title: Effects of a single 10mg dose of empagliflozin on postprandial insulin kinetics in patients with postbariatric hypoglycaemia

abstract:
IntroductionPostbariatric hypoglycaemia (PBH) is an increasingly recognized late metabolic complication of Roux-en-Y gastric bypass (GB) surgery. PBH typically manifests with a fact occurring post-meal hyperglycaemic peak, followed by a disproportionately exaggerated insulin response leading to low glucose levels. On this basis, we evaluated the effect of a single dose of empagliflozin 10mg vs. placebo on parameters of insulin kinetics.

Materials and methodsInsulin secretion, hepatic insulin extraction and total insulin clearance were evaluated after a single of empagliflozin 10mg vs. placebo followed by a standardized liquid mixed meal were evaluated in 11 subjects with confirmed PBH after GB over 3h. Parameters of interest were calculated using established mathematical models. Indices were compared between the groups using the Wilcoxon signed-rank test.

ResultsTotal beta-cell responsiveness tends to be lower with empagliflozin vs. placebo (24.83{+/-}11.00 vs. 27.15{+/-}9.68 [10-9 min-1], p=0.150). Total first-pass hepatic insulin extraction increased after empagliflozin compared to placebo (49.6{+/-}14.2 vs. 39.7{+/-}12.1 %, p=0.006), while no significant effect of empaglizflozin on basal first-pass hepatic insulin extraction was observed (79.7{+/-}7.1 vs. 81.1{+/-}6.6 %, p=0.521). Total insulin clearance resulted to be significantly lower after empagliflozin compared to placebo (3.91{+/-}1.58 vs. 3.00{+/-}1.27 l/min, p=0.002).

ConclusionThe present analysis suggests that the hypoglycaemia-attenuating effect of SGLT2-inhibition in patients with PBH is mainly mediated by an increment in insulin clearance, with also a tendency to a reduction in insulin secretion.


title: Comparative genomics and characterization of SARS-CoV-2 P.1 (Gamma) Variant of Concern (VOC) from Amazonas, Brazil

abstract:
BackgroundP.1 lineage (Gamma) was first described in the State of Amazonas, northern Brazil, in the end of 2020, and has emerged as a very important variant of concern (VOC) of SARS-CoV-2 worldwide. P.1 has been linked to increased infectivity, higher mortality and immune evasion, leading to reinfections and potentially reduced efficacy of vaccines and neutralizing antibodies.

MethodsThe samples of 276 patients from the State of Amazonas were sent to a central referral laboratory for sequencing by gold standard techniques, through Illumina MiSeq platform. Both global and regional phylogenetic analyses of the successfully sequenced genomes were conducted through maximum likelihood method. Multiple alignments were obtained including previously obtained unique human SARS-CoV-2 sequences. The evolutionary histories of spike and non-structural proteins from ORF1a of northern genomes were described and their molecular evolution was analyzed for detection of positive (FUBAR, FEL, and MEME) and negative (FEL and SLAC) selective pressures. To further evaluate the possible pathways of evolution leading to the emergence of P.1, we performed specific analysis for copy-choice recombination events. A global phylogenomic analysis with subsampled P.1 and B.1.1.28 genomes was applied to evaluate the relationship among samples.

ResultsForty-four samples from the State of Amazonas were successfully sequenced and confirmed as P.1 (Gamma) lineage. In addition to previously described P.1 characteristic mutations, we find evidence of continuous diversification of SARS-CoV-2, as rare and previously unseen P.1 mutations were detected in spike and non-structural protein from ORF1a. No evidence of recombination was found. Several sites were demonstrated to be under positive and negative selection, with various mutations identified mostly in P.1 lineage. According to the Pango assignment, phylogenomic analyses indicate all samples as belonging to the P.1 lineage.

ConclusionP.1 has shown continuous evolution after its emergence. The lack of clear evidence for recombination and the positive selection demonstrated for several sites suggest that this lineage emergence resulted mainly from strong evolutionary forces and progressive accumulation of a favorable signature set of mutations.

category: epidemiology


title: Equipment-free detection of SARS-CoV-2 and Variants of Concern using Cas13

abstract: The COVID-19 pandemic, and the recent rise and widespread transmission of SARS-CoV-2 Variants of Concern (VOCs), have demonstrated the need for ubiquitous nucleic acid testing outside of centralized clinical laboratories. Here, we develop SHINEv2, a Cas13-based nucleic acid diagnostic that combines quick and ambient temperature sample processing and lyophilized reagents to greatly simplify the test procedure and assay distribution. We benchmarked a SHINEv2 assay for SARS-CoV-2 detection against state-of-the-art antigen-capture tests using 96 patient samples, demonstrating 50-fold greater sensitivity and 100% specificity. We designed SHINEv2 assays for discriminating the Alpha, Beta, Gamma and Delta VOCs, which can be read out visually using lateral flow technology. We further demonstrate that our assays can be performed without any equipment in less than 90 minutes. SHINEv2 represents an important advance towards rapid nucleic acid tests that can be performed in any location.

category: infectious diseases


title: The UK COVID-19 furlough scheme and associations with smoking, alcohol consumption and vaping: evidence from 8 UK longitudinal population surveys.

abstract:
BackgroundDisruptions to employment status can impact smoking and alcohol consumption. During the COVID-19 pandemic, the UK implemented a furlough scheme to prevent job loss. We examine how furlough was associated with participants smoking, vaping and alcohol consumption behaviours in the early stages of the pandemic.

MethodsData were from 27,841 participants in eight UK adult longitudinal surveys. Participants self-reported employment status and current smoking, current vaping and drinking alcohol (>4 days/week or 5+ drinks per typical occasion) both before and during the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. Sub-group analyses were used to identify whether associations differed by gender, age or education.

ResultsCompared to stable employment, neither furlough, no longer being employed, nor stable unemployment were associated with smoking, vaping or drinking, following adjustment for pre-pandemic characteristics. However, some sex differences in these associations were observed, with stable unemployment associated with smoking for women (ARR=1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR=2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR=1.25; 95% CI: 0.83-1.87; I2: 0%). There was little indication of associations with drinking differing by age, gender or education.

ConclusionsWe found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK, with differences in risk compared to those who remained employed largely explained by pre-pandemic characteristics.


abstract:
The SARS-CoV-2 Gamma variant spread rapidly across Brazil, causing substantial infection and death waves. We use individual-level patient records following hospitalisation with suspected or confirmed COVID-19 to document the extensive shocks in hospital fatality rates that followed Gammas spread across 14 state capitals, and in which more than half of hospitalised patients died over sustained time periods. We show that extensive fluctuations in COVID-19 in-hospital fatality rates also existed prior to Gammas detection, and were largely transient after Gammas detection, subsiding with hospital demand. Using a Bayesian fatality rate model, we find that the geographic and temporal fluctuations in Brazils COVID-19 in-hospital fatality rates are primarily associated with geographic inequities and shortages in healthcare capacity. We project that approximately half of Brazils COVID-19 deaths in hospitals could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization, and pandemic preparedness are critical to minimize population wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries.

NoteThe following manuscript has appeared as  Report 46 - Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals at https://spiral.imperial.ac.uk:8443/handle/10044/1/91875.

One sentence summaryCOVID-19 in-hospital fatality rates fluctuate dramatically in Brazil, and these fluctuations are primarily associated with geographic inequities and shortages in healthcare capacity.


title: SARS-CoV-2 infection induces cross-reactive autoantibodies against angiotensin II

abstract: Patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme-2 (ACE-2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized COVID-19 patients developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or RBD, to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.


title: Religiosity and stigmatization related to mental illness among African-Americans and Black immigrants: cross-sectional observational study and moderation analysis

abstract:
ObjectivesStigma about mental illness is a known barrier to engagement in mental health services. This study aimed to estimate the associations between religiosity and mental illness stigma among Black adults.

DesignWe conducted an online cross-sectional study of Black adults in the United States (n=269, ages 18-65) from diverse ethnic backgrounds.

ResultsMost (n=248 [92%]) participants attended religious services; while 21 (8%) never attended. Social distance was assessed as an index of past or current stigmatizing behavior. After adjusting for demographic factors, respondents with higher attendance at religious services or greater engagement in religious activities (e.g., prayer, meditation or Bible study) reported greater proximity to people living with mental health problems (RR=1.72; 95% CI: 1.14, 2.59 and RR=1.82; CI: 1.18, 2.79, respectively). Despite reporting greater past or current social proximity, respondents with higher religiosity indices also reported greater future intended stigmatizing behavior (or lower future intended social proximity) (RRs=0.92-0.98). Ethnicity moderated the association between religiosity and future intended stigmatizing behavior. Black immigrants with higher religiosity reported lower future intended stigmatizing behavior (RR=1.16 CI: 1.02 - 1.32) whereas African-Americans with higher religiosity reported greater future intended stigmatizing behavior (RR = 0.83 CI: 0.76, 0.91).

ConclusionsHigher indices of religiosity were associated with lower past or current stigmatizing behavior towards individuals living with mental health problems but not lower future intended stigmatizing behavior. Focusing specifically on future intended stigmatizing behavior and the respondents level of religiosity, age, and ethnicity may be critical for designing effective stigma-reducing interventions for Black adults.

category: psychiatry and clinical psychology


title: Everyday functioning in a community-based volunteer population: Differences between participant- and study partner-report

abstract:
INTRODUCTIONImpaired awareness in dementia due to Alzheimers disease and related disorders, made study partner-report the preferred method of measuring interference in  instrumental activities of daily living (IADL). However, with a shifting focus towards earlier disease stages and prevention, the question arises whether self-report might be equally or even more appropriate. This study aims to investigate how participant and study partner report IADL perform in a community-based volunteer population without dementia, and which factors relate to differences between participant and study partner report.

METHODSParticipants (N=3288; 18-97 years, 70.4% females) and their study partners (N=1213; 18-88 years, 45.8% females) were recruited from the Dutch brain research registry. IADL was measured using the Amsterdam IADL Questionnaire. Concordance between participant and study partner-reported IADL difficulties was examined using intraclass correlation coefficient (ICC). Multinomial logistic regressions were used to investigate which demographic, cognitive and psychosocial factors related to participant and study partner differences, by looking at the over- and underreport of IADL difficulties by the participant, relative to their study partner.

RESULTSThe vast majority of A-IADL-Q scores represented no difficulties for both participants (87.9%) and study partners (89.4%). Concordance between participants and study partners was moderate (ICC=.55, 95%CI=[.51, .59]), 24.5% (N=297) of participants overreported their IADL difficulties compared to study partners, and 17.8% (N=216) underreported difficulties. The presence of depressive symptoms (odds ratio (OR)=1.31, 95%CI=[1.12, 1.54]), as well as memory complaints (OR=2.45, 95%CI=[1.80, 3.34]), increased the odds of participants overreporting their IADL difficulties. Higher IADL ratings decreased the odds of participant underreport (OR=0.71, 95%CI=[0.67, 0.74]).

CONCLUSIONIn this sample of community-based volunteers, the majority of participants and study partners reported no major IADL difficulties. Differences between participant and study partner were, however, quite prevalent, with subjective factors indicative of increased report of IADL difficulties by the participant in particular. These findings suggest that self- and study partner-report measures may not be interchangeable, and that the level of awareness needs to be taken into account, even in cognitively healthy individuals.

category: neurology


title: Cell-Free Tumor DNA Dominant Clone Allele Frequency (DCAF) Is Associated With Poor Outcomes In Advanced Biliary Cancers Treated With Platinum-Based Chemotherapy

abstract:
PURPOSEThis investigation sough to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment.

METHODSWe performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF) as the dominant clone allele frequency (DCAF). Results of ctDNA analysis were correlated with patients demographics, progression-free survival (PFS) and overall survival (OS).

RESULTSThe median age of patients was 67 years (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancers. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 16.4% of patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 15% of patients were treated on a clinical trial with gemcitabine and cisplatin plus additional agents (CX4945, PEGPH20 or nab-paclitaxel). TP53, KRAS, FGFR2, ARID1A, STK11 and IDH1 were the genes with highest frequency as DCAF. Median DCAF was 3% (0-97%). DCAF >3% was associated with worse OS (median OS: 10.8 vs. 18.8 months, p=0.032). Stratifying DCAF in quartiles, DCAF>10% was significantly related to worse PFS (median PFS: 3 months, p=0.014) and worse OS (median OS: 7.0 months, p=0.001). Each 1% increase in ctDNA was associated with a hazard ratio of 13.1 in OS when adjusting for subtypes, metastatic sites, size of largest tumor, age, sex, and CA19-9.

CONCLUSIONDCAF at diagnosis of advanced BTC can stratify patients who have worse outcomes when treated with upfront platinum-based chemotherapy. Each increase in %ctDNA decrease survival probabilities.

category: oncology


title: Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19

abstract:
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.

BackgroundWe find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections.

Translational SignificanceWe develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.

category: genetic and genomic medicine


title: Heart-brain connections: phenotypic and genetic insights from 40,000 cardiac and brain magnetic resonance images

abstract: Cardiovascular health interacts with cognitive and psychological health in complex ways. Yet, little is known about the phenotypic and genetic links of heart-brain systems. Using cardiac and brain magnetic resonance imaging (CMR and brain MRI) data from over 40,000 UK Biobank subjects, we developed detailed analyses of the structural and functional connections between the heart and the brain. CMR measures of the cardiovascular system were strongly correlated with brain basic morphometry, structural connectivity, and functional connectivity after controlling for body size and body mass index. The effects of cardiovascular risk factors on the brain were partially mediated by cardiac structures and functions. Using 82 CMR traits, genome-wide association study identified 80 CMR-associated genomic loci (P < 6.09 x 10-10), which were colocalized with a wide spectrum of heart and brain diseases. Genetic correlations were observed between CMR traits and brain-related complex traits and disorders, including schizophrenia, bipolar disorder, anorexia nervosa, stroke, cognitive function, and neuroticism. Our results reveal a strong heart-brain connection and the shared genetic influences at play, advancing a multi-organ perspective on human health and clinical outcomes.


title: Effectiveness, Explainability and Reliability of Machine Meta-Learning Methods for Predicting Mortality in Patients with COVID-19: Results of the Brazilian COVID-19 Registry

abstract:
ObjectiveTo provide a thorough comparative study among state-of-the-art machine learning methods and statistical methods for determining in-hospital mortality in COVID-19 patients using data upon hospital admission; to study the reliability of the predictions of the most effective methods by correlating the probability of the outcome and the accuracy of the methods; to investigate how explainable are the predictions produced by the most effective methods.

Materials and MethodsDe-identified data were obtained from COVID-19 positive patients in 36 participating hospitals, from March 1 to September 30, 2020. Demographic, comorbidity, clinical presentation and laboratory data were used as training data to develop COVID-19 mortality prediction models. Multiple machine learning and traditional statistics models were trained on this prediction task using a folded cross-validation procedure, from which we assessed performance and interpretability metrics.

ResultsThe Stacking of machine learning models improved over the previous state-of-the-art results by more than 26% in predicting the class of interest (death), achieving 87.1% of AUROC and macro F1 of 73.9%. We also show that some machine learning models can be very interpretable and reliable, yielding more accurate predictions while providing a good explanation for the  why.

ConclusionThe best results were obtained using the meta-learning ensemble model - Stacking. State-of the art explainability techniques such as SHAP-values can be used to draw useful insights into the patterns learned by machine-learning algorithms. Machine-learning models can be more explainable than traditional statistics models while also yielding highly reliable predictions.

category: health informatics


title: A combination of variant genotypes at two loci in the APOL1 gene is associated with adverse outcomes in SARS-CoV-2: a UK Biobank study.

abstract:
Risk of hospitalisation or death from COVID-19 in the UK is disproportionately high in people of African ancestry. Two APOL1 haplotypes (G1 and G2) found at high frequency only in populations of African descent are associated with increased risk of non-communicable and infectious diseases. Here, we test the hypothesis that adverse COVID-19 outcomes are also associated with these APOL1 high-risk variants.

Within 9,433 individuals with African ancestry in the UK Biobank, there were 172 hospitalisations and 47 deaths attributed to COVID-19 as of December 2021. We examined APOL1 genotypes for association with hospitalisation and death while controlling for risk factors previously associated with poor COVID-19 outcomes.

We identified an association between carriage of two APOL1 high-risk variants and death from COVID-19 (OR=2.7, 95% CI: 1. 2-6.4). Stratified by genotype, those with G1/G2 had a higher odds of COVID-19 hospitalisation (OR=2.1, 95% CI: 1.1-3.8) and death (OR=5.9, 95% CI: 2.2-15.3) than G0/G0. There was no significant association detected in carriers of G1/G1 and G2/G2.

These data suggest that the APOL1 G1/G2 genotype contributes to the increased rates of hospitalisation and mortality from COVID-19 in people of African ancestry, and could help to identify those at higher risk of severe COVID-19. This is especially relevant to geographical regions where APOL1 G1 and G2 high-risk variants are common, such as West and Central Africa and their diaspora.


title: Adverse outcomes in SARS-CoV-2 infections are associated with a combination of variant genotypes at two loci in the APOL1 gene: a UK Biobank study


title: Highly-Sensitive Lineage Discrimination of SARS-CoV-2 Variants through Allele-Specific Probe Polymerase Chain Reaction

abstract:
IntroductionTools to detect SARS-Coronavirus-2 variants of concern and track the ongoing evolution of the virus are necessary to support public health efforts and the design and evaluation of novel COVID-19 therapeutics and vaccines. Although next-generation sequencing (NGS) has been adopted as the gold standard method for discriminating SARS-CoV-2 lineages, alternative methods may be required when processing samples with low viral loads or low RNA quality.

MethodsAn allele-specific probe polymerase chain reaction (ASP-PCR) targeting lineage-specific single nucleotide polymorphisms (SNPs) was developed and used to screen 1,082 samples from two clinical trials in the United Kingdom and Brazil. Probit regression models were developed to compare ASP-PCR performance against 1,771 NGS results for the same cohorts.

ResultsIndividual SNPs were shown to readily identify specific variants of concern. ASP-PCR was shown to discriminate SARS-CoV-2 lineages with a higher likelihood than NGS over a wide range of viral loads. Comparative advantage for ASP-PCR over NGS was most pronounced in samples with Ct values between 26-30 and in samples that showed evidence of degradation. Results for samples screened by ASP-PCR and NGS showed 99% concordant results.

DiscussionASP-PCR is well-suited to augment but not replace NGS. The method can differentiate SARS-COV-2 lineages with high accuracy and would be best deployed to screen samples with lower viral loads or that may suffer from degradation. Future work should investigate further destabilization from primer:target base mismatch through altered oligonucleotide chemistry or chemical additives.


title: Association between stroke and psychosis across four nationally representative epidemiological studies

abstract:
BackgroundBoth stroke and psychosis are independently associated with high levels of disability. However, psychosis in the context of stroke has received remarkably little interest from clinicians and researchers. To date there are currently no population studies on their joint prevalence and association.

MethodsWe estimated the prevalence of i) probable psychosis in stroke and, ii) stroke in probable psychosis using four nationally representative cross-sectional psychiatric epidemiological studies: two from high-income countries (United Kingdom and United States) and two from middle-income countries (Chile and Colombia) and, subsequently, a combined dataset from all four countries. We also tested the statistical association between stroke and psychosis using single and multi-level regression models to estimate the unadjusted association between stroke and psychosis, and the association adjusted for potential demographic confounders.

ResultsAcross the combined countries dataset the prevalence of probable psychosis in stroke was 3.81% [95% CIs 2.34 - 5.82] and stroke in probable psychosis was 3.15% [95% CIs 1.94 - 4.83] suggesting approximately 1 in 26 people with probable psychosis have stroke and 1 in 32 people with stroke have probable psychosis. The adjusted association between stroke and probable psychosis from the combined dataset was estimated at OR = 3.32 [95% CIs 2.05 - 5.38]. We also examined the association between stroke and paranoia, hallucinated voices, and thought passivity delusion, and although we found significant variation in the reliability and strength of association across countries, all three psychotic symptoms were associated with stroke in the unadjusted and adjusted analyses in the combined countries dataset.

ConclusionsThere are high rates of association between psychosis and stroke, meaning there is likely a high clinical need group who are under-researched and may be poorly served by existing services. Notably, stroke is a known risk factor for psychosis, and psychosis and antipsychotic treatment for psychosis are known risk factors for stroke, meaning causality is likely to be bidirectional and treatment pathways should be integrated across traditional service boundaries.


title: Association between stroke and psychosis across four nationally representative psychiatric epidemiological studies


title: Polygenic effect on accelerated tau pathology accumulation in Alzheimer's disease: Implications for patient selection in clinical trials

abstract: Progression of fibrillar tau is a key driver of dementia symptoms in Alzheimers disease (AD), but predictors of the rate of tau accumulation at patient-level are missing. Here we combined the to-date largest number of genetic risk variants of AD (n=85 lead SNPs) from recent GWAS to generate a polygenic score (PGS) predicting the rate of change in fibrillar tau. We found that a higher PGS was associated with higher rates of PET-assessed fibrillar-tau accumulation over a mean of 1.8 yrs (range = 0.6 - 4 yrs). This, in turn, mediated effects of the PGS on faster rates of cognitive decline. Sensitivity analysis showed that the effects were similar for men and women but pronounced in individuals with elevated levels of beta-amyloid and strongest for lead SNPs expressed in microglia. Together, our results demonstrate that the PGS predicts tau progression in Alzheimers disease, which could afford sample size savings by up to 34% when used alone and up to 61% when combined with APOE {varepsilon}4 genotype in clinical trials targeting tau pathology.


title: Estimating the relationship between mobility, non-pharmaceutical interventions, and COVID-19 transmission in Ghana

abstract:
BackgroundGovernments around the world have implemented non-pharmaceutical interventions to limit the transmission of COVID-19. While lockdowns and physical distancing have proven effective for reducing COVID-19 transmission, there is still limited understanding of how NPI measures are reflected in indicators of human mobility. Further, there is a lack of understanding about how findings from high-income settings correspond to low and middle-income contexts.

MethodsIn this study, we assess the relationship between indicators of human mobility, NPIs, and estimates of Rt, a real-time measure of the intensity of COVID-19 transmission. We construct a multilevel generalised linear mixed model, combining local disease surveillance data from subnational districts of Ghana with the timing of NPIs and indicators of human mobility from Google and Vodafone Ghana.

FindingsWe observe a relationship between reductions in human mobility and decreases in Rt during the early stages of the COVID-19 epidemic in Ghana. We find that the strength of this relationship varies through time, decreasing after the most stringent period of interventions in the early epidemic.

InterpretationOur findings demonstrate how the association of NPI and mobility indicators with COVID-19 transmission may vary through time. Further, we demonstrate the utility of combining local disease surveillance data with large scale human mobility data to augment existing surveillance capacity and monitor the impact of NPI policies.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint archives for articles published in English that contained information about the COVID-19 pandemic published up to Nov 1, 2021, using the search terms "coronavirus", "CoV", "COVID-19", "mobility", "movement", and "flow". The data thus far suggests that NPI measures including physical distancing, reduction of travel, and use of personal protective equipment have been demonstrated to reduce COVID-19 transmission. Much of the existing research focuses on comparisons of NPI stringency with COVID-19 transmission among different high-income countries, or on high-income countries, leaving critical questions about the applicability of these findings to low- and middle-income settings.

Added value of this studyWe used a detailed COVID-19 surveillance dataset from Ghana, and unique high resolution spatial data on human mobility from Vodafone Ghana as well as Google smartphone GPS location data. We show how human mobility and NPI stringency were associated with changes in the effective reproduction number (Rt). We further demonstrate how this association was strongest in the early COVID-19 outbreak in Ghana, decreasing after the relaxation of national restrictions.

Implications of all the available evidenceThe change in association between human mobility, NPI stringency, and Rt may reflect a "decoupling" of NPI stringency and human mobility from disease transmission in Ghana as the COVID-19 epidemic progressed. This finding provides public health decision makers with important insights for the understanding of the utility of mobility data for predicting the spread of COVID-19.


title: Association between mobility, non-pharmaceutical interventions, and COVID-19 transmission in Ghana: a modelling study using mobile phone data


title: The Brief Observation of Symptoms of Autism (BOSA): Development of a New Adapted Assessment Measure for Remote Telehealth Administration through COVID-19 and Beyond

abstract: Interest in telehealth assessment for autism has increased due to COVID-19 and subsequent expansion of remote psychological services, though options that are easy for clinicians to adopt and available through the lifespan are limited. The Brief Observation of Symptoms of Autism (BOSA) provides a social context with standardized materials and activities that can be coded by clinicians trained in the Autism Diagnostic Observation Schedule (ADOS). The current project examined psychometric properties to determine optimal use for each BOSA version. Three hundred and seven participants with 453 BOSAs were included to determine best performing items for algorithms, validity, sensitivity, specificity, recommended cut-offs, and proposed ranges of concern. While preliminary, the BOSA provides a promising new option for telehealth-administered assessment for autism.


title: Using portable air purifiers to reduce airborne transmission of infectious respiratory viruses - a computational fluid dynamics study

abstract: Aerosols and droplets generated from expiratory events play a critical role in the transmission of infectious respiratory viruses. Increasingly robust evidence has suggested the crucial role of fine aerosols in airborne transmission of respiratory diseases, which is now widely regarded as an important transmission path of COVID-19. In this report, we used CFD modelling to investigate the efficiency of using portable air purifiers containing HEPA filters to reduce airborne aerosols in hospitals and serve as a potential retrofit mitigation strategy. We used a consulting room to set up our simulations because currently the clearance time between consultations is the controlling factor that limits the patient turnover rate. The results suggest the inlet/suction of the air purifier unit should be lifted above the floor to achieve better clearance efficiency, with up to 40% improvement possible. If multiple air purifiers are used, the combined efficiency can increase to 62%. This work provides practical guidance on a mitigation strategy that can be easily implemented in an expedient, cost-effective and rapid manner, and paves the way for developing more science-informed strategies to mitigate the airborne transmission of respiratory infections in hospitals.

category: public and global health


title: Chronic elevation of serum S100B but not neurofilament-light due to frequent choking/strangulation during sex in young adult women

abstract: Being choked/strangled during a partnered sex is an emerging sexual behavior, particularly prevalent among adolescent and young adult women, but the neurobiological impact of choking remains unknown. This case-control study aimed to test whether frequent choking during sex influences neurological health in young adult women, as assessed by serum levels of S100B and neurofilament-light (NfL). Participants who reported being choking [≥]4 times during sex in the past 30 days were enrolled into a choking group, whereas those without were assigned to a control group. Serum samples were collected and assessed for S100B and NfL levels. Demographic questionnaires as well as alcohol use, depression, and anxiety scales were also obtained. Fifty-seven participants were enrolled initially. Due to voluntary withdrawal, phlebotomy difficulties, and scheduling conflicts, the final sample size of 32 subjects (choking n=15; control n=17) was eligible for analysis. After adjusting for a significant covariate (race), the choking group exhibited significantly elevated levels of S100B relative to controls (B=13.96 pg/mL, SE=5.41, p=0.016) but no significant group differences in NfL levels. A follow-up receiver operating characteristic analysis revealed that serum levels of S100B had very good accuracy for distinguishing between the choking and control groups [AUC=0.811, 95%CI (0.651, 0.971), p=0.0033]. Our S100B provide evidence of recurring astrocyte activation due to frequent choking while the NfL data indicate that axonal microstructural integrity may be resilient to these transient hypoxic stressors. Further clinical investigation is needed to clarify the acute and chronic neurological consequences of being choked during sex using a multimodal neurologic assessment.


title: Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer

abstract: Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.


title: Allelic Complexity of KMT2A Partial Tandem Duplications in Acute Myeloid Leukemia and Myelodysplastic Syndromes

abstract: KMT2A partial tandem duplication (KMT2A-PTD) at 11q23.3 is associated with adverse risk in AML and MDS, is a potential therapeutic target, and is an attractive marker of measurable residual disease. High initial KMT2A-PTD RNA levels have been linked to poor prognosis, but mechanisms regulating KMT2A-PTD expression are not well understood. While it has been reported that KMT2A-PTD affects only a single allele, it has been theorized but not proven that duplications or genomic gains of a monoallelic KMT2A-PTD may occur, thereby potentially driving high expression and disease progression. Copy neutral loss of heterozygosity (CN-LOH) of 11q has also been described and is known to be associated with mutations in CBL but has not been reported to involve KMT2A-PTD. In this study, we identified 94 patients with KMT2A-PTDs using targeted DNA next-generation sequencing (NGS) and found that 16% (15/94) had complex secondary events, including CN-LOH and selective gain involving the KMT2A-PTD allele. High copy numbers indicating complexity were significantly enriched in AML versus MDS and correlated with higher RNA expression. Moreover, in serial samples, complexity was associated with relapse and secondary transformation. Taken together, we provide approaches to integrate quantitative and allelic assessment of KMT2A-PTDs into targeted DNA NGS and demonstrate that secondary genetic events occur in KMT2A-PTD by multiple mechanisms that may be linked to myeloid disease progression by driving increased expression from the affected allele.


title: Examining the Unit Costs of COVID-19 Vaccine Delivery in Kenya

abstract:
IntroductionVaccines are considered the path out of the COVID-19 pandemic. The government of Kenya is implementing a phased strategy to vaccinate the Kenyan population, initially targeting populations at high risk of severe disease and infection. We estimated the financial and economic unit costs of procuring and delivering the COVID-19 vaccine in Kenya across various vaccination strategies.

MethodsWe used an activity-based costing approach to estimate the incremental costs of COVID-19 vaccine delivery, from a health systems perspective. Document reviews and key informant interviews (n=12) were done to inform the activities, assumptions and the resources required. Unit prices were derived from document reviews or from market prices. Both financial and economic vaccine procurement costs per person vaccinated with 2-doses, and the vaccine delivery costs per person vaccinated with 2-doses were estimated and reported in 2021USD.

ResultsThe financial costs of vaccine procurement per person vaccinated with 2-doses ranged from $2.89-$13.09 in the 30% and 100% coverage levels respectively, however, the economic cost was $17.34 across all strategies. Financial vaccine delivery costs per person vaccinated with 2-doses, ranged from $4.28-$3.29 in the 30% and 100% coverage strategies: While the economic delivery costs were two to three times higher than the financial costs. The total procurement and delivery costs per person vaccinated with 2-doses ranged from $7.34-$16.47 for the financial costs and $29.7-$24.68 for the economic costs for the 30% and 100% coverage respectively. With the exception of procurement costs, the main cost driver of financial and economic delivery costs was supply chain costs (47-59%) and advocacy, communication and social mobilization (29-35%) respectively.

ConclusionThis analysis presents cost estimates that can be used to inform local policy and may further inform parameters used in cost-effectiveness models. The results could potentially be adapted and adjusted to country-specific assumptions to enhance applicability in similar low-and middle-income settings.

category: health economics


title: A Framework for Falsifiable Explanations of Machine Learning Models with an Application in Computational Pathology

abstract: In recent years, deep learning has been the key driver of breakthrough developments in computational pathology and other image based approaches that support medical diagnosis and treatment. The underlying neural networks as inherent black boxes lack transparency, and are often accompanied by approaches to explain their output. However, formally defining explainability has been a notorious unsolved riddle. Here, we introduce a hypothesis-based framework for falsifiable explanations of machine learning models. A falsifiable explanation is a hypothesis that connects an intermediate space induced by the model with the sample from which the data originate. We instantiate this framework in a computational pathology setting using label-free infrared microscopy. The intermediate space is an activation map, which is trained with an inductive bias to localize tumor. An explanation is constituted by hypothesizing that activation corresponds to tumor and associated structures, which we validate by histological staining as an independent secondary experiment.


title: Emergence and spread of a sub-lineage of SARS-CoV-2 Alpha variant B.1.1.7 in Europe, and with further evolution of spike mutation accumulations shared with the Beta and Gamma variants

abstract: SARS-CoV-2 evolution plays a significant role in shaping the dynamics of the COVD-19 pandemic. To monitor the evolution of SARS-CoV-2 variants, through international collaborations, we performed genomic epidemiology analyses on a weekly basis with SARS-CoV-2 samples collected from a border region between Germany, Poland and the Czech Republic in a global background. For identified virus mutant variants, active viruses were isolated and functional evaluations were performed to test their replication fitness and neutralization sensitivity against vaccine elicited serum neutralizing antibodies. Thereby we identified a new B.1.1.7 sub-lineage carrying additional mutations of nucleoprotein G204P and open-reading-frame-8 K68stop. Of note, this B.1.1.7 sub-lineage is the predominant B.1.1.7 variant in several European countries, such as Czech Republic, Austria and Slovakia. The earliest samples belonging to this sub-lineage were detected in November 2020 in a few countries in the European continent, but not in the UK. We have also detected its further evolution with extra spike mutations D138Y and A701V, which are signature mutations shared with the Beta and Gamma variants, respectively. Antibody neutralization assay of virus variant isolations has revealed that the variant with extra spike mutations is 3.2-fold less sensitive to vaccine-elicited antibodies as compared to other B.1.1.7 variants tested, indicating potential for immune evasion, but it also exhibited reduced replication fitness. The wide spread of this B.1.1.7 sub-lineage was related to the pandemic waves in early 2021 in various European countries. These findings about the emergence, spread, evolution, infection and transmission abilities of this B.1.1.7 sub-lineage add to our understanding about the pandemic development in Europe, and could possibly help to prevent similar scenarios in future.


title: Using Machine Learning to Elucidate the Spatial and Genetic Complexity of the Ascending Aorta

abstract:
BackgroundThe left ventricular outflow tract (LVOT) and ascending aorta are spatially complex, with distinct pathologies and embryologic origins. Prior work examined genetics of thoracic aortic diameter in a single plane. We sought to elucidate the genetic basis for the diameter of the LVOT, the aortic root, and the ascending aorta.

MethodsWe used deep learning to analyze 2.3 million cardiac magnetic resonance images from 43,317 UK Biobank participants. We computed the diameters of the LVOT, the aortic root, and at six locations in the ascending aorta. For each diameter, we conducted a genome-wide association study and generated a polygenic score. Finally, we investigated associations between these polygenic scores and disease incidence.

Results79 loci were significantly associated with at least one diameter. Of these, 35 were novel, and a majority were associated with one or two diameters. A polygenic score of aortic diameter approximately 13mm from the sinotubular junction most strongly predicted thoracic aortic aneurysm in UK Biobank participants (n=427,016; HR=1.42 per standard deviation; CI=1.34-1.50, P=6.67x10-21). A polygenic score predicting a smaller aortic root was predictive of aortic stenosis (n=426,502; HR=1.08 per standard deviation; CI=1.03-1.12, P=5x10-6).

ConclusionsWe detected distinct common genetic loci underpinning the diameters of the LVOT, the aortic root, and at several segments in the ascending aorta. We spatially defined a region of aorta whose genetics may be most relevant to predicting thoracic aortic aneurysm. We further described a genetic signature that may predispose to aortic stenosis. Understanding the genetic contributions to the diameter of the proximal aorta may enable identification of individuals at risk for life-threatening aortic disease and facilitate prioritization of therapeutic targets.

category: cardiovascular medicine


title: Impact of antibiotics to off-target infant gut microbiota and resistance genes in cohort studies

abstract:
BackgroundYoung children are frequently exposed to antibiotics for otitis media and respiratory infections, with the potential for collateral consequences on the gut microbiome. The impact of antibiotic exposures to off-target microbes (i.e., bacteria not targeted by antibiotic treatment) and antibiotic resistance genes (ARGs) is unknown.

MethodsWe used metagenomic sequencing data from paired stool samples collected prior to antibiotic exposure and at 1 year from over 200 infants and a difference-in-differences approach to assess the relationship between subsequent exposures and the abundance or compositional diversity of off-target microbes and ARGs while adjusting for covariates.

ResultsBy 1 year, the relative abundance of multiple species and ARGs differed by antibiotic exposure. Compared to infants never exposed to antibiotics, Bacteroides vulgatus relative abundance increased by 1.72% (95%CI:0.19,3.24) while Bacteroides fragilis decreased by 1.56% (95%CI:-4.32,1.21). Bifidobacterium species also exhibited opposing trends suggesting differential antibiotic selection. Overall, antibiotic exposure was associated with a dose-dependent decrease in alpha diversity of off-target microbes. ARGs associated with antibiotic exposure included class A beta-lactamase gene CfxA6. Among infants attending day care, Escherichia coli and ARG abundance were both positively associated with antibiotic use.

ConclusionFurther quantifying impacts to off-target microbes and ARGs has implications for antibiotic stewardship

ImpactO_LIInfants are frequently exposed to antibiotics for respiratory illnesses, but the extent of impact to off-target gut microbiota and antibiotic resistance genes is unknown.
C_LIO_LIWe quantified these impacts in 2 cohort studies using a difference-in-differences approach. Novel to the microbiome space, this enabled us to use pre/post antibiotic data to emulate a randomized controlled trial.
C_LIO_LICompared to infants unexposed to antibiotics between six weeks and 1 year, the relative abundance of multiple off-target species and antibiotic resistance genes was altered.
C_LIO_LIThis research highlights the need to consider the microbiome in antibiotic stewardship and offers a new framework for quantifying change.
C_LI


title: Serum neurofilament light as a biomarker for prognosis in patients with newly diagnosed Parkinson disease

abstract:
BackgroundPatients with Parkinsons disease (PD) have variable disease progression. More accurate prediction of progression could improve clinical trial design. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be improved by blood biomarkers.

ObjectiveTo determine if serum neurofilament light (NfL) is a useful biomarker for prognostic modelling in PD.

MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients genetic (GBA and APOE) status in a large clinical dataset. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model and explored whether serum NfL could distinguish prognostic phenotypes. We compared NfL with baseline candidate predictor variables and studied the combination of clinical, serum and genetic data.

ResultsSerum NfL was associated with patients cognitive status at baseline. Baseline NfL was associated with the progression of motor and functional impairment and with increased mortality (Survival HR 1.85, CI: 1.03-3.33, p=0.04). Baseline NfL levels predicted unfavourable progression to a similar extent as previously validated clinical predictors (AUC: 0.74 vs 0.78, p=0.22). The combination of clinical, genetic and biomarker data produced a strong predication of unfavourable outcomes as compared to age and gender alone (AUC: 0.71-age/gender vs 0.83-ALL p = 0.0076)

ConclusionsBaseline serum NfL provides an objective measure of neurodegeneration in PD patients. Clinical trials of disease-modifying therapies might usefully stratify patients according using clinical, genetic and NfL status at the time of recruitment.


title: Less efficacy of valproic acid monotherapy may be caused by neural excitatory rebound in seizures

abstract: Valproic acid (VPA) represents one of the most efficient antiepileptic drugs (AEDs) with either general or focal seizures, but a certain percentage of patients are not recovered or even worse, the mechanism under this phenomenon remains unclear. Here, we retrospectively reviewed 16 patients who received awake craniotomy surgery. Intro-operative high density electrocorticogram (ECoG) was used to record the local field potential (LFP) response to VPA treatment. We found the less efficacy of VPA monotherapy was associated with ECoG spectrum power shift from higher to lower frequency after VPA injection, together with increased synchronization of the LFP. Furthermore, we established the computational model to testify the hypothesis that the ineffectivity of VPA may be caused by excitatory dynamic rebound during the inhibitory power increasing. In addition to test the hypothesis, we employed the mice with Kanic Acid (KA)-induced epileptic model to confirm that it would be inhibited by VPA on behavior and neural activity. Also, the neural activity shows significant rebound on spike firing. Then we discovered that the LFP would increase the power spectral density in multiple wave bands after the VPA delivers. These findings suggest that less efficacy of valproic acid monotherapy in focal seizures may be caused by neural excitatory rebound which mediated by elevated inhibitory power.


title: Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

abstract:
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various stages of the disease. However, therapy resistance inevitably occurs and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multi-omics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from high-risk prostate cancer patients enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors towards a neuroendocrine-like disease state. In addition, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 - from inactive chromatin binding sites towards active cis-regulatory elements that dictate pro-survival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian rhythm core component ARNTL. Post-treatment ARNTL levels associated with poor outcome, and ARNTL suppression decreased cell growth in vitro. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy, and revealed an acquired dependency on circadian regulator ARNTL, a novel candidate therapeutic target.

SignificanceUnderstanding how prostate cancer cells adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenetic plasticity towards pro-survival signaling, and uncovered circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel clinical lead for therapeutic development.


title: Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis

abstract: Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of genes important to bone biology in general, and particularly for identifying components unique to intramembranous ossification, which cannot be captured at other skeletal sites. We assessed genetic determinants of SK-BMD in 43,800 individuals, identifying 59 genome-wide significant loci (4 novel), explaining 12.5% of its variance. Pathway and enrichment analyses of the association signals resulted in clustering within gene-sets involved in regulating the development of the skeleton; overexpressed in the musculoskeletal system; and enriched in enhancer and transcribed regions in osteoblasts. From the four novel loci (mapping to ZIC1, PRKAR1A, ATP6V1C1, GLRX3), two (ZIC1 and PRKAR1A) have previously been related to craniofacial developmental defects. Functional validation of skull development in zebrafish revealed abnormal cranial bone initiation that culminated in ectopic sutures and reduced BMD in mutated zic1 and atp6v1c1 fish and asymmetric bone growth and elevated BMD in mutated prkar1a fish. We confirmed a role of ZIC1 loss-of-function in suture patterning and discovered ATP6V1C1 gene associated with suture development. In light of the evidence presented suggesting that SK-BMD is genetically related to craniofacial abnormalities, our study opens new avenues to the understanding of the pathophysiology of craniofacial defects and towards the effective pharmacological treatment of bone diseases.


title: ClinGen CDH1 specifications for the ACMG/AMP guidelines: improvement of germline variant clinical assertions and updated curation guidelines

abstract:
PurposeThe Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines.

MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar.

ResultsUpdated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications.

ConclusionThe development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.


title: dynaPhenoM: Dynamic Phenotype Modeling from Longitudinal Patient Records Using Machine Learning

abstract: Identification of clinically meaningful subphenotypes of disease progression can facilitate better understanding of disease heterogeneity and underlying pathophysiology. We propose a machine learning algorithm, termed dynaPhenoM, to achieve this goal based on longitudinal patient records such as electronic health records (EHR) or insurance claims. Specifically, dynaPhenoM first learns a set of coherent clinical topics from the events across different patient visits within the records along with the topic transition probability matrix, and then employs the time-aware latent class analysis (T-LCA) procedure to characterize each subphenotype as the evolution of these learned topics over time. The patients in the same subphenotype have similar such topic evolution patterns. We demonstrate the effectiveness and robustness of dynaPhenoM on the case of mild cognitive impairment (MCI) to Alzheimers disease (AD) progression on three patient cohorts, and five informative subphenotypes were identified which suggest the different clinical trajectories for disease progression from MCI to AD.


title: Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study

abstract:
BackgroundAtrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation.

MethodsSingle nucleotide polymorphisms (SNPs) strongly associated (P < 5x10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium.

Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study(including 65,446 atrial fibrillation cases and 522,744 controls). We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis.

ResultsGenetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation.

ConclusionIn conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.


title: Targeting Versus Tailoring Educational Videos for Encouraging Deceased Organ Donor Registration in Black-Owned Barbershops

abstract: In the U.S., Black men have highest risk for requiring kidney transplants but are among those least likely to register for organ donation. Prior outreach used videos culturally targeted for Black communities, yet registration rates remain insufficient to meet demand. Therefore, we assessed whether generic versus videos culturally targeted or personally tailored based on prior organ donation beliefs differentially increase organ donor registration. In a randomized controlled trial, 1,353 participants in Black-owned barbershops viewed generic, targeted, or tailored videos about organ donation. Logistic regression models assessed relative impact of videos on: 1) immediate organ donor registration, 2) taking brochures, and 3) change in organ donation willingness stage of change from baseline. Randomization yielded approximately equal groups related to demographics and baseline willingness and beliefs. Neither targeted nor tailored videos differentially affected registration compared with the generic video, but participants in targeted and tailored groups were more likely to take brochures. Targeted (OR=1.74) and tailored (OR=1.57) videos were associated with incremental increases in organ donation willingness stage of change compared to the generic video. Distributing culturally targeted and individually tailored videos increased organ donor willingness stage of change among Black men in black-owned barbershops but was insufficient for encouraging registration.

category: transplantation


title: A Retrospective Cohort Study of COVID-19 among Children in Fulton County, Georgia, March 2020 - June 2021

abstract:
ObjectiveTo describe case rates, testing rates, and percent positivity of coronavirus disease 2019 (COVID-19) among children aged 0-18 years by school-age grouping.

DesignWe abstracted data from Georgias State Electronic Notifiable Disease Surveillance System on all 10,437 laboratory-confirmed COVID-19 cases among children aged 0-18 years during March 30, 2020 to June 6, 2021. We examined case rates, testing rates, and percent positivity by school-aged groupings, namely: preschool (0-4 years), elementary school (5-10 years), middle school (11-13 years), and high school (14-18 years) and compared these data among school aged children to those in the adult population (19 years and older).

SettingFulton County, Georgia.

Main outcome measuresCOVID-19 case rates, testing rates, and percent positivity.

ResultsOver time, the proportion of pediatric cases rose substantially from 1.1% (April 2020) to 21.6% (April 2021) of all cases in the county. Age-specific case rates and test rates were consistently highest among high-school aged children. Test positivity was similar across school-age groups, with periods of higher positivity among high-school aged children.

ConclusionsLow COVID-19 testing rates among children, especially early in the pandemic, likely underestimate the true burden of disease in this age group. Despite children having lower measured incidence of COVID-19, we found when broader community incidence increased, incidence also increased among all pediatric age groups. As the COVID-19 pandemic continues to evolve, it remains critical to continue learning about the incidence and transmissibility of COVID-19 in children.


title: Prevalence and Associated Factors of Diabetic ketoacidosis among Patients Living with Type 1 Diabetes in Makkah City

abstract:
ObjectiveTo assess magnitude of diabetic ketoacidosis (DKA) among type-1 diabetics and to identify associated risk factors.

MethodsA cross-sectional study was conducted among 236 type-1 diabetics in Makkah Al-Mukarramah City, Saudi Arabia.

ResultsAmong participants, 59.3% were males, 44.1% were diabetic for more than 5 years, while 70.8% reported past history of DKA. The main causes of DKA were "first presentation of the disease" (40.9%), and "discontinued treatment" (37%). The HbA1c among 53.6% was above 9%. Almost all cases who experienced DKA were hospitalised (98.8%). Out of them, 9 (5.4%) suffered complications. Female patients were more likely to suffer from episodes of DKA than males (76% and 68.3%, respectively). Most patients whose parents highest education was primary level had DKA more frequently than those whose parents had postgraduate education. Patients with unemployed fathers had significantly higher frequency of DKA (p=0.004). Ketoacidosis was significantly more frequent among patients with parents consanguinity (p<0.001). Patients who had their current HbA1c level exceeding 9% had positive history of DKA compared to those with HbA1c level [≤]7% (87.9% and 28.6%, respectively, p<0.001).

ConclusionMost type-1 diabetics experience DKA, mainly with their first presentation of disease or due to discontinuation of treatment. DKA tends to occur more frequently among female patients, those with less educated parents or when their parents are relatives.

ADVANCES IN KNOWLEDGEO_LIThis study rang a warning bell towards parents consanguinity among type-1 diabetics as a risk factor for diabetic ketoacidosis.
C_LIO_LIThe current search revealed the lack of publics awareness about type-1 diabetes and its complications as well as their low compliance towards its treatment, since diabetic ketoacidosis occurred mainly at the first presentation of the disease among diabetics, or due to treatment discontinuation.
C_LI

APPLICATION TO PATIENT CAREO_LIThis study indicated the importance of raising the publics awareness regarding early symptoms of diabetes among their children so as to be ready to seek medical advice as early as possible before the occurrence of complications.
C_LIO_LIHealth education messages should be repeatedly broadcast via mass media explaining the hazards associated with consanguineous marriages.
C_LIO_LIHealth care providers should stress to diabetic patients and/or their caregivers the importance of compliance to treatment.
C_LI

category: endocrinology


title: Fidaxomicin as first line: What will it cost in the USA and Canada?

abstract:
ImportanceRecent changes in the Infectious Diseases and Healthcare Epidemiology Societies of America (IDSA-SHEA) guidelines for managing Clostridioides difficile infections (CDI) have placed fidaxomicin as first-line treatment for CDI.

ObjectiveTo estimate the net cost of first line fidaxomicin as compared to vancomycin in the American and Canadian healthcare systems and to estimate the price points at which fidaxomicin would become cost saving.

Data sourcesWe identified all randomized controlled trials comparing fidaxomicin with vancomycin through the 2021 IDSA-SHEA guideline update. Medication costs were obtained from wholesale prices (US) and the Quebec drug formulary (Canada). The average cost of a CDI recurrence was established through two systematic reviews using PubMed.

Study selectionFor fidaxomicin efficacy, we included double-blind and placebo-controlled trials. For the systematic review of recurrence costs, studies were included if they were primary research articles, had a cost-analysis of CDI, included cases of recurrent CDI, and were calculated with cost parameters from American or Canadian healthcare systems. Studies were excluded if the population was solely pediatric or hospitalized.

Data extraction and SynthesisFor the efficacy meta-analysis, data was pooled using a random effects model. For the costs review, literature screening was performed by 2 independent reviewers. The mean cost across identified studies was adjusted to 2021 dollars.

Main Outcomes and MeasuresThe primary outcome of the meta-analysis was CDI recurrence at day 40. The primary outcome of the systematic review was the average cost of a CDI recurrence in the American and Canadian healthcare systems. The objective was to estimate the net cost per recurrence prevented and the price point below which fidaxomicin would be cost saving.

ResultsAt current drug pricing, the estimated additional cost of a 10-day course of fidaxomicin compared to vancomycin in order to prevent one recurrence was $46,178USD (95%CI $36,942-$69,267) and $13,760CAD (95%CI $11,008-$20,640), respectively. The estimated mean systemic cost of a CDI recurrence was $14,506USD and $8,588CAD, respectively. When priced below $1550USD and $800CAD, fidaxomicin was likely to become cost saving.

Conclusions and RelevanceThe increased drug expenditure on fidaxomicin will not be offset through recurrence prevention unless fidaxomicin price is re-negotiated.

Key PointsO_ST_ABSQuestionC_ST_ABSAt what price point does new guideline recommendations for changing from vancomycin to fidaxomicin for first line C. difficile infection (CDI) therapy become cost saving?

FindingsFor a 10-day course, we estimated that compared to vancomycin, treatment with fidaxomicin costs an additional $46,178USD to prevent one CDI recurrence and that treating one recurrence costs $14,506USD. The current cost of fidaxomicin is only partially offset through prevention of recurrences. Upfront therapy with fidaxomicin would be cost saving if the price were reduced below $1550USD per treatment.

MeaningNew guideline updates could add billions in additional drug costs for CDI treatment.


title: Downsizing of contact tracing during COVID-19 vaccine roll-out

abstract: Contact tracing is a key component of successful management of COVID-19. Contacts of infected individuals are asked to quarantine, which can significantly slow down (or prevent) community spread. Contact tracing is particularly effective when infections are detected quickly (e.g., through rapid testing), when contacts are traced with high probability, when the initial number of cases is low, and when social distancing and border restrictions are in place. However, the magnitude of the individual contribution of these factors in reducing epidemic spread and the impact of vaccination in determining contact tracing outputs is not fully understood. We present a delayed differential equation model to investigate how vaccine roll-out and the relaxation of social distancing requirements affect contact tracing practises. We provide an analytical criteria to determine the minimal contact tracing efficiency (defined as the the probability of identifying and quarantining contacts of symptomatic individuals) required to keep an outbreak under control, with respect to the contact rate and vaccination status of the population. Additionally, we consider how delays in outbreak detection and increased case importation rates affect the number of contacts to be traced daily. We show that in vaccinated communities a lower contact tracing efficiency is required to avoid uncontrolled epidemic spread, and delayed outbreak detection and relaxation of border restrictions do not lead to a significantly higher risk of overwhelming contact tracing. We find that investing in testing programs, rather than increasing the contact tracing capacity, has a larger impact in determining whether an outbreak will be controllable. This is because early detection activates contact tracing, which will slow, and eventually reverse exponential growth, while the contact tracing capacity is a threshold that will easily become overwhelmed if exponential growth is not curbed. Finally, we evaluate quarantine effectiveness during vaccine roll-out, by considering the proportion of people that will develop an infection while in isolation in relation to the vaccination status of the population and for different viral variants. We show that quarantine effectiveness decreases with increasing proportion of fully vaccinated individuals, and increases in the presence of more transmissible variants. These results suggest that a cost-effective approach during vaccine roll-out is to establish different quarantine rules for vaccinated and unvaccinated individuals, where rules should depend on viral trans-missibility. Altogether, our study provides quantitative information for contact tracing downsizing during vaccine roll-out, to guide COVID-19 exit strategies.


title: A RCT of a third dose CoronaVac or BNT162b2 vaccine in adults with two doses of CoronaVac

abstract:
BackgroundPoor immunogenicity and antibody waning were found in vaccinees of CoronaVac. There is lack of randomized controlled trial (RCT) data to compare the immunogenicity and safety of schedules using homologous and heterologous vaccine as a booster dose.

MethodsWe randomly assigned adults who had received 2 doses of CoronaVac with low antibody response to receive an additional booster dose of either BNT162b2 or CoronaVac. The local and systemic adverse reactions were recorded. Levels of SARS-CoV-2 neutralizing and spike binding antibody in plasma were measured.

FindingsAt one month after the third dose of vaccine, BNT162b2 vaccines elicited significantly higher surrogate virus neutralizing test (sVNT), spike receptor binding, spike N terminal domain binding, spike S2 domain binding levels than CoronaVac. More participants from the BNT162b2 group reported injection site pain and swelling as well as fatigue and muscle pain than those who received CoronaVac as the third dose. The mean results of the sVNT against the wild type, beta, gamma and delta variants in the BNT162b2 boosted group was 96.83%, 92.29%, 92.51% and 95.33% respectively which were significantly higher than the CoronaVac boosted group (Wild type: 57.75%; Beta: 38.79 %; Gamma: 32.22%; Delta: 48.87%)

ConclusionOur RCT study shows that BNT162b2 booster dose for those people who poorly responded to the previous vaccination of CoronaVac is significantly more immunogenic than a CoronaVac booster. BNT162b2 also elicits higher levels of SARS-CoV-2 specific neutralizing antibodies to different variants of concern. The adverse reactions were only mild and short-lived.

At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSPoor immunogenicity and antibody waning were found in vaccinees of CoronaVac. There is lack of randomized controlled trial (RCT) data to compare the immunogenicity and safety of schedules using homologous and heterologous vaccine as a booster dose.

What This Study Adds to the FieldOur RCT study shows that BNT162b2 booster dose for those people who poorly responded to the previous vaccination of CoronaVac is significantly more immunogenic than a CoronaVac booster. The adverse reactions were only mild and short-lived.


title: Metabolome-defined obesity and the risk of future diabetes and mortality

abstract:
BackgroundObesity is a key risk factor for type 2 diabetes, however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI, and subsequently to test if lean individuals who carry an obese metabolome are at hidden high risk of obesity related diseases, such as diabetes.

MethodsWe measured 109 metabolites in fasted plasma samples of 7663 individuals from two Swedish and one Italian population-based cohort. Ridge regression models were used to predict BMI using the plasma metabolites. Individuals with a predicted BMI either more than 5 kg/m2 higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity related risk factors and future risk of diabetes and mortality.

ResultsThe plasma metabolome could predict BMI in all cohorts (r2 = 0.48, 0.26 and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, similar waist circumference, were not more likely to change weight over time but had a 2 times higher risk of future diabetes and an 80 % increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters.

ConclusionsWe found that lean individuals with an obese metabolome, have an increased risk for diabetes and all-cause mortality compared to lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals, in order to initiate lifestyle and pharmacological interventions.


title: Black and Native Overdose Mortality Overtook that of White Individuals During the COVID-19 Pandemic

abstract: Drug overdose mortality rates have increased sharply during the COVID-19 pandemic. In recent years, overdose death rates were rising most rapidly among racial/ethnic minority communities. The pandemic has disproportionately affected communities of color in a wide swath of health, social, and economic outcomes. Careful attention is therefore warranted to trends in overdose mortality by race/ethnicity during COVID-19. We calculated total drug overdose death rates per 100,000 population by race/ethnicity for the 1999-2020 time period. We find that Black overdose mortality overtook that of White individuals in 2020 for the first time since 1999. Between 2019 and 2020 Black individuals had the largest percent increase in overdose mortality, of 48.8%, compared to 26.3% among White individuals. In 2020, Black overdose death rates rose to 36.8 per 100,000, representing 16.3% higher than the rate for White individuals for the same period. American Indian and Alaska Native (AI/AN) individuals experienced the highest rate of overdose mortality in 2020, of 41.4 per 100,000, representing 30.8% higher than the rate among White individuals. Our findings suggest that drug overdose mortality is increasingly becoming a racial justice issue in the United States and appears to have been exacerbated by the COVID-19 pandemic. Providing individuals with a safer supply of drugs, closing gaps in access to MOUD and harm reductions services, and ending routine incarceration of individuals with substance use disorders represent urgently needed, evidence-based strategies that can be employed to reduce rising inequalities in overdose.


title: Locus Coeruleus Integrity in Older Adults with and without Chronic Pain

abstract: The locus coeruleus (LC) is a brainstem region involved in regulating pain. Chronic pain is common in older adulthood, but no studies have examined its association with the LC in humans. We used neuromelanin-sensitive imaging to study differences in LC integrity in older adults with and without chronic pain. Chronic pain was assessed in community-dwelling men from the Vietnam Era Twin Study of Aging (VETSA) in 3 study waves covering an average of 12 years. Pain was self-reported on the SF-36 Bodily Pain Scale. Chronic pain was defined as moderate to severe pain severity at the current and at least one prior wave; 17% had chronic pain (n=80). At the third wave, 481 participants (mean age=67.57) underwent neuromelanin-sensitive MRI scans from which we calculated an LC contrast-to-noise ratio (LCCNR) - an index of LC integrity. We examined associations between chronic pain and LCCNR (in the rostral LC and caudal regions) with generalized estimating equations after adjusting for age, race, education, depressive symptoms, medical comorbidities, and opioid medication use. Individuals with chronic pain had .35 standard deviation lower rostral LCCNR (95% CI: -.62 to -.05) compared to those without chronic pain. No differences in the caudal LCCNR were detected. Chronic pain was associated with decreased rostral LC integrity in older adults. Differences in the rostral LC, rather than caudal LC, suggest the association between lower LC integrity and chronic pain may be related to pain processing in cortical regions where rostral LC projections typically connect.


title: Comprehensive care programmes in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized controlled trials and real-world studies

abstract:
BackgroundDifferent comprehensive care programmes (CCPs) have been developed for patients with chronic obstructive pulmonary disorder (COPD), but data regarding their effectiveness have been controversial. PubMed and Embase were searched to 1st June 2017 for articles that investigated the effects of the different types of CCPs on hospitalization or mortality rates in COPD.

ResultsA total of 67 studies including 3472633 patients (mean age: 76.1{+/-}12.7 years old; 41% male) were analyzed. CCPs reduced all-cause hospitalizations (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.63-0.79; P<0.001; I2:96%) and mortality (HR: 0.69, 95% CI: 0.573-0.83; P<0.001; I2:75%). Subgroup analyses for different CCP types were performed. Hospitalizations were reduced by pharmacist-led medication reviews (HR: 0.54; 95% CI: 0.37-0.78; P=0.001; I2:49%), structured care programmes (HR: 0.76; 95% CI: 0.66-0.87; P<0.0001; I2:88%) and self-management programmes (HR: 0.79; 95% CI: 0.64-0.99; P<0.05; I2:78%), but not continuity of care programmes (HR: 0.70; 95% CI: 0.36-1.36; P=0.29; I2:100%), early support discharge or home care packages (HR: 0.97; 95% CI: 0.91-1.04; P=0.37; I2:0%) or telemonitoring (HR: 0.61; 95% CI: 0.32-1.18; P=0.14; I2:94%). Mortality was reduced by early support discharge or home care packages (HR: 0.49; 95% CI: 0.30-0.80; P<0.01; I2:72%), structured care programmes (HR: 0.69; 95% CI: 0.53-0.90; P<0.01; I2:61%) and telemonitoring (HR: 0.52; 95% CI: 0.31-0.89; P<0.05; I2:0%), but not self-management programmes (HR: 0.79; 95% CI: 0.64-0.99; P<0.05; I2:78%).

ConclusionsComprehensive care programmes reduce hospitalization and mortality in COPD patients.

category: respiratory medicine


title: Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor

abstract:
Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n=23; tremor associated with dystonia: n=4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n=27) and matched controls (n=27).

We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral ventral intermediate (VIM) and ventro-oralis posterior nuclei (VOp) of the thalamus, contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power.

These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.


title: Effects of non-invasive brain stimulation in dystonia: a systematic review and meta-analysis

abstract:
BackgroundDeep brain stimulation is a highly effective treatment of dystonia, but is invasive and associated with risks, such as intraoperative bleeding and infections. Previous research has used non-invasive brain stimulation (NIBS) in an attempt to alleviate symptoms of dystonia. The results of these studies, however, have been variable, leaving efficacy unclear. This study aimed to evaluate the effects of NIBS on symptoms of dystonia and determine whether methodological characteristics are associated with variability in effect size.

MethodsEmbase and MEDLINE Complete databases were searched for articles using any type of NIBS as an intervention in dystonia patients, with changes in dystonia symptoms the primary outcome of interest.

ResultsMeta-analysis of 26 studies demonstrated a small effect size for NIBS in reducing symptoms of dystonia (random-effects Hedges g = 0.21, p = .002). Differences in the type of NIBS, type of dystonia, and brain region stimulated had a significant effect on dystonia symptoms. Meta-regression revealed that 10 sessions of active stimulation, and the application of concurrent motor training programs resulted in significantly larger mean effect sizes.

ConclusionNIBS has yielded small improvements to dystonic symptoms, but effect sizes depended on methodological characteristics, with more sessions of stimulation producing a larger response. Future research should further investigate the application of NIBS parallel to motor training, in addition to providing a greater quantity of sessions, to help define optimal parameters for NIBS protocols in dystonia.

RegistrationPROSPERO 2020, CRD42020175944.


title: Phase-locked transcranial electrical brain stimulation for tremor suppression in dystonic tremor syndromes

abstract:
BackgroundTremor is a common and burdensome symptom in patients with dystonia, which is clinically heterogeneous and often resistant to treatment. The pathophysiology is suggested to involve abnormal activity in the cerebellum and motor cortex, but the causal role of these brain regions remains to be established. Transcranial alternating current stimulaton (TACS) can suppress rhytmic cerebral activity in other tremor disorders when phase-locked to the ongoing arm tremor, but the effect on dystonic tremor syndromes is unknown.

Objective/HypothesisWe aimed to establish the causal role of the cerebellum and motor cortex in dystonic tremor syndromes, and explore the therapeutic efficacy of phase-locked TACS.

MethodsWe applied phase-locked TACS over the ipsilateral cerebellum (N=14) and contralateral motor cortex (N=17) in dystonic tremor syndrome patients, while patients assumed a tremor-evoking posture. We measured tremor power using accelerometery during 30s stimulation periods at 10 different phase-lags (36-degrees increments) between tremor and TACS for each target. Post-hoc, TACS-effects were related to a key clinical feature: the jerkiness (regularity) of tremor.

ResultsCerebellar TACS modulated tremor amplitude in a phase-dependent manner, such that tremor amplitude was suppressed or enhanced at opposite sides of the phase-cycle. This effect was specific for patients with non-jerky (sinusoidal) tremor (n=10), but absent in patients with jerky (irregular) tremor (n=4). Phase-locked stimulation over the motor cortex did not modulate tremor amplitude.

ConclusionsThis study indicates that the cerebellum plays a causal role in the generation of (non-jerky) dystonic tremor syndrome. Our findings suggest pathophysiologic heterogeneity between patients with dystonic tremor syndrome, which mirrors clinical variability.


title: Multiplex Solid-Phase RPA Coupled CRISPR-Based Visual Detection of SARS-CoV-2

abstract:
COVID-19 has challenged the worlds public health and led to over 4.5 million deaths. A rapid, sensitive, and cost-effective point-of-care virus detection device is crucial to the control and surveillance of the contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Here we demonstrate a solid phase isothermal recombinase polymerase amplification coupled CRISPR-based (spRPA-CRISPR) assay for on-chip multiplexed, sensitive and visual COVID-19 DNA detection. By targeting the SARS-CoV-2 structure protein encoded genomes, two specific genes were simultaneously detected with the control sample without cross-interaction with other sequences. The endpoint signal can be directly visualized for rapid detection of COVID-19. The amplified target sequences were immobilized on the one-pot device surface and detected using the mixed Cas12a-crRNA collateral cleavage of reporter released fluorescent signal when specific genes were recognized. The system was tested with samples of a broad range of concentrations (20 to 2x105 copies) and showed analytical sensitivity down to 20 copies per reaction. Furthermore, a low-cost LED UV flashlight ([~]$12) was used to provide a visible SARS-CoV-2 detection signal of the spRPA-CRISPR assay which could be purchased online easily. Thus, our platform provides a sensitive and easy-to-read multiplexed gene detection method with the capacity to specifically identify low concentration genes. Similar CRISPR biosensor chips can support a broad range of applications such as HPV DNA detection, influenza SARS-CoV-2 multiplex detection, and other infectious disease testing assays.

HighlightsO_LIA commercially available UV flashlight excited CRISPR-Cas12a based visual sensor combined with solid-phase RPA
C_LIO_LIThe developed assay could detect SARS-CoV-2 down to 20 copies with no signal crosswalk
C_LIO_LIThis multiplexed on-chip virus detection system would provide great insight for detecting and differentiating SARS-CoV-2 from other viral infections with a single sample simultaneously.
C_LI


title: Effectiveness of COVID-19 Vaccines and Post-vaccination SARS-COV 2 Infection, Hospitalization, and Mortality: a Systematic Review and Meta-analysis of Observational Studies

abstract:
Introduction & ObjectiveVaccination is one of the most important and effective ways of preventing infectious diseases, and has recently been used in the COVID-19 epidemic and pandemic. The present meta-analysis study aimed to evaluate the effectiveness of COVID-19 vaccines in reducing the incidence of infection, hospitalization, and mortality in observational studies.

Materials and MethodsA systematic search was performed independently in Scopus, PubMed, ProQuest, and Google Scholar electronic databases as well as Preprint servers using the keywords under study. The heterogeneity of the studies was assessed using I2 and {chi}2 statistics, according to which the I2 of > 50% and P -value <0.1 was reported as heterogeneity of the studies. In addition, the Pooled Vaccine Effectiveness (PVE) obtained from the studies was calculated by converting (1-Pooled estimate x 100%) based on the type of outcome.

ResultsA total of 54 records were included in this meta-analysis. The rate of PVE against SARS-COV 2 infection was about 71% (OR = 0.29, 95% CI: 0.23-0.36) in the first dose and 87% (OR = 0.13, 95% CI: 0.08-0.21) in the second, and the highest effectiveness in the first and second doses was that of BNT162b2 mRNA and combined studies. The PVE versus COVID-19-associated hospitalization was 73% (OR = 0.27, 95% CI: 0.18-0.41) in the first dose and 89% (OR = 0.11, 95% CI: 0.07-0.17) in the second. mRNA-1273 and combined studies in the first dose and ChAdOx1 and mRNA-1273 in the second dose had the highest effectiveness. Regarding the COVID-19-related mortality, PVE was about 28% (HR = 0.39, 95% CI: 0.23-0.45) in the first dose and 89% (HR = 0.11, 95% CI: 0.03-0.43) in the second.

ConclusionThe evidence obtained from this study showed that the effectiveness of BNT162b2 mRNA, mRNA-1273, and ChAdOx1 in the first and second doses, and even combined studies were associated with increased effectiveness against SARS-COV2 infection, hospitalization, and death from COVID-19. In addition, considering that the second dose was significantly more efficient than the first one, a booster dose injection could be effective in high-risk individuals. On the other hand, it was important to observe other prevention considerations in the first days after taking the first dose.


title: The basic reproduction number of COVID-19 across Africa

abstract: The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) took the world by surprise. Following the first outbreak of COVID-19 in December 2019, several models have been developed to study and understand its transmission dynamics. Although the spread of COVID-19 is being slowed down by vaccination and other interventions, there is still a need to have a clear understanding of the evolution of the pandemic across countries, states and communities. To this end, there is a need to have a clearer picture of the initial spread of the disease in different regions. In this project, we used a simple SEIR model and a Bayesian inference framework to estimate the basic reproduction number of COVID-19 across Africa. Our estimates vary between 1.98 (Sudan) and 9.66 (Mauritius), with a median of 3.67 (90% CrI: 3.31 - 4.12). The estimates provided in this paper will help to inform COVID-19 modeling in the respective countries/regions.