title: Altered immunity to microbiota, B cell activation and depleted γδ / resident memory T cells in colorectal cancer

abstract: We sought methods of rectifying microbiota:immune dysregulation as a route to prophylaxis and improved immunotherapy of colorectal cancer (CRC). CRC develops in gut epithelium, accompanied by low level inflammatory signaling, intestinal microbial dysbiosis and immune dysfunction. We examined populations of intraepithelial lymphocytes in non-affected colonic mucosa of CRC and healthy donors and circulating immune memory to commensal bacterial species and yeasts. Colonic tissue in CRC was significantly depleted of {gamma}{delta} T cells and resident memory T cells, populations with a regulatory CD39-expressing phenotype. T cell memory responses to a panel of commensals were distinct in CRC, while B cell memory responses to several bacteria/yeast were significantly increased, accompanied by increased proportions of effector memory B cells, transitional B cells and plasmablasts in blood. IgA responses to mucosal microbes were unchanged. Our data describe a novel immune signature with similarities to and differences from that of inflammatory bowel disease. They implicate B cell dysregulation as a potential contributor to parainflammation and identify pathways of weakened barrier function and tumor surveillance in CRC-susceptible individuals.

category: gastroenterology


title: A comparison of performance metrics for cloth face masks as source control devices for simulated cough and exhalation aerosols

abstract: Universal mask wearing is recommended by the Centers for Disease Control and Prevention to help control the spread of COVID-19. Masks reduce the expulsion of respiratory aerosols (called source control) and offer some protection to the wearer. However, masks vary greatly in their designs and construction materials, and it is not clear which are most effective. Our study tested 15 reusable cloth masks (which included face masks, neck gaiters, and bandanas), two medical masks, and two N95 filtering facepiece respirators as source control devices for aerosols [≤] 7 {micro}m produced during simulated coughing and exhalation. These measurements were compared with the mask filtration efficiencies, airflow resistances, and fit factors. The source control collection efficiencies for the cloth masks ranged from 17% to 71% for coughing and 35% to 66% for exhalation. The filtration efficiencies of the cloth masks ranged from 1.4% to 98%, while the fit factors were 1.3 to 7.4 on an elastomeric manikin headform and 1.0 to 4.0 on human test subjects. The correlation coefficients between the source control efficacies and the other performance metrics ranged from 0.31 to 0.66 and were significant in all but one case. However, none of the alternative metrics were strong predictors of the source control performance of cloth masks. Our results suggest that a better understanding of the relationships between source control performance and metrics like filtration efficiency, airflow resistance, and fit factor are needed to develop simple methods to estimate the effectiveness of masks as source control devices for respiratory aerosols.

category: public and global health


title: Evaluating social and spatial inequalities of large scale rapid lateral flow SARS-CoV-2 antigen testing in COVID-19 management: An observational study of Liverpool, UK (November 2020 to January 2021)

abstract:
ObjectiveTo explore social and spatial inequalities in uptake and case-detection of rapid lateral flow SARS-CoV-2 antigen tests (LFTs) offered to people without symptoms of COVID-19.

DesignObservational study.

SettingLiverpool, UK.

Participants496 784 residents.

InterventionFree LFTs to all people living and working in Liverpool (6th November 2020 to 31st January 2021).

Main outcome measuresResidents who received a LFT, residents who had multiple LFTs, and positive test results.

Results214 525 residents (43%) received a LFT identifying 5557 individuals as positive cases of COVID-19 (1.3%) between 6th November 2020 and 31st January 2021. 89 047 residents had more than one test (18%). Uptake was highest in November when there was military assistance. High uptake was observed again in the week preceding Christmas and was sustained into a national lockdown. Overall uptake and repeat testing were lower among males (e.g. 40% uptake over the whole period), Black Asian and other Minority Ethnic groups (e.g. 27% uptake for  Mixed ethnicity) and in the most deprived areas (e.g. 32% uptake in most deprived areas). These population groups were also more likely to have received positive tests for COVID-19. Spatial regression models demonstrated that uptake and repeat testing were lower in areas of higher deprivation, areas located further from test sites and areas containing populations less confident in the using Internet technologies. Positive tests were spatially clustered in deprived areas.

ConclusionsLarge-scale voluntary asymptomatic community testing saw social, ethnic, and spatial inequalities in an  inverse care pattern, but with an added digital exclusion factor. COVID-19 testing and support to isolate need to be more accessible to the vulnerable communities most impacted by the pandemic, including non-digital means of access.

What is already known on this topicO_LITesting asymptomatic individuals with rapid lateral flow SARS-CoV-2 antigen devices detects the most infectious individuals who otherwise would have been unaware they were likely to infect others.
C_LIO_LILiverpool (UK) conducted the worlds first whole population, open-access, voluntary asymptomatic testing programme for COVID-19 management.
C_LIO_LIThe impacts of such testing on inequalities are unknown.
C_LI

What this study addsO_LITesting uptake was lower, and test positivity was higher, among deprived populations, Black Asian and other Minority Ethnic groups and areas classified as having low Internet use.
C_LIO_LIPopulation-wide asymptomatic testing programmes need to account for social, spatial, and digital access issues in their design, communication and delivery to minimise inequalities in outcomes.
C_LI


title: Longitudinal changes in brain diffusion MRI indices during and after proton beam therapy in a child with pilocytic astrocytoma: a case report

abstract:
BackgroundProton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied Diffusion-Tensor-Imaging (DTI) and Free-Water-Imaging (FWI) on diffusion-weighted Magnetic Resonance Imaging (dMRI) data to monitor microstructural changes during-PBT and after 8 months, in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM).

MethodsWe evaluated conventional MRI and dMRI-derived indices from six MRI sessions in a child with a hypothalamic PA: at baseline (t0), during-PBT (t1-t4), and after 8 months (t5). Tumor voxels were classified as "solid" or "fluid" based on FWI.

ResultsWhile during PBT tumor volume remained stable, dMRI analyses identified two different response patterns: i) an increase in fluid content and diffusivity with anisotropy reductions in solid voxels at t1, followed by ii) smaller variations in fluid content but higher anisotropy in solid voxels at t2-t4. At follow-up (t5), tumor volume, its fluid content, and diffusivity in solid voxels increased. NAWM showed dose-dependent microstructural changes.

ConclusionsThe use of dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumor and surrounding tissues.

category: radiology and imaging


title: CREBRF missense variant rs373863828 has both direct and indirect effects on type 2 diabetes and fasting glucose in Polynesians living in Samoa and Aotearoa New Zealand.

abstract:
ObjectiveThe minor allele of rs373863828 in CREBRF is associated with higher BMI, lower fasting glucose, and lower odds of type 2 diabetes. We examined the associations between BMI and rs373863828 on type 2 diabetes and fasting glucose with a large sample of adult Polynesians from Samoa, American Samoa and Aotearoa New Zealand and estimated direct and indirect (via BMI) effects of rs373863828 on type 2 diabetes and fasting glucose.

Research Design and MethodsWe regressed type 2 diabetes and fasting glucose on BMI and rs373863828 stratified by obesity, regressed type 2 diabetes and fasting glucose on BMI stratified by rs373863828 genotype, and assessed the effects of rs373863828 on type 2 diabetes and fasting glucose with path analysis.

ResultsAssociation of BMI with fasting glucose was greater in those without obesity than in those with obesity. We did not observe evidence of differences by genotype. In the path analysis, the minor allele has direct negative and indirect positive effects on type 2 diabetes risk and fasting glucose, with the indirect effect mediated through a direct positive effect on BMI.

ConclusionsThere may be a stronger effect of BMI on fasting glucose in Polynesians without obesity than in those with obesity. Carrying the rs373863828 minor allele does not decouple higher BMI from odds of type 2 diabetes. Given the current cost of genotyping compared to the accessibility of measuring BMI, including rs373863828 as a clinical predictor of type 2 diabetes may not be indicated.

category: genetic and genomic medicine


title: Protective lipid-lowering genetic variants in healthy older individuals without coronary heart disease

abstract:
BackgroundDisruptive genetic variants in the PCSK9 and APOB genes result in lower serum low-density lipoprotein cholesterol (LDL-C) levels and confer protection against coronary heart disease (CHD). Few studies have measured the prevalence and selective advantage of such variants among healthy older individuals without prior CHD events.

Methods and ResultsWe performed targeted sequencing of the PCSK9 and APOB genes in 13,131 healthy older individuals without CHD aged 70 years or older enrolled into the ASPirin in Reducing Events in the Elderly (ASPREE) trial. We detected predicted loss-of-function (pLoF) variants in the PCSK9 and APOB genes, and associated variant carrier status with blood lipid levels. We detected 22 different rare PCSK9/APOB candidate variants with lipid-lowering effect, carried by 104 participants (carrier rate 1 in 126). Rare variant carrier status was associated with 19.4 mg/dl (14.6%) lower LDL-C, compared with non-carriers (P=<0.001, adjusted for statin use). Statin prescriptions were less prevalent in rare variant carriers (16%) than non-carriers (35%). The PCSK9 R46L variant (rs11591147-T) was associated with 15.5mg/dl (11.8%) lower LDL-C in heterozygotes, and 25.2 mg/dl (19.2%) lower LDL-C in homozygotes, respectively (both P=<0.001).

ConclusionsLipid-lowering genetic variants are carried by healthy older individuals and contribute to CHD-free survival.


title: Predictive Modeling of COVID-19 Case Growth Highlights Evolving Demographic Risk Factors in Tennessee and Georgia

abstract:
The COVID-19 pandemic has exposed the need to understand the unique risk drivers that contribute to uneven morbidity and mortality in US communities. Addressing the community-specific social determinants of health that correlate with spread of SARS-CoV-2 provides an opportunity for targeted public health intervention to promote greater resilience to viral respiratory infections in the future.

Our work combined publicly available COVID-19 statistics with county-level social determinants of health information. Machine learning models were trained to predict COVID-19 case growth and understand the unique social, physical and environmental risk factors associated with higher rates of SARS-CoV-2 infection in Tennessee and Georgia counties. Model accuracy was assessed comparing predicted case counts to actual positive case counts in each county. The predictive models achieved a mean r-squared (R2) of 0.998 in both states with accuracy above 90% for all time points examined. Using these models, we tracked the social determinants of health, with a specific focus on demographics, that were strongly associated with COVID-19 case growth in Tennessee and Georgia counties. The demographic results point to dynamic racial trends in both states over time and varying, localized patterns of risk among counties within the same state.

Identifying the specific risk factors tied to COVID-19 case growth can assist public health officials and policymakers target regional interventions to mitigate the burden of future outbreaks and minimize long-term consequences including emergence or exacerbation of chronic diseases that are a direct consequence of infection.

category: health informatics


title: SARS-CoV-2 seropositivity after infection and antibody response to mRNA-based vaccination

abstract: The effect of SARS-CoV-2 seropositivity on the immune response to mRNA-based SARS-CoV-2 vaccines has not been well-described. Here we report longitudinal SARS-CoV-2-specific antibody responses pre- and post-vaccination among a cohort of healthcare personnel, with and without prior infection, from a large academic medical center. Our results provide preliminary evidence that prior SARS-CoV-2 infection may prime the response to the first mRNA-based SARS-CoV-2 vaccine dose. These findings could have significant impact on the allocation of mRNA-based vaccines and support the need for future research into the effect of prior infection on magnitude and durability of vaccination response.

category: infectious diseases


title: Healthcare-associated COVID-19 in England: a national data linkage study

abstract:
ObjectivesNosocomial transmission was an important aspect of SARS-CoV-1 and MERS-CoV outbreaks. Healthcare-associated SARS-CoV-2 infection has been reported in single and multi-site hospital-based studies in England, but not nationally.

MethodsAdmission records for all hospitals in England were linked to SARS-CoV-2 national test data for the period 01/03/2020 to 31/08/2020. Case definitions were: community-onset community-acquired (CO.CA), first positive test (FPT) <14 days pre-admission, up to day 2 of admission; hospital-onset indeterminate healthcare-associated (HO.iHA), FPT on day 3-7; hospital-onset probable healthcare-associated (HO.pHA), FPT on day 8-14; hospital-onset definite healthcare-associated (HO.HA), FPT from day 15 of admission until discharge; community-onset possible healthcare-associated (CO.pHA), FPT [≤]14 days post-discharge.

ResultsOne-third (34.4%, 100,859/293,204) of all laboratory-confirmed COVID-19 cases were linked to a hospital record. HO.pHA and HO.HA cases represented 5.3% (15,564/293,204) of all laboratory-confirmed cases and 15.4% (15,564/100,859) of laboratory-confirmed cases among hospital patients. CO.CA and CO.pHA cases represented 86.5% (253,582/293,204) and 5.1% (14,913/293,204) of all laboratory-confirmed cases, respectively.

ConclusionsUp to 1 in 6 SARS-CoV-2 infections among hospitalised patients with COVID-19 in England during the first 6 months of the pandemic could be attributed to nosocomial transmission, but these represent less than 1% of the estimated 3 million COVID-19 cases in this period.


title: An exploratory study on the correlation of population SARS-CoV-2 cycle threshold values to local disease dynamics

abstract:
IntroductionDespite limitations on the use of cycle threshold (CT) values for individual patient care, population distributions of CT values may be useful indicators of local outbreaks.

MethodsSpecimens from the greater El Paso area were processed in the Dascena COVID-19 Laboratory. Daily median CT value, daily transmission rate R(t), daily count of COVID-19 hospitalizations, daily change in percent positivity, and rolling averages of these features were plotted over time. Two-way scatterplots and linear regression evaluated possible associations between daily median CT and outbreak measures. Cross-correlation plots determined whether a time delay existed between changes in the daily median CT value and measure of community disease dynamics.

ResultsDaily median CT was negatively correlated with the daily R(t), the daily COVID-19 hospitalization count (with a time delay), and the daily change in percent positivity among testing samples. Despite visual trends suggesting time delays in the plots for median CT and outbreak measures, a statistically significant delay was only detected between changes in median CT and COVID-19 hospitalization count.

ConclusionsThis study adds to the literature by analyzing samples collected from an entire geographical area, and contextualizing the results with other research investigating population CT values.


title: SARS-CoV-2 detection by rRT-PCR on self-collected anterior nares swabs or saliva compared with clinician-collected nasopharyngeal swabs--Denver and Atlanta, August--November, 2020

abstract: Nasopharyngeal swabs (NPS) collected by trained healthcare professionals are the preferred specimen for SARS-CoV-2 testing. Self-collected specimens might decrease patient discomfort, conserve healthcare resources, and be preferred by patients. During August - November 2020, 1,806 adults undergoing SARS-CoV-2 testing in Denver, Colorado and Atlanta, Georgia, provided self-collected anterior nares swabs (ANS) and saliva specimens before NPS collection. Compared to NPS, sensitivity for SARS-CoV-2 detection by rRT-PCR appeared higher for saliva than for ANS (85% versus 80% in Denver; 67% versus 58% in Atlanta) and higher among participants reporting current symptoms (94% and 87% in Denver; 72% and 62% in Atlanta, for saliva and ANS, respectively) than among those reporting no symptoms (29% and 50% in Denver; 50% and 44% in Atlanta, for saliva and ANS, respectively). Compared to ANS, saliva was more challenging to collect and process. Self-collected saliva and ANS are less sensitive than NPS for SARS-CoV-2 detection; however, they offer practical advantages and might be most useful for currently symptomatic patients.


title: The rise of SARS-CoV-2 variant B.1.1.7 in Israel intensifies the role of surveillance and vaccination in elderly

abstract: Since the emergence of the SARS-CoV-2 pandemic various generic variants have been described. Of specific interest is a new variant, which was observed in England during December 2020 and is now termed B.1.1.7. This variant is now associated with increased infectivity and therefore its spread within the community is of great importance. The Israeli government established three noteworthy programs namely, mass PCR testing, focused protection of the elderly and more recently an unparalleled prioritized vaccination program. In this study we analyzed primary data of >300,000 RT-PCR samples collected throughout December 6th 2020 until February 10th 2021 in the general community and nursing homes. We identified that within a period of six weeks, the B.1.1.7 variant was capable of out competing the wildtype SARS-CoV-2 strain to become the main strain. Furthermore, we show that the transmission of B.1.1.7 in the 60+ population reached a near complete halt, due to an ongoing surveillance testing program in nursing homes and the vaccination program of Israel. Thus, proactive protection programs such as routine surveillance and monitoring of populations at risk combined with prioritized vaccination, is achievable and will result in a reduction of severe illness and subsequent death.


title: Circulatory Cytokines and Chemokines Profile in Human Coronaviruses: A systematic review and meta-analysis

abstract:
BackgroundSARS, MERS, and COVID-19 share similar characteristics as the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50% respectively and cause similar clinical features. Uncontrolled release of proinflammatory mediators (cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 leads to severe phenotype development.

AimThis systematic review and meta-analysis aimed to evaluate the inflammatory cytokines profile associated with severe human coronavirus diseases, including three stains: MERS-CoV, SARS-CoV SARS-CoV-2, in severe patients.

MethodPubMed, Embase, and Cochrane Library databases were searched up to July 2020. Randomized and Observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV SARS-CoV-2 were included. Two reviewers independently screened articles, extracted data, and assessed the quality of included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval (CI) to estimate the pooled mean of inflammatory biomarkers.

ResultsA high level of circulating IL-6 could be associated with the severity of the three strains of coronaviruses infection. TNF, IL-10, and IL-8 is associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS.

ConclusionThis study suggests that the immune response and immunopathology in the three severe human coronavirus strains are similar to some extent. These findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6, which could be used as a potential therapeutic target to improve patients outcomes in severe cases.

category: allergy and immunology


title: Densely sampled viral trajectories suggest longer duration of acute infection with B.1.1.7 variant relative to non-B.1.1.7 SARS-CoV-2

abstract:
BackgroundThe alpha and delta SARS-CoV-2 variants have been responsible for major recent waves of COVID-19 despite increasing vaccination rates. The reasons for the increased transmissibility of these variants and for the reduced transmissibility of vaccine breakthrough infections are unclear.

MethodsWe quantified the course of viral proliferation and clearance for 173 individuals with acute SARS-CoV-2 infections using longitudinal quantitative RT-PCR tests conducted using anterior nares/oropharyngeal samples (n = 199,941) as part of the National Basketball Associations (NBA) occupational health program between November 28th, 2020, and August 11th, 2021. We measured the duration of viral proliferation and clearance and the peak viral concentration separately for individuals infected with alpha, delta, and non-variants of interest/variants of concern (non-VOI/VOC), and for vaccinated and unvaccinated individuals.

ResultsThe mean viral trajectories of alpha and delta infections resembled those of non-VOI/VOC infections. Vaccine breakthrough infections exhibited similar proliferation dynamics as infections in unvaccinated individuals (mean peak Ct: 20.5, 95% credible interval [19.0, 21.0] vs. 20.7 [19.8, 20.2], and mean proliferation time 3.2 days [2.5, 4.0] vs. 3.5 days [3.0, 4.0]); however, vaccinated individuals exhibited faster clearance (mean clearance time: 5.5 days [4.6, 6.6] vs. 7.5 days [6.8, 8.2]).

ConclusionsAlpha, delta, and non-VOI/VOC infections feature similar viral trajectories. Acute infections in vaccinated and unvaccinated people feature similar proliferation and peak Ct, but vaccinated individuals cleared the infection more quickly. Viral concentrations do not fully explain the differences in infectiousness between SARS-CoV-2 variants, and mitigation measures are needed to limit transmission from vaccinated individuals.

category: epidemiology


title: Densely sampled viral trajectories for SARS-CoV-2 variants alpha (B.1.1.7) and epsilon (B.1.429)


title: Viral dynamics of SARS-CoV-2 variants in vaccinated and unvaccinated individuals


title: Mortality in COVID-19 amongst women on Hormone Replacement Therapy or Combined Oral Contraception: A cohort study

abstract:
ObjectiveTo investigate the association between Hormone Replacement Therapy (HRT) or Combined Oral Contraception (COCP) use, and the likelihood of death in women with COVID-19.

DesignA cohort study

Setting465 general practices in England within the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database.

Population1,863,478 women aged over 18 years

MethodsWe identified a cohort of women with COVID-19 from the computerised medical records of the RCGP RSC database. Mixed-effects logistic regression models were used to quantify the association between HRT or COCP use, and all-cause mortality among women with COVID-19 in unadjusted and adjusted models.

ResultsThere were 5451 COVID-19 cases within the cohort. HRT was associated with a significantly lower likelihood of all-cause mortality in COVID-19 (adjusted OR 0.22, 95%{square}CI 0.05 to 0.94). There were no reported events for all-cause mortality in women prescribed COCPs. This prevented further examination of the impact of COCP.

ConclusionsWomen on HRT with COVID-19 had a lower likelihood of death. Further work is needed in larger cohorts to examine the association of COCP in COVID-19. Our findings support the current hypothesis that oestrogens may contribute a protective effect against COVID-19 severity.

FundingThis study was funded by a School for Primary Care National Institute for Health Research grant (SPCR2014-10043).


title: SEIR Filter: A Stochastic Model of Epidemic

abstract:
There are many epidemiological models at hand to cope with the present pandemic; it is, however, difficult to calibrate these models when data are noisy, partial or observed only indirectly. It is also difficult to distinguish relevant data from noise, and to distinguish the impact of individual determinants of the epidemic.

In mathematical statistics, the tools to handle all of these phenomena exist; however, they are seldom used for epidemiological models. The goal of this paper is to start filling this gap by proposing a general stochastic epidemiological model, which we call SEIR Filter.

Technically our model is a heterogeneous partially observable vector autoregression model, in which we are able to express closed form formulas for the distribution of compartments and observations, so both maximum likelihood and least square estimators are analytically tractable. We give conditions for vanishing, explosion and stationary behaviour of the epidemic and we are able to express a closed form formula for reproduction number.

Finally, we present several examples of the models application. We construct an estimate age-cohort model of the COVID-19 pandemic in the Czech Republic. To demonstrate the strengths of the model, we employ it to analyse and compare three vaccination scenarios.


title: Transcranial direct current stimulation (tDCS) targeting the medial prefrontal cortex (mPFC) modulates functional connectivity and enhances inhibitory safety learning in obsessive-compulsive disorder (OCD)

abstract:
BackgroundPsychotherapy based on fear extinction is a mainstay of treatment for obsessive-compulsive disorder (OCD). The default mode network (DMN) is important to safety signal processing, fear extinction, and exposure-based therapies. The medial prefrontal cortex (mPFC) is an anchor of the DMN. Neuromodulation targeting the mPFC might augment therapeutic learning and thereby enhance response to exposure-based therapies.

MethodsTo characterize the effects of mPFC neuromodulation, 17 community volunteers completed resting-state fMRI scans before and after receiving 20 minutes of frontopolar multifocal transcranial direct current stimulation (tDCS). To examine the effects of tDCS on therapeutic learning, 24 patients with OCD were randomly assigned (double-blind, 50:50) to receive active or sham tDCS immediately before completing a two-day exposure and response prevention (ERP) challenge.

ResultsAfter tDCS, frontal pole functional connectivity with regions in the anterior insula and basal ganglia decreased, while connectivity in the middle and superior frontal gyri increased (ps<.001, corrected). Functional connectivity between DMN and salience network (SN) increased after tDCS (ps<.001). OCD patients who received active tDCS exhibited more rapid within- and between-trial therapeutic extinction learning (ps<.05) during the ERP challenge compared to those who received sham tDCS.

ConclusiontDCS targeting the mPFC may modulate SN and DMN functional connectivity and can accelerate therapeutic learning. Though limited by small samples, these promising findings motivate further exploration of the effects of tDCS on neural and behavioral targets associated with exposure-based treatments for OCD and for other anxiety and related disorders.

category: psychiatry and clinical psychology


title: Relationship Between Depression, Prefrontal Creatine and Gray Matter Volume

abstract:
BackgroundDepression and low mood are leading contributors to disability worldwide. Research indicates that clinical depression may be associated with low creatine concentrations in the brain and low prefrontal gray matter volume. Because sub-clinical depression also contributes to difficulties in day-to-day life, understanding the neural mechanisms of depressive symptoms in all individuals, even at a sub-clinical level, may aid public health.

MethodsEighty-four young adult participants completed the Depression, Anxiety and Stress Scale (DASS) to quantify severity of depression, anxiety and stress, and underwent 1H-Magnetic Resonance Spectroscopy of the medial prefrontal cortex and structural MRI to determine whole-brain gray matter volume.

Results/OutcomesDASS depression scores were negatively associated with A) concentrations of creatine (but not other metabolites) in the prefrontal cortex, and B) with gray matter volume in the right superior medial frontal gyrus. Medial prefrontal creatine concentrations and right superior medial frontal gray matter volume were positively correlated. DASS anxiety and DASS stress scores were not related to prefrontal metabolite concentrations or whole-brain gray matter volume.

Conclusions/InterpretationsThis study provides preliminary evidence from a representative group of individuals who exhibit a range of depression levels, that prefrontal creatine and gray matter volume are negatively associated with depression. While future research is needed to fully understand this relationship, these results provide support for previous findings which indicate that increasing creatine concentrations in the prefrontal cortex may improve mood and wellbeing.

Declaration of Interest/FundingThis research was partly funded by a British Academy/Leverhulme Trust Research Grant, awarded to PA.


title: The Impact of a Night Travel Ban Policy on Road Traffic Accidents: Interrupted Time Series evidence in Zambia.

abstract:
The burden of road traffic accidents has been increasing globally with Injuries and deaths from road traffic accidents accounting for a significant share of the global disease burden. This is evident especially in low and middle income countries (LMICs), were these injuries and deaths account for a reasonable share of the disease burden. In Zambia, for example, road traffic accidents are the third leading cause of death after HIV/AIDS and Malaria and more than half of these accidents happen at night. To reverse the growing incidence of road crushes, the government of Zambia put a ban on night travel for public service vehicles in November, 2016. While other countries such as Kenya have implemented similar bans, there is no evidence on the extent to which such a ban may reduce accidents.

Objectiveto examine the effect of the night travel ban on road traffic accidents in Zambia after the implementation of the night travel ban. The study set out to established whether there was a change in the number of accidents.

Designthe study design was a single group interrupted time series analysis. Administrative data on road traffic accidents in Zambia for the period 1964 to 2018 was used.

Settingthis research was a national study, therefore it encompassed national statistics on road accidents of the entire country of Zambia.

Main outcome measureThe total counts of road traffic accidents in Zambia recorded during the study period 1964 to 2018.

Resultsit was found that the night travel ban reduced the number of road crushes by 1,211 within one year of implementing the intervention. (p value 0.001, CI -1878.079 to -543.130).

Conclusionthe night travel ban may be an effective way of reducing the burden of road traffic injuries in Zambia and other LMICs.

O_TEXTBOXSection 1: What is already known on this topicO_LIIn Zambia, there is a high number of road traffic accidents that occur during the night compared to the day time (fisa et al, 2019, ikabungo 2015 and patel 1979).
C_LIO_LIInterventions have been put in place to reduce the number of accidents but there is no evidence of their effectiveness.
C_LIO_LIIn light of the lack of evidence of such interventions, the study was carried out to provide evidence to policy makers so that their decisions can be evidence based.
C_LI

Section 2: what the study addsO_LIOur study suggests that the policy proved to be effective in reducing the total number of accidents in Zambia.
C_LIO_LIThis study provides evidence of the effectiveness of an intervention which in turn provides policy makers with grounds on which to maintain such a policy.
C_LIO_LIThe study triggers further research on other effects of banning night time travel
C_LI

C_TEXTBOX

Copyright/licence for publicationThe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, a worldwide licence to the Publishers and its licensees in perpetuity, in all forms, formats and media (whether known now or created in the future), to i) publish, reproduce, distribute, display and store the Contribution, ii) translate the Contribution into other languages, create adaptations, reprints, include within collections and create summaries, extracts and/or, abstracts of the Contribution, iii) create any other derivative work(s) based on the Contribution, iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links from the Contribution to third party material where- ever it may be located; and, vi) licence any third party to do any or all of the above."


title: When efficacy and adherence conflict: preferences and patterns of response to public health advice during the COVID-19 pandemic

abstract: With recurring waves of the Covid-19 pandemic, a dilemma facing public health leadership is whether to provide public advice that is medically optimal (e.g., most protective against infection if followed), but unlikely to be adhered to, or advice that is less protective but is more likely to be followed. To provide insight about this dilemma, we examined and quantified public perceptions about the tradeoff between (a) the stand-alone value of health behavior advice, and (b) the advices adherence likelihood. In a series of studies about preference for public health leadership advice, we asked 1,061 participants to choose between (1) strict advice that is medically optimal if adhered to but which is less likely to be broadly followed, and (2) relaxed advice, which is less medically effective but more likely to gain adherence - given varying infection expectancies. Participants preference was consistent with risk aversion. Offering an informed choice alternative that shifts volition to advice recipients only strengthened risk aversion, but also demonstrated that informed choice was preferred as much or more than the risk-averse strict advice.


title: When efficacy and adherence conflict: preferences and patterns of response to mask-wearing and social distancing public health advice during the COVID-19 pandemic


title: Preferences and patterns of response to public health advice during the COVID-19 pandemic


title: Incidence and Outcomes of Pulmonary embolism among hospitalized COVID-19 patients

abstract:
BackgroundPatients with COVID-19 may be at high risk for thrombotic complications due to excess inflammatory response and stasis of blood flow. This study aims to assess the incidence of pulmonary embolism among hospitalized patients with COVID-19, risk factors and the impact on survival.

MethodA retrospective case-control study was conducted at Al-Noor Specialist Hospital in, Saudi Arabia between March 15, 2020, and June 15, 2020. Patients with confirmed COVID-19 diagnosis by a real-time polymerase chain reaction (PCR) and confirmed diagnosis of pulmonary embolism by Computed Tomography pulmonary angiogram (CTPA) formed the case group. Patients with confirmed COVID-19 diagnosis by a real-time polymerase chain reaction (PCR) and without confirmed diagnose of pulmonary embolism formed the control group. Logistic regression analysis was used to identify predictors of pulmonary embolism and its survival.

ResultsA total of 159 patients participated were included in the study, of which 51 were the cases (patients with pulmonary embolism) and 108 patients formed the control group (patients without pulmonary embolism). The incidence of PE among hospitalized was around 32%. Smoking history, low level of oxygen saturation and higher D-dimer values were important risk factors that were associated with a higher risk of developing PE (p< 0.05). Higher respiratory rate was associated with higher odds of death, and decrease the possibility of survival among hospitalised patients with PE.

ConclusionPulmonary embolism is common among hospitalized patients with COVID-19. Preventive measures should be considered for hospitalized patients with smoking history, low level of oxygen saturation, high D-dimer values, and high respiratory rate.

category: respiratory medicine


title: Modafinil for Wakefulness in the Critical Care Units: A Case Series including COVID-19 Patients at a Tertiary Care Saudi Hospital

abstract: Cognitive improvement after critical illness is complex. Neuro-stimulants are used to speed up physical and mental processes through the increase in arousal, and wakefulness. In this case series, we reviewed the literature and described the effect of modafinil for wakefulness in a cohort of adult patients admitted to our COVID and non-COVID intensive care unit (ICU) between January 2017 and June 2020. A total of 8 patients included; 3 admitted to COVID-19, 4 surgical, and 1 transplant ICU. Obstructive sleep apnea was noted in 2 (25%), 2 patients (25 %) had an initial neuroimaging that showed hemorrhagic stroke, and 1 (12.5%) showed ischemic stroke with hemorrhagic transformation. Modafinil 100-200 mg daily was started for a median duration of 4 days and the median initiation time in relation to ICU admission was 11 (IQR 9-17) days. Glasgow coma Scale improvement was noted on 5 patients (62.5%). The median duration of mechanical ventilation was 17.5 (IQR 15-31.75) days, and the median ICU stay was 28.5 (IQR 20.25-48) days. All-cause mortality rate was 25 % at 28 days and 62.5 % at 90 days. Modafinil prevented tracheostomy in 1 COVID-19 patient. No significant adverse drug reactions were documented. In our case series, we described our experience for modafinil use for wakefulness in ICU ventilated patients including COVID-19 patients. Based on our observations, the known effects of modafinil, and its safety profile, it holds the potential to facilitate recovery from cognitive impairment. Larger studies are warranted to fully evaluate its role for this indication.

category: neurology


title: Worries about COVID-19 infection and psychological distress at work and while commuting

abstract:
ObjectiveThis study examined the relationship between worry about COVID-19 infection in the workplace and while commuting to work and psychological distress in Japan.

MethodsAn internet monitor study was conducted. Out of a total of 33,302 participants, 26,841 people were included. The subjects were asked single-item questions about whether they were worried about COVID-19 infection in general, at work and while commuting to work. Kessler 6 (K6) was used to assess psychological distress.

ResultsThe OR was significantly higher in association with worry about infection in the workplace at 1.71 (95%CI 1.53-1.92) and worry about infection while commuting at 1.49 (95%CI 1.32-1.67).

ConclusionsThis study suggests the need for psychological intervention to reduce worry about infection in response to public mental health challenges associated with the COVID-19 pandemic.

category: occupational and environmental health


title: Digital cognitive behavioural therapy for insomnia and primary care costs in England: an interrupted time series analysis

abstract:
BackgroundSleepio is an automated digital programme that delivers cognitive behavioural therapy for insomnia. Sleepio has been proven effective in improving sleep difficulties. However, evidence for the possible impact of Sleepio use on health care costs in the United Kingdom has not previously been developed. In this study, we assessed the effect of a population-wide rollout of Sleepio in terms of primary care costs in the National Health Service (NHS) in England.

MethodsThe study was conducted in the Thames Valley region of England, where access to Sleepio was made freely available to all residents between October 2018 and January 2020. We use primary care data for people with relevant characteristics from nine general practices in Buckinghamshire. The study relies on a quasi-experimental design, using an interrupted time series to compare the trend in primary care costs before and after the rollout of Sleepio. Primary care costs include general practice contacts and prescriptions. Segmented regression analysis was used to estimate primary and secondary outcomes.

ResultsFor the 10,704 patients included in our sample, the total saving over the 65-week follow-up period was {pound}71,027. This corresponds to {pound}6.64 per person in our sample or around {pound}70.44 per Sleepio user. Secondary analyses suggest that savings may be driven primarily by reductions in prescriptions.

ConclusionSleepio rollout reduced primary care costs. National adoption of Sleepio may reduce primary care costs by {pound}20 million in the first year. The expected impact on primary care costs in any particular setting will depend on the uptake of Sleepio.

category: health economics


title: One Shot Model For COVID-19 Classification and Lesions Segmentation In Chest CT Scans Using LSTM With Attention Mechanism

abstract: We present a model that fuses instance segmentation, Long Short-Term Memory Network and Attention mechanism to predict COVID-19 and segment chest CT scans. The model works by extracting a sequence of Regions of Interest that contain class-relevant information, and applies two Long Short-Term Memory networks with attention to this sequence to extract class-relevant features. The model is trained in one shot: both segmentation and classification branches, using two different sets of data. We achieve a 95.74% COVID-19 sensitivity, 98.13% Common Pneumonia sensitivity, 99.27% Control sensitivity and 98.15% class-adjusted F1 score on the main dataset of 21191 chest CT scan slices, and also run a number of ablation studies in which we achieve 97.73% COVID-19 sensitivity and 98.41% F1 score. All source code and models are available on https://github.com/AlexTS1980/COVID-LSTM-Attention.


title: Co-development of a best practice checklist for mental health data science: A Delphi study

abstract:
BackgroundMental health research is commonly affected by difficulties in recruiting and retaining participants, resulting in findings which are based on a sub-sample of those actually living with mental illness. Increasing the use of Big Data for mental health research, especially routinely-collected data, could improve this situation. However, steps to facilitate this must be enacted in collaboration with those who would provide the data - people with mental health conditions.

MethodsWe used the Delphi method to create a best practice checklist for mental health data science. Twenty participants with both expertise in data science and personal experience of mental illness worked together over three phases. In the Phase 1, participants rated a list of 63 statements and added any statements or topics that were missing. Statements receiving a mean score of 5 or more (out of 7) were retained. These were then combined with the results of a rapid thematic analysis of participants comments to produce a 14-item draft checklist, with each item split into two components: best practice now and best practice in the future. In Phase 2, participants indicated whether or not each item should remain in the checklist, and items that scored more than 50% endorsement were retained. In Phase 3 participants rated their satisfaction with the final checklist.

ResultsThe final checklist was made up of 14 "best practice" items, with each item covering best practice now and best practice in the future. At the end of the three phases, 85% of participants were (very) satisfied with the two best practice checklists, with no participants expressing dissatisfaction.

ConclusionsIncreased stakeholder involvement is essential at every stage of mental health data science. The checklist produced through this work represents the views of people with experience of mental illness, and it is hoped that it will be used to facilitate trustworthy and innovative research which is inclusive of a wider range of individuals.


title: Evaluating the effect of COVID-19 on dispensing patterns: a national cohort analysis

abstract:
BackgroundMedication prescribing and dispensing often regarded as one of the most effective ways to manage and improve population health. Prescribed and dispensed medications can be monitored through data linkage for each patient. We hypothesised that changes in patient care resulting from COVID-19, changed the way patients access their prescribed medication.

ObjectiveTo develop an efficient approach for evaluation of the impact of COVID-19 on drug dispensing patterns.

MethodsRetrospective observational study using national patient-level dispensing records in Wales-UK. Total dispensed drug items between 01-Jan-2016 and 31-Dec-2019 (counterfactual pre-COVID-19) were compared to 2020 (COVID-19 year). We compared trends of dispensed items in three main British National Formulary (BNF) sections(Cardiovascular system, Central Nervous System, Immunological & Vaccine) using European Age-Standardized rates. We developed an online tool to enable monitoring of changes in dispensing as the pandemic evolves.

ResultAmongst all BNF chapters, 52,357,639 items were dispensed in 2020 compared to 49,747,141 items in 2019 demonstrating a relative increase of 5.25% in 2020(95%CI[5.21,5.29]). Comparison of monthly patterns of 2020 and 2019 dispensed items showed a notable difference between the total number of dispensed drug items each month, with an average difference (D) of +290,055 and average Relative Change (RC) of +5.52%. The greatest RC was observed in a substantial March-2020 increase (D=+1,501,242 and RC=+28%), followed by second peak in June (D=+565,004, RC=+10.97%). May was characterised by lower dispensing (D=-399,244, RC=-5.9%). Cardiovascular categories were characterised, across all age groups, by dramatic March-2020 increases, at the epidemic peak, followed by months of lower than expected dispensing, and gradual recovery by September. The Central Nervous System category was similar, but with only a short decline in May, and quicker recovery. A stand-out grouping was Immunological and Vaccine, which dropped to very low levels across all age groups, and all months (including the March dispensing peak).

ConclusionsAberration in clinical service delivery during COVID-19 led to substantial changes in community pharmacy drug dispensing. This change may contribute to a long-term burden of COVID-19, raising the importance of a comprehensive and timely monitoring of changes for evaluation of the potential impact on clinical care and outcomes

category: health systems and quality improvement


title: Clinical performance of oral sponge sampling for detection by RT-PCR of SARS-CoV-2

abstract:
BackgroundThe current standard for coronavirus 2019 disease (COVID-19) diagnosis is reverse transcriptase-polymerase chain reaction (RT-PCR) testing of naso-pharyngeal swabs (NPS), Sampling with NPS is invasive and requires specialized and trained personnel, which limits rapid and repeated screening for the disease. A less invasive and possibly self-administered sampling method may increase the capacity for testing and be more effective in identifying, isolating, and filtering out currently infected persons.

MethodsOver a period of three months, we included volunteers presenting with recent symptoms suggestive of a SARS-CoV-2 infection at a free COVID-19 screening center in the city of Nice, France. NPS as well as nasal and oral sponges were collected in parallel and analyzed by RT-PCR for SARS-CoV-2.

ResultsOne hundred and forty-seven subjects were included, of whom, 41.5% were diagnosed with COVID-19 using NPS RT-PCR. RT-PCR on nasal and oral sponges showed a sensitivity of 87 to 98% and 72 to 87%, respectively for diagnosis of COVID-19 in symptomatic subjects, depending on the type of RT-PCR technique used. The specificity was 100% whatever the RT-PCR test. The viral load determined with the oral samples was significantly lower than with NPS.

ConclusionTaken together, these results demonstrated that the oral sponge sampling method can be standardized, is easy to use and cheap. The acceptability makes it a repeatable test, notably for elderly people or children. It may become a high-frequency - low analytical sensitive testing strategy.

Summary of the "take home" messageOral sponge sampling for SARS-CoV2 RT-PCR, is easy to use, can be self-administered with a sensitivity of up to 87 % in symptomatic patients.


title: Salivary detection of COVID-19. Clinical performance of oral sponge sampling for SARS-CoV-2 testing


title: 'Trained immunity' from Mycobacterium spp. (environmental or BCG) exposure predicts protection from Coronavirus disease 2019 (COVID-19)

abstract:
Endeavors to identify potentially protective variables for COVID-19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID-19 impact on populations to their bacillus Calmette-Guerin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID-19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous  trained immunity (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI of populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (twenty-four), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID-19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase-matched COVID-19 incidences (r(24): - 0.79 to -0.57; p-value: <0.004), mortality (r(24): -0.63 to -0.45; p-value: <0.03), and interim case fatality rates(i-CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID-19, the ongoing/planned randomized controlled trials should consciously consider including measures of TI as - a) all individuals immunized do not respond equally, b)small study groups from higher background TI could fail to indicate any protective effect.

O_TEXTBOXSummary BoxO_ST_ABSWhat is already known?C_ST_ABSO_LIPreviously, COVID-19 incidence (SARS-CoV-2 infections) and mortality datasets of disparate populations with regard to phase of pandemic, demographics, medical infrastructure etc. have been modelled to negatively associate with highly transformed BCG vaccination coverage and policy of the countries.
C_LIO_LIRecently BCG vaccination has been linked to risk of COVID-19 using vaccinated individuals from disparate populations (different underlying trained immunity) without any estimation of the underlying immune status or attempt to make the confounders for the groups being compared to be equal.
C_LIO_LIAbout 8 out of 10 COVID-19 deaths have been in aged >65 years old.
C_LIO_LIBCG vaccination is known to provide-cross protection from a number of unrelated diseases.
C_LIO_LIBCG vaccination given in childhood protects children from milliary tuberculosis and the conferred protective trained-Immunity correlate or  TIC (loosely equals  tuberculin positivity) wanes away within 5 years from most in the absence of boosters or rechallenge from environmental Mycobacterium spp.
C_LI

New FindingsO_LIDisregarding BCG vaccination coverage or policy, the prevailing TIC correlate of populations predict protection from COVID-19 in socially similar European countries, i.e., the countries which are more similar to each other than other parts of the world with regard to various supposed confounders (e.g., exposure, phase of pandemic, health services, social support, food, genetic relatedness etc.).
C_LI

Recommendations for Policy and PracticeO_LIThe planned and ongoing studies or clinical trials assessing the effectiveness of BCG vaccination in protecting populations against COVID-19 or making them vulnerable to COVID-19 should include TIC correlates information of the participants (both controls and vaccinated) to arrive at dependable conclusions about potential benefit of BCG vaccination in controlling COVID-19 infections and mortality.
C_LI

C_TEXTBOX


title: The detection of SARS-CoV-2 in autolysed samples from an exhumed decomposed body: Implications to virus survival, genome stability, and spatial distribution in tissues

abstract: Here we report for the first time the SARS-CoV-2 detection in autolysed samples from an exhumed decomposed body post-thirty six days after death. Both naso-oropharyngeal swabs and visceral samples from the lung, intestine, liver, and kidney were collected from the body exhumed post-fifteen days after burial, stored in viral transport medium and in saturated salt solution respectively. Naso-oropharyngeal swabs showed the presence of the SARS-CoV-2 genome as identified by the amplification of viral E, N, RdRP, or ORF1ab genes by RT-PCR. Subsequent examination of tissues reveal the detection of the virus genome in the intestine and liver, while no detection in the kidney and lung. These results signify the genome stability and implicate the virus survival in decomposed swab samples and in tissues and thereafter in storage solution. Further results also indicate spatial distribution of the virus in tissues during the early stage of infection in the subject with no respiratory distress. Considering the presence of cool, humid, and moist location of the exhumation, the presence of virus genome might also indicate that SARS-CoV-2 can persist for more than seven days on the surface of dead bodies similar to the Ebola virus, confirming that transmission from deceased subjects is possible for an extended period after death. These results further reaffirm the robustness of the RT-PCR aiding in the detection of viruses or their genome in decomposed samples when other methods of detection could not be useful.


title: IMMUNO-COV™ v2.0: Development and Validation of a High-Throughput Clinical Assay for Measuring SARS-CoV-2-Neutralizing Antibody Titers

abstract: Neutralizing antibodies are key determinants of protection from future infection, yet well-validated high-throughput assays for measuring titers of SARS-CoV-2-neutralizing antibodies are not generally available. Here we describe the development and validation of IMMUNO-COV v2.0 a scalable surrogate virus assay, which titrates antibodies that block infection of Vero-ACE2 cells by a luciferase-encoding vesicular stomatitis virus displaying SARS-CoV-2 spike glycoproteins (VSV-SARS2-Fluc). Antibody titers, calculated using a standard curve consisting of stepped concentrations of SARS-CoV-2 spike monoclonal antibody, correlated closely (p < 0.0001) with titers obtained from a gold-standard PRNT50% assay performed using a clinical isolate of SARS-CoV-2. IMMUNO-COV v2.0 was comprehensively validated using data acquired from 242 assay runs performed over seven days by five analysts, utilizing two separate virus lots, and 176 blood samples. Assay performance was acceptable for clinical use in human serum and plasma based on parameters including linearity, dynamic range, limit of blank and limit of detection, dilutional linearity and parallelism, precision, clinical agreement, matrix equivalence, clinical specificity and sensitivity, and robustness. Sufficient VSV-SARS2-Fluc virus reagent has been banked to test 5 million clinical samples. Notably, a significant drop in IMMUNO-COV v2.0 neutralizing antibody titers was observed over a six-month period in people recovered from SARS-CoV-2 infection. Together, our results demonstrate the feasibility and utility of IMMUNO-COV v2.0 for measuring SARS-CoV-2-neutralizing antibodies in vaccinated individuals and those recovering from natural infections. Such monitoring can be used to better understand what levels of neutralizing antibodies are required for protection from SARS-CoV-2, and what booster dosing schedules are needed to sustain vaccine-induced immunity.


title: Use of convalescent plasma in patients with coronavirus disease (Covid-19): Systematic review and meta-analysis

abstract:
ObjetivesTo assess the effects of convalescent plasma treatment in patients with coronavirus disease (COVID-19).

Study designSystematic review and Meta-analysis

Data sourcesA systematic search was carried out on the L {middle dot} OVE (Living OVerview of Evidence) platform for COVID-19 until October 31, 2020

Study selectionRandomized clinical trials in which people with probable or confirmed COVID-19 were randomized to drug treatment, standard care, or placebo. Pairs of reviewers independently screened potentially eligible articles.

MethodsThe PRISMA guidelines were followed for conducting a systematic review and meta-analysis. The risk of bias of the included studies was assessed using the Cochrane risk of bias tool 2.0, and the certainty of the evidence using the recommendation assessment, development and evaluation (GRADE) approach. For each outcome, the interventions were classified into groups, from most to least beneficial or harmful.

ResultsWe identified 10 RCTs (randomized controlled trials) involving 11854 patients in which convalescent plasma was compared with standard of care or other treatments. The results of five RCTs that evaluated the use of convalescent plasma in patients with COVID-19 did not show significant differences in the effect on mortality and the need for invasive mechanical ventilation.

ConclusionsCurrent evidence is insufficient to recommend the use of convalescent plasma in the treatment of moderate or severe COVID-19.

Contribution of the authors

O_TBL View this table:
org.highwire.dtl.DTLVardef@1485b91org.highwire.dtl.DTLVardef@173b855org.highwire.dtl.DTLVardef@4ad531org.highwire.dtl.DTLVardef@f2af32org.highwire.dtl.DTLVardef@cc3bb4_HPS_FORMAT_FIGEXP  M_TBL C_TBL


title: covid19.Explorer: A web application and R package to explore United States COVID-19 data

abstract: Appearing at the end of 2019, a novel virus (later identified as SARS-CoV-2) was characterized in the city of Wuhan in Hubei Province, China. As of the time of writing, the disease caused by this virus (known as COVID-19) has already resulted in over 3 million deaths worldwide. SARS-CoV-2 infections and deaths, however, have been highly unevenly distributed among age groups, sexes, countries, and jurisdictions over the course of the pandemic. Herein, I present a tool (the covid19.Explorer R package and web application) that has been designed to explore and analyze publicly available United States COVID-19 infection and death data from the 2020/21 U.S. SARS-CoV-2 pandemic. The analyses and visualizations that this R package and web application facilitate can help users better comprehend the geographic progress of the pandemic, the effectiveness of non-pharmaceutical interventions (such as lockdowns and other measures, which have varied widely among U.S. states), and the relative risks posed by COVID-19 to different age groups within the U.S. population. The end result is an interactive tool that will help its users develop an improved understanding of the temporal and geographic dynamics of the SARS-CoV-2 pandemic, accessible to lay people and scientists alike.


title: Clustering of Countries for COVID-19 Cases based on Disease Prevalence, Health Systems and Environmental Indicators

abstract: The coronavirus has a high basic reproduction number (R0) and has caused the global COVID-19 pandemic. Governments are implementing lockdowns that are leading to economic fallout in many countries. Policy makers can take better decisions if provided with the indicators connected with the disease spread. This study is aimed to cluster the countries using social, economic, health and environmental related metrics affecting the disease spread so as to implement the policies to control the widespread of disease. Thus, countries with similar factors can take proactive steps to fight against the pandemic. The data is acquired for 79 countries and 18 different feature variables (the factors that are associated with COVID-19 spread) are selected. Pearson Product Moment Correlation Analysis is performed between all the feature variables with cumulative death cases and cumulative confirmed cases individually to get an insight of relation of these factors with the spread of COVID-19. Unsupervised k-means algorithm is used and the feature set includes economic, environmental indicators and disease prevalence along with COVID-19 variables. The learning model is able to group the countries into 4 clusters on the basis of relation with all 18 feature variables. We also present an analysis of correlation between the selected feature variables, and COVID-19 confirmed cases and deaths. Prevalence of underlying diseases shows strong correlation with COVID-19 whereas environmental health indicators are weakly correlated with COVID-19.


title: Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer's Disease

abstract:
BackgroundEducation and cognition demonstrate consistent inverse associations with Alzheimers Disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites can reflect the endpoint of biological processes and are accessible and malleable. Identifying metabolites with aetiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms.

MethodsUsing data from the largest metabolomics genome-wide association study (N{approx}24,925) and three independent AD cohorts (N=4,725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization (MR) interrogated univariable causal relationships between (i) metabolites and AD, (ii) metabolites, education and cognition (iii) education, cognition and AD, and (iv) education and cognition. Mediating relationships were computed using multivariable MR.

ResultsThirty-four metabolites were genetically associated with AD at p<0.05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins (XL.HDL.FC) demonstrated a protective causal effect (Glutamine: 95% CI=0.70-0.92; XL.HDL.FC: 95% CI=0.75-0.92). An AD-protective effect was also observed for education (95% CI=0.61-0.85) and cognition (95% CI=0.60-0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice-versa, however. No evidence of mediation via any metabolite was found.

ConclusionsGlutamine and XL.HDL.FC show protective causal effects on AD. Education and cognition also demonstrate protection, though educations effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multi-modal work and progressing towards effective intervention strategies.


title: The impact of COVID-19 on children with oesophageal atresia and/or tracheo-oesophageal fistula (OA/TOF)

abstract:
PurposeThe COVID-19 pandemic has resulted in a global health crisis of unparalleled magnitude. The direct risk to the health of children is low. However, disease containment measures have society-wide impacts. This study explored the pandemic experiences of parents of children with oesophageal atresia/tracheo-oesophageal fistula in the UK.

DesignAn online forum was conducted using a private group on Facebook, in collaboration with a patient support group. Thematic analysis was used to identify key themes.

ResultsThe online forum ran between 7th November-18th December 2020 with 109 participants. Themes related to healthcare and non-healthcare impacts. Parents experienced changes and limitations to healthcare access, anxiety regarding health risks, "collateral" damage to well-being because of isolation and an impact on finances and employment. Parents described a transition from worry about direct health risks to concern about the impact of isolation on socialisation and development. A process of risk-benefit analysis led some to transition to a more "normal life", while others continued to isolate. Benefits to their childs health from isolation, positive experiences with remote healthcare and a gradual easing of anxiety were also identified.

Implications and relevanceThis study highlights the wide-ranging impact of the COVID-19 pandemic on children and their families. Although focussed on oesophageal atresia/tracheo-oesophageal fistula, the emerging themes will be relevant to many children with complex, chronic health conditions. There are implications for healthcare delivery, including telehealth, during and after the pandemic period. Accurate and consistent messaging is required. Third sector organisations are ideally positioned support this.

category: pediatrics


title: Magnetic resonance imaging of the gastrointestinal tract shows reduced small bowel motility and altered chyme in cystic fibrosis compared to controls

abstract:
Cystic fibrosis (CF) is a genetic disease affecting mucosal secretions. Most patients experience digestive symptoms, but the mechanisms are incompletely understood. Here we explore causes and consequences of slower gastrointestinal transit using magnetic resonance imaging (MRI).

Twelve people with CF and 12 healthy controls, matched for age and gender, underwent MRI scans both fasted and after standardised meals over a period of 6.5 hours. Images were assessed for small bowel motility, longitudinal relaxation time (T1) of ascending colon chyme, chyme texture and appearance of the colon wall.

Small bowel motility scores were significantly lower in CF than in healthy controls in the fasting state (CF median 40 arbitrary units IQR [31, 46] vs Control 86 a.u. [52, 106], P=0.034). This difference was less pronounced postprandially. Furthermore, ascending colon chyme T1 was lower in CF than in controls (CF 0.59 s [0.38, 0.77] vs Control 0.79 s [0.55, 1.31], P=0.010). The difference in texture between small bowel and colon chyme, seen in health, was diminished in CF (difference in Haralick contrast 0.90 a.u. [0.38, 1.67] vs Control 2.11 a.u. [0.71, 3.30], P=0.010). Ascending colon mucosa in CF participants had an abnormal appearance compared to controls (Score 1-3, CF 2 [1, 3] vs Controls 1 [1, 1], P=0.019).

Reduced small bowel motility and water content of ascending colon chyme are consistent with slower transit and constipation. MRI provides unique insights into chyme texture in the small bowel (suggesting bacterial overgrowth) and the appearance of the colon mucosa (suggesting altered mucus) in CF.

Key point summary- People with cystic fibrosis (CF) have intrusive digestive symptoms and severe gut complications, but mechanisms are incompletely understood.
- In this study, 12 people with CF were compared to healthy controls, undergoing repeated MRI scans before and after standardised meals.
- Fasted small bowel motility is reduced in people with CF, consistent with slower transit. In addition, a reduced colonic chyme water content and abnormal appearance of small bowel and colonic chyme as well as colonic mucosa suggest small bowel bacterial overgrowth, fat malabsorption and abnormal mucus production
- These MRI outcomes hold promise in the assessment of therapeutic interventions.


title: Structural differences between healthy subjects and patients with schizophrenia and schizoaffective disorder: A graph and control theoretical perspective

abstract: The coordinated, dynamical interactions of large-scale networks give rise to cognitive function. Recent advances in network neuroscience have suggested that the anatomical organization of such networks puts a fundamental constraint on the dynamical landscape of the brain. Consequently, changes in large-scale brain activity have been hypothesized to underlie many neurological and psychiatric disorders. Specifically, evidence has emerged that large-scale dysconnectivity might play a crucial role in the pathophysiology of schizophrenia. To investigate potential differences in graph and control theoretic measures between patients with schizophrenia (SCZ), patients with schizoaffective disorder (SCZaff) and matched healthy controls (HC), we use structural MRI data. More specifically, we first calculate seven graph measures of integration, segregation, centrality and resilience and test for group differences. Second, we extend our analysis beyond these traditional measures and employ a simplified noise-free linear discrete-time and time-invariant network model to calculate two complementary measures of controllability. Average controllability identifies brain areas that can guide brain activity into different, easily reachable states with little input energy. Modal controllability on the other hand, characterizes regions that can push the brain into difficult-to-reach states, i.e. states that require substantial input energy. We identified differences in standard network and controllability measures for both patient groups compared to HCs. Specifically, we found a strong reduction of betweenness centrality for both patient groups and a strong reduction in average controllability for the SCZ group again in comparison to the HC group. Our findings of network level deficits might help to explain the many cognitive deficits associated with these disorders.


title: The interaction between lifetime depression severity and BMI is related to altered activation pattern in the right inferior frontal gyrus during food anticipation

abstract:
BackgroundDepression and obesity often co-occur but the underlying neural mechanisms for this bidirectional link are not well understood. Using fMRI, we examined how the relationship between Body Mass Index (BMI) and dimensional lifetime depression severity was associated with brain activation during food anticipation and pleasant/unpleasant rating.

Methods90 participants (48 healthy controls, 42 with unipolar depression (UD), 69 female, age=28.5{+/-}6.6) were fMRI-scanned while performing the Food and Object Cued Encoding task consisting of food/object anticipation and food/object pleasant/unpleasant rating phases.

ResultsThe analysis across all participants revealed a significant BMI-by-lifetime depression severity interaction on RIFG activation during food anticipation (p<0.0125). Most symptomatic and overweight/obese individuals with UD showed decreased right inferior frontal gyrus (RIFG) activation during food anticipation, while less symptomatic and/or normal-weight individuals with UD showed increased RIFG activation during food anticipation. RIFG activation during food anticipation was negatively correlated with RIFG activation during pleasant/unpleasant rating (r= -0.63, p<0.001). Individuals with UD who showed higher RIFG activation for food items during pleasant/unpleasant rating reported liking or wanting those food items less than those with lower RIFG activation (p<0.05).

ConclusionsThe IFG is involved in emotion regulation and response inhibition necessary to control appetitive behavior. Greater RIFG activation during pleasant/unpleasant rating of food coupled with low ratings of food liking and wanting could be associated with inhibition of cognitive and emotional response to food in UD. This process may be cognitively challenging and stressful thus putting affected individuals with UD at risk for weight gain and worsening of depression.


title: Predictors of suicidal thoughts and behavior in children: results from penalized logistic regression analyses in the ABCD study

abstract: Despite numerous efforts to predict suicide risk in children, the ability to reliably identify youth that will engage in suicide thoughts or behaviors (STB) has remained remarkably unsuccessful. To further knowledge in this area, we apply a novel machine learning approach and examine whether children with STB could be differentiated from children without STB based on a combination of sociodemographic, physical health, social environmental, clinical psychiatric, cognitive, biological and genetic characteristics. The study sample included 5,885 unrelated children (50% female, 67% white) between 9 and 11 years old from the Adolescent Brain Cognitive Development (ABCD) study. Both parents and youth reported on childrens STB and based on these reports, we divided children into three subgroups: 1. children with current or past STB, 2. children with psychiatric disorder but no STB (clinical controls) and 3. healthy control children. We performed binomial penalized logistic regression analysis to distinguish between groups. The analyses were performed separately for child-reported STB and parent-reported STB. Results showed that we were able to distinguish the STB group from healthy controls and clinical controls (area under the receiver operating characteristics curve (AUROC) range: 0.79-0.81 and 0.70-0.78 respectively). However, we could not distinguish children with suicidal ideation from those who attempted suicide (AUROC range 0.49-0.59). Factors that differentiated the STB group from the clinical control group included family conflict, prodromal psychosis symptoms, impulsivity, depression severity and a history of mental health treatment. Future research is needed to determine if these variables prospectively predict subsequent suicidal behavior.


title: Probiotic supplements reduce antipsychotic-induced metabolic disturbances in drug-naive first-episode schizophrenia

abstract: Probiotic supplements have demonstrated efficacy in improving metabolic abnormalities and may prevent antipsychotic-induced metabolic disturbance and weight gain. A few studies in rodents have found that antipsychotic-induced metabolic dysfunctions are associated with the altered composition of gut microbiota. Here, we conducted a randomized-controlled clinical trial to determine the effectiveness and safety of probiotic supplements on antipsychotic-induced metabolic disturbance and weight gain. Patients with drug-naive first-episode schizophrenia were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy and scheduled to evaluate with follow-ups for clinical and metabolic profiles. After a treatment of 12 weeks with addition of probiotics, the increase of mean fasting insulin was significantly lower than olanzapine monotherapy. Insulin resistance increased considerably in the olanzapine plus probiotics, but also significantly lower than olanzapine monotherapy. We noted a difference in the increase in body mass index and body weight between treatments at a nominal level of significance, but it became non-significant after adjusting for appetite increase. Probiotics concurrently used with olanzapine is effective and safe in attenuating antipsychotic-induced elevation of fasting insulin and insulin resistance, but not the weight gain in drug-naive first-episode schizophrenia. Further study is warranted to assess the longer-term maintenance of efficacy and safety.


title: Antimicrobial use in COVID-19 patients in the first phase of the SARS-CoV-2 pandemic: Rapid review and evidence synthesis

abstract:
BackgroundAs the numbers of people with COVID-19 continue to increase globally, concerns have been raised regarding the widespread use of antibiotics for the treatment of COVID-19 patients and its consequences for antimicrobial resistance during the pandemic and beyond. The scale and determinants of antibiotic use in the early phase of the pandemic, and whether antibiotic prescribing is beneficial to treatment effectiveness in COVID-19 patients, are still unknown. Unwarranted treatment of this viral infection with antibiotics may exacerbate the problem of antibiotic resistance, while antibiotic resistance may render presumptive treatment of secondary infections in COVID-19 patients ineffective.

MethodsThis rapid review was undertaken to identify studies reporting antimicrobial use in the treatment of hospitalised COVID-19 patients. The review was conducted to comply with PRISMA guidelines for Scoping Reviews (http://www.prisma-statement.org/Extensions/ScopingReviews) and the protocol was registered with the Open Science Framework (OSF): http://osf.io/vp6t5. The following databases: Web of Science, EMBASE, PubMed, CNKI & VIP were searched to identify the relevant studies from 1 Dec 2019 up to 15 June 2020; no limits were set on the language or the country where studies were conducted. The search terms used were: (("Covid-19" or "SARS-CoV-2" or "Coronavirus disease 2019" or "severe acute respiratory syndrome coronavirus-2") and (("antibiotic prescribing" or "antibiotic use" or "antibiotic*") or "antimicrobial *" or "antimicrobial therapy" or "antimicrobial resistance" or "antimicrobial stewardship")). A total of 1216 records were identified through database searching and 118 clinical studies met the inclusion criteria and were taken into data extraction. A bespoke data extraction form was developed and validated through two independent, duplicate extraction of data from five Records. As all the included studies were descriptive in nature, we conducted descriptive synthesis of data and reported pooled estimates such as mean, percentage and frequency. We created a series of scenarios to capture the range of rationales for antibiotic prescribing presented in the included studies.

ResultsOur results show that during the early phase of the pandemic, 8501 out of 10 329 COVID-19 patients (82{middle dot}3%) were prescribed antibiotics; antibiotics were prescribed for COVID-19 patients regardless of reported severity, with a similar mean antibiotic prescribing rate between patients with severe or critical illness (75{middle dot}4%) and patients with mild or moderate illness (75{middle dot}1%). The top five frequently prescribed antibiotics for hospitalised COVID-19 patients were azithromycin (28{middle dot}0 % of studies), ceftriaxone (17{middle dot}8%), moxifloxacin (14{middle dot}4%), meropenem (14{middle dot}4%) and piperacillin/tazobactam (12{middle dot}7%). The proportion of patients prescribed antibiotics without clinical justification was 51{middle dot}5% vs 41{middle dot}9 % for patients with mild or moderate illness and those with severe or critical illness respectively. Comparison of patients who were provided antibiotics with a clinical justification with those who were given antibiotics without clinical justification showed lower mortality rates (9{middle dot}5% vs 13{middle dot}1%), higher discharge rates (80{middle dot}9% vs 69{middle dot}3%) and shorter length of hospital of stay (9{middle dot}3 days vs 12{middle dot}2 days). Only 9{middle dot}7% of patients in our included studies were reported to have secondary infections.

ConclusionsAntibiotics were prescribed indiscriminately for hospitalised COVID-19 patients regardless of severity of illness during the early phase of the pandemic. COVID-19 related concerns and lack of knowledge drove a large proportion of antibiotic use without specific clinical justification. Although we are still in the midst of the pandemic, the goals of antimicrobial stewardship should remain unchanged for the treatment of COVID-19 patients.


title: Detection and quantification of enteric pathogens in aerosols near uncontained fecal waste streams in cities with poor sanitation

abstract:
Urban sanitation infrastructure is inadequate in many low-income countries, leading to the presence of highly concentrated, uncontained fecal waste streams in densely populated areas. Combined with mechanisms of aerosolization, airborne transport of enteric microbes and their genetic material is possible in such settings but remains poorly characterized. We detected and quantified enteric pathogen-associated gene targets in aerosol samples near open wastewater canals (OWCs) or wastewater-impacted surface waters and control sites in La Paz, Bolivia; Kanpur, India; and Atlanta, USA via multiplex reverse-transcription qPCR (37 targets) and ddPCR (13 targets). We detected a wide range of enteric targets, some not previously reported in extramural urban aerosols, with more frequent detections of all enteric targets at higher densities in La Paz and Kanpur near OWCs. We report density estimates ranging up to 4.7 x 102 gc per m3air across all targets including heat stabile enterotoxigenic E. coli, C. jejuni, enteroinvasive E. coli/Shigella spp., Salmonella spp., norovirus, and Cryptosporidium spp. An estimated 25%, 76%, and 0% of samples containing positive pathogen detects were accompanied by culturable E. coli in La Paz, Kanpur, and Atlanta, respectively, suggesting potential for viability of enteric microbes at the point of sampling. Airborne transmission of enteric pathogens merits further investigation in cities with poor sanitation.

SYNOPSISWe detected and quantified molecular targets associated with important enteric pathogens in outdoor aerosols in cities with poor sanitation to assess the potential role of the aeromicrobiological pathway in enteric infection transmission in such settings.


title: Detection and quantification of enteric pathogens in aerosols near open wastewater canals in cities with poor sanitation


title: Knowledge, attitudes and perceptions towards COVID-19 vaccinations: a cross-sectional community survey in Bangladesh

abstract:
BackgroundSeveral vaccines have been approved against coronavirus disease (COVID-19) and distributed globally in different regions. However, general community knowledge, attitudes and perceptions towards COVID-19 vaccinations are poorly understood. Thus, the study aimed to investigate community knowledge, attitudes and perceptions towards COVID-19 vaccinations in Bangladesh.

MethodsAn exploratory and anonymous population-based e-survey was conducted among 1658 general individuals (55.6% male; mean age=23.17{+/-}6.05 years; age range=18-65 years). The survey was conducted using a semi-structured and self-reported questionnaire containing informed consent along with four sections (i.e., socio-demographics, knowledge, attitudes, and perceptions). Multiple linear regression was performed to determine the variables predicting knowledge, and attitudes towards COVID-19 vaccinations.

ResultsThe mean scores of knowledge and attitudes were 2.83{+/-}1.48 (out of 5) and 9.34{+/-}2.39 (out of 12) respectively. About a quarter of participants thought that the COVID-19 vaccination available in Bangladesh is safe, only 60% will have the vaccination and about two-thirds will recommend it to family and friends. In the multiple regression model, higher SES, having university/ higher levels of education, holding nuclear families and having previous history of essential vaccines uptake were associated with knowledge; whilst attitudes were significantly associated with being female and having previous history of essential vaccines uptake. Just over half of the participants thought that everyone should be vaccinated and 61% responded that health workers should be vaccinated first on priority basis. 95% vaccine should be administered free of charge in Bangladesh and almost 90% believed that the COVID-19 vaccine used in Bangladesh may have side effects.

ConclusionsThe findings reflect inadequate knowledge but more positive attitudes towards COVID-19 vaccine among the general population in Bangladesh. In order to improve knowledge, immediate health education programs need to be initiated before mass vaccination schedule.


title: Experiences of supported isolation in returning travellers during the early COVID-19 response: an interview study

abstract:
ObjectivesTo understand the experiences of those who underwent supported isolation as part of the response to the COVID-19 pandemic, after returning to the UK from Wuhan, China.

DesignWe used semi-structured interviews to capture participants experiences and perceptions of supported isolation.

SettingTelephone interviews carried out within approximately one month of an individual leaving supported isolation.

Participants26 people who underwent supported isolation at either Arrowe Park Hospital (n = 18) or Kents Hill Park Conference Centre (n = 8) after being repatriated from Wuhan in January - February 2020.

ResultsParticipants were willing to undergo supported isolation because they understood that it would protect themselves and others. Positive treatment by staff was fundamental to participants willingness to comply with isolation procedures. Despite the high level of compliance, participants expressed some uncertainty about what the process would involve.

ConclusionsAs hotel quarantine is introduced across the UK for international arrivals, our findings suggest that those in charge should: communicate effectively before, during and after quarantine, emphasising why quarantine is important and how it will protect others; avoid enforcement and focus on supporting and promoting voluntary compliance; facilitate shared social experiences for those in quarantine; and ensure all necessary supplies are provided. Doing so will increase adherence and reduce any negative effects on wellbeing.


title: Associations of Race/Ethnicity and Other Demographic and Socioeconomic Factors with Vaccination During the COVID-19 Pandemic in the United States

abstract:
BackgroundTo date, there has been limited data available to understand the associations between race/ethnicity and socioeconomic and related characteristics with novel coronavirus disease (COVID-19) vaccine initiation and planned vaccination in the United States.

MethodsTo better characterize COVID-19 vaccinations nationally, we leveraged large cross-sectional surveys conducted between January and March 2021 with relatively complete race/ethnicity and socioeconomic data and nationally-representative of U.S. households to estimate trends in levels of COVID-19 vaccine initiation and vaccine intention. We further used survey data from January and March 2021 in adults aged 18-85 years to analyze the associations between race/ethnicity, education, pre-pandemic household income, and financial hardship during the pandemic and the adjusted odds of: 1) receipt of [≥]1 dose of a COVID-19 vaccine; and 2) among those unvaccinated, the definite intention to receive a vaccine, controlling for other demographic and socioeconomic factors.

ResultsWe observed persistent disparities in vaccine initiation for non-Hispanic Blacks, Hispanics, and non-Hispanic multiracial persons, and in vaccine intention for Blacks and multiracial persons, compared to non-Hispanic Whites and non-Hispanic Asians. In late March 2021, the prevalence estimates of Hispanics and Blacks receiving a vaccine were 12 percentage points and 8 percentage points lower than for Whites, respectively. Moreover, both education and income levels exhibited positive dose-response relationships with vaccine initiation (P for trend[≤]01 and <.001, respectively). Substantial financial hardship was linked to 35-44% lower odds of vaccination (P<.001). The most common reasons for vaccine hesitancy were concerns about side effects and safety, with evidence of higher levels of concerns about vaccine safety among Blacks vs. Whites.

ConclusionsIn this large, nationally-representative study with relatively complete race/ethnicity and socioeconomic data, we find that being Black non-Hispanic and having the least education and income were each independently associated with a markedly lower likelihood of definitely planning to get vaccinated or having been vaccinated. In the ensuing months of the pandemic, addressing the persevering racial/ethnic and socioeconomic inequities in vaccination due to differential access and vaccine hesitancy is essential to mitigate the pandemics higher risks of infection and adverse health outcomes in Hispanic, Black, and socioeconomically-disadvantaged communities.


title: Associations of Race/Ethnicity and Other Demographic and Socioeconomic Factors with Vaccine Initiation and Intention During the COVID-19 Pandemic in the United States


title: A proteomics workflow reveals predictive autoantigens in idiopathic pulmonary fibrosis

abstract:
RationaleThe diagnosis of idiopathic pulmonary fibrosis (IPF) requires exclusion of known underlying autoimmunity, as present in interstitial lung diseases associated with connective tissue diseases (CTD-ILD). However, autoantibodies of unknown significance have been repeatedly detected in IPF patients.

ObjectivesWe aimed to characterize autoreactivities in IPF patients beyond clinically established autoimmune panels by establishing an unbiased assay for de novo discovery of autoantigens in different forms of ILD and healthy controls.

MethodsWe developed the proteomic Differential Antigen Capture (DAC) assay, capturing patient antibodies from plasma, followed by affinity purification of lung proteins coupled to mass spectrometry. Plasma antibodies from patients with IPF (n=35), CTD-ILD (n=24) and age-matched controls (n=32) were analyzed and validated in an independent cohort (IPF: n=40; CTD-ILD: n=20). Plasma antibody binding profiles were associated with clinical meta-data including diagnosis, lung function and transplant free survival.

Measurements and Main ResultsWe identified 586 putative autoantigens in both study cohorts with a broad heterogeneity among disease entities and cohorts. The prevalence of autoantibodies was higher in IPF compared to CTD-ILD. We identified a predictive autoimmune signature that was significantly associated with reduced transplant free survival in IPF. In particular, presence of autoantibodies to Thrombospondin 1 (THBS1) was associated with a significantly reduced survival in patients with IPF (p=0.002), independent of the study cohort, suggesting clinical relevance as predictive biomarker.

ConclusionsUnbiased proteomic profiling reveals that the overall prevalence of autoantibodies is similar in IPF and CTD-ILD patients and identifies novel IPF specific autoantigens associated with patient survival.


title: Adrenaline (epinephrine) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis

abstract:
BackgroundInternational asthma guidelines recommend against adrenaline administration in acute asthma unless associated with anaphylaxis or angioedema. However, administration of intra-muscular adrenaline in addition to nebulised selective {beta}2-agonist is recommended for acute severe or life-threatening asthma in many pre-hospital guidelines. We conducted a systematic review to determine the efficacy of adrenaline in comparison to selective {beta}2-agonist in acute asthma.

MethodsWe included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared adrenaline by any route to selective {beta}2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, as indicated by hospitalisation, stay >24hrs in emergency department, need for intubation, or death.

ResultsThirty-eight of 1,140 studies were included, involving 2,275 participants. Overall quality of evidence was low. There was significant statistical heterogeneity, I2=56%. The pooled odds ratio for treatment failure with adrenaline versus selective {beta}2-agonist was 0.99 (0.74 to 1.34), p=0.96. There was strong evidence that recruitment age-group was associated with different estimates of the risk of treatment failure; with studies recruiting adults-only having a lower risk of treatment failure with adrenaline. It was not possible to determine whether adrenaline in addition to selective {beta}2-agonist improved outcomes.

ConclusionThe limited evidence available suggests that adrenaline and selective {beta}2-agonists have similar efficacy in acute asthma and does not support the use of adrenaline in addition to selective {beta}2-agonists in acute asthma. There is a need for high-quality double-blind RCTs to address this issue.

PROSPERO registration number CRD42017079472


title: Sensorimotor deficits in distance runners with medial plantar pain

abstract:
ContextMedial plantar pain is a complex and multifactorial condition experienced by some distance runners, which makes etiological differentiation and diagnosis challenging.

ObjectiveTo assess plantar sensation, pain perception and sensitivity, intrinsic foot strength, and foot morphology before and after a 9.7 km run in long-distance runners with and without medial plantar pain.

DesignDescriptive laboratory study

SettingLaboratory.

PatientsSeven distance runners with medial plantar pain (four males, three females; aged 22.3{+/-}3.7 years; BMI 22.3{+/-}3.5 kg/m2) and seven matched healthy controls (four males, three females; aged 20.3{+/-}1.0 years; BMI 22.0{+/-}1.7 kg/m2) were recruited from a public university.

Intervention(s)Participants ran a six-mile course in their own footwear at a self-selected pace.

Main Outcome MeasuresPain visual analogue scale (VAS), pressure pain thresholds (PPT), plantar sensation, foot morphology, weight-bearing dorsiflexion (WBDF), forefoot joint mobility, toe flexion, intrinsic foot muscle strength, and a seated neural provocation test were analyzed pre-and post-run utilizing mixed model group by time ANOVAs, post hoc effect size point estimates, and 95% confidence intervals.

ResultsA significant group by time interaction was observed for PPT at the mid-arch (Control: pre: 83.0{+/-}27.4N, post: 79.5{+/-}22.6N; Symptomatic: pre: 90.5{+/-}31.9N, post: 70.1{+/-}32.7 N; p=.03) and posterior tibialis (PT) (Control: pre: 75.7{+/-}19.5 N, post: 65.7{+/-}14.2N; Symptomatic: pre: 75.8{+/-}20.4 N, post: 51.1{+/-}11.9 N; p=.05) sites. PPT in the posterior tibialis significantly decreased in the symptomatic group following the run (ES=1.5, 95% CI: 0.3, 2.7). Both groups demonstrated significantly decreased plantar sensation thresholds at the base of the 5th metatarsal (p=.04), PPT at the calcaneal tuberosity (p=.001), and increased TMT extension (p=.01) and WBDF (p=.01) following the run.

ConclusionsThe etiology of medial plantar pain observed in our sample was likely attributed to central sensitization and running-induced sensory changes. Clinicians should include sensorimotor testing when managing patients with medial plantar pain.

Key PointsMedial plantar pain is a unique pathologic entity that has not been previously well described and likely caused by central sensitization. Clinicians should include sensorimotor testing and interventions when managing patients with medial plantar pain.

category: sports medicine


title: Genetic Connection to Drug-Induced Liver Injury (DILI) Through Statistical Learning Methods

abstract: Drug-Induced Liver Injury (DILI) is one of the major causes of drug development failure or drug withdrawal from the market after development. Therefore, investigating factors associated with DILI is of paramount importance. Environmental factors that contribute to DILI have been investigated and are, by and large, known. However, recent genomic studies have indicated that genetic diversity can lead to inter-individual differences in drug response. Consequently, it has become necessary to also investigate how genetic factors contribute to the development of DILI in the presence of environmental factors. Thus, our aim is to find appropriate statistical methods to investigate gene-gene and/or gene-environment interactions that are associated with DILI. This is an initial study that only explores statistical learning methods to find gen-gene interactions (epistasis). We introduce Multifactor Dimensionality Reduction (MDR), Random Forest (plus logistic regression), and Multivariate Adaptive Regression Splines (MARS), as the few potential methodological approaches that we found. Next, we attempt to improve the MARS method by combining it with a variable selection method.

category: toxicology


title: Vagus nerve cross-sectional area in patients with Parkinsons Disease; an ultrasound case-control study

abstract:
BackgroundVagal parasympathetic neurons are prone to degeneration in Parkinsons disease (PD). High-resolution ultrasound can precisely estimate the cross-sectional area (CSA) of peripheral nerves. Here, we tested the hypothesis that vagus CSA is reduced in PD.

MethodsWe included 56 healthy controls (HCs) and 63 patients with PD. Using a high-end ultrasound system equipped with a high-frequency transducer, five images were obtained of each nerve. The hypoechoic neuronal tissue was delineated offline with dedicated software and the CSA extracted.

ResultsIn the initial PD vs. HC comparison, no statistically significant differences were observed in mean left vagus CSA (HC: 1.97mm2, PD: 1.89mm2, P=0.36) or in mean right vagus CSA (HC: 2.37mm2, PD: 2.23mm2, P=0.17). The right vagus CSA was significantly larger than the left vagus CSA in both groups (P<0.0001). Females were overrepresented in the HC group and presented with generally smaller vagus CSAs. Consequently, sex-adjusted CSA was significantly smaller for the right vagus nerve of the PD group (P=0.041), but not for the left.

ConclusionA small but significant reduction in sex-adjusted right vagus CSA was observed in patients with PD. The left vagus CSA was not significantly reduced in patients with PD. Ultrasound may not be a suitable method to detecting vagal axonal loss in individual patients.