveals genetically-influenced liver cell types for primary biliary cholangitis

abstract:
ImportancePrimary biliary cholangitis (PBC) is a classical autoimmune disease, which is highly influenced by genetic determinants. Many genome-wide association studies (GWAS) have reported that numerous genetic loci were significantly associated with PBC susceptibility. However, the effects of genetic determinants on liver cells and its immune microenvironment for PBC remain unclear.

ObjectiveTo identify genetics-modulated functional liver cell subsets involved in the pathogenesis of PBC.

Design, Setting, and ParticipantsIn this present study, 13,239 European participants were collected from IEU open GWAS project on PBC. There were 1,124,241 qualified SNPs used for GWAS analysis. Expression quantitative trait loci (eQTL) data across 49 tissues were downloaded from the GTEx database. Two single cell RNA sequencing (scRNA-seq) profiles and two bulk-based RNA transcriptomes were downloaded from the GEO database. Data collection and analyses were performed from August 2020 to June 2021.

Main outcomes and measuresWe constructed a powerful computational framework to integrate GWAS summary statistics with scRNA-seq data to uncover genetics-modulated liver cell subpopulations.

ResultsBased on our multi-omics integrative analysis, we found that 29 risk genes including ORMDL3, GSNK2B, and DDAH2 were significantly associated with PBC susceptibility. Gene-property analysis revealed that four immune cell types, including Cst3+ dendritic cell, Chil3+ macrophage, Trbc2+ T cell, and Gzma+ T cell, were significantly enriched by PBC-risk genes. By combining GWAS summary statistics with scRNA-seq data, we found that cholangiocytes exhibited a notable enrichment by PBC-related genetic association signals (Permuted P < 0.05). The risk gene of ORMDL3 showed the highest expression proportion in cholangiocytes than other liver cells (22.38%). Compared with ORMDL3+ cholangiocytes, there were 71 significantly highly-expressed genes among ORMDL3- cholangiocytes (FDR < 0.05), such as inflammatory cytokine genes CXCL8, CCL3, IFI16, and IRF1. These highly-expressed genes were significantly enriched in numerous biological pathways and functional terms associated with autoimmune diseases (FDR < 0.05).

Conclusions and relevanceTo the best of our knowledge, this is the first study to integrate genetic information with single cell sequencing data for parsing genetics-influenced liver cells for PBC risk. We identified that ORMDL3- cholangiocytes play important immune-modulatory roles in the etiology of PBC.

Key pointsO_ST_ABSQuestionC_ST_ABSAre genetics factors influenced liver cell subpopulations and its immune microenvironment for PBC?

FindingsIn this comprehensive genomics study based on multi-omics data, genetic determinants were significantly enriched in cholangiocytes and immune cells including subsets of macrophage, dendritic cells, and T cells. ORMDL3- cholangiocytes have crucial immune-modulatory roles in developing PBC.

MeaningFindings suggest that integration of single cell sequencing data with GWAS summary statistics contribute to pinpoint PBC-relevant cell types and risk genes.


title: Costs of hand hygiene for all in household settings - estimating the price tag for the 46 least developed countries

abstract:
IntroductionDomestic hand hygiene could prevent over 500,000 attributable deaths per year, but 6 in 10 people in least developed countries (LDCs) do not have a handwashing facility with soap and water available at home. We estimated the economic costs of universal access to basic hand hygiene services in household settings in 46 LDCs.

MethodsOur model combines quantities of households with no handwashing facility (HWF) and prices of promotion campaigns, HWFs, soap, and water. For quantities, we used estimates from the WHO/UNICEF Joint Monitoring Programme. For prices, we collated data from recent impact evaluations and electronic searches. Accounting for inflation and purchasing power, we calculated costs over 2021-2030, and estimated total cost probabilistically using Monte Carlo simulation.

ResultsAn estimated US$ 12.2 - 15.3 billion over 10 years is needed for universal hand hygiene in household settings in 46 LDCs. The average annual cost of hand hygiene promotion is $334 million (24% of annual total), with a further $233 million for  top-up promotion (17%). Together, these promotion costs represent $0.47 annually per head of LDC population. The annual cost of HWFs, a purpose-built drum with tap and stand, is $174 million (13%). The annual cost of soap is $497 million (36%), and water $127 million (9%).

ConclusionThe annual cost of behaviour change promotion to those with no handwashing facility represents 4.7% of median government health expenditure in LDCs, and 1% of their annual aid receipts. These costs could be covered by mobilising resources from across government and partners, and could be reduced by harnessing economies of scale and integrating hand hygiene with other behaviour change campaigns where appropriate. Innovation is required to make soap more affordable and available for the poorest households.

Summary boxO_ST_ABSWhat is already known?C_ST_ABSO_LIUnderstanding resource requirements is important for planning, but data on the costs of improving domestic hand hygiene are scarce.
C_LIO_LIWhile a 2016 study estimated the global cost of drinking water, sanitation and hygiene, it did not report hygiene-specific estimates of recurrent or total cost, nor did it describe the assumed promotion intervention and handwashing facility or consider alternatives to them.
C_LI

What are the new findings?O_LIThe total economic cost over 10 years is US$ 12.2 - 15.3 billion, of which $4.9 - 6.6 billion (42%) is for behaviour change promotion interventions.
C_LIO_LIThe remainder is for facilities and supplies, with soap the biggest cost category (36%) followed by handwashing facilities (13%) and water (9%).
C_LIO_LIThe facility and supply costs per household comprise an initial investment in a handwashing facility (lasting 5 years) at a median of US$ 17, accompanied by an annual cost of $17 for soap and $5 for water.
C_LI

What do the new findings imply?O_LIThe annual cost of behaviour change promotion to those with no handwashing facility represents 4.7% of median government health expenditure in LDCs.
C_LIO_LIOn top of this, investments in infrastructure and supplies are required. Soap in particular is a substantial and recurrent cost, which may be unaffordable for the poorest households.
C_LIO_LIPromotion costs could be covered by mobilising resources from across government and partners, and could be reduced by harnessing economies of scale and integrating hand hygiene with other behaviour change campaigns where appropriate.
C_LI

category: health economics


title: Modelling the cost-effectiveness of essential and advanced critical care for COVID-19 patients in Kenya

abstract:
BackgroundCase management of symptomatic COVID-19 patients is a key health system intervention. The Kenyan government embarked to fill capacity gaps in essential and advanced critical care needed for the management of severe and critical COVID-19. However, given scarce resources, gaps in both essential and advanced critical care persist. This study assessed the cost-effectiveness of investments in essential and advanced critical care to inform the prioritization of investment decisions.

MethodsWe employed a decision tree model to assess the incremental cost-effectiveness of investment in essential care (EC) and investment in both essential and advanced critical care (EC+ACC) compared to current health care provision capacity (status quo) for COVID-19 patients in Kenya. We used a health system perspective, and an inpatient care episode time horizon. Cost data was obtained from primary empirical analysis while outcomes data was obtained from epidemiological model estimates. We used univariate and probabilistic sensitivity analysis (PSA) to assess the robustness of the results.

ResultsThe status quo option is more costly and less effective compared to investment in essential care and is thus dominated by the later. The incremental cost effectiveness ratio (ICER) of Investment in essential and advanced critical care (EC+ACC) was US $1,378.21 per DALY averted and hence not a cost-effective strategy when compared to Kenyas cost-effectiveness threshold (USD 908).

ConclusionWhen the criterion of cost-effectiveness is considered, and within the context of resource scarcity, Kenya will achieve better value for money if it prioritizes investments in essential care before investments in advanced critical care. This information on cost-effectiveness will however need to be considered as part of a multi-criteria decision-making framework that uses a range of criteria that reflect societal values of the Kenyan society.

Key questionsO_ST_ABSWhat is already known?C_ST_ABSO_LIThe COVID-19 pandemic is responsible for substantial health effects in low- and middle-income countries
C_LIO_LIThe case management of COVID-19 is one of the key control interventions deployed by country health systems.
C_LIO_LISimilar to other low- and middle-income countries, Kenya had substantial gaps in both essential and advanced critical care at the beginning of the pandemic.
C_LI

What are the new findings?O_LIProvision of essential care and advanced critical care for COVID-19 at the current health system capacity (status quo) was costly and the least effective strategy.
C_LIO_LIInvestment in both essential care and advanced critical care for COVID-19 is not cost-effective in Kenya when compared to investment in essential care.
C_LI

What do the new findings imply?O_LIPrioritizing investments in filling capacity gaps in essential care before investing in filling capacity gaps in advanced critical care for COVID-19 is more cost-effective in Kenya
C_LIO_LIThese findings are intended to inform the sequencing of investments in case management rather than the selection of either strategy, within a context of substantial resource constraint, and capacity gaps in both essential and advanced critical care or COVID-19
C_LIO_LIKenya will need to consider these findings on cost-effectiveness within a multi-criteria decision-making framework that use a range of criteria that reflect societal values.
C_LI


title: Point-of-care semiquantitative test for adherence to tenofovir alafenamide or tenofovir disoproxil fumarate

abstract:
SynopsisO_ST_ABSObjectiveC_ST_ABSObjective measurement of antiretrovirals may aid clinical interventions for improving adherence to HIV prevention or treatment regimens. A point-of-care urine test could provide real-time information about recent adherence to regimens containing tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). We developed a lateral flow immunoassay (LFA) and enzyme-linked immunoassay (ELISA) for urinary tenofovir.

MethodsIntensity of the LFA test line was quantified using an optical reader and visually scored 0 - 5 by two independent people, using a reference card. The sensitivity and specificity of both the ELISA and LFA were determined for two different tenofovir concentration cutoffs for TDF and TAF adherence--1,500 ng/mL and 150 ng/mL, respectively. To validate the assays, we measured 586 urine samples from 28 individuals collected as part of a study of tenofovir pharmacokinetics in adults, which were also measured by mass spectrometry as ground truth.

ResultsBoth the LFA signal and ELISA signal were each strongly correlated to drug concentrations (0.91 and 0.92 respectively). The LFA signal and ELISA were highly sensitive and specific at both thresholds (LFA se/sp TDF 89%/96%, TAF 90%/96%; ELISA se/sp TDF 94%/94%, TAF 92%/84%). Visual scoring of the LFA was also highly sensitive and specific at both the TDF and TAF thresholds (se/sp TDF 91%/94%, TAF 87%/90%).

ConclusionsOur rapid semi-quantitative test can measure TFV concentrations relevant to both TAF or TDF adherence, which may support adherence-promoting interventions across a range of HIV care settings.

category: hiv aids


title: Physician Reimbursement and Retention in HIV Care: Racial Disparities in the US South

abstract: Fewer than 60% of Americans diagnosed with HIV are retained in care, with racial disparities. Addressing structural barriers to care may improve outcomes along the HIV care continuum, such as retention, and promote health equity. We examined the relationship between physician reimbursement and retention in HIV care, including racial differences. Data included person-level demographic information and administrative claims (Medicaid Analytic eXtract, 2008-12), state Medicaid-to-Medicare fee ratios (Urban Institute, 2008, 2012), and county characteristics for 15 Southern states plus District of Columbia. The fee ratio is a standardized measure of physician reimbursement capturing state variation in Medicaid relative to Medicare physician reimbursement, which is largely consistent across states. We used generalized estimating equations to assess the association between physician reimbursement ratio and retention in HIV care ([≥]2 claims for physician visits, antiretroviral prescriptions, or CD4 or HIV RNA viral load tests [≥]90 days apart in a calendar-year). We also evaluated an increase in the fee ratio to parity, where Medicaid and Medicare physician reimbursement are equal. Stratified analysis assessed racial differences. The sample included 55,237 adult Medicaid enrollees living with HIV (179,002 enrollee-years). Enrollees were retained in HIV care for approximately three-quarters (76.8%) of their enrollment-years, with retention lower among non-Hispanic Black (76.2%) versus non-Hispanic White (81.3%, p<0.001) enrollees. A 10-percentage point increase in physician reimbursement was associated with a 4% increase in the odds of retention (aOR 1.04, 95% CI 1.01, 1.08). In stratified analysis, increased physician reimbursement was significantly associated with retention among non-Hispanic Black but not non-Hispanic White enrollees. At parity, predicted retention was 81.1% (80.0%, 82.1%) and 80.4% (79%, 81.7%) of enrollment-years, overall and for non-Hispanic Black enrollees, respectively. Higher physician reimbursement improves retention in HIV care, particularly among non-Hispanic Black individuals living with HIV, and could be a structural mechanism to promote racial equity in retention.


title: Inexpensive workflow for simultaneous monitoring of HIV viral load and detection of SARS-CoV-2 infection

abstract:
BackgroundCOVID-19 pandemic interrupted routine care for individuals living with HIV, putting them at risk of becoming virologically unsuppressed and ill. Often they are at high risk for exposure to SARS-CoV-2 infection and severe disease once infected. For this population, it is urgent to closely monitor HIV plasma viral load (VL) and screen for SARS-COV-2 infection.

MethodWe have developed a non-proprietary method to isolate RNA from plasma, nasal secretions (NS), or both. HIV, SARS-CoV-2, and human RP targets in extracted RNA are then RT-qPCR to estimate the VL and classify HIV/SARS-CoV-2 status (i.e., HIV as VL failure or suppressed; SARS-CoV-2 as positive, presumptive positive, negative, or indeterminate). We evaluated this workflow on 133 clinical specimens: 40 plasma specimens (30 HIV-seropositive), 67 NS specimens (31 SARS-CoV-2-positive), and 26 pooled plasma/NS specimens (26 HIV-positive with 10 SARS-CoV-2-positive), and compared the results obtained using the in-house extraction to those using a commercial extraction kit.

ResultsIn-house extraction had a detection limit of 200-copies/mL for HIV and 100-copies/mL for SARS-CoV-2. In-house and commercial methods yielded positively correlated HIV VL (R2: 0.98 for contrived samples; 0.81 for seropositive plasma). SARS-CoV-2 detection had 100% concordant classifications in contrived samples, and in clinical NS extracted by in-house method, excluding indeterminate results, was 95% concordant (25 positives, 6 presumptive positives, and 31 negatives) to those using the commercial method. Analysis of pooled plasma/NS showed R2 of 0.91 (contrived samples) and 0.71 (clinical specimens) for HIV VL correlations obtained by both extraction methods, while SARS-CoV-2 detection showed 100% concordance in contrived and clinical specimens.

InterpretationOur low-cost workflow for molecular testing of HIV and SARS-CoV-2 could serve as an alternative to current standard assays for laboratories in low-resource settings.


title: The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection

abstract: Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The emergence of C.1.2, associated with a high substitution rate, includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 VOC/VOIs. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta showed high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2.

category: infectious diseases


title: Emergence and phenotypic characterization of C.1.2, a globally detected lineage that rapidly accumulated mutations of concern


title: Agent-based Investigation of the Impact of Low Rates of Influenza on Next Season Influenza Infections

abstract:
IntroductionInterventions to curb the spread of SARS-CoV-2 during the 2020-21 influenza season essentially eliminated influenza during that season. Given waning antibody titers over time, future residual population immunity against influenza will be reduced. The implication for the subsequent 2021-22 influenza season is unknown.

MethodsWe used an agent-based model of influenza implemented in the FRED (Framework for Reconstructing Epidemiological Dynamics) simulation platform to estimate cases and hospitalization over two succeeding influenza seasons. The model uses a synthetic population to represent an actual population, and individual interactions in workplaces, school, households and neighborhoods. The impact of reduced residual immunity was estimated as a consequence of increased protective measures (e.g., social distancing and school closure) in the first season. The impact was contrasted by the level of similarity (cross-immunity) between influenza strains over the seasons.

ResultsWhen the second season strains were dissimilar to the first season (have a low level of cross immunity), a low first season has limited impact on second season cases. When a high level of cross-immunity exists between strains in the 2 seasons, the first season has a much greater impact on the second season. In both cases this is modified by the transmissibility of strains in the 2 seasons. In the context of the 2021-22 season, the worst case scenario is a highly transmissible strain causing increased cases and hospitalizations over average influenza seasons, with a possible significant increase in cases in some scenarios. The most likely overall scenario for 2021-22 is a more modest increase in flu cases over an average season.

DiscussionGiven the light 2020-21 season, we found that a large, compensatory second season might occur in 2021-22, depending on cross-immunity from past infection and transmissibility of strains. Furthermore, we found that enhanced vaccine coverage could reduce this high, compensatory season. Young children may be especially at risk in 2021-22 since very young children were unlikely to have had any exposure to infection and most immunity in that age group would be from vaccination, which wanes quickly.


title: Urban Tertiary Care Centre Experience of Characteristics of Severe COVID-19 Pneumonia

abstract:
IntroductionThe global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019, and has since spread worldwide.[1] This study attempts to summarize current evidence regarding major inflammatory markers, severity predictors and its impact on outcome, which provide current clinical experience and treatment guidance for this novel coronavirus.

MethodsThis is a retrospective observational study done at an urban teaching covid-19 designated hospital. Hospital data were analysed with aim of studying inflammatory markers, predictors and outcome. Patients were classified in Mild, Moderate, Severe & Critical categories of COVID cases. Their clinical parameters, laboratory investigations, radiological findings & Outcome measures were studied. Strength of association & correlation of those parameters with severity and in-hospital mortality were studied.

ResultsA total 204 (N) patients were clinically classified into different severity groups, as per MOHFW and qCSI(quick Covid Severity Index) guidelines, as Mild (34), Moderate (56), Severe (39) and Critical (75). The mean(SD) age of the cohort was 55.1+13.2 years; 74.02% were male. Severe COVID-19 illness is seen more in patients more than 50 years of age. COVID-19 patients having IHD develop worse disease with excess early in-hospital mortality. Respiratory rate & Heart Rate on admission are correlated with severe and stormy disease. Among Inflammatory markers, on admission LDH, D-Dimer and CRP are related with severity and excess in-hospital death rate.

ConclusionAdvanced age, male gender, IHD, Respiratory Rate & Heart Rate on admission were associated with severe covid-19 illness. S. Lactate Dehydrogenase & D-dimer was associated with severe covid-19 illness and early in-hospital death.


abstract: The isothermal molecular diagnosis with CRISPR has attracted particular interest for the sensitive, specific detection of nucleic acids. However, most of the assays with Cas enzymes were performed in bulk assays using multistep approaches and hard to realize quantitative detection. Herein, we report Microfluidics-Enabled Digital Isothermal Cas13a Assay (MEDICA), a digital format of SHERLOCK with enhanced robustness and sensitivity. We first address the macromolecular crowding problems when combining the recombinase polymerase amplification (RPA) and Cas13a detection into a one-pot SHERLOCK assay. After the assay optimization, the enhanced one-pot SHERLOCK (E-SHERLOCK) achieves high robustness and 200-fold increased sensitivity. Leveraging droplet microfluidics, we streamline the E-SHERLOCK to eliminate undesired input targets caused by pre-amplification before partition, enabling background-free absolute quantification. From the real-time monitoring, MEDICA enables qualitative detection within 10 min and absolute quantification within 25 min. For the proof of concept, we applied MEDICA to quantify HPV 16 and 18 viral loads in 44 clinical samples, indicating perfect accordance with qPCR results. MEDICA highlights the CRISPR-based isothermal assays are promising for the next generation of point-of-care diagnostics.


title: Assessing the impact of adherence to Non-pharmaceutical interventions and indirect transmission on the dynamics of COVID-19: a mathematical modelling study

abstract: Adherence to public health policies such as the non-pharmaceutical interventions implemented against COVID-19 plays a major role in reducing infections and controlling the spread of the diseases. In addition, understanding the transmission dynamics of the disease is also important in order to make and implement efficient public health policies. In this paper, we developed an SEIR-type compartmental model to assess the impact of adherence to COVID-19 non-pharmaceutical interventions and indirect transmission on the dynamics of the disease. Our model considers both direct and indirect transmission routes and stratifies the population into two groups: those that adhere to COVID-19 non-pharmaceutical interventions (NPIs) and those that do not adhere to the NPIs. We compute the control reproduction number and the final epidemic size relation for our model and study the effect of different parameters of the model on these quantities. Our results show that direct transmission has more effect on the reproduction number and final epidemic size, relative to indirect transmission. In addition, we showed that there is a significant benefit in adhering to the COVID-19 NPIs.


title: External validation of 4C ISARIC mortality score in the setting of a Saudi Arabian ICU. Retrospective study.

abstract:
COVID-19 pandemic has burdened healthcare systems, necessitating the development of mortality prediction scores to guide clinical decisions and resource allocation. 4C ISARIC mortality score was developed and validated on a British cohort.

ObjectivesExternal validation of the score in the setting of a large Saudi Arabian ICU.

MethodRetrospective chart review of COVID-19 patients admitted to ICU of King Saud Medical City, Riyadh, Saudi Arabia. Collecting data to calculate the score, then fitting a ROC curve against known patients outcome.

ResultsCohort included 1493 patients with 38% mortality, AUC of the score was 0.81 (95% CI: 0.79 - 0.83, p < 0.001), correctly classifying 72.67% of the cohort. Cut-off value of > 9 had sensitivity of 70.5% (95% CI: 66.6 - 74.3), specificity 73.97% (95% CI: 71 - 76.8), positive predictive value 62.4% (95% CI: 59.5 - 65.2), and negative predictive value 80.2% (95% CI: 78.2 - 82.4).

Conclusion4C ISARIC mortality risk score performed well with a good discriminatory ability for critically ill patients admitted to ICU in our setting. Cut-off > 9 was the optimal criterion.

category: intensive care and critical care medicine


title: Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK

abstract: The effectiveness of BNT162b2, ChAdOx1, and mRNA-1273 vaccines against new SARS-CoV-2 infections requires continuous re-evaluation, given the increasingly dominant Delta variant. We investigated the effectiveness of the vaccines in a large community-based survey of randomly selected households across the UK. We found that the effectiveness of BNT162b2 and ChAd0x1 against any infections (new PCR positives) and infections with symptoms or high viral burden is reduced with the Delta variant. A single dose of the mRNA-1273 vaccine had similar or greater effectiveness compared to a single dose of BNT162b2 or ChAdOx1. Effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity following second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positives but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher among those vaccinated following a prior infection and younger adults. With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.

category: epidemiology


title: Association of cerebral venous thrombosis with recent COVID-19 vaccination: case-crossover study using ascertainment through neuroimaging in Scotland.

abstract:
ObjectivesTo investigate the association of primary acute cerebral venous thrombosis (CVT) with COVID-19 vaccination through complete ascertainment of all diagnosed CVT in the population of Scotland.

DesignCase-crossover study comparing recent (1-14 days after vaccination) with less recent exposure to vaccination among cases of CVT.

SettingNational data for Scotland from 1 December 2020, with diagnosed CVT case ascertainment through neuroimaging studies up to 17 May 2021 and diagnostic coding of hospital discharges up to 28 April 2021 and with linkage to vaccination records.

Main outcome measurePrimary acute cerebral venous thrombosis

ResultsOf 50 primary acute CVT cases, 29 were ascertained only from neuroimaging studies, 2 were ascertained only from hospital discharges, and 19 were ascertained from both sources. Of these 50 cases, 14 had received the Astra-Zeneca ChAdOx1 vaccine and 3 the Pfizer BNT162b2 vaccine. The incidence of CVT per million doses in the first 14 days after vaccination was 2.2 (95% credible interval 0.9 to 4.1) for ChAdOx1 and 1 (95% credible interval 0.1 to 2.9) for BNT162b2. The rate ratio for CVT associated with exposure to ChAdOx1 in the first 14 days compared with exposure 15-84 days after vaccination was 3.2 (95% credible interval 1.1 to 9.5). The 95% credible interval for the rate ratio associated with recent versus less recent exposure to BNT162b2 (0.6 to 95.8) was too wide for useful inference.

ConclusionsThese findings support a causal association between CVT and the AstraZeneca vaccine. The absolute risk of post-vaccination CVT in this population-wide study in Scotland was lower than has been reported for populations in Scandinavia and Germany; the explanation for this is not clear.

What is already known on this topicThe risk of cerebral venous thrombosis (CVT) within 28 days of receiving the AstraZeneca ChAdOx1 vaccine has been estimated as 18 to 25 per million doses in Germany and Scandinavia, but only 5 per million doses in the UK based on the Yellow Card reporting scheme. Risk estimates based on adverse event reporting systems are subject to under-ascertainment and other biases.

What this study addsAll diagnosed cases of CVT in Scotland were ascertained by searching neuroimaging studies from December 2020 to May 2021 and linked to national vaccination records. The risk of CVT within 28 days of vaccination with ChAdOx1 was estimated as 3.5 per million doses with an upper bound of 6 per million doses, against a background incidence of about 12 per million adults per year. This indicates that the Yellow Card system has not seriously underestimated the risk in the UK; the explanation for higher risk in other European countries is not clear.


title: Men are the main COVID-19 transmitters: lessons from couples

abstract:
BackgroundCOVID-19 has affected millions of people worldwide. Clinical manifestations range from severe cases with a lethal outcome to mild or asymptomatic cases. Although there is the same proportion of infected genders, men are more susceptible to severe COVID-19, with a higher risk of death than women. This sex-bias may be explained by biological pathways.

MethodsWe performed an epidemiological survey from July 2020 to July 2021 including 1744 unvaccinated adult Brazilian couples with at least one infected spouse despite living together during the COVID-19 infection without protective measures. The presence or absence of infection was confirmed by RT-PCR and/or serology results. The couples were divided between groups where both partners were infected (concordant couples) or only one spouse remained asymptomatic despite the close contact with the infected one (discordant couples). Statistical analysis of the collected data was performed aiming to verify a differential transmitter potential between genders in household contact.

ResultsThe combination of our data collected from concordant and discordant couples showed that the man is the first (or the only) affected in the major occurrences when compared to women. Our findings support other published surveys and are in concordance with previous studies of our group.

ConclusionsThese observations support the hypothesis according to which male individuals are more efficient virus transmitters than females, independently of the use of protective masks. In short, the present study confirmed the existence of gender differences not only for susceptibility to infection and resistance to COVID-19 but also in the transmission rate.

HIGHLIGHTSO_LIThere are sex differences in COVID-19 susceptibility and transmission between couples with direct contact without protective measures;
C_LIO_LIMen are more efficient virus transmitters than women;
C_LIO_LISex-bias in COVID-19 transmission can be explained by differences in viral load in saliva, immune response and also behavioural protective differences between genders.
C_LI


title: The SARS-CoV-2 Alpha variant is associated with increased clinical severity of disease

abstract:
BackgroundThe SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death.

MethodsIn this prospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced and analysed for the presence of Alpha variant defining mutations. We prospectively matched sequence data to clinical outcomes as the variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. Additionally, we calculated an estimate of the growth rate of Alpha variant-associated infections following its introduction into Scotland, using phylogenetic data.

ResultsThe Alpha variant was responsible for a third wave of SARS-CoV-2 in Scotland, and rapidly replaced the previously dominant second wave lineage B.1.177 due to a significantly higher transmission rate ([~]5 fold). Of 1475 patients, 364 were infected with Alpha/B.1.1.7, 1030 with B.1.177, and 81 with other lineages. Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus non-Alpha variant). Viral load was higher in Alpha variant samples than in non-Alpha variant samples as measured by cycle threshold (Ct) value (mean Ct change: -2.46, 95% CI: -4.22, -0.70).

ConclusionsThe Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages.

FundingCOG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. Funding was also provided by UKRI through the JUNIPER consortium (grant number MR/V038613/1). Sequencing and bioinformatics support was funded by the Medical Research Council (MRC) core award (MC UU 1201412).


title: The SARS-CoV-2 Alpha variant caused increased clinical severity of disease in Scotland: a genomics-based prospective cohort analysis


title: Child Mortality in England During the First Year of the COVID-19 Pandemic

abstract:
OBJECTIVESThe aim of this analysis was to quantify the relative risk of childhood deaths across the whole of England during the first year of the COVID pandemic, compared to a similar period of 2019.

DESIGNThis work is based on data collected by the National Child Mortality Database (NCMD) which collates data on all children who die in England. The number of deaths, and their characteristics, from 1st April 2020 until 31st of March 2021 (2020-21), were compared to those from the same period of 2019-20. Relative risk and excess mortality were derived for deaths in 2020-21 vs 2019-20.

SETTINGAll deaths reported to NCMD in England of children under 18 years of age, between April 2019 and March 2021.

PARTICIPANTS6490 deaths of children, under the age of 18 years, reported to the NCMD over the study period.

RESULTSChildren who died between April 2020 and March 2021 had similar demographics to those who died in 2019-20. Overall, there were 356 (198 to 514) fewer deaths in 2020-21 than in 2019-20 (RR 0.90 (0.85-0.94), p<0.001). Repeating the analysis by category of death, suggested that deaths from infection (RR 0.49 (0.38-0.64)) and from other underlying medical conditions (RR 0.75 (0.68-0.82)) were lower in 2020-21 than 2019-20, and weak evidence (p=0.074) that this was also true of deaths from substance abuse.

CONCLUSIONSChildhood mortality in England during the first year of the SARS-CoV-2 pandemic was the lowest on record, with over 300 fewer deaths than the preceding 12 months. The greatest reduction was seen in children less than 10 years old. It is important that we learn from this effect, that potentially offers alternative ways to improve the outcome for the most vulnerable children in our society.

category: pediatrics


title: Cerebrospinal fluid concentration of complement component 4A is increased in first-episode schizophrenia

abstract: Excessive synapse loss is a core feature of schizophrenia and is linked to the complement component 4A gene (C4A). In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in first-episode psychosis patients who develop schizophrenia and correlates with CSF measurements of synapse density. Using patient-derived cellular modeling, we find that disease-associated cytokines increase neuronal C4A expression and that IL-1{beta} associates with C4A in patient-derived CSF.

category: psychiatry and clinical psychology


title: White Matter Abnormalities in Body Integrity Dysphoria

abstract: "Body integrity dysphoria" (BID) is a severe condition affecting non-psychotic individuals where a limb may be experienced as not being part of the body, despite normal anatomical development and intact sensorimotor functions. Limb amputation is desired for restoring their own identity. We previously demonstrated altered brain structural (gray matter) and functional connectivity in 16 men with a long-lasting and exclusive desire for left leg amputation. Here we aimed to identify in the same sample altered patterns of white matter structural connectivity. Fractional anisotropy (FA), derived from Diffusion Tensor Imaging data, was considered as a measure of structural connectivity. Results showed reduced structural connectivity of: i) the right superior parietal lobule (rSPL) with the right cuneus, superior occipital and posterior cingulate gyri ii) the pars orbitalis of the right middle frontal gyrus (rMFGOrb) with the putamen iii) the left middle temporal gyrus (lMTG) with the pars triangularis of the left inferior frontal gyrus. Increased connectivity was observed between the right paracentral lobule (rPLC) and the right caudate nucleus. By using a complementary method of investigation, we confirmed and extended previous results showing alterations in areas tuned to the processing of the sensorimotor representations of the affected leg (rPCL), and to higher-order components of bodily representation such as the body image (rSPL). Alongside this network for bodily awareness, other networks such as the limbic (rMFGOrb) and the mirror (lMTG) systems showed structural alterations as well. These findings consolidate current understanding of the neural correlates of BID, which might in turn guide diagnostics and rehabilitative treatments.


title: Interplay of ADHD polygenic liability with birth-related, somatic and psychosocial factors in ADHD - a nationwide study

abstract:
BackgroundADHD is multifactorial, yet the interplay ADHD polygenic risks scores (ADHD-PRS) and other ADHD associated risk-factors remains relatively unexplored. The aim of this study was to investigate associations, confounding and interactions of ADHD-PRS with birth, somatic and psychosocial risk-factors previously associated with ADHD.

MethodsParticipants came from the Danish iPSYCH2012 case-cohort, including a randomly selected general population sample (N=21,578), and all ADHD cases with an ICD-10 diagnosis F90.0 (N=13,697), born in Denmark 1981-2005. We derived ADHD-PRS and identified 25 ADHD risk-factors in Danish national registers. Logistic regression was used to estimate associations of ADHD-PRS with each risk-factors in the general population. Cox models were applied in the full case-cohort to evaluate confounding of risk-factor associations by ADHD-PRS and family psychiatry history, and interactions between ADHD-PRS and each risk-factor.

ResultsADHD-PRS was associated with 14 out of 25 ADHD risk-factors in the general population, e.g., maternal autoimmune disorder, mild traumatic brain injury (TBI), and most psychosocial risk-factors. In the full case-cohort, 21 risk-factors were associated with ADHD diagnosis. Adjusting for ADHD-PRS and parental psychiatric history only led to minor attenuations of these associations. Interactions were observed between ADHD-PRS and sex, maternal autoimmune disease, TBI, paternal employment and age at child-birth.

ConclusionHigher ADHD-PRS is associated with exposure to certain birth and somatic ADHD risk-factors, and broadly to psychosocial adversity. Evidence of gene-environment interactions were weak and ADHD-PRS and/or family psychiatric history have limited confounding effect on ADHD risk-factor associations, suggesting that majority of the investigated risk-factors act largely independently of ADHD-PRS to increase risk of ADHD.


title: Segregation of children into small groups for in-person learning during the COVID-19 pandemic

abstract: The COVID-19 pandemic affected in-person learning worldwide due to fears that schools could contribute to the propagation of the virus within their communities. Using computational modeling, we compare the reopening of schools with mitigation measures with a strategy in which schoolchildren are segregated into small isolated groups or "bubbles," where children physically interact without restrictions while receiving remote instruction from their teachers. This strategy is robust to common perturbations and is more flexible and stable than reopening of schools. Our modeling results and a real-world implementation of a bubbles program in an elementary school in Mexico City support that this strategy is an effective transition alternative, especially in communities with low vaccination rates or where operational costs associated to safely reopening schools cannot be afforded.

category: public and global health


title: Feasibility, Acceptability, and Effectiveness of Non-Pharmaceutical Interventions for Infectious Disease Prevention and Control in Crisis-Affected Settings and Informal Settlements: A Scoping Review

abstract:
IntroductionNon-pharmaceutical interventions (NPIs) are a crucial suite of measures to prevent and control infectious disease outbreaks. They are particularly important for crisis-affected populations that typically reside in settings characterised by overcrowding, inadequate access to healthcare and resource limitations. To describe the landscape of research and identify evidence gaps concerning the acceptability, feasibility, and effectiveness of NPIs among crisis-affected populations and informal settings, we conducted a systematic scoping review of the published evidence.

MethodsWe systematically reviewed peer-reviewed articles published between 1970 and 2020 to collate available evidence on the feasibility, acceptability, and effectiveness of NPIs in crisis-affected populations and informal settlements. We performed quality assessments of each study using a standardised questionnaire.

ResultsOur review included 158 studies published in 85 peer-reviewed articles. Most research used low quality study designs. The acceptability, feasibility, and effectiveness of NPIs was highly context dependent. In general, simple and cost-effective interventions such as community-level environmental cleaning and provision of water, sanitation and hygiene services, and distribution of items for personal protection such as insecticide-treated nets, were both highly feasible and acceptable. Logistical, financial, and human resource constraints affected both the implementation and sustainability of measures. Community engagement emerged as a strong factor contributing to the effectiveness of NPIs. Conversely, measures that involve potential restriction on personal liberty such as case isolation were found to be less acceptable to the community.

ConclusionOverall, the evidence base was patchy, with substantial knowledge gaps between differing between settings and pathogens. Although implementation of NPIs presents unique practical challenges, it is critical that the lessons learned are shared with the wider community to build a robust evidence base.

Summary boxO_ST_ABSWhat is already known?C_ST_ABS- NPIs are a crucial suite of tools for the prevention and control of infectious diseases, either as a complement to, or in the absence of, effective pharmaceutical interventions (i.e., therapeutics and vaccination).
- Despite being disproportionately vulnerable, crisis-affected populations and those living in informal settlements are often neglected by research and guidance. NPIs are, however, vital and adaptation is necessary within these settings due to poor living conditions and resource limitations that intensify disease transmission risk.

What are the new findings?- We conducted a scoping review to produce a landscape analysis of the existing evidence concerning NPIs within crisis-affected settings and informal settlements.
- The existing evidence is patchy, uneven, occasionally contradictory, and of generally low quality, but building over time.
- Although limited, some findings are generalisable across settings, populations and NPIs.

What do the new findings imply?- There is a need for greater investments in research to strengthen the guidance and policies on NPIs in these settings.
- In particular, upstream pilot feasibility and acceptability studies should be conducted prior to the widespread roll-out of interventions to ensure they are feasible, acceptable, and ultimately effective for the target populations.


title: Genetic Risk for Hemochromatosis is Associated with Movement Disorders

abstract: Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that can lead to iron overload, causing oxidative damage to affected organs. HH type 1 is predominantly associated with homozygosity for the mutation p.C282Y. Previous case studies have reported tentative links between HH and movement disorders, e.g., Parkinsons disease, and basal ganglia abnormalities on magnetic resonance imaging. We investigated the impact of p.C282Y homozygosity: on whole brain T2 intensity differences, a measure of iron deposition, and; on measures of movement abnormalities and disorders within UK Biobank. The neuroimaging analysis (154 p.C282Y homozygotes, 595 matched controls) showed that p.C282Y homozygosity was associated with decreased T2 signal intensity in motor circuits (basal ganglia, thalamus, red nucleus, and cerebellum; Cohens d > 1) consistent with substantial iron deposition. Across the whole UK Biobank (2,889 p.C282Y homozygotes, 496,968 controls), we found a significant enrichment for movement abnormalities in male homozygotes (OR (95% CI) = 1.82 (1.27-2.61), p=0.001), but not females (OR (95% CI) = 1.10 (0.69-1.78), p=0.71). Among the 31 p.C282Y homozygote males with a movement disorder only 7 had a concurrent HH diagnosis. These findings indicate susceptibility to iron overload in subcortical structures in p.C282Y homozygotes, and confirmed an increased risk of movement abnormalities and disorders in males. Given the effectiveness of early treatment in HH, screening for p.C282Y homozygosity in high risk individuals may offer a potential avenue to reduce iron accumulation in the brain and limit additional risk for the development of movement disorders among males.

category: neurology


title: Development and validation of a deep learning algorithm based on fundus photographs for estimating the CAIDE dementia risk score

abstract: The Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score is a recognized tool for dementia risk stratification. However, its application is limited due to the requirements for multidimensional information and fasting blood draw. Consequently, effective, convenient and noninvasive tool for screening individuals with high dementia risk in large population-based settings is urgently needed. A deep learning algorithm based on fundus photographs for estimating the CAIDE dementia risk score was developed and internally validated by a medical check-up dataset included 271,864 participants in 19 province-level administrative regions of China, and externally validated based on an independent dataset included 20,690 check-up participants in Beijing. The performance for identifying individuals with high dementia risk (CAIDE dementia risk score [≥]10 points) was evaluated by area under the receiver operating curve (AUC) with 95% confidence interval (CI). We found that the algorithm achieved an AUC of 0.944 (95% CI 0.939-0.950) in the internal validation group and 0.926 (95% CI, 0.913-0.939) in the external group, respectively. Besides, the estimated CAIDE dementia risk score derived from the algorithm was significantly associated with both comprehensive cognitive function and specific cognitive domains. In conclusion, this algorithm trained via fundus photographs could well identify individuals with high dementia risk in a population setting. Therefore, it has potential to be utilized as a noninvasive and more expedient method for dementia risk stratification. It might also be adopted in dementia clinical trials, incorporated as inclusion criteria to efficiently select eligible participants.


title: Medical laboratory waste generation rate, management practices, and associated factors in Addis Ababa, Ethiopia

abstract:
BackgroundBiomedical wastes (BMW) generated from medical laboratories are hazardous and can be deleterious to humans and the environment. Highly infectious types of biomedical wastes are commonly generated at an unacceptably high rate from health laboratories of developing countries with a poor management system like Ethiopia. This study was aimed to evaluate the generation rate of biomedical wastes, management practices and associated factors among public healthcare medical laboratories in Addis Ababa, Ethiopia.

Materials and methodsHealth institution based cross-sectional study was conducted from July 13 to September 25, 2020 in 6 hospital laboratories and 20 health center laboratories in Addis Ababa, Ethiopia.Data on socio-demographic characteristics, knowledge and practice of biomedical wast managment of the health facilities, Biomedical waste generation rate were collected using data collection tools. Data were managed using SPSS version 20 software. Descriptive statistcs,Pearson correlation, linear and logistic regression analysis were computed to identify indepedent predictors of the dependent variable. Odds ratio with 95% confidence interval was used to determine the strength of association.

ResultsThe finding revealed that the mean {+/-} SD of the daily generation rate of biomedical wastes was 4.9 {+/-} 3.13 kg/day per medical laboratory. Nineteen (74.3%) medical laboratories had a proper practice of biomedical waste management which is significantly associated with knowledge of professsionals on biomedical waste management policies and guidelines, availability of separate financial sources for biomedical waste management and training level of professionals.

ConclusionThe study showed high generation of biomedical waste from medical laboratories in public healthcare of Addis Ababa,Ethiopia. Near two-thirds of health facilities had a proper practice of waste segregation, collection, storage, and treatment of biomedical wastes generated from their laboratory. However, there was a poor practice of transportation and disposal. Hence, due attention and practicing as per the current national guidelines of biomedical waste management is recoomended.

category: occupational and environmental health


title: A Longitudinal Normative Dataset and Protocol for Speech and Language Biomarker Research

abstract: Although speech and language biomarker (SLB) research studies have shown methodological and clinical promise, some common limitations of these studies include small sample sizes, limited longitudinal data, and a lack of a standardized survey protocol. Here, we introduce the Voiceome Protocol and the corresponding Voiceome Dataset as standards which can be utilized and adapted by other SLB researchers. The Voiceome Protocol includes 12 types of voice tasks, along with health and demographic questions that have been shown to affect speech. The longitudinal Voiceome Dataset consisted of the Voiceome Protocol survey taken on (up to) four occasions, each separated by roughly three weeks (22.80 +/- 20.91 days). Of 6,650 total participants, 1,382 completed at least two Voiceome surveys. The results of the Voiceome Dataset are largely consistent with results from standard clinical literature, suggesting that the Voiceome Study is a high-fidelity, normative dataset and scalable protocol that can be used to advance SLB research.

category: health informatics


title: Federal Vaccine Policy and Interstate Variation in COVID-19 Vaccine Coverage in India

abstract:
IntroductionOn August 13, 2021, India completed 30 weeks of vaccination against COVID-19 for its eligible citizens. While the vaccination has made progress, there has been no study analyzing the federal/union vaccine policy and its effect on vaccination coverage across Indian states. In this context, this study analyses the federal vaccination policy and its effect on interstate variation in vaccine coverage and the correlation of state economy with vaccination coverage.

MethodsThe study analyses vaccine policy documents, secondary data on vaccination coverage and state gross domestic product (GDP) available in public domain. ANOVA test has been used to assess the effect of vaccine policy on interstate vaccine coverage and correlation-regression analysis has been conducted to assess the type and strength of association between gross state domestic product and vaccination coverage.

ResultsInterstate variation in vaccination coverage in the first 15 weeks was the least (F=3.5), when vaccine procurement and supply was entirely provided by the union/federal government and vaccination was limited to priority groups. However, with the extension of vaccine policy to other groups and reduction in federal government involvement in vaccine procurement, the interstate variation in vaccination coverage increased significantly (F=10.74) by the end of 30 weeks. The highest interstate variation was observed in the period between 23-30 weeks (F=25.31). State GDP was positively and strongly correlated with state vaccination coverage with a high coefficient of correlation (R=0.94) and high coefficient of determination (R2= 0.88).

ConclusionsThe study finds that federal procurement and supply of vaccination among prioritized groups has been the best strategy till date to address the inequity in vaccination coverage across the states of India.

category: health policy


title: Adaptive T cells regulate disease tolerance in human malaria

abstract: Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance in human malaria remains unknown. We developed a re-challenge model of falciparum malaria in which healthy naive adult volunteers were infected three times over a 12-month period to track the development of disease tolerance in real-time. We found that parasitaemia triggered a hardwired emergency myeloid response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, CD4+ T cell activation was quickly modified to reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence critical helper T cell functions but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage and injury. Host control of T cell activation can therefore be established after a single infection and in the absence of anti-parasite immunity. And furthermore, this rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and sequestration.


title: Symptoms and SARS-CoV-2 positivity in the general population in the UK

abstract:
BackgroundSeveral community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status.

MethodsUsing data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls.

ResultsFrom 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms ("symptomatic positive episodes"). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms ("symptomatic negative visit"). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7.

ConclusionsWhilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications.

SummaryWithin the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.


title: Dynamics of the Third wave, modelling COVID-19 pandemic with an outlook towards India

abstract: Since 2020, the COVID-19 pandemic has devastated human civilization throughout the earth. The pandemic is returning in different waves because of constant changes in the genetic components of the virus. Had we been able to predict the nature and timing of these waves earlier, numerous lives could, in essence, have been saved. It is evident that the situation has spiraled out of control in several countries for want of proper preventive measures. In this article, we described a comprehensive mathematical approach to understand the nature of the pandemic waves. Also, we determined the probable timing of the third wave that will help the concerned government(s) to take the necessary steps to better prepare for the unforeseen situation.


title: Avoiding bias in Mendelian randomization when stratifying on a collider

abstract:
BackgroundMendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effect of a risk factor on an outcome. A collider is a variable influenced by two or more other variables. Naive calculation of MR estimates in strata of the population defined by a variable affected by the risk factor can result in collider bias.

MethodsWe propose an approach that allows MR estimation in strata of the population while avoiding collider bias. This approach constructs a new variable, the residual collider, as the residual from regression of the collider on the genetic instrument, and then calculates causal estimates in strata defined by quantiles of the residual collider. Estimates stratified on the residual collider will typically have an equivalent interpretation to estimates stratified on the collider, but they are not subject to collider bias. We apply the approach in several simulation scenarios considering different characteristics of the collider variable and strengths of the instrument. We then apply the proposed approach to investigate the causal effect of smoking on bladder cancer in strata of the population defined by bodyweight.

ResultsThe new approach generated unbiased estimates in all the simulation settings. In the applied example, we observed a trend in the stratum-specific MR estimates at different bodyweight levels that suggested stronger effects of smoking on bladder cancer among individuals with lower bodyweight.

ConclusionsThe proposed approach can be used to perform MR studying heterogeneity among subgroups of the population while avoiding collider bias.


title: The IHME vs Me: Modeling USA CoVID-19 Spread, Early Data to the Fifth Wave

abstract: Epidemiologists have never had such high-quality real-time pandemic data. Modeling CoVID-19 pandemic data became a predictive tool in-stead of an afterwards analysis. How early CoVID-19 model predictions impacted US Government policies and practices is first reviewed here as an important part of the pandemic history. It spurred independent modeling efforts, such as this, to help develop a better understanding of CoVID-19 spread, and to provide a substitute for the IHME (Institute for Health Metrics & Evaluation, U. Washington) 4-month predictions for the expected pandemic evolution, which they had to revise every couple of weeks. Our alternative model, which was developed over the course of several earlier medrxiv.org preprints, is shown here to provide a good description for the entire USA CoVID-19 pandemic to date, covering: (1) the original CoVID-19 wave [3/21/20-6/07/20], (2) the Summer 2020 Resurgence [6/07/20-9/25/20], (3) the large Winter 2020 Resurgence [9/25/20-3/19/21], (4) a small Spring 2021 "Fourth Wave", [3/19/21-6/07/21], and (5) the present-day Summer 2021 "Fifth Wave" [6/07/21-present], which the USA is now in the midst of. Our analysis of the initial "Fifth Wave" data shows that this wave presently has the capacity to infect virtually all susceptible non-vaccinated persons who practice NO Mask-Wearing and minimal Social Distancing.


title: Closed Doors: Predictors of Stress, Anxiety, Depression, and PTSD During the Onset of COVID-19 Pandemic in Brazil

abstract:
BackgroundThe rise of mental health problems in the population directly or indirectly by the COVID-19 pandemic is a major concern. The aim of this study was to investigate and compare independent predictors of symptoms of stress, anxiety, depression, and post-traumatic stress disorder (PTSD) in Brazilians, one month after the implementation of measures of social distancing.

MethodsIt was a cross-sectional study, performed through a web-based survey. Depression, Anxiety, and Stress Scale (DASS-21) and PTSD Checklist for DSM-5 (PCL-5) were the outcomes. Data were gathered regarding demographics, social distancing, economic problems, exposure to the news of the pandemic, psychiatric history, sleep disturbances, traumatic situations, and substance use. The Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) was also included. Predictors of symptoms were investigated through hierarchical multiple linear regression.

ResultOf a sample of 3,587 participants, approximately two-thirds considered that their mental health worsened after the beginning of the social restriction measures. The most important predictors of the symptoms investigated were the intensity of the distress related to pandemic news, younger age, current psychiatric diagnosis, trouble sleeping, emotional abuse or violence, and economic problems.

LimitationsThe convenience sample assessed online may have limited external validity. It does not represent the northern regions of the country and most participants was white wealthier females.

ConclusionsThese results confirm the hypothesis that a pandemic would have important impacts on the mental health of the population and indicate the level of distress related to the media as an important predictor of psychological suffering.

HighlightsO_LIDistress triggered by news was the main predictor of psychological symptoms
C_LIO_LISleeping problems were strong indicators of mental health problems
C_LIO_LIPeople with ongoing psychiatric disorders are especially vulnerable
C_LIO_LIMeasures to prevent interpersonal trauma and financial loss are crucial
C_LIO_LIYoung people may experience great suffering at the onset of the pandemic
C_LI


title: COVID-19 related messaging, beliefs, information sources, and mitigation behaviors in Virginia: A cross-sectional survey in the summer of 2020

abstract: Conflicting messages and misinformation related to the coronavirus (COVID-19) pandemic (SARS-CoV-2) have hindered mitigation efforts. To gain insight and inform effective evidence-based public health messaging, we distributed an online cross-sectional survey from May to July, 2020. Among 3,488 respondents, systematic differences were observed in information sources that people trust, events that impacted beliefs and behaviors, and how behaviors changed by socio-demographics, political identity, and geography within Virginia. Characteristics significantly associated (p<0.05) with not wearing a mask in public included identifying as non-Hispanic white, men, Republican, younger age, lower income, not trusting national science and health organizations, believing a non-evidence-based messages, and Southwest Virginia in logistic regression. Similar, lesser in magnitude correlations, were observed for distancing in public. This study can assist decision makers and the public to improve and effectively target public health messaging related to the ongoing COVID-19 pandemic and future public health challenges in Virginia and similar jurisdictions.


title: Photoreceptor layer thinning is an early biomarker for age-related macular degeneration development: Epidemiological and genetic evidence from UK Biobank optical coherence tomography data

abstract:
IntroductionAge-related macular degeneration (AMD) is a blinding condition for which there is currently no early-stage clinical biomarker. AMD is characterized by thinning of the outer retina and drusen formation leading to thickening of the Bruchs membrane and RPE complex, but the timing between these two events, as well as the role of genetic variants in these processes, are unclear. Here, we jointly analyzed genomic, electronic health record, and optical coherence tomography (OCT) data across 44,823 individuals from the UK Biobank to characterize the epidemiological and genetic associations between retinal layer thicknesses and AMD.

MethodsThe Topcon Advanced Boundary Segmentation algorithm was used for automated retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model, and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we tested the association of AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age2, sex, smoking status, and principal components of ancestry.

ResultsPhotoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed and accelerated at age 45, while retinal pigment epithelium and Bruchs membrane complex (RPE+BM) thickening started after age 57. Each standard deviation (SD) of PS thinning and RPE+BM thickening were associated with prevalent AMD (PS: OR 1.37, 95% CI 1.25-1.49, P=2.5x10-12; RPE+BM: OR=1.34, 95% CI 1.27-1.41, P=8.4x10-28) and incident AMD (PS: HR 1.35, 95% CI 1.23-1.47, P=3.7x10-11; RPE+BM: HR 1.14, 95% CI 1.06-1.22, P=0.00024). An AMD polygenic risk score (PRS) was associated with PS thinning (Beta -0.21 SD per 2-fold genetically increased risk of AMD, 95% CI -0.23 to -0.19, P=2.8x10-74), and its association with RPE+BM was U-shaped (thinning with AMD PRS<92nd percentile and thickening with AMD PRS>92nd percentile suggestive of drusen formation). The loci with strongest support were AMD risk-raising variants CFH:rs570618-T, CFH:10922109-C, and ARMS2/HTRA1:rs3750846-C on PS thinning, and SYN3/TIMP3:rs5754227-T on RPE+BM thickening.

ConclusionsEpidemiologically, PS thinning precedes RPE+BM thickening by decades, and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage clinical biomarker for future AMD development.

category: ophthalmology


title: Ambulatory Duchenne Muscular Dystrophy Children: Cross-sectional Correlation between Function, Quantitative Muscle Ultrasound and MRI

abstract:
Introduction/AimsDuchenne muscular dystrophy (DMD) is a progressive genetic muscle disease. Quantitative muscle ultrasound (MUS), muscle MRI, and functional tools are important to delineate characteristics of muscle involvement. We aimed to establish correlations between clinical/functional and above-named imaging tools respecting their diagnostic and prognostic role in DMD children.

MethodsA Prognostic cross-sectional retrospective study of 27 steroid-naive, ambulant male children/adolescents with genetically-confirmed DMD (mean age, 8.8 {+/-} 3.3 years). Functional performance was assessed using motor function measure (MFM) which assess standing/transfer (D1), proximal (D2) and distal (D3) motor function. And six-minute-walk test (6MWT). Imaging evaluation included quantitative muscle MRI which measured muscle fat content in a specific location of right rectus femoris by mDixon sequence. Quantitative MUS measured muscle brightness in standardized US image as an indicator of muscle fat content.

ResultsWe found a highly significant positive correlation between the mean MFM total score and 6MWT (R=0.537, P=0.007). And a highly significant negative correlation between fat content by MUS and MFM total score (R=-0.603, P=0.006) and its D1 subscore (R=-0.712, P=0.001). And a significant negative correlation between fat content by US and 6MWT (R=-0.529, P=0.02). And a significant positive correlation between muscle fat content by mDixon MRI and patients age (R=0.617, P=0.01).

DiscussionQuantitative MUS correlates significantly with clinical/functional assessment tools as MFM and 6MWT, and augments their role in disease-tracking of DMD. Quantitative MUS has the potential to act as a substitute to functional assessment tools. The role for quantitative muscle MRI in disease-tracking should be further explored after elimination of confounding factors.

Graphical abstractDivergent arrows represent negative correlations, while convergent the arrow represents a positive correlation.

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title: Evolutionary dynamics of a virus in a vaccinated population

abstract: The progress of an epidemic in a small closed community is simulated by an agent-based model which allows vaccination and variation. The attributes of the virus are governed by two genetic loci: the P-locus, which determines growth, and the M-locus, which determines immune characteristics. Mutation at either locus modifies the attributes of the virus and leads to evolution through natural selection. For both loci the crucial variable is the potential mutation supply UPot, because evolution is likely to happen when UPot > 1. Mutation at the P-locus causes a limited increase in virulence, which may be affected by vaccine design. Mutation at the M-locus may cause a qualitative shift of dynamic regime from a simple limited epidemic to a perennial endemic disease by giving rise to escape mutants which may themselves mutate. A broad vaccine that remains efficacious despite several mutations at the M-locus prevents this shift and provides protection despite the evolution of the virus. Escape variants may nevertheless arise through recombination after coinfection, and can be suppressed by timely revaccination, using the prevalent strain to design the vaccine.


title: Cognitive Training and Transcranial Direct Current Stimulation in Older Persons with HIV-associated Neurocognitive Disorder

abstract:
ObjectiveHIV infection is associated with impaired cognition, and as individuals grow older, they may also experience age-related changes in mental abilities. Previous studies have shown that computer-based cognitive training (CCT) and transcranial direct current stimulation (tDCS) may be useful in improving cognition in older persons. This study evaluated the acceptability of CCT and tDCS to older adults with HIV-associated neurocognitive disorder, and assessed their impact on reaction time, attention, and psychomotor speed.

MethodsIn a single-blind randomized study, 46 individuals with HIV-associated mild neurocognitive disorder completed neuropsychological assessments and six 20-minute training sessions to which they had been randomly assigned to one of the following conditions: (1) CCT with active tDCS; (2) CCT with sham tDCS, or (3) watching educational videos with sham tDCS. Immediately after training and again one month later, participants completed follow-up assessments. Outcomes were evaluated via repeated measures mixed effects models.

ResultsParticipant ratings of the intervention were positive. Effects on reaction time were not significant, but measures of attention and psychomotor speed suggested positive effects of the intervention.

ConclusionBoth CCT and tDCS were highly acceptable to older persons with HIV infection. CCT and tDCS may improve cognitive in affected individuals.

Registered at ClinicalTrials.gov (NCT03440840).


title: All-cause excess mortality in the State of Gujarat, India, during the COVID-19 pandemic (March 2020-April 2021)

abstract: Official COVID-19 mortality statistics are strongly influenced by local diagnostic capacity, strength of the healthcare and vital registration systems, and death certification criteria and capacity, often resulting in significant undercounting of COVID-19 attributable deaths. Excess mortality, which is defined as the increase in observed death counts compared to a baseline expectation, provides an alternate measure of the mortality shock - both direct and indirect - of the COVID-19 pandemic. Here, we use data from civil death registers from a convenience sample of 90 municipalities across the state of Gujarat, India, to estimate the impact of the COVID-19 pandemic on all-cause mortality. Using a model fit to weekly data from January 2019 to February 2020, we estimated excess mortality over the course of the pandemic from March 2020 to April 2021. We estimated 21,300 [95% CI: 20,700, 22,000] excess deaths across these municipalities in this period, representing a 44% [95% CI: 43%, 45%] increase over the expected baseline. The sharpest increase in deaths in our sample was observed in late April 2021, with an estimated 678% [95% CI: 649%, 707%] increase in mortality from expected counts. The 40 to 65 age group experienced the highest increase in mortality relative to the other age groups. We found substantial, yet similar, increases in mortality for males and females. Our excess mortality estimate for these 90 municipalities, representing approximately 5% of the states population, exceeds the official COVID-19 death count for the entire state of Gujarat, even before the delta wave of the pandemic in India peaked in May 2021. Prior studies have concluded that true pandemic-related mortality in India greatly exceeds official counts. This study, using data directly from the first point of official death registration data recording, provides incontrovertible evidence of the high excess mortality in Gujarat from March 2020 to April 2021.


title: Cost-effectiveness of internet-delivered cognitive behaviour therapy for body dysmorphic disorder: results from a randomised controlled trial

abstract:
ObjectivesTo evaluate the cost-effectiveness of internet-delivered cognitive behaviour therapy for body dysmorphic disorder (BDD-NET).

DesignSecondary cost-effectiveness analysis from a randomised controlled trial on BDD-NET versus online supportive psychotherapy.

SettingAcademic medical centre.

ParticipantsSelf-referred adult patients with a primary diagnosis of body dysmorphic disorder and a score of 20 or higher on the modified Yale-Brown obsessive compulsive scale (n = 94). Patients receiving concurrent psychotropic drug treatment were included if the dose had been stable for at least two months and remained unchanged during the trial.

InterventionsParticipants received either BDD-NET (n = 47) or online supportive psychotherapy (n = 47) for 12 weeks.

Primary and secondary outcome measuresThe primary outcome measures were cost-effectiveness and cost-utility from a societal perspective, using remission status from a diagnostic interview and quality-adjusted life years from EQ-5D, respectively. Secondary outcome measures were cost-effectiveness and cost-utility from a health care perspective and the clinics perspective.

ResultsCompared to supportive psychotherapy, BDD-NET produced one additional remission for an average societal cost of $4132. The cost-utility analysis showed that BDD-NET generated one additional QALY to an average cost of $14319 from a societal perspective.

ConclusionsBDD-NET is a cost-effective treatment for body dysmorphic disorder, compared to online supportive psychotherapy. The efficacy and cost-effectiveness of BDD-NET should be directly compared to face-to-face cognitive behaviour therapy.

Trial registrationNCT02010619

Strengths and limitations of this studyO_LIThis is the first cost-effectiveness evaluation of a novel internet-delivered treatment designed to increase access to cognitive behaviour therapy for patients with body dysmorphic disorder
C_LIO_LICost estimations were self-rated and might not capture all costs associated with treatment
C_LIO_LIThe self-referred participants were likely motivated to undergo treatment.
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title: A Lagrangian Approach Towards Quantitative Analysis Of Flow-mediated Infection Transmission In Indoor Spaces With Application To SARS-COV-2

abstract: The ongoing SARS-CoV-2 (Covid-19) pandemic has ushered an unforeseen level of global health and economic burden. As a respiratory infection, Covid-19 is known to have a dominant airborne transmission modality, wherein fluid flow plays a central role. Quantification of complex non-intuitive dynamics and transport of pathogen laden respiratory particles in indoor flows has been of specific interest. Here we present a Lagrangian computational approach towards quantification of human-to-human exposure quantifiers, and identification of pathways by which flow organizes transmission. We develop a Lagrangian viral exposure index in a parametric form, accounting for key parameters such as building and layout, ventilation, occupancy, biological variables. We also employ a Lagrangian computation of the Finite Time Lyapunov Exponent field to identify hidden patterns of transport. A systematic parametric study comprising a set of 120 simulations, yielding a total of 1,320 different exposure index computations are presented. Results from these simulations enable: (a) understanding the otherwise hidden ways in which air flow organizes the long-range transport of such particles; and (b) translating the micro-particle transport data into a quantifier for understanding infection exposure risks.


title: Evaluating Diuretics in Normal Care (EVIDENCE): A feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension

abstract:
BackgroundObtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence.

In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK.

MethodsPatients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating General Practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the Practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt-out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalization and death data in the NHS will be used to compare cardiovascular event rates between the two policies.

ResultsThis pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients), and 15 to bendroflumethiazide (3437 patients); a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch.

ConclusionThe pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study, currently 102 GP practices (>12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach, has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas.

Trial registration numberISRCTN 46635087; registered pre-results, 11/08/2017.

SummaryWe report on a Chief Scientist Office for Scotland-funded pilot of the feasibility of the (Evaluating Diuretics in Usual Care) EVIDENCE study. This report will describe:

O_LIRecruitment and policy randomisation of 30 GP practices across 5 NHS health board regions in Scotland.
C_LIO_LIAcceptability of study implementation information provided to primary healthcare practitioners and patients.
C_LIO_LIRecruitment rates, staffing, training, and funding requirement estimations to inform the full-sized project.
C_LIO_LIHow knowledge and practical experience gained has informed scaling of activities to realise a fully powered EVIDENCE study, including 250 practices.
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Key messages regarding feasibilityO_LIWhat uncertainties existed regarding the feasibility?
For widely prescribed medicines with similar mode of action and similar indications differences in effectiveness are likely to be quite small indicating the need for very large study sizes. Previous work has demonstrated that practices would be reluctant to take part in this kind of study if it involved any extra work within already limited practice capacity. Would NHS Primary Care leads be willing to endorse the study taking place in their region? In addition, the large size and geographically distributed nature of this study meant devising solutions for work to take place remotely or using pre-existing regional staff needed to be devised. There was also uncertainty about the overall acceptability for patients in having their medication changed for research purposes.
C_LIO_LIWhat are the key feasibility findings?
The experience from the pilot and subsequent successful expanded recruitment shows that the solutions we developed seemed to be acceptable and achievable both for general practice staff and the patients they care for. Obtaining endorsement from key stakeholders in NHS health boards improved recruitment success with the practices and sustained support for the study. Negotiations with pharmacy regional leads around workforce implications enabled us to approach practices with a range of solutions for study implementation. It was found that offering training for the EVIDENCE study along with general clinical trials training for regional Pharmacists was key to recruitment of pharmacy delegates on a large scale. We were able to develop the IT infrastructure around the study to allow remote delivery of both training and implementation providing a framework that could be delivered during the covid-19 pandemic. We found that concerns from patients constituted a very small minority indeed indicating overwhelming tacit support for the objectives of the study
C_LIO_LIWhat are the implications of the feasibility findings for the design of the main study?
The initial engagement with a range of healthcare providers offered support for the study in areas that may otherwise have become a potential barrier to success. We will use this approach in the main study. Many of the practical skills required to undertake the EVIDENCE study were also useful skills for pharmacy teams in their everyday practice so acceptance of the study training and implementation was higher. We will continue to progress the study using this methodology as this provided beneficial professional development for pharmacy staff and a platform for a future research ready workforce. Demonstrating the success of this approach we have currently recruited over 100 practices and have 29 pharmacy delegates across Scotland outside the core study team. This indicates that recruiting the target of 250 practices (approximately 50,000 individuals is entirely feasible.
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category: primary care research


title: HLA Class I and Plasma Viral Load of HIV-1 in Sexually Transmitted and Reproductive Tract Infections among Heterosexual Serodiscordant couples in Nigeria

abstract:
BackgroundThis study investigated HLA Class I in Long Term Non-progressors (LTNPs) and plasma viral load in Sexually Transmitted and Reproductive Tract Infections (STIs/RTIs) associated with Heterosexual HIV-1 transmission among serodiscordant couples in Nigeria.

MethodsA total of 271 serodiscordant and concordant couples (HIV positive and negative) were enrolled, blood samples were collected from the subjects by venipuncture. HLA class I (with specific primers), plasma viral load, CD4+ analysis was done. Endocervical/urethral swabs and early morning urine samples were collected by standard microbiological methods. These were screened by microscopy, culture, antibiogram, and biochemical tests with a view to identify aetiologic agents of co-infections with HIV.

ResultsThe Participants age ranged from [≥] 21- < 50years. The index whose plasma viral loads were 10,001-100,000 copies/ml had STIs/RTIs 32(60.9% p=0.059). Staphylococcus aureus and Escherichia coli (22.1%) were isolated from the index (HIV positive subject) while 14.5% of Staphylococcus aureus and 27.2% of E coli were isolated from their partners (HIV negative subject). Staphylococcus aureus and E coli are normal flora but because the patients are Immunocompromised as a result of positivity to HIV, Staphylococcus aureus and E. coli in this context becomes opportunistic thereby, causing genital tract infections. Staphylococcus from the index showed more sensitivity to Amoxicillin/clavulanate (95.4%/90.4%) compared to the partners (55.1%/73.5%) and more resistant to Ceftazidime (81.4%) compared to the partners (68.9%). LTNPs were 28(8.51%) among the index. HLA-B alleles: B*5701 (9.2%), B*5703 (4.6%) and B*5801(12.5%) were identified for viral control at late stage of HIV infection while A*1 (4.6%), and C*0701 (29.1%) were protective alleles observed. HLA-B*0702 (33.3%), B*4201/A*2301(4.6%) respectively were susceptible alleles associated with seroconversion among LTNPs.

ConclusionThe microorganisms isolated from the index were associated with high viral loads and are independent makers to HIV-1 transmission among serodiscordant couples. Individuals associated with HLA class I alleles identified among LTNPs were those significantly associated with resistance and susceptible to HIV-1 infections.


title: Temporal Increase in Neutralization Potency of SARS-CoV-2 Antibodies and Reduced Viral Variant Escape after Sputnik V Vaccination

abstract: Recent studies have shown a temporal increase in the neutralizing antibody potency and breadth to SARS-CoV-2 variants in coronavirus disease 2019 (COVID-19) convalescent individuals. Here, we examined longitudinal antibody responses and viral neutralizing capacity to the B.1 lineage virus (Wuhan related), to variants of concern (VOCs: Alpha, Beta, Gamma, and Delta) and a local variant of interest (VOI: Lambda) in volunteers receiving the Sputnik V vaccine in Argentina. A collection of 472 serum samples obtained between January and September 2021 was used. The analysis indicates that while anti-spike IgG levels significantly wane over time, the neutralizing capacity to the first-wave linages of SARS-CoV-2 and VOC are maintained within four months of vaccination. In addition, an improved antibody cross-neutralizing ability to circulating variants of concern (Beta, Gamma and Delta) was observed over time of vaccination. The viral variants that displayed higher escape to neutralizing antibodies with respect to the original virus (Beta and Gamma variants) were the ones showing the largest increase in susceptibility to neutralization over time after vaccination. Our observations indicate that serum neutralizing antibodies are maintained for at least four month and show a reduction of VOC escape over time of vaccination.


title: Longitudinal Study after Sputnik V Vaccination Shows Durable SARS-CoV-2 Neutralizing Antibodies and Reduced Viral Variant Escape over Time


title: Longitudinal Associations between Hair Cortisol, PTSD Symptoms, and Sleep Disturbances in a Sample of Firefighters with Duty-related Trauma Exposure

abstract: Several studies have found evidence of altered cortisol levels in patients with posttraumatic stress disorder (PTSD). Based on these findings, it is assumed that these patients may show signs of cortisol dysregulation after trauma. Posttrauma cortisol levels are thus considered a potential biomarker of PTSD. However, longitudinal studies using indicators of long-term cortisol secretion (such as hair cortisol concentrations; HCC) are scarce. The current study investigated prospective associations between HCC and PTSD symptoms in a sample of Dutch firefighters taking into account varying levels of work-related trauma severity. In addition, we assessed posttraumatic sleep disturbances as a secondary outcome measure to investigate whether effects generalize to this frequent comorbidity of PTSD. Three hundred seventy-one Dutch firefighters with a mean of 14.01 years of work experience were included in the analyses. Baseline assessment included the collection of hair samples and the measurement of work-related trauma severity, PTSD symptoms, and sleep disturbances. PTSD symptoms and sleep disturbance were re-assessed after six and twelve months. Multilevel analyses indicate a significant positive correlation between HCC and baseline PTSD symptoms in those with average or above-average work-related trauma severity. A similar pattern was evident for posttraumatic sleep disturbances at baseline. Moreover, higher HCC predicted more posttraumatic sleep disturbances after 6 months in participants with above-average work-related trauma severity. No other associations emerged for PTSD symptoms or posttraumatic sleep disturbances at six or twelve months. As such, our study supports the existence of a cross-sectional association between HCC and trauma symptoms, which may vary for different levels of subjective trauma severity. The longitudinal stability of this association should be reinvestigated by future research.


title: Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

abstract: The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = -4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.

category: genetic and genomic medicine


title: Evidence of a causal relationship between genetic tendency to gain muscle mass and uterine leiomyomata

abstract: Uterine leiomyomata (UL) are the most common benign tumours of the female genital tract with an estimated lifetime incidence of up to 70%1. To date, 7 genome-wide association studies (GWASs) have identified 35 loci predisposing to UL. To improve the understanding of the underlying genetic pathways, we conducted the largest genetic association study of UL to date in 426,558 European women from FinnGen and a previously published UL meta-GWAS2. We identified 36 novel and replicated 31 previously reported loci. Annotations of the potential candidate genes suggest involvement of smooth muscle cell (SMC) differentiation and/or proliferation-regulating genes in modulating UL risk. Our results further advocate that genetic predisposition to increased fat-free mass may be causally related to UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings provide novel insights into genetic risk factors related to UL, which may aid in developing novel treatment strategies.


title: Distance from home to motor vehicle crash location: Implications for license restrictions among medically-at-risk older drivers

abstract:
Background/ObjectivesThirty states allow licensing agencies to restrict the distance from home that "medically-at-risk" drivers are permitted to drive. However, there is little information on where older drivers crash relative to their home or how distance to crash varies by medical condition, and thus, what impact distance limits may have on motor vehicle crash rates for "medically-at-risk" drivers.

DesignObservational study of crash-involved drivers.

SettingMedicare fee-for-service claims linked to geocoded crash locations and residential addresses from police crash reports in the state of New Jersey from 2007 through 2017.

ParticipantsNew Jersey Medicare fee-for-service beneficiaries aged 68 years and older involved in police-reported crashes.

MeasurementsThe outcome was Euclidian distance from home to crash location. Covariates included driving-relevant medical conditions from Medicare claims, crash characteristics from police reports, and demographics from both sources.

ResultsThere were 197,122 crash-involved older drivers for whom approximately 70% of crashes occurred within 5 miles and 95% within 25 miles of the drivers residence. The mean distance to crash was 6.0 miles. Although distance from home to the crash was generally lower among drivers with (versus without) each of the medical conditions studied, the differences were small (maximum mean difference of 2.1 miles). The largest difference in distance was by licensure status, where unlicensed/suspended drivers crashed significantly farther from home than validly licensed drivers (8.8 miles, 95% Confidence Interval [CI]: 8.4-9.1 vs 5.9 miles, 95% CI: 5.9 - 6.0).

ConclusionsFindings suggest that the majority of older adults who crash do so within a few miles from home and that the distance to crash does not differ substantially by the presence of a driving-relevant medical condition. Thus, distance restrictions may not reduce crash rates among older adults and the tradeoff between safety and mobility warrants consideration.

KEYPOINTSO_LI30 states permit restriction of driving distance for medically-at-risk drivers
C_LIO_LIThe vast majority of crashes involving older drivers occur [≤] 25 miles of home
C_LIO_LIDistance to crash does not differ markedly across driving-relevant medical conditions
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Why does this matter?O_LIDistance restrictions are likely to impact mobility and autonomy but not crash rates
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category: geriatric medicine