title: Spatial frequency discrimination in patients with schizophrenia spectrum and bipolar disorders: Evidence of early visual processing deficits and associations with intellectual abilities

abstract:
ObjectiveLow-level sensory disruption is hypothesized as a precursor to clinical and cognitive symptoms in severe mental disorders. We compared visual discrimination performance in patients with schizophrenia spectrum disorder or bipolar disorder with healthy controls, and investigated associations with clinical symptoms and IQ.

MethodsPatients with schizophrenia spectrum disorder (n=32), bipolar disorder (n=55) and healthy controls (n=152) completed a computerized visual discrimination task. Participants responded whether the latter of two consecutive grids had higher or lower spatial frequency, and discrimination thresholds were estimated using an adaptive maximum likelihood procedure. Case-control differences in threshold were assessed using linear regression, F-test and post-hoc pair-wise comparisons. Linear models were used to test for associations between visual discrimination threshold and psychotic symptoms derived from the PANSS and IQ assessed using the Matrix Reasoning and Vocabulary subtests from the Wechsler Abbreviated Scale of Intelligence (WASI).

ResultsRobust regression revealed a significant main effect of diagnosis on discrimination threshold (robust F=6.76, p=.001). Post-hoc comparisons revealed that patients with a schizophrenia spectrum disorder (mean=14%, SD=0.08) had higher thresholds compared to healthy controls (mean=10.8%, SD = 0.07, {beta} = 0.35, t=3.4, p=0.002), as did patients with bipolar disorder (12.23%, SD=0.07, {beta}= 0.21, t=2.42, p=0.04). There was no significant difference between bipolar disorder and schizophrenia ({beta}=-0.14, t=-1.2, p=0.45). Linear models revealed negative associations between IQ and threshold across all participants when controlling for diagnostic group ({beta} = -0.3, t=-3.43, p=0.0007). This association was found within healthy controls (t=-3.72, p=.0003) and patients with bipolar disorder (t=-2.53, p=.015), and no significant group by IQ interaction on threshold (F=0.044, p=.97). There were no significant associations between PANSS domain scores and discrimination threshold.

ConclusionPatients with schizophrenia spectrum or bipolar disorders exhibited higher visual discrimination thresholds than healthy controls, supporting early visual deficits among patients with severe mental illness. Discrimination threshold was negatively associated with IQ among healthy controls and bipolar disorder patients. These findings elucidate perception-related disease mechanisms in severe mental illness, which warrants replication in independent samples.


title: Estimating the death toll of the Covid-19 pandemic in India

abstract:
The absence of reliable registration of Covid-19 deaths in India has prevented the proper assessment and monitoring of coronavirus pandemic. Indias relatively young age structure tends to conceal the severity of Covid-19 mortality, which is concentrated in older age groups. In this paper, we present four different demographic samples of Indian populations for which we have information on both their demographic structures and death outcomes. We show that we can model the age gradient of Covid-19 mortality in India and use this modeling for estimating the level of Covid-19 mortality in the country. Our findings point to a death toll of about 2.2 million persons by late May 2021. Once Indias age structure is taken into account, these figures correspond to one of the most severe cases of Covid-19 mortality in the world.

BackgroundIndia has recorded after February a second outbreak of coronavirus that has affected the entire country. The accuracy of official statistics of Covid-19 mortality has been called in question and the real number of Covid-19 deaths is thought to be several times higher than reported. In this paper, we assembled four independent population samples to model and estimate the level of Covid-19 mortality in India.

MethodsWe first used a first population sample with age and sex of Covid-19 victims to develop a Gompertz model of Covid-19 mortality in India. We applied and adjusted this mortality model on two other national population samples after factoring in the demographic characteristics of these samples. We finally derive from one of these samples the most reasonable estimate of Covid-19 mortality level in India and confirm this result with the use of a fourth population sample.

FindingsOur findings point to a death toll of about 2.2 million persons by late May 2021. This is the largest number of Covid-19 deaths in the world. Once standardized for its age and sex structure, Indias Covid-19 mortality rate is above that of Brazil or the USA.

InterpretationOur analysis shows that existing population samples allow for an alternative estimation of deaths due to Covid-19 in India. The results confirm that only one out 7 Covid-19 deaths appear to be registered in India. The estimates point to a very Covid-19 mortality rate, which is even higher after age and sex standardization. The magnitude of the pandemic in India requires immediate attention and calls for a strong response based on a combination of non-pharmaceutical interventions and the scale-up of vaccination to make them accessible to all, with an improved surveillance system to monitor the progression of the pandemic.

category: public and global health


title: Accuracy of machine learning algorithms for the diagnosis of autism spectrum disorder based on cerebral sMRI, rs-fMRI, and EEG: protocols for three systematic reviews and meta-analyses

abstract:
ObjectiveTo determine the diagnostic accuracy of the applied machine learning algorithms for the diagnosis of autism spectrum disorder (ASD) based on structural magnetic resonance imaging (sMRI), resting-state functional MRI (rs-fMRI), and electroencephalography (EEG).

MethodsWe will include cross-sectional studies (both single-gates and two-gates) that have evaluated the diagnostic accuracy of machine learning algorithms on the sMRI data of ASD patients regardless of age, sex, and ethnicity. On the 22nd of May 2021, we searched Embase, MEDLINE, APA PsycINFO, IEEE Xplore, Scopus, and Web of Science for eligible studies. We also searched grey literature within various sources. We will use an adapted version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess the risk of bias and applicability. Data will be synthesized using the relatively new Split Component Synthesis (SCS) method. We plan to assess heterogeneity using the I2 statistics and assess publication bias using trim and fill tests combined with ln DOR. Certainty of evidence will be assessed using the GRADE approach for diagnostic studies.

FundingThese studies are funded by Sports Medicine Research Center, Tehran, Iran.

RegistrationPROSPERO submission IDs: 262575, 262825, and 262831.

Administrative informationO_ST_ABSRegistrationC_ST_ABSSubmitted in the International Prospective Register of Systematic Reviews (PROSPERO) under the submission numbers: 262575 (sMRI), 262825 (rs-fMRI), and 262831 (EEG).

ContributionsAV is the leading author for protocol development, analyses, and dissemination.

AmendmentsImportant protocol amendments post registration will be recorded and included in dissemination.

SupportThese studies are funded by the Sports Medicine Research Center, Tehran, Iran.

Conflicts of interestAll authors declare there are no conflicts of interest regarding this study or its possible results.

category: neurology


title: Functional Characterization of Lipid Regulatory Effects of Three Genes Using Knockout Mouse Models

abstract: Integrative analysis that combines genome-wide association data with expression quantitative trait analysis and network representation may illuminate causal relationships between genes and diseases. To identify causal lipid genes, we utilized genotype, gene expression, protein-protein interaction networks, and phenotype data from 5,257 Framingham Heart Study participants and performed Mendelian randomization to investigate possible mechanistic explanations for observed associations. We selected three putatively causal candidate genes (ABCA6, ALDH2, and SIDT2) for lipid traits (LDL cholesterol, HDL cholesterol and triglycerides) in humans and conducted mouse knockout studies for each gene to confirm its causal effect on the corresponding lipid trait. We conducted the RNA-seq from mouse livers to explore transcriptome-wide alterations after knocking out the target genes. Our work builds upon a lipid-related gene network and expands upon it by including protein-protein interactions. These resources, along with the innovative combination of emerging analytical techniques, provide a groundwork upon which future studies can be designed to more fully understand genetic contributions to cardiovascular diseases.

category: genetic and genomic medicine


title: Efficacy, safety, and lot to lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): a double-blind, randomised, controlled phase 3 trial

abstract:
BackgroundWe report the clinical efficacy against COVID-19 infection of BBV152, a whole-virion inactivated SARS-CoV-2 vaccine formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG).

MethodsWe did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18-98 years) randomised 1:1 using a computer-generated randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory-confirmed symptomatic COVID-19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in sub-groups for age (18-< 60 years and [≥] 60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots.

FindingsBetween November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0{middle dot}77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77{middle dot}8% (95% CI: 65{middle dot}2-86{middle dot}4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93{middle dot}4% (57{middle dot}1-99{middle dot}8). Efficacy against asymptomatic COVID-19 was 63{middle dot}6% (29{middle dot}0-82{middle dot}4). BBV152 conferred 65{middle dot}2% (95% CI: 33{middle dot}1-83{middle dot}0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported.

InterpretationBBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID-19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines.

FundingThis work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research.

Clinicaltrials.gov: NCT04641481

category: infectious diseases


title: Proxalutamide (GT0918) Improves Lung Injury in Hospitalized COVID-19 Patients - an Analysis of the Radiological Findings of the Proxa-Rescue AndroCoV Trial

abstract:
IntroductionAntiandrogens are candidates against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) due to host cell entry inhibition by the suppression of TMPRSS2. Proxalutamide is a nonsteroidal anti-androgen (NSAA) with strong antagonism on androgen receptor (AR) and angiotensin-converting enzyme 2 (ACE2). Efficacy of proxalutamide was previously demonstrated for early COVID-19 outpatients, and also reduction of deaths in hospitalized COVID-19 patients. Whether radiological changes would follow the improvement in clinical outcomes with proxalutamide is not established. The present post-hoc analysis aims to evaluate whether proxalutamide improves lung injury observed through chest computerized tomography (CT) scans.

MethodsThis is a post-hoc analysis of the radiological findings of The Proxa-Rescue AndroCoV Trial with all enrolled patients from the three participating institutions of the city of Manaus, Brazil, that had at least two chest CT scans during hospitalization. The quantification of lung parenchyma involvement was performed by blinded radiologists with expertise in analysis of COVID-19 images. A first chest CT scan was performed upon randomization and a second CT scan was performed approximately five days later, whenever feasible. Improvement rate was the first endpoint, and relative and absolute changes between the first and second CT scans were the second endpoints.

ResultsOf the 395 patients initially evaluated, 77 and 169 patients from the proxalutamide and placebo arms, respectively, were included (n=246). Baseline characteristics and percentage of lung parenchyma affected in the baseline chest CT scan were similar between groups. In the second chest CT scan, the percentage of lungs affected (Median - IQR) was 35.0% (25.0-57.5%) in the proxalutamide group versus 67.5% (50.0-80.0%) in the placebo group (p < 0.001). The absolute and relative change between the second and first chest CT scans (Median - IQR) were -15.0 percent points (p.p.) (-30.0 - 0.0p.p.) and -25.0% (-50.0 - 0.0%) in the proxalutamide group, respectively, and +15.0p.p. (0.0 - +30.0p.p.) and +32.7% (0.0 - +80.0%) in the placebo group, respectively (p < 0.001 for both absolute and relative changes). The improvement rate, i.e., the percentage of subjects that had improvement from the first to the second CT scan, was 72.3% in the proxalutamide group and 23.1% in the placebo group (p < 0.0001), with an improvement rate ratio (95%CI) of 3.15 (2.32 - 4.28).

ConclusionProxalutamide improves lung opacities in hospitalized COVID-19 patients when compared to placebo. (NCT04728802)


title: Proxalutamide Improves Lung Injury in Hospitalized COVID-19 Patients - an Analysis of the Radiological Findings of the Proxa-Rescue AndroCoV Trial


title: Proxalutamide (GT0918) Reduction of Mortality Rate in Hospitalized COVID-19 Patients Depends on Treatment Duration - an Exploratory Analysis of the Proxa-Rescue AndroCoV Trial

abstract:
IntroductionProxalutamide, a second-generation non-steroidal antiandrogen (NSAA), primarily developed for castration-resistant prostate cancer, demonstrated reduction in 28-day mortality rate of 77.7% in hospitalized COVID-19 patients in a double-blind, placebo-controlled, two-arm randomized clinical trial (RCT), through intention-to-treat (ITT) analysis. We observed a high 28-day mortality rate of patients that did not complete the 14-day treatment with proxalutamide, compared to the placebo arm. These differences may raise hypotheses to explain the wide differences between ITT and on-treatment (OT) analysis in terms of efficacy. Despite the inherent limitations of OT analysis, we aimed to respond to unanswered questions regarding the drug efficacy when the 14-day treatment with proxalutamide was complete, and secondarily understand the causality relationship between treatment interruption and mortality rate.

MethodsThis is a post-hoc exploratory analysis of a double-blinded, randomized, placebo-controlled, prospective, multicentric, two-arm RCT of 300mg-daily 14-day proxalutamide therapy for hospitalized COVID-19 patients not requiring mechanical ventilation. OT population excluded patients that did not complete the full 14-day course of therapy or died from COVID-19 complications within 24 hours of randomization. The primary outcome was the 28-day COVID-19 mortality rate. Secondary outcomes included median hospital length, 14-day and 28-day alive hospital discharge rate and 28-day all-cause mortality rate of those who discontinued intervention.

ResultsIn total, 580 patients completed the 14-day treatment or died during treatment, including 288 patients in the proxalutamide arm and 292 patients in the placebo arm, with similar baseline characteristics between groups. The 28-day COVID-19 mortality rate was 4.2% in the proxalutamide group and 49.0% in the placebo group. The mortality risk ratio (RR) was 0.08 (95% CI, 0.05-0.15), with a number needed to treat (NNT) of 2.2 to prevent death. The median hospital length stay after randomization was 5 days (interquartile range [IQR] = 3 to 7.2 days) in the proxalutamide group and 9 days (IQR = 6 to 15 days) in the placebo group (p <0.001). The 28-day all-cause mortality rate of patients that received proxalutamide but interrupted treatment before 14 days was 79.3%, while those that received placebo and interrupted before 14 days was 52.8% (p = 0.054 between groups).

ConclusionThe reduction in 28-day all-cause mortality rate with 14-day proxalutamide treatment for hospitalized COVID-19 patients was more significant while on treatment adhesion (92%), compared to the reduction when all patients enrolled in the proxalutamide arm were considered (77.7%). However, the magnitude of statistical significance of the reduction in all-cause mortality and the NNT were similar between the OT and ITT analysis. The apparent high mortality risk rate with early interruption of proxalutamide treatments suggests that strategies for treatment compliance should be reinforced for future RCTs with proxalutamide. (NCT04728802)


title: Ventilation and detection of airborne SARS-CoV-2: elucidating high-risk spaces in naturally ventilated healthcare settings

abstract:
BackgroundIn healthcare settings in low- and middle-income countries, which frequently rely upon natural ventilation, the risk of aerosol transmission of SARS-CoV-2 remains poorly understood. We aimed to evaluate the risk of exposure to SARS-CoV-2 in naturally-ventilated hospital settings by measuring parameters of ventilation and comparing these findings with results of bioaerosol sampling.

MethodsWe measured outdoor and room CO2 to estimate absolute ventilation (liters per second [L/s]) from 9 hospitals in Bangladesh during October 2020 - February 2021. We estimated infectious risk across different spaces using a modified Wells-Riley equation. We collected air samples from these same spaces at 12.5 L/min over 30 minutes and performed RT-qPCR to detect SARS-CoV-2 N-gene. We used multivariable linear regression and calculated elasticity to identify characteristics associated with ventilation.

ResultsBased on ventilation of 86 patient care areas and COVID-19 case numbers, we found that over a 40-hour exposure period, outpatient departments posed the highest median risk for infection (5.4%), followed by COVID intensive care units (1.8%). We detected SARS-CoV-2 RNA in 18.6% (16/86) of air samples. Ceiling height and total open area of doors and windows were found to have the greatest impact on ventilation.

ConclusionOur findings provide evidence that naturally-ventilated healthcare settings may pose a high risk for exposure to SARS-CoV-2, particularly among non-COVID designated spaces, but improving parameters of ventilation can mitigate this risk.


title: The Genetic Architecture of Amygdala Nuclei

abstract:
BackgroundWhereas a number of genetic variants influencing total amygdala volume have been identified in previous research, genetic architecture of its distinct nuclei have yet to be thoroughly explored. We aimed to investigate whether increased phenotypic specificity through segmentation of the nuclei aids genetic discoverability and sheds light on the extent of shared genetic architecture and biological pathways between the nuclei and disorders associated with the amygdala.

MethodsT1-weighted brain MRI scans (n=36,352, mean age= 64.26 years, 52% female) of trans-ancestry individuals from the UK Biobank were segmented into nine amygdala nuclei with FreeSurfer v6.1, and genome-wide association analyses were performed on the full sample and a European-only subset (n=31,690). We estimated heritability using Genome-wide Complex Trait Analysis, derived estimates of polygenicity, discoverability and power using MiXeR, and determined genetic correlations and shared loci between the nuclei using Linkage Disequilibrium Score Regression, followed by functional annotation using FUMA.

ResultsThe SNP-based heritability of the nuclei ranged between 0.17-0.33, and the central nucleus had the greatest statistical power for discovery. Across the whole amygdala and the nuclei volumes, 38 novel significant (p < 5x10-9) loci were identified, with most loci mapped to the central nucleus. The mapped genes and associated pathways revealed both unique and shared effects across the nuclei, and immune-related pathways were particularly enriched across several nuclei.

ConclusionsThese findings indicate that the amygdala nuclei volumes have significant genetic heritability, increased power for discovery compared to whole amygdala volume, may have unique and shared genetic architectures, and a significant immune component to their aetiology.


title: The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens

abstract:
ObjectivesWe aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19.

MethodsA pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain, B.1.351 and B.1.617.2 variants) and Vero E6 assay with a quadratic optimization workflow.

ResultsWithin 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived.

ConclusionsIDentif.AI 2.0 rapidly revealed promising drug combinations for clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/21259321v2_ufig1.gif" ALT="Figure 1">
View larger version (32K):
org.highwire.dtl.DTLVardef@f8a159org.highwire.dtl.DTLVardef@12908b7org.highwire.dtl.DTLVardef@fb6485org.highwire.dtl.DTLVardef@8493c3_HPS_FORMAT_FIGEXP  M_FIG C_FIG Highlights- When novel pathogens emerge, the immediate strategy is to repurpose drugs.
- Good drugs delivered together in suboptimal combinations and doses can yield low or no efficacy, leading to misperception that the drugs are ineffective.
- IDentif.AI 2.0 does not use in silico modeling or pre-existing data.
- IDentif.AI 2.0 pairs optimization with prospectively acquired experimental data using a SARS-CoV-2/Vero E6 assay.
- IDentif.AI 2.0 pinpoints EIDD-1931 as a foundation for optimized anti-SARS-CoV-2 combination therapies.


title: Unifying diagnostic criteria for gestational diabetes mellitus

abstract:
AIMSDisagreement about the appropriate criteria for the diagnosis of gestational diabetes mellitus (GDM) persists. This study examines an alternative approach which combines information from all time-points on the glucose tolerance test (GTT) into a single index and expands the GDM spectrum into four categories using data from three geographically and ethnically distinct populations.

METHODSA retrospective observational study design was used. Data from Wisconsin, USA (723 women) was used in derivation of the criterion and data from Doha, Qatar (1284 women) and Cape Town, South Africa (220 women) for confirmation. Pregnant women without pre-existing diabetes with a GTT done between 23 and 30 weeks gestation were included. A novel index was derived from the GTT termed the weighted average glucose (wAG). This was categorized into four pre-defined groups (henceforth National Priorities Research Program (NPRP) criterion); i) normal gestational glycemia (NGG), ii) impaired gestational glycemia (IGG), iii) GDM and iv) high risk GDM (hGDM).

RESULTSIn the Doha cohort, compared to the NGG group, the odds of large for gestational age babies increased 1.33 fold (P=0.432), 2.86 fold (P<0.001) and 3.35 fold (P<0.001) in the IGG, GDM and hGDM groups respectively. The odds of pregnancy induced hypertension increased 2.10 fold (P=0.024) in GDM & hGDM groups compared to the IGG and NGG groups. In the Cape Town cohort, a third of women in the GDM group and two-thirds in the hGDM group progressed to T2DM at 5 years.

CONCLUSIONSThe NPRP categorization identifies four distinct risk clusters of glycemia in pregnancy which may aid better decision making in routine management, avoid potential over-diagnosis of women at lower risk of complications and assist with diabetes prevention in women at high-risk after an index pregnancy with GDM.

category: endocrinology


title: Low mitochondrial copy number drives atherogenic cardiovascular disease: evidence from prospective cohort analyses in the UK Biobank combined with Mendelian Randomization

abstract:
BackgroundMitochondrial DNA (mtDNA) content might be involved in the risk of cardiovascular disease. We aimed to investigate the association of mtDNA copy number (mtDNA-CN), as a proxy of mtDNA content, and coronary artery disease (CAD) and heart failure (HF) using multivariable adjusted and Mendelian Randomizations (MR) analyses.

MethodsMultivariable-adjusted analyses were conducted using Cox-proportional hazard models in 273,619 unrelated European descendants from UK Biobank (UKB). MtDNA-CN in peripheral blood cells was computed based on the weighted intensities of the mitochondrial genome probes. For the two-sample MR analyses, single nucleotide polymorphisms (SNPs) associated with mtDNA-CN were retrieved from genome-wide association studies in UKB. SNP-outcome associations were obtained for CAD from CARDIoGRAMplusC4D, UKB and FinnGen, comprising 902,538 participants (134,759 cases), and for HF from the HERMES consortium and FinnGen, collectively having data on 1,195,531 participants (70,706 cases). MR analyses were performed per database and results were subsequently meta analyzed using fixed-effects models per study.

ResultsDuring a median follow-up of 11.8 years, participants in the lowest quintile of mtDNA-CN had higher risk for CAD (hazard ratio [95% CI]: 1.08 [1.03, 1.14]) and HF (hazard ratio [95% CI]: 1.15 [1.05, 1.24]) compared to those in the highest quintile. In MR analyses, the pooled odds ratios of genetically predicted per one-SD decrease in mtDNA were 1.16 (95% CI: 1.05, 1.27) for CAD and 1.00 (95% CI: 0.90, 1.10) for HF, respectively.

ConclusionOur findings support a possible causal role of lower mtDNA-CN in higher CAD risk, but not in higher HF risk.

category: epidemiology


title: Pre-morbid risk factors for amyotrophic lateral sclerosis: prospective cohort study

abstract:
BackgroundAs a neurodegenerative disorder with high case-fatality, there is a need to identify primary, modifiable risk factors for amyotrophic lateral sclerosis (ALS). Their detection has, however, proved elusive and this may be ascribed to the scarcity of well-characterised, sufficiently-powered cohort studies necessary to explore the aetiology of this rare condition.

MethodsUK Biobank is an on-going, closed, prospective cohort study in which 502,524 participants (273,420 women) have been linked to national hospital and mortality registries. Baseline data collection took place between 2006 and 2010 when a range of psychosocial, physiological, and demographic data were captured.

ResultsApproximately 11 years of event surveillance gave rise to 301 hospitalisations and 279 deaths ascribed to ALS. After left censoring to account for reverse causality and adjustment for confounding factors, being older (hazard ratio per 10 year increase; 95% confidence interval: 1.92; 1.58, 2.33) and male (1.37; 1.00, 1.87) were associated with elevated rates of hospitalisation for ALS. Similar effects were apparent when death due to the disorder was the outcome of interest. Of the remaining 23 potential risk indices, however, there was only a suggestion that taller people experienced an increased risk of hospitalisation (per SD increase: 1.31; 1.09, 1.59).

ConclusionsIn the present study, a comprehensive array of potential risk indices were essentially unrelated to later ALS.


title: Combining genomic and epidemiological data to compare the transmissibility of SARS-CoV-2 lineages

abstract: Emerging SARS-CoV-2 variants have shaped the second year of the COVID-19 pandemic and the public health discourse around effective control measures. Evaluating the public health threat posed by a new variant is essential for appropriately adapting response efforts when community transmission is detected. However, this assessment requires that a true comparison can be made between the new variant and its predecessors because factors other than the virus genotype may influence spread and transmission. In this study, we develop a framework that integrates genomic surveillance data to estimate the relative effective reproduction number (Rt) of co-circulating lineages. We use Connecticut, a state in the northeastern United States in which the SARS-CoV-2 variants B.1.1.7 and B.1.526 co-circulated in early 2021, as a case study for implementing this framework. We find that the Rt of B.1.1.7 was 6-10% larger than that of B.1.526 in Connecticut in the midst of a COVID-19 vaccination campaign. To assess the generalizability of this framework, we apply it to genomic surveillance data from New York City and observe the same trend. Finally, we use discrete phylogeography to demonstrate that while both variants were introduced into Connecticut at comparable frequencies, clades that resulted from introductions of B.1.1.7 were larger than those resulting from B.1.526 introductions. Our framework, which uses open-source methods requiring minimal computational resources, may be used to monitor near real-time variant dynamics in a myriad of settings.


title: Accuracy-time optimisation with cost-sensitive feature selection for Alzheimer's disease diagnosis

abstract:
ObjectiveDespite the potential of machine learning techniques to improve dementia diagnostic processes, research outcomes are often not readily translated to or adopted in clinical practice. Importantly, the time taken to administer diagnostic assessment has yet to be taken into account in feature-selection based optimisation for dementia diagnosis. We address these issues by considering the impact of assessment time as a practical constraint for feature selection of cognitive and functional assessments in Alzheimers disease diagnosis.

MethodsWe use three different feature selection algorithms to select informative subsets of dementia assessment items from a large open-source dementia dataset. We use cost-sensitive feature selection to optimise our feature selection results for assessment time as well as diagnostic accuracy. To encourage clinical adoption and further evaluation of our proposed accuracy-vs-cost optimisation algorithms, we also implement a sandbox-like toolbox with graphical user interface to evaluate user-chosen subsets of assessment items.

ResultsWe find that there are subsets of accuracy-cost optimised assessment items that can perform better in terms of diagnostic accuracy and/or total assessment time than most other standard assessments.

DiscussionOverall, our analysis and accompanying sandbox tool can facilitate clinical users and other stakeholders to apply their own domain knowledge to analyse and decide which dementia diagnostic assessment items are useful, and aid the redesigning of dementia diagnostic assessments. Clinical Impact (Clinical Research): By optimising diagnostic accuracy and assessment time, we redesign predictive and efficient dementia diagnostic assessments and develop a sandbox interface to facilitate evaluation and testing by clinicians and non-specialists.

category: health informatics


title: Alzheimer's Disease Assessments Optimised for Diagnostic Accuracy and Administration Time


title: The mediating role of epigenetic clocks underlying educational inequalities in mortality: a multi-cohort study

abstract: Educational inequalities in mortality have been observed for decades, however the underlying biological mechanisms are not well known. We assessed the mediating role of altered aging of immune cells functioning captured by DNA methylation changes in blood (known as epigenetic clocks) in educational associated all-cause mortality. Data were from eight prospective population-based cohort studies, representing 13,021 participants. We found educational inequalities in mortality were larger for men than for women, estimated by hazard differences and ratios. Epigenetic clocks explained approximately 50% of educational inequalities in mortality for men, while the proportion was small for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the WHO risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.


title: Airborne PM2.5 and the Emergence of 10 SARS-CoV-2 Variants: The Multifaceted Influence of an Airborne Pollutant on Viral Natural Selection determining SARS-CoV-2 Evolution - An Environmental Wake-up Call or an Ecological Fallacy?

abstract:
BackgroundAirborne particulate matter has been suggested as a co-factor for SARS-CoV-2 infection. Besides the deleterious effect this pollutant has on pulmonary immunity and the propagation of respiratory ACE-2 receptors (angiotensin converting enzyme II), the SARS-CoV-2s point of entry, particulate matter has also been proposed as a vector for this virus transmission. Particulate matter may also be a marker for anthropogenic activity acting as a surrogate for increased human to human contact, increasing both transmission and the mutagenic viral load. Genes coding for SARS-CoV-2 have been detected on airborne particulate matter and its proximity to the virus, may have caused this pollutant to act as a mutagen causing the inception of SARS-CoV-2s variants and simultaneously being genotoxic to the progenitor viruses, differentially favouring variant emergence.

Since the initial phases of the pandemic, a multitude of SARS-CoV-2 variants have been detected, but the few that survive to promulgate human infection have increased transmissibility. It also appears that there is a limited set of persistent mutations SARS-CoV-2 can produce. This set of mutations has been found in widely disparate and distant regions. This may suggest that besides intra-host mutation in an inflammatory ambience, an ubiquitous factor such as an environmental mutagen, may have resulted in convergent evolution leading to the emergence of similar variants. This paper examines a possible association in a multi-modal manner between the airborne pollutant PM2.5 and the emergence of ten of the most clinically and epidemiologically relevant SARS-CoV-2 variants.

MethodsThe daily average levels of PM2.5 of a number of cities, where variants were detected, were obtained from the World Air Quality Index (WAQI), a real-time assessment of atmospheric pollution. PM2.5 levels were correlated with SARS-CoV-2 variants including Variants of Concern (VOC) or Variants of Interest (VOI). These variants included the G614 variant in Beijing, the 20A.EU1 variant in Valencia, the B.1.351 variant in South Africa, the B.1.1.7 variant in the UK, the USA variants B.1.429 in Los Angeles, B.1.2 in Louisiana and New Mexico, the B.1.526 variant found in New York, the variant B.1.1.248 in Brazil. During mid-March 2021, the B.1.617 variant first detected in October 2020, surged in Nagpur, India and the R.1 variant was detected in Kentucky U.S.A. The average daily PM2.5 levels were assessed, the evaluation initiating just before the occurrence of the first spike/s in this pollutants atmospheric concentration, till after the emergence of the variants. Where available the daily number of new cases of COVID-19 diagnosed was matched to the PM2.5 levels.

ResultsThere appears a common pattern of PM2.5 in most of the regions prior and during the emergence of the SARS-CoV-2 variants. An initial spike/s of PM2.5 were noted on average 50 days prior to the emergence of the variants and another smaller spike/s in PM2.5 were noted just before or contemporaneous with the emergence of the variant. Prior to the emergence of to the G614 variant in Beijing, the average PM2.5 level during its peaks was 153.4{micro}g/m3 (SD+/-63.9) to settle to a baseline of 94.4{micro}g/m3 (SD+/-47.8)(p<0.001). Before the appearance of the 20A.EU1 variant in Valencia, the PM2.5 spikes averaged at 61.3{micro}g/m3 (SD+/-21.8) to decrease to a mean of 41.2{micro}g/m3 (SD+/-15.5) (p<0.04). In Kent, U.K. a solitary PM2.5 spike averaged 82{micro}g/m3 (SD+/-29) before the detection of the B.1.1.7 and following the PM2.5 spike the baseline level of this pollutant was 27.8{micro}g/m3 (SD+/-18.0) (p<0.03). In Nelson Mandela Bay South Africa, where B.1.351 was first detected, the PM2.5 mean baseline level was reported as 40.4{micro}g/m3 (SD+/-14.0), while prior to this variants emergence, the PM2.5 spike averaged 85.1{micro}g/m3 (SD +/-17.3)(p<0.0001). In Brazil the average PM2.5 during its spike was 107.4{micro}g/m3 (SD+/-34.2) before B.1.1.248 variant emerged and after the spike the baseline PM2.5 was 48.3{micro}g/m3 (SD+/-18) (p<0.0001). In the USA the average PM2.5 peak levels prior to the emergence of the SARS-CoV-2 variants were 118{micro}g/m3 (SD+/-28.8) in Los Angeles (baseline 66.1{micro}g/m3 (SD+/-25.1), 75+/-27.8{micro}g/m3 (baseline 43.3(SD+/-14.4){micro}g/m3 in Louisiana, 71.4+/-11.3{micro}g/m3 (baseline 43.6(SD+/-12.4){micro}g/m3 New Mexico, 54.3+/-13.8{micro}g/m3 (baseline 34.4(SD+/-11.6){micro}g/m3 in New York and 37.7+/-7{micro}g/m3 (baseline 28.5 SD+/-6.8){micro}g/m3{micro}g/m3 in Eastern Kentucky. All the spike patterns of PM2.5 levels noted in the USA were significantly higher when compared to their respective baselines (p<0.0001). Prior to the surge of the variant in India, the PM2.5 spike in Nagpur averaged 166.8+/-10.8{micro}g/m3 (baseline 123.2SD+/-16.9{micro}g/m3) (p<0.0001). In the regions where the quantity of daily new cases was available, a number of significant correlations were obtained between PM2.5 levels and the number of new cases of SARS-CoV-2 in most of the regions reviewed.

ConclusionThere appears to be an association between the levels of atmospheric PM2.5 and the emergence of SARS-CoV-2 variants. In most regions two groups of spike/s of PM2.5 were noted prior to the emergence of these variants. The first PM2.5 spike/s approximately 50 days before the variants emergence may suggest that anthropogenic activity was increased possibly reflecting augmented human to human contact, consequently increasing the viral burden of the progenitor virus. The first PM2.5 spike may also have made populations more susceptible to SARS-CoV-2 through the propagation of the respiratory ACE receptor. There is the potential that coronavirus-laden, PM2.5 induced mutagenesis in the SARS-CoV-2 genome resulted in establishing persistent variants and contemporaneously was genotoxic to the progenitor virus, expediting the latters disappearance. PM2.5 may have further diminished the pulmonary immunity inviting further viral invasion. The second spike/s prior to the emergence of variants, may suggest another anthropogenic spike in human activity. With the second spike/s in PM2.5, this airborne pollutant may have acted as a viral vector encouraging variant emergence. This may have not only led to increasing viral transmission, catalysed by the preceding risk factors, but resulted in an overwhelming viral load, providing fertile ground for variant emergence. The above findings suggest that antecedent spikes in PM2.5 prior to variant emergence not only contributed to transmission, but also impacted the immediate viral environs which resulted in its natural selection, effecting SARS-CoV-2s evolution.


title: A phase 1/2 randomized, double-blinded, placebo controlled ascending dose trial to assess the safety, tolerability and immunogenicity of ARCT-021 in healthy adults

abstract:
BackgroundThe pandemic of coronavirus disease-19 (Covid-19) continues to afflict the lives and livelihoods of many as global demand for vaccine supply remains unmet.

MethodsPhase 1 of this trial (N=42) assessed the safety, tolerability and immunogenicity of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19. Phase 2 (N=64) tested two-doses of ARCT-021 given 28 days apart. Both young and older adults were enrolled. The primary safety outcomes were local and systemic solicited adverse events (AEs) reported immediately and up to 7 days post-inoculation and unsolicited events reported up to 56 days after inoculation. Secondary and exploratory outcomes were antibody and T cell responses to vaccination, respectively.

ResultsARCT-021 was well tolerated up to one 7.5 g dose and two 5.0 g doses. Local solicited AEs, namely injection-site pain and tenderness, as well as systemic solicited AEs, such as fatigue, headache and myalgia, were more common in ARCT-021 than placebo recipients, and in younger than older adults. Seroconversion rate for anti-S IgG was 100% in all cohorts except for the 1 g one-dose in younger adults and the 7.5 g one-dose in older adults, which were each 80%. Neutralizing antibody titers increased with increasing dose although the responses following 5.0 g and 7.5 g ARCT-021 were similar. Anti-S IgG titers overlapped with those in Covid-19 convalescent plasma. ARCT-021 also elicited T-cell responses against the S glycoprotein.

ConclusionTaken collectively, the favorable safety and immunogenicity profiles support further clinical development of ARCT-021.


title: The safety and efficacy of mesenchymal stem cells in the treatment of COVID-19-associated pneumonia: a systematic review and meta-analysis

abstract: Mesenchymal stem cells (MSCs) therapy is considered one of the most promising treatments in the context of the coronavirus disease 2019 (COVID-19) pandemic. However, the safety and effectiveness of MSCs in the treatment of COVID-19-associated pneumonia patients need to be systematically reviewed and analyzed. Two independent researchers searched for the relevant studies published between October 2019 and April 2021 in PubMed, Embase, Cochrane Library, WAN FANG, and CNKI databases. A total of 22 studies involving 371 patients were included in the present study. MSCs were administered in 247 participants, and MSCs were allogeneic from umbilical cord, adipose tissue, menstrual blood, placenta, Whartons jelly, or unreported sources. Combined results found that MSCs group significantly reduced the incidence of adverse events (OR = 0.43, 95%CI. = 0.22[~]0.84, P = 0.01) and mortality (OR = 0.17, 95%CI. = 0.06[~]0.49, P < 0.01), and the difference compared with control group was statistically significant. No MSCs treat-related serious adverse events were reported. The lung function and radiographic outcomes, and biomarker levels of inflammation and immunity all showed improvement trends. Therefore, MSCs therapy is an effective and safe method in the treatment of COVID-19-associated pneumonia and shows advantages in less adverse events and mortality. However, a standard and effective MSCs treatment program needs to be developed.

category: intensive care and critical care medicine


title: Placental vascular remodeling in pregnant women with COVID-19

abstract: Severe acute respiratory syndrome coronavirus 2 has been causing the pandemic of coronavirus disease 2019 (COVID-19) that has so far resulted in over 180 million infections and nearly 4 million deaths. This respiratory virus uses angiotensin-converting enzyme 2 as a receptor to enter host cells, exhibiting a unique feature that affects various tissues in addition to the lungs. The present study reports that the placental arteries from women who gave birth to live full-term newborns while developing of COVID-19 during pregnancy exhibit severe vascular wall thickening and the occlusion of the vascular lumen. A morphometric analysis of the placental arteries stained with hematoxylin and eosin suggest a 2-fold increase in wall thickness and a 5-fold decrease in the lumen area. Immunohistochemistry with -smooth muscle actin and Massons trichrome staining showed that such placental vascular remodeling in COVID-19 is associated with smooth muscle proliferation and fibrosis. Placental vascular remodeling may represent a mechanism of the clinical problems associated with childbirth in COVID-19 patients.

category: sexual and reproductive health


title: The drop in reported invasive pneumococcal disease among adults during the first COVID-19 wave in the Netherlands explained.

abstract: Streptococcus pneumoniae is the main bacterial pathogen causing respiratory infections. Since the COVID-19 pandemic emerged, less pneumococcal disease was identified by surveillance systems around the world. Measures to prevent transmission of SARS-CoV-2 also reduce transmission of pneumococci, but this would gradually lead to lower disease rates. Here, we explore additional factors that have contributed to the instant drop in pneumococcal disease cases captured in surveillance. Our observations on referral practices and other impediments to diagnostic testing indicate that residual IPD has likely occurred but remained undetected by conventional hospital-based surveillance. Depending on setting, we discuss alternative monitoring strategies that could improve sight on pneumococcal disease dynamics.


title: Longitudinal Risk Factor for Developing Depression in Parkinson's Disease

abstract:
BackgroundDespite the established importance of identifying depression in Parkinsons disease, our understanding of the factors which place the Parkinsons disease patient at future risk of depression is limited.

MethodsOur sample consisted of 874 patients from two longitudinal cohorts, PPMI and PDBP, with median follow-up durations of 7 and 3 years respectively. Risk factors for depression at baseline were determined using logistic regression. A Cox regression model was then used to identify baseline factors that predisposed the non-depressed patient to develop depressive symptoms that were sustained for at least one year, while adjusting for antidepressant use and cognitive impairment. Common predictors between the two cohorts were identified with a random-effects meta-analysis.

ResultsWe found in our analyses that the majority of baseline non-depressed patients would develop sustained depressive symptoms at least once during the course of the study. Probable REM sleep disorder (pRBD), age, duration of diagnosis, impairment in daily activities, mild constipation, and antidepressant use were among the baseline risk factors for depression in either cohort. Our Cox regression model indicated that pRBD, impairment in daily activities, hyposmia, and mild constipation could serve as longitudinal predictors of sustained depressive symptoms.

ConclusionsWe identified several potential risk factors to aid physicians in the early detection of depression in Parkinsons disease patients. Our findings also underline the importance of adjusting for multiple covariates when analyzing risk factors for depression.


title: Uptake of SARS-CoV-2 workplace testing programs, March 2020 to March 2021

abstract:
Structured AbstractO_ST_ABSObjectiveC_ST_ABSTo track uptake of workplace SARS-CoV-2 testing programs using publicly-available data (e.g., press releases), supplementing findings from employer surveys.

MethodsWe tracked testing programs reported by 1,159 Canadian and 1,081 international employers across sectors from March 1, 2020 to March 31, 2021. We analyzed trends in uptake of testing programs, including over time and by workplace setting.

Results9.5% (n=110) of Canadian employers and 24.6% (n=266) of international employers tracked reported testing. The prevalence of reported testing programs was less than 20% in some settings associated with high risk of transmission including retail and customer-facing environments, and indoor and mixed blue collar workplaces.

ConclusionsPublicly-available data suggest that fewer employers are testing than indicated by surveys. Workplace safety in high-risk workplaces could be further improved by implementing testing strategies that deploy both screening and diagnostic tests.

category: occupational and environmental health


title: Implementation of Individualised Polygenic Risk Score Analysis: A Test Case of a Family of Four

abstract: Polygenic risk scores (PRS) have been widely applied in research studies, showing how population groups can be stratified into risk categories for many common conditions. As healthcare systems consider applying PRS to keep their populations healthy, little work has been carried out demonstrating their implementation at an individual level. We performed a systematic curation of PRS sources from established data repositories, selecting 27 phenotypes, comprising almost 40 million SNPs related to cancer, cardiovascular, metabolic and autoimmune diseases. We tested selected phenotypes using whole genome sequencing data for a family of four family related individuals, with the 1000 Genomes Project (1000G) Phase III participants as background populations. Over 98 billion allele effects were calculated in order to obtain the PRS for each of the individuals analysed here. PRS calculation for the 1000G cohort of 2,504 participants allows us to develop a methodology for risk inference and general PRS deployment. Our approach for PRS implementation advances the discussion on the adoption of PRS in a preventative healthcare setting.


title: Connection between two historical tuberculosis outbreak sites in Japan, Honshu, due to a new ancestral L2 sublineage

abstract: By gathering an initial collection of 680 public Sequence Read Archives from the Mycobacterium tuberculosis complex (MTC) including 190 belonging to the lineage 2 Beijing, and using a new bioinformatical pipeline, TB-Annotator, that analyzes more than 50,000 characters, we characterized a phylogenetically significant L2 sublineage from isolates found in Tochigi province, that we designate as Asia Ancestral 5. These isolates harbor a number of specific criteria (42 specific SNPs) and their intra-cluster pairwise distance suggested historical and not epidemiological transmission. These isolates harbor a mutation in rpoC, and do not fulfill, either the Modern Beijing lineage criteria (L2.2.1.2.2) or the other currently known Ancestral Beijing lineages described so far. Asia Ancestral 5 isolates do not possess mutT2 58 and ogt 12 characteristics of Modern Beijing, but possess ancient evolutionary characteristics. By looking into the literature, we found in a reference isolate ID381, found in Kobe and Osaka, and defined as "G3", 36 out of 42 shared and specific SNPs in the same sublineage. Using this study, we also confirmed the intermediate position of the Asia Ancestral 4 recently described in Thailand and suggest an improved classification of the L2 that now includes Asia Ancestral 4 and 5. Increasing the recruitment to around 3000 genomes (including 642 belonging to L2) confirmed our results and suggest new historical ancestral L2 phylogenetically relevant branches that remain to be investigated in detail. We discuss some anthropological and historical data from Japan history and its link to Korea and China. This study shows that the reconstruction of the early history of tuberculosis pandemia in Asia is likely to reveal complex patterns since its emergence.


title: Awareness and perceptions among members of a Japanese cancer patient advocacy group concerning the financial relationships between the pharmaceutical industry and physicians: a mixed-methods analysis of survey data

abstract:
ObjectivesFinancial conflicts of interest (FCOI) between pharmaceutical companies (Pharma) and healthcare domains may unduly influence physician-led clinical practice and patient-centered care. However, the extent of awareness and perceptions of FCOI among Japanese cancer patients remains unclear. This study aimed to assess these factors and their impacts on physician trustworthiness among Japanese cancer patients.

MethodsA cross-sectional study using self-administered surveys was conducted on a Japanese cancer patient advocacy group with 800 registered members from January to February 2019. Main outcome measures included awareness and perceptions of physician-Pharma interactions, their impact on physician trustworthiness, and attitudes towards FCOI among professions. We also performed thematic analyses on additional comments responders provided in the surveys.

ResultsAmong the 524 invited members, 96 (18.3%) completed the questionnaire. Of these, 69 (77.5%) were cancer patients. The proportion of participants aware of such interactions ranged from 2.1% to 65.3%, depending on the interaction type. Participants were generally neutral on how the interactions would affect physician trustworthiness. A large proportion of participants agreed that these interactions were unethical, could influence physicians prescribing behavior leading to unnecessary prescriptions, and negatively affect physician trustworthiness. Qualitative responses (n=56) indicated that patients expected physicians to use sound ethical judgment and avoid accepting incentives. Participants were also concerned about their treatment and the undue influence of FCOI on physicians.

ConclusionMost participants were aware of at least one FCOI between Pharma and physicians and perceived them negatively. Further efforts to regulate FCOI appear necessary to protect patient-centered care.

category: health policy


title: Prospective sero surveillance among healthcare workers vaccinated with ChAdOx1 nCoV-19 Corona vaccine in a tertiary hospital of Kerala, India

abstract:
BackgroundIndia started Covid-19 vaccination from January 16, 2021 after the approval of two candidate vaccines namely Covishield  and Covaxin . We report antibody responses among healthcare workers following two doses of Covishield  vaccination in a tertiary care setting.

MethodsThis prospective serosurveillance study was done among healthcare workers of Jubilee Mission Medical College, vaccinated during January- March 2021. Blood samples were drawn from 170 participants after their 1st dose and from 156 participants after their 2nd dose of Covishield  to measure the specific Ig G antibodies against the recombinant S1 subunit of the S protein of SARS-CoV-2.

ResultsThe median level of anti SARS CoV-2 Ig G antibody 28 days after the first dose vaccination is 3.64 S/C (IQR=5.91) and 11.6 S/C (IQR= 5.97) after 14 days of second dose vaccination. Protective levels of anti SARS CoV-2 Ig G antibodies is developed by 25 participants (14.7%) after 28 days of first dose of vaccination and by 109 participants (69.9%) after 14 days of second dose. 18-44 years age group (p=0.027) and absence of comorbidities (p=0.079) are associated with protective IgG levels.

ConclusionsRise in specific Ig G is observed after vaccination. Higher antibody response is observed with younger age group and absence of comorbidities, though statistically not significant. The influence of BMI is also not significant.


title: Convalescent plasma for hospitalized patients with COVID-19 and the effect of plasma antibodies: a randomized controlled, open-label trial

abstract:
The efficacy of convalescent plasma for COVID-19 is unclear. While most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content may influence patient outcomes.

We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 days of respiratory symptom onset. Patients were allocated 2:1 to 500 mL of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 days. The effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression.

The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. 940 patients were randomized and 921 patients were included in the intent-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) in the convalescent plasma arm and 86/307 (28.0%) in the standard of care arm; relative risk (RR) 1.16 (95% confidence interval (CI) 0.94-1.43; p=0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% vs. 26.4%; RR=1.27, 95% CI 1.02-1.57, p=0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standard log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (OR=0.74; 0.57-0.95 and OR=0.66; 0.50-0.87, respectively), while IgG against the full transmembrane Spike protein increased it (OR=1.53, 95% CI 1.14-2.05).

Convalescent plasma did not reduce the risk of intubation or death at 30 days among hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavourable antibody profiles may be associated with worse clinical outcomes compared to standard care.

Trial registrationCONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1); NCT04348656; https://www.clinicaltrials.gov/ct2/show/NCT04348656


title: Longitudinal testing for SARS-CoV-2 RNA in day care centers in Hesse, Germany, during increased local incidence and with VOC Alpha as dominant variant: Results of the SAFE KiDS 2 and SAFE KiDS 3 study

abstract:
In the summer of 2020, we investigated the rate of inapparent shedding of SARS-CoV-2 in a representative sample of day care centers from Hesse, Germany, and found a low positivity rate during a period of low local community spread.

To investigate the influence of a high local incidence setting, we conducted the SAFE KiDS 2 study. 577 children and 334 staff members of 47 day care centers were tested for respiratory and gastrointestinal shedding of SARS-CoV-2, and three infections with SARS-CoV-2 in the infectious period were detected. We conclude that viral shedding occurred infrequently while the original "wild-type" variant was dominant.

The more transmissible SARS-CoV-2 variant Alpha (B.1.1.7) became the dominant strain after SAFE KiDS 2 was concluded. The SAFE KiDS 3 study investigated the impact of the Alpha variant of SARS-CoV-2 on inapparent viral shedding in the day care setting. In this study, 756 children and 226 staff members from 46 day care centers provided self-collected saliva swabs, the so-called "Lollipop" swabs, which were tested by RT-PCR. In the four-week study period, none of the participants tested positive for SARS-CoV-2 RNA, demonstrating that inapparent shedding of SARS-CoV-2 in the day care setting was also rare during the dominance of the Alpha variant.

The influence of the variant of concern Delta on day care centers has yet to be studied.


title: SARS-CoV-2 vaccine breakthrough infections are asymptomatic or mildly symptomatic and are infrequently transmitted.

abstract: Vaccine breakthrough SARS-CoV-2 infection has been monitored in 3720 healthcare workers receiving 2 doses of BNT162b2. SARS-CoV-2 infection is detected in 33 subjects, with a 100-day cumulative incidence of 0.93%. Vaccine protection against acquisition of SARS-CoV-2 infection is 83% (95%CI: 58-93%) in the overall population and 93% (95%CI: 69-99%) in SARS-CoV-2-experienced subjects, when compared with a non-vaccinated control group from the same Institution, in which SARS-CoV-2 infection occurs in 20/346 subjects (100-day cumulative incidence: 5.78%). The infection is symptomatic in 16 (48%) vaccinated subjects vs 17 (85%) controls (p=0.001). All analyzed patients, in whom the amount of viral RNA was sufficient for genome sequencing, results infected by the alpha variant. Antibody and T-cell responses are not reduced in subjects with breakthrough infection. Evidence of virus transmission, determined by contact tracing, is observed in two (6.1%) cases. This real-world data support the protective effect of BNT162b2 vaccine. A triple antigenic exposure, such as two-dose vaccine schedule in experienced subjects, may confer a higher protection.


title: SARS-CoV-2 vaccine breakthrough infections with the alpha variant are asymptomatic or mildly symptomatic among health care workers.


title: Gene and metabolite expression dependence on body mass index in human myocardium.

abstract: We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI<25, 25[≤]BMI[≤]32, and BMI>32. The group analysis indicated that protein translation-related pathways were downregulated in 25[≤]BMI[≥]32 compared with BMI<25 patients. Muscle contraction transcripts were upregulated in 25[≤]BMI[≥]32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI>32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and -ketoglutarate increasing in the BMI<25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.

category: cardiovascular medicine


title: Examining spousal and family support as predictors of long-term weight loss and remission of type 2 diabetes following bariatric surgery

abstract:
BackgroundPostoperative outcomes vary considerably across bariatric patients and may be related to psychosocial factors. In this study, we examined whether a patients family support predicts weight loss and the remission of type 2 diabetes (T2DM) up to 5 years following surgery.

MethodsBetween 2008 to 2018, 359 patients completed a pre-surgical questionnaire before undergoing gastric bypass or sleeve gastrectomy. As part of the questionnaire, patients described their family support in terms of structure (marital status, number of family members in the household) and function (marriage satisfaction, family emotional support, family practical support). These were applied as predictors to percent total weight loss (%TWL) and T2DM remission at 1, 2, 3, 4, and 5 years following surgery.

ResultsMarital satisfaction was found to be a significant predictor of post-surgical weight trajectories. Namely, patients who reported higher marital satisfaction were more likely to sustain weight loss than patients who reported lower marital satisfaction ({beta} = 0.92, SE = 0.37, p = 0.02).

ConclusionsGiven the link between marital support and long-term weight outcomes, providers could consider asking patients about their spousal relationships during pre-surgical counselling.

Key Points Psychosocial factors may influence postoperative outcomes
 Family support was examined as a predictor of weight loss and type 2 diabetes
 Marital satisfaction significantly predicted post-surgical weight trajectories


title: Modeling robust COVID-19 intensive care unit occupancy thresholds for imposing mitigation to prevent exceeding capacities

abstract: In managing COVID-19 with non-pharmaceutical interventions, occupancy of intensive care units (ICU) is often used as an indicator to inform when to intensify mitigation and thus reduce SARS-CoV-2 transmission, strain on ICUs, and deaths. However, ICU occupancy thresholds at which action should be taken are often selected arbitrarily. We propose a quantitative approach using mathematical modeling to identify ICU occupancy thresholds at which mitigation should be triggered to avoid exceeding the ICU capacity available for COVID-19 patients. We used a stochastic compartmental model to simulate SARS-CoV-2 transmission and disease progression, including critical cases that would require intensive care. We calibrated the model for the United States city of Chicago using daily COVID-19 ICU and hospital census data between March and August 2020. We projected ICU occupancies from September to May 2021 under two possible levels of transmission increase. The effect of combined mitigation measures was modeled as a decrease in the transmission rate that took effect when projected ICU occupancy reached a specified threshold. We found that mitigation did not immediately eliminate the risk of exceeding ICU capacity. Delaying action by 7 days increased the probability of exceeding ICU capacity by 10-60% and this increase could not be counteracted by stronger mitigation. Even under modest transmission increase, a threshold occupancy no higher than 60% was required when mitigation reduced the reproductive number Rt to just below 1. At higher transmission increase, a threshold of at most 40% was required with mitigation that reduced Rt below 0.75 within the first two weeks after mitigation. Our analysis demonstrates a quantitative approach for the selection of ICU occupancy thresholds that considers parameter uncertainty and compares relevant mitigation and transmission scenarios. An appropriate threshold will depend on the location, number of ICU beds available for COVID-19, available mitigation options, feasible mitigation strengths, and tolerated durations of intensified mitigation.


title: Prominent Spatiotemporal Waves of COVID-19 Incidence in the United States: Implications for Causality, Forecasting, and Control

abstract:
Better understanding of the spatiotemporal structure of the COVID-19 epidemic in the USA may help inform more effective prevention and control strategies. By analyzing daily COVID-19 case data in the United States, Mexico and Canada, we found four continental-scale epidemic wave patterns, including travelling waves, that spanned multiple state and even international boundaries. These major epidemic patterns co-varied strongly with continental-scale seasonal temperature change patterns. Geo-contiguous states shared similar timing and amplitude of epidemic wave patterns irrespective of similarities or differences in state government political party affiliations. These analyses provide evidence that seasonal factors, probably weather changes, have exerted major effects on local COVID-19 incidence rates. Seasonal wave patterns observed during the first year of the epidemic may become repeated in the subsequent years.

One Sentence SummaryThe COVID-19 epidemic in the United States has consisted of four continental-scale spatiotemporal waves of case incidence that have spanned multiple states and even international boundaries.


title: Infection spread simulation technology in a mixed state of multi valiant viruses

abstract: ATLM was extended to simulate the spread of infection in a mixed state of mutant virus and conventional virus. It is applied to the 4th wave of infection spread in Tokyo, and (1) the 4th wave bottoms out near the end of the state of emergency, and the number of infected people increases again. (2) The rate of increase will be mainly by L452R virus, while the increase by N501Y virus will be suppressed. (3) It is anticipated that the infection will spread during the Olympic Games. (4) When mutant virus competes, the infection of highly infectious virus rises sharply while the infection by weakly infectious ones has converged. (5) It is effective as an infection control measure to find an infected person early and shorten the period from infection to quarantine by PCR test or antigen test as a measure other than vaccine.


title: Infection spread simulation technology in a mixed state of multi variant viruses


title: The Impact of Non-Pharmaceutical Interventions on the First COVID-19 Epidemic Wave in South Africa

abstract: On the 5th of March 2020, South Africa reported its first cases of COVID-19. This signalled the onset of the first COVID-19 epidemic wave in South Africa. The response by the Government of South Africa to the COVID-19 epidemic in South Africa was the use of non-pharmaceutical interventions (NPIs). In this study, a semi-reactive COVID-19 model, the ARI COVID-19 SEIR model, was used to investigate the impact of NPIs in South Africa to understand their effectiveness in the reduction of COVID-19 transmission in the South African population. This study also investigated the COVID-19 testing, reporting, hospitalised cases and excess deaths in the first COVID-19 epidemic wave in South Africa. The results from this study show that the COVID-19 NPI policies implemented by the Government of South Africa played a significant role in the reduction of COVID-19 active, hospitalised cases and deaths in South Africas first COVID-19 epidemic wave.


title: A new model of unreported COVID-19 cases outperforms three known epidemic-growth models in describing data from Cuba and Spain

abstract: Estimating the unreported cases of Covid-19 in a region/country is a complicated problem. We propose a new mathematical model that, combined with a deterministic model of the total growth of cases, describes the time evolution of the unreported cases for each reported Covid-19 case. The new model considers the growth of unreported cases in plateau periods and the decrease towards the end of an epidemic wave. We combined the new model with a Gompertz-growth model, a generalized logistic model, and a susceptible-infectious-removed (SIR) model; and fitted them via Bayesian methods to data from Cuba and Spain. The combined-model fits yielded better Bayesian-Information-Criterion values than the Gompertz, logistic, and SIR models alone. This suggests the new model can achieve improved descriptions of the evolution of a Covid-19 epidemic wave. The new model is also able to provide reliable predictions of the epidemic evolution in a short period of time. We include in the paper the steps that researchers should take to use the new model for predictions with other data.


title: The development and usability testing of digital knowledge translation tools for parents of children with acute otitis media

abstract:
Acute otitis media (AOM) is the most common bacterial ear infection affecting up to 80% of children before the age of three. Despite the common occurrence of the illness and the wide range of material available at clinics and online, parents are not always aware of these resources and they are often difficult to understand. We worked with parents to develop and assess the usability of a whiteboard animation video and interactive infographic for AOM in children. Parents rated the tools highly across all usability items, suggesting that creative tools developed using multi-method development processes can be useful, relevant, understandable, and will be used by the intended audience.

Following the completion of the English-language products, our team culturally adapted the tools for the Pakistan context and evaluated the usability of these adapted tools. During usability testing, parents indicated that they felt the tools were useful, demonstrating that culturally adapted version of knowledge translations tools are effective in ensuring that parents could understand complex health information.

category: pediatrics


title: Predictors of Depression and Anxiety Symptoms in Brazil during COVID-19

abstract: The COVID-19 pandemic in Brazil is extremely severe, and Brazil has the third-highest number of cases in the world. The goal of the study is to identify the prevalence rates and several predictors of depression and anxiety in Brazil during the initial outbreak of COVID-19. We surveyed 482 adults in 23 Brazilian states online on 9-22 May 2020, and found 70.3% of the adults (N=339) had depressive symptoms and 67.2% (N=320) had anxiety symptoms. The results of multi-class logistic regression models revealed that females, younger adults and those with fewer children had a higher likelihood of depression and anxiety symptoms; adults who worked as employees were more likely to have anxiety symptoms than those who were self-employed or unemployed; adults who spent more time browsing COVID-19 information online were more likely to have depression and anxiety symptoms. Our results provide preliminary evidence and early warning for psychiatrists and healthcare organizations to better identify and focus on the more vulnerable sub-populations in Brazil during the ongoing COVID-19 pandemic.

category: psychiatry and clinical psychology


title: DNA methylation partially mediates the relationship between childhood adversity and depressive symptoms in adolescence

abstract:
BackgroundExposure to adversity during childhood is estimated to at least double the risk of depression later in life. Some evidence suggests childhood adversity may have a greater impact on depression risk, if experienced during specific windows of development called sensitive periods. During these sensitive periods, there is evidence that adversity may leave behind biological memories, including changes in DNA methylation (DNAm). Here we ask if those changes play a role in the link between adversity and later adolescent depressive symptoms.

MethodsWe applied a method for high-dimensional mediation analysis using data from a subsample (n=627-675) of the Avon Longitudinal Study of Parents and Children. We first assessed the possibility of time-dependent relationships between seven types of childhood adversity (caregiver abuse, physical/sexual abuse, maternal psychopathology, one-adult household, family instability, financial stress, neighborhood disadvantage), measured on at least four occasions between ages 0-7 years, and adolescent depression at mean age 10.6. Specifically, we considered three types of life course hypotheses (sensitive periods, accumulation, and recency), and then evaluated which of these hypotheses had the strongest association in each adversity-adolescent depression relationship using the structured life course modeling approach (SLCMA; pronounced "slick-mah"). To conduct the mediation analyses, we used a combination of pruning and sure independence screening (a dimension reduction method) to reduce the number of methylated CpG sites under consideration to a viable subset for our sample size. We then applied a sparse group lasso penalized model to identify the top mediating loci from that subset using the combined strength of the coefficient measuring the relationship between the childhood adversity and a CpG site () and of the coefficient measuring the relationship between the CpG site and depressive symptoms ({beta}) as a metric. Using a Monte Carlo method for assessing mediation (MCMAM), we assigned a significance level and confidence interval to each identified mediator.

ResultsAcross all seven adversities, we identified a total of 70 CpG sites that showed evidence of mediating the relationship between adversity and adolescent depression symptoms. Of these 70 mediators, 37 were significant at the p < 0.05 level when applying the MCMAM, a method tailored to estimating the significance of SEM-derived mediation effects. These sites exhibited four different mediating patterns, differentiated by the direction of  and {beta}. These patterns had signals that were: (1) both positive (19 loci), (2) both negative (18 loci), (3) positive  and negative {beta} (23 loci) or (4) negative  and positive {beta} (10 loci).

ConclusionOur results suggest that DNAm partially mediates the relationship between different types of childhood adversity and depressive symptoms in adolescence. These findings provide insight into the biological mechanisms that link childhood adversity to depression, which will ultimately help develop treatments to prevent depression in more vulnerable populations.


title: Post-viral mental health sequelae: Systematic review and meta-analysis of prevalence proportions

abstract:
AimsPost-viral mental health problems (MHP) in COVID-19 patients and survivors were anticipated already during early stages of this pandemic. We aimed to synthesize the prevalence of the anxiety, depression, post-traumatic and general distress domain associated with virus epidemics since 2002.

MethodsIn this systematic review and meta-analysis, we searched PubMed, PsycINFO, and Embase from 2002 until April 14, 2021 for peer-reviewed studies reporting prevalence of MHP in adults with laboratory-confirmed or suspected SARS-CoV-1, H1N1, MERS-CoV, H7N9, Ebolavirus, or SARS-CoV-2 infection. We included studies that assessed post-viral MHP with validated and frequently used scales. A three-level random-effects meta-analysis for dependent sizes was conducted to account for multiple outcome reporting. We pooled MHP across all domains and separately by severity (above mild or moderate-to-severe) and by acute (one month), ongoing (one to three months), and post-illness stages (longer than three months). A meta-regression was conducted to test for moderating effects, particularly for exploring estimate differences between SARS-Cov-2 and previous pandemics and epidemics. PROSPERO registration: CRD42020194535.

ResultsWe identified 59 studies including between 14 to 1002 participants and providing 187 prevalence estimates. MHP, in general, decreased from acute to post-illness from 46{square}3% to 38{square}8% and for mild and moderate-to-severe from 22{square}3% to 18{square}8%, respectively. We found no evidence of moderating effects except for non-random sampling and H1N1 showing higher prevalence. Pooled MHP differed somewhat between previous pandemics/ epidemics and SARS-CoV-2 but were in a comparable range.

ConclusionsMHP prevalence estimates decreased over time but were still on a substantial level at post-illness. Post-viral mental health problems caused by SARS-CoV-2 could have been expected much earlier, given the previous post-viral sequelae.


title: Post-viral mental health sequelae in infected persons associated with COVID-19 and previous epidemics and pandemics: Systematic review and meta-analysis of prevalence estimates


title: Tracing and testing multiple generations of contacts to COVID-19 cases: cost-benefit tradeoffs

abstract:
Traditional contact tracing for COVID-19 tests the direct contacts of those who test positive even if the contacts do not show any symptom. But, by the time an infected individual is tested, the infection starting from the person may have infected a chain of individuals. Hence, why should the testing stop at direct contacts, and not test secondary, tertiary contacts or even contacts further down? One deterrent in testing long chains of individuals right away may be that it substantially increases the testing load, or does it? We investigate the costs and benefits of such multi-hop contact tracing for different number of hops. Considering a large number of contact topologies, spanning synthetic networks of divergent characteristics and those constructed from recorded interactions, we show that the cost-benefit tradeoff can be characterized in terms of a single measurable attribute, the initial epidemic growth rate. Once this growth rate crosses a threshold, multi-hop contact tracing substantially reduces the outbreak size compared to traditional contact tracing. Multi-hop even incurs a lower cost compared to the traditional contact tracing for a large range of values of the growth rate. The cost-benefit tradeoffs and the choice of the number of hops can be classified into three phases, with sharp transitions between them, depending on the value of the growth rate. The need for choosing a larger number of hops becomes greater as the growth rate increases or the environment becomes less conducive toward containing the disease.

Author summaryThe COVID-19 pandemic has wrecked havoc on lives and livelihoods worldwide. Other epidemics may well emerge in future and one needs a preparedness to prevent their growth into another pandemic. During the early stages of a new epidemic, or even a mutated version of an earlier epidemic, pharmaceutical interventions may not be available but contact tracing and timely quarantine are among the few available control measures. We show that 1) traditional contact tracing may not successfully contain the outbreak depending on the rate of growth of the epidemic, but 2) the cost-benefit tradeoffs may be substantially enhanced through the deployment of a natural multi-hop generalization which tests contact chains starting from those who test positive.


title: Effectiveness of COVID-19 vaccines against variants of concern, Canada

abstract: SARS-CoV-2 variants of concern (VOC) are more transmissible and have the potential for increased disease severity and decreased vaccine effectiveness. We estimated the effectiveness of BNT162b2 (Pfizer-BioNTech Comirnaty), mRNA-1273 (Moderna Spikevax), and ChAdOx1 (AstraZeneca Vaxzevria) vaccines against symptomatic SARS-CoV-2 infection and COVID-19 hospitalization or death caused by the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) VOCs in Ontario, Canada using a test-negative design study. Effectiveness against symptomatic infection [≥]7 days after two doses was 89-92% against Alpha, 87% against Beta, 88% against Gamma, 82-89% against Beta/Gamma, and 87-95% against Delta across vaccine products. The corresponding estimates [≥]14 days after one dose were lower. Effectiveness estimates against hospitalization or death were similar to, or higher than, against symptomatic infection. Effectiveness against symptomatic infection is generally lower for older adults ([≥]60 years) compared to younger adults (<60 years) for most of the VOC-vaccine combinations.


title: Effectiveness of COVID-19 vaccines against variants of concern in Ontario, Canada


title: Effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario


title: A national survey of attitudes towards and intentions to vaccinate against COVID-19: implications for communications

abstract:
BackgroundHesitancy about COVID-19 vaccination threatens comprehensive vaccination. It is important to examine vaccination acceptance when people are making real rather than hypothetical decisions, to identify whether targeted support is needed, and to identify implications for communications.

MethodsCross-sectional online and telephone survey with probability-based sample (n=4,978) of British adults, conducted January-February 2021. Measures: socio-demographic characteristics (age, gender, ethnicity, education, financial status), COVID-19 status, vaccine acceptance, trust in COVID-19 vaccination information sources, perceptions of vaccination priority groups, and perceptions of importance of second dose.

FindingsAmong 5,931 individuals invited, survey response rate was 84%. COVID-19 vaccine acceptance (83%) was associated with increasing age, higher level of education and having been invited for vaccination. Acceptance decreased with unconfirmed past COVID-19, greater financial hardship, and non-White British ethnicity; Black/Black British participants had lowest acceptance. Overall, healthcare and scientific sources of information were most trusted. Compared with White British participants, other ethnicities had lower trust in healthcare and scientific sources. Those with lower educational attainment or financial hardship had lower trust in healthcare and scientific sources. Those with no qualifications had higher trust in media and family/friends. While trust was low overall in community or faith leaders it was higher among those with Asian/Asian British and Black/Black British ethnicity compared with White British participants. Views of vaccine prioritisation were mostly consistent with UK official policy but there was support for prioritising additional groups. There was high support for having the second vaccine dose.

ConclusionsTargeted engagement is needed to address COVID-19 vaccine hesitancy in non-White British ethnic groups, in younger adults, and among those with lower education, greater financial hardship and unconfirmed past infection. Healthcare professionals and scientific advisors should play a central role in communications and tailored messaging is needed for hesitant groups. Careful communication around vaccination prioritisation continues to be required.


title: Characterization and Mitigation of Model Bias in Parametric Mapping of Dopamine Response to Behavioral Challenge

abstract:
AO_SCPLOWBSTRACTC_SCPLOWCompartmental modeling of 11C-raclopride (RAC) is commonly used to measure dopamine response to intra-scan behavioral tasks. Bias in estimates of binding potential (BPND) and its dynamic changes ({Delta}BPND) can arise when the selected compartmental model deviates from the underlying biology. In this work, we characterize the bias associated with assuming a single target compartment and propose a model for reducing this bias by selectively discounting the contribution of the initial uptake period.

Methods69 healthy young adult participants were scanned using RAC PET/MR while simultaneously performing a rewarded behavioral task. BPND and {Delta}BPND were estimated using an extension of the Multilinear Reference Tissue Model (MRTM2) with the task challenge encoded as a Heaviside step function. Bias was estimated using simulations designed to match the acquired data and was reduced by introducing a new model (DE-MRTM2) that reduces the biasing influence of the initial uptake period in the modeled estimation of BPND for both simulations and participant data.

ResultsBias in {Delta}BPND was observed to vary both spatially with BPND and with the assumed value of k4. At the most likely value of k4 (0.13 min-1), the average bias and the maximum voxel bias magnitude in the nucleus accumbens were estimated to be 1.2% and 3.9% respectively. Simulations estimated that debiasing the contribution of the first 27 minutes of acquired data reduced average bias and maximum voxel bias in the nucleus accumbens {Delta}BPND to -0.3% and 2.4% respectively. In the acquired participant data, DE-MRTM2 produced modest changes in the experimental estimates of striatal {Delta}BPND, while extrastriatal bias patterns were greatly reduced. DE-MRTM2 also considerably reduced the dependence of {Delta}BPND upon the first-pass selection of k2.

ConclusionSelectively discounting the contribution of the initial uptake period can help mitigate BPND- and k4-dependent bias in single compartment models of {Delta}BPND, while also reducing the dependence of {Delta}BPND on the first-pass estimation of k2.

category: radiology and imaging


title: Autonomic dysfunction after moderate-severe traumatic brain injury: symptom spectrum and clinical testing outcomes

abstract:
Background and ObjectiveSurvivors of moderate-severe traumatic brain injury (msTBI) frequently experience chronic, debilitating somatic symptoms, which are largely unexplained. The phenomenon of paroxysmal sympathetic hyperactivity, reflecting hyperacute autonomic dysfunction, is well-documented after msTBI. Limited animal and human studies, using experimental measures, have found evidence for autonomic dysfunction after msTBI. However, no studies have investigated the range and type of autonomic symptoms and autonomic dysfunction existing in msTBI.

We set out to investigate the presence and type of subjective and objective autonomic dysfunction in msTBI.

MethodsWe conducted two cohort studies. Cohort 1 comprises msTBI patients prospectively recruited from a national TBI outpatient clinic, in whom we assessed burden of autonomic symptoms using the Composite Autonomic Symptom Score (COMPASS31) autonomic symptom questionnaire. Cohort 2 comprises msTBI patients who had standard clinical autonomic function testing (supine/tilted catecholamine levels, head-up tilt, Valsalva manoeuvre, respiratory sinus arrhythmia assessment), retrospectively identified from the database of a regional clinical autonomic unit.

ResultsCohort 1 comprises 29 msTBI patients (6 females, median age 40 years, range 19-76), with a median time since injury of 19 months (range 4-105). There was multi-domain symptom burden, with all but 3 patients reporting symptoms on the COMPASS31 questionnaire, and 17/29 reporting symptoms in 3+ domains. The most commonly reported symptoms were gastrointestinal (22/29), followed by orthostatic (17/29), pupillomotor (14/29), secretomotor (14/29), bladder (12/29) and, least commonly, vasomotor (6/29). Cohort 2 comprises 18 msTBI patients (7 females, median age 44 years, range 21-64), with a median time between injury and testing of 57.5 months (range: 2-416). The majority of patients (15/18) had orthostatic symptoms as part of the reason for referral. Clinical autonomic function testing revealed a broad spectrum of autonomic dysfunction: 3/18 had evidence of sympathetic dysfunction, 10/18 had evidence of parasympathetic dysfunction, of which 6 also had evidence of mixed dysfunction.

DiscussionOur results provide evidence for clinically relevant autonomic dysfunction after moderate-severe TBI at the chronic stage. Our study advocates for routine enquiry about potential autonomic symptoms in this population, and the utility of formal clinical autonomic testing in providing diagnoses.


title: Mendelian randomization analysis identified potential genes pleiotropically associated with polycystic ovary syndrome

abstract:
Research questionPolycystic ovary syndrome (PCOS) is a common endocrine disorder with unclear etiology. Are there any genes that are pleiotropically or potentially causally associated with PCOS?

DesignWe applied the summary data-based Mendelian randomization (SMR) method integrating genome-wide association study (GWAS) for PCOS and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with PCOS. We performed separate SMR analysis using eQTL data in the ovary and whole blood.

ResultsAlthough no genes showed significant pleiotropic association with PCOS after correction for multiple testing, some of the genes exhibited suggestive significance. RPS26 showed the strongest suggestive pleiotropic association with PCOS in both SMR analyses ({beta}[SE]=0.10[0.03], PSMR=1.72x10-4 for ovary; {beta}[SE]=0.11[0.03], PSMR=1.40x10-4 for whole blood). PM20D1 showed the second strongest suggestive pleiotropic association with PCOS in the SMR analysis using eQTL data for the whole blood, and was also among the top ten hit genes in the SMR analysis using eQTL data for the ovary. Two other genes, including CTC-457L16.2 and NEIL2, were among the top ten hit genes in both SMR analyses.

ConclusionWe identified multiple genes that were potentially involved in the pathogenesis of PCOS. Our findings provided helpful leads to a better understanding of the mechanisms underlying PCOS, and revealed potential therapeutic targets for the effective treatment of PCOS.

KEY MESSAGEPolycystic ovary syndrome (PCOS) is a common endocrine disorder, and its etiology can be multifaceted. We found that multiple genes were potentially involved in the pathogenesis of PCOS. The findings revealed the genetic mechanisms underlying PCOS and potential therapeutic targets for the effective treatment of PCOS.

category: obstetrics and gynecology


title: Temozolomide sensitivity of malignant glioma cell lines: a systematic review assessing consistencies between in vitro studies

abstract:
Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that these models are reliable and consistent. We assessed this by examining the reporting of experimental conditions and sensitivity to temozolomide in glioma cells lines.

We searched Medline and Embase (Jan 1994-Jan 2021) for studies that evaluated the effect of temozolomide monotherapy on cell viability of at least one malignant glioma cell line. Studies using a drug-resistant cell line or a modified preparation of temozolomide were excluded. Key data items included type of cell lines, temozolomide exposure duration, and cell viability measure (IC50).

We included 212 eligible studies from 2,789 non-duplicate records that reported 248 distinct cell lines. The commonest cell line was U87 (60.4%). Only 10.4% studies used a patient-derived cell line. The proportion of studies not reporting each experimental condition ranged from 8.0-27.4%, including base medium (8.0%), serum supplementation (9.9%) and number of replicates (27.4%). In studies reporting IC50 the median value for U87 cell line at 24 hours, 48 hours and 72 hours was 123.9M (IQR 75.3-277.7M), 223.1M (IQR 92.0-590.1M) and 230.0M (IQR 34.1-650.0M), respectively (Figure 2A). The median IC50 at 72 hours for patient-derived cell lines was 220M (IQR 81.1-800.0M).

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/21259733v1_fig2.gif" ALT="Figure 2">
View larger version (13K):
org.highwire.dtl.DTLVardef@882449org.highwire.dtl.DTLVardef@64a6forg.highwire.dtl.DTLVardef@100e674org.highwire.dtl.DTLVardef@19f12a_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOFigure 2.C_FLOATNO Temozolomide sensitivity measured by half-maximal inhibitory concentration (IC50) in different cell lines stratified by temozolomide exposure time.

(A) IC50 summarised for cell lines that had at least 10 measurements reported in the included studies at the specified exposure time. Tests for homogeneity of variances showed no evidence of a difference between cell lines at 72 hours (Levene s test: p=0.249; Fligner-Killeen test: p=0.389). References for these studies are: U87 at 24hr,s9 s21 s26 s56 s57 s60 s83 s91 s105 s120 s146 s209 U87 at 48hr,s31 s58 s67 s88 s96 s109 s112 s114 s121 s156 s160 s163 s189 s197 s205 s209 s211 U251 at 48hr,s17 s44 s29 s31 s58 s67 s88 s96 s99 s109 s112 s114 s116 s149 s152 s156 s175 s184 s186 s187 s189 s197 s211 U87 at 72hr,s7 s13 s14 s48 s50 s63 s94 s97 s98 s104 s106 s128 s130 s134 s135 s137 s138 s145 s154 s158 s166 s169 s174 s195 s196 s198 s200 s203 s212 U251 at 72hr,s2 s30 s37 s46 s59 s97 s125 s131 s134 s135 s145 s154 s166 s167 s174 s181 s185 s196 s200 s203 s212 T98G at 72hr,s2 s28 s46 s48 s63 s94 s145 s166 s167 s192 s196 s200 and patient-derived cell lines at 72hr.s14 s122 s123 s127

(B) Further restricting to studies that did not use a hypoxic environment and quantified cell viability using MTT. Exposure time in hours is shown on the top panel. IC50 = half-maximal inhibitory concentration. References for these studies are: U251 at 48hr s31 s44 s58 s96 s149 s152 s156 s175 s187 s189 and U87 at 72 hours.s7 s13 s98 s106 s128 s130 s134 s137 s145 s166 s195 s200 s212

C_FIG Temozolomide sensitivity reported in comparable studies was not consistent between and within individual malignant glioma cell lines. Drug discovery science performed on these models cannot reliably inform clinical translation. A consensus model of reporting can maximise reproducibility and consistency among in vitro studies.

Key pointsO_LIThere is a wide variety of study designs for malignant glioma cell line studies.
C_LIO_LIReporting of experimental designs of cell line studies was suboptimal.
C_LIO_LITemozolomide sensitivity was inconsistent between and within individual cell lines.
C_LI

Importance of the studyO_LIThere is a wide variety of experimental designs for malignant glioma cell line studies but the reporting of these is suboptimal.
C_LIO_LITemozolomide sensitivity reported in comparable studies was not consistent between and within individual malignant glioma cell lines.
C_LIO_LIWhile there will be variations of opinion on what the optimal design is, a consensus model of a reporting structure is the only rational way to maximise the yield from in vitro studies to find novel therapies for our patients.
C_LI

category: oncology