title: BNT162b2 Vaccine Induces Divergent B cell responses to SARS-CoV-2 S1 and S2

abstract: The first ever messenger RNA (mRNA) vaccines received emergency approvals in December 2020 and are highly protective against SARS-CoV-21-3. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants, including delta, warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating repertoire analysis with single-cell transcriptomics of B cells from serial blood collections pre- and post-vaccination. The first vaccine dose elicits highly mutated IgA+ plasmablasts against the S protein subunit S2 at day 7, suggestive of recall of a memory B cell response generated by prior infections with heterologous coronaviruses. On day 21, we observed minimally-mutated IgG+ activated switched memory B cells targeting the receptor binding domain (RBD) of the S protein, likely representing a primary response derived from naive B cells. The B cell response against RBD is specifically boosted by the second vaccine dose, and encodes antibodies that potently neutralize SARS-CoV-2 pseudovirus and partially neutralize novel variants, including delta. These results demonstrate that the first vaccine dose activates a non-neutralizing recall response predominantly targeting S2, while the second vaccine dose is vital to boosting neutralizing anti-S1 RBD B cell responses.


title: Clusters consisting only of virus types with two mutations in the helicase found by Autoencoder analysis in Washington State, USA

abstract: Using an autoencoder-based analysis to classify genomes of SARS-CoV-2 coronaviruses, we found a cluster consisting only of a specific genotype with two mutations in the helicase. This virus genotype, called C-type SARS-CoV-2, was almost exclusively prevalent in the United States from March to July 2020. This type of virus, characterized by a pair of the C17747T (P504L) and A17858G (Y541C) mutations on the nsp13 gene, had never been highly prevalent at any other time or in any other part of the world. In the U.S., Washington State was the center of the epidemic, and the C-type viruses, along with the viruses with wild-type helicase, seemed to have aroused the pandemic. In Washington State, USA, the CoViD-19 epidemic during the first two months of the year, starting at the end of February 2020, was mainly caused by the type-C virus. During this period, the infection spread rapidly; from May onwards, the number of viruses with wild-type helicases became higher than that of type-C viruses, and no type-C viruses have been collected since early July. The involvement of the helicase in this COVID-19 disease was discussed.

category: infectious diseases


title: An operationally implementable model for predicting the effects of an infectious disease on a comprehensive regional healthcare system

abstract: An operationally implementable predictive model has been developed to forecast the number of COVID-19 infections in the patient population, hospital floor and ICU censuses, ventilator and related supply chain demand. The model is intended for clinical, operational, financial and supply chain leaders and executives of a comprehensive healthcare system responsible for making decisions that depend on epidemiological contingencies. This paper describes the model that was implemented at NorthShore University HealthSystem and is applicable to any communicable disease whose risk of reinfection for the duration of the pandemic is negligible.


title: Potentially effective drugs for the treatment of COVID-19 in children: a systematic review

abstract:
IntroductionThe purpose of this systematic review is to evaluate the efficacy and safety of using potential drugs: remdesivir and glucocorticoid in treating children and adolescents with COVID-19 and intravenous immunoglobulin (IVIG) in treating MIS-C.

MethodsWe searched seven databases, three preprint platform, ClinicalTrials.gov, and Google from December 1, 2019, to August 5, 2021, to collect evidence of remdesivir, glucocorticoid, and IVIG which were used in children and adolescents with COVID-19 or MIS-C.

ResultsA total of six cohort studies and one case series study were included in this systematic review. In terms of remdesivir, the meta-analysis of single-arm cohort studies have shown that, after the treatment, 37.1% (95%CI, 0.0% to 74.5%) experienced adverse events, 5.9% (95%CI, 1.5% to 10.2%) died, 37.2% (95%CI, 0% to 76.0%) needed extracorporeal membrane oxygenation or invasive mechanical ventilation. As for glucocorticoids, the results of the meta-analysis showed that the fixed-effect summary odds ratio for the association with mortality was 2.79 (95%CI, 0.13 to 60.87), and the mechanical ventilation rate was 3.12 (95%CI, 0.80 to 12.08) for glucocorticoids compared with the control group. In terms of IVIG, the two included cohort studies showed that for MIS-C patients with more severe clinical symptoms, IVIG combined with methylprednisolone could achieve better clinical efficacy than IVIG alone.

ConclusionsOverall, the current evidence in the included studies is insignificant and of low quality. It is recommended to conduct high-quality randomized controlled trials of remdesivir, glucocorticoids, and IVIG in children and adolescents with COVID-19 or MIS-C to provide substantial evidence for the development of guidelines.


title: Maternal Urinary Phthalate Metabolites are Associated with Lipidomic Signatures Among Pregnant Women in Puerto Rico

abstract:
BackgroundPhthalates have been reported to alter circulating lipid concentrations in animals, and investigation of these associations in humans will provide greater understanding of potential mechanisms for health outcomes.

Objectiveto explore associations between phthalate metabolite biomarkers and lipidomic profiles among pregnant women (n = 99) in the Puerto Rico PROTECT cohort.

MethodsWe measured 19 urinary phthalate metabolites during 24-28 weeks of pregnancy. Lipidomic profiles were identified from plasma samples by liquid chromatography-mass spectrometry-based shotgun lipidomics. Relationships between phthalates and lipid profiles were estimated using compound-by-compound comparisons in multiple linear regression and dimension reduction techniques. We derived sums for each lipid class and sub-class (saturated, monounsaturated, polyunsaturated) which were then regressed on phthalates. Associations were adjusted for false discovery.

ResultsAfter controlling for multiple comparisons, 33 phthalate-lipid associations were identified (q-value<0.05), and diacylglycerol 40:7 and plasmenyl-phosphatidylcholine 35:1 were the most strongly associated with multiple phthalate metabolites. Metabolites of di-2-ethylhexyl phthalate, bis(2-ethylhexyl) phthalate, dibutyl phthalates, and diisobutyl phthalate were associated with increased ceramides, lysophosphatidylcholines, lysophosphatidylethanolamines, and triacylglycerols, particularly those containing saturated and monounsaturated fatty acid chains.

SignificanceCharacterization of associations between lipidomic markers and phthalates during pregnancy will yield mechanistic insight for maternal and child health outcomes.

Impact StatementThis study leverages emerging technology to evaluate lipidome-wide signatures of phthalate exposure during pregnancy. Circulating lipids are critical for biological processes including inflammation, cell-to-cell communication, and metabolism. Therefore, lipid signatures of phthalate exposure provide insight into potential toxicological mechanisms. Characterization of these mechanisms are relevant for informing the etiology of maternal and childrens health outcomes.

category: epidemiology


title: Turnover of SARS-CoV-2 lineages shaped the pandemic and enabled the emergence of new variants in the state of Rio de Janeiro, Brazil

abstract: In the present study, we provide a retrospective genomic epidemiology analysis of the SARS-CoV-2 pandemic in the state of Rio de Janeiro, Brazil. We gathered publicly available data from GISAD and sequenced more 1,927 new genomes sampled periodically from March 2021 to June 2021 from 91 out of the 92 cities of the state. Our results showed that the pandemic was characterized by three different phases driven by a successive replacement of lineages. All stages occurred in distinct mortality and mobility contexts, with higher evidence of social distancing measures being observed in early pandemic and relaxed in the last two phases. Interestingly, we noticed that viral supercarriers accounted for the overwhelming majority of the circulating virus (> 90%) among symptomatic individuals in the state. Moreover, SARS-CoV-2 genomic surveillance also revealed the emergence and spread of two new variants (P.5 and P.1.2) firstly reported in this study. Altogether, our findings provided important lessons learned from the different epidemiological aspects of the SARS-CoV-2 dynamic in the state of Rio de Janeiro that have a strong potential to shape future decisions aiming to improve public health management and understanding mechanisms underlying virus dispersion.


title: 1H-NMR metabolomics-based surrogates to impute common clinical risk factors and endpoints

abstract: Missing or incomplete phenotypic information can severely deteriorate the statistical power in epidemiological studies. High-throughput quantification of small-molecules in bio-samples, i.e.  metabolomics, is steadily gaining popularity, as it is highly informative for various phenotypical characteristics. Here we aim to leverage metabolomics to impute missing data in clinical variables routinely assessed in large epidemiological and clinical studies. To this end, we have employed [~]25,000 1H-NMR metabolomics samples from 28 Dutch cohorts collected within the BBMRI-NL consortium, to create 19 metabolomics-based predictors for clinical variables, including diabetes status (AUC5-Fold CV = 0.94) and lipid medication usage (AUC5-Fold CV = 0.90). Subsequent application in independent cohorts confirmed that our metabolomics-based predictors can indeed be used to impute a wide array of missing clinical variables from a single metabolomics data resource. In addition, application highlighted the potential use of our predictors to explore the effects of totally unobserved confounders in omics association studies. Finally, we show that our predictors can be used to explore risk factor profiles contributing to mortality in older participants. To conclude, we provide 1H-NMR metabolomics-based models to impute clinical variables routinely assessed in epidemiological studies and illustrate their merit in scenarios when phenotypic variables are partially incomplete or totally unobserved.


title: Secondary Analyses for Genome-wide Association Studies using Expression Quantitative Trait Loci

abstract: Genome-wide association studies (GWAS) have successfully identified thousands of single nucleotide polymorphisms (SNPs) associated with complex traits; however, the identified SNPs account for a fraction of trait heritability, and identifying the functional elements through which genetic variants exert their effects remains a challenge. Recent evidence suggests that SNPs associated with complex traits are more likely to be expression quantitative trait loci (eQTL). Thus, incorporating eQTL information can potentially improve power to detect causal variants missed by traditional GWAS approaches. Using genomic, transcriptomic, and platelet phenotype data from the Genetic Study of Atherosclerosis Risk family-based study, we investigated the potential to detect novel genomic risk loci by incorporating information from eQTL in the relevant target tissues (i.e. platelets and megakaryocytes). Permutation analyses were performed to obtain family-wise error rates for eQTL associations, substantially lowering the genome-wide significance threshold for SNP-phenotype associations. In addition to confirming the well known association between PEAR1 and platelet aggregation, our eQTL focused approach identified a novel locus (rs1354034) and gene (ARHGEF3) not previously identified in a GWAS of platelet aggregation phenotypes. A colocalization analysis showed strong evidence for a functional role of this eQTL.


title: Effect of Bacillus coagulans Unique IS-2 in Inflammatory Bowel Disease (IBD): A Randomized Controlled Trial

abstract: Probiotic intervention is an important approach for the treatment and health restoration in inflammatory bowel disease (IBD). A study was conducted to assess the effect of Bacillus coagulans Unique IS-2 in IBD patients. Recruited subjects were given either probiotic B. coagulans Unique IS-2 or placebo for 4 weeks as per randomization. Survival of the given probiotic strain in GI, presence of beneficial gut bacteria, serum cytokines, serum serotonin and serum dopamine, symptoms of disease, physical, behavioral and psychological parameters of the subjects were evaluated before and after intervention. In this study B. coagulans Unique IS-2 was well tolerated with no severe adverse events in IBD patients and demonstrated good survival in GI tract by significantly high detection in probiotic treated group (p <0.001). Significant enhancement in beneficial Lactobacilli was observed in probiotic treated group (p <0.01). Metagenomic analysis also showed an increase in the abundance of bacterial genera Bacillus, Lactobacillus, Bifidobacterium, Faecalibacterium, Bacteroides, Megamonas, Lachnospira, Blautia, Alistipes and decrease in Sutterella, Dialister, Roseburia and Megasphaera was observed in the post intervention samples in the treatment group. Increased secretion of cytokine IL-10 and variable decrease in the secretion of IL-6, IL-1{beta}, TNF-, IL -17 and IL -23 was observed in in the probiotic treated group. Post intervention change in serum serotonin and serum dopamine was not significant in both the groups. A reduction in the severity of disease symptoms and improvement in the physical, behavioral and psychological parameter was observed in the probiotic treated group. The observed results demonstrated that B. coagulans Unique IS-2 with SMT was effective in adult IBD patients. Study was registered with Clinical Trials Registry India (CTRI) - (registration no.-CTRI/2019/11/022087).

category: gastroenterology


title: Impaired learning, memory, and extinction in posttraumatic stress disorder: translational meta-analysis of clinical and preclinical studies

abstract:
BackgroundCurrent evidence-based treatments for post-traumatic stress disorder (PTSD) are efficacious in only part of PTSD patients. Therefore, novel neurobiologically-informed approaches are urgently needed. Clinical and translational neuroscience point to altered learning and memory processes as key in (models of) PTSD psychopathology. We extended this notion by clarifying at a meta-level i) the role of information valence, i.e. neutral versus emotional/fearful, and ii) comparability between clinical and preclinical phenotypes. We hypothesized that, cross-species, neutral versus emotional/fearful information processing is, respectively, impaired and enhanced in PTSD.

MethodsThis preregistered meta-analysis involved a literature search on PTSD+Learning/Memory+Behavior, performed in PubMed. First, the effect of information valence was estimated with a random-effects meta-regression. Then sources of variation were explored with a random forest-based analysis.

ResultsThe analyses included 92 clinical (N=6732 humans) and 182 preclinical (N=6834 animals) studies. A general impairment of learning, memory and extinction processes was observed in PTSD patients, regardless of information valence. Impaired neutral learning/memory and fear extinction were also present in animal models of PTSD. Yet, PTSD enhanced fear/trauma memory in preclinical studies and impaired emotional memory in patients. Clinical data on fear/trauma memory was limited. Mnemonic phase and valence explained most variation in rodents but not humans.

ConclusionsImpaired neutral learning/memory and fear extinction show very stable cross-species PTSD phenotypes. These could be targeted for novel PTSD treatments, building on neurobiological animal studies. We argue that seemingly cross-species discrepancies in emotional/fearful memory deserve further study; until then animal models targeting this phenotype should be applied with care.

category: psychiatry and clinical psychology


title: Impact of real-time assessment on the training of trainers for the introduction of rotavirus vaccine in India

abstract:
ObjectivesTo assess the effectiveness of training workshops for knowledge enhancement of program managers prior to rotavirus vaccine (RVV) introduction in the routine immunization program.

MethodThe study was conducted among the participants attending two training workshops for the introduction of RVV; a state workshop in Pune and a regional workshop in Guwahati. The participants who attended the workshops and participated in both the pre and post-test - 53 for Guwahati and 59 for Pune. Data was collected in real-time via pre-post-test.

ResultsIn both workshops, a comparison of pre-test and post-test scores of all questions taken together showed a significant increase in the knowledge level of the participants (p<0.05). In Guwahati, the knowledge of the participants regarding doses of RVV, inadequate dosing, Vaccine Vial Monitor (VVM), open vial policy, operationalization of RVV, and monetary incentive increased significantly. In Pune, the knowledge of the participants regarding doses of RVV, bundling approach, schedule and dose, storage temperature for Rotavirus vaccine, VVM, open vial policy, vaccine delivery, and operationalization of RVV increased significantly after the training.

ConclusionsA pre-planned and well-designed knowledge assessment tool can be used to understand the impact of training workshops in enhancing the knowledge and practical skills of the participants prior to the introduction of a new vaccine.

category: public and global health


title: B cell numbers predict humoral and cellular response upon SARS-CoV-2 vaccination among patients treated with rituximab

abstract:
ObjectivesPatients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy show substantially impaired anti-SARS-CoV-2 vaccine humoral but partly inducible cellular immune responses. However, the complex relationship between antigen-specific B and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown.

MethodsAntibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) patients receiving RTX, 12 RA patients on other therapies and 30 healthy controls after SARS-CoV-2 vaccination with either mRNA or vector based vaccines.

ResultsA minimum of 10 B cells/{micro}L in the peripheral circulation was necessary in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced antigen-specific B cells, lower frequency of TfH-like cells as well as less activated CD4 and CD8 T cells compared to IgG seroconverted RTX patients. Functionally relevant B cell depletion resulted in impaired IFN{gamma} secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients independently of IgG formation.

ConclusionsPatients receiving rituximab with B cell numbers above 10 B cells/{micro}l were able to mount humoral and more robust cellular responses after SARS-CoV-2 vaccination that may permit optimization of vaccination in these patients. Mechanistically, the data emphasize the crucial role of co-stimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B and plasma cell differentiation.

category: rheumatology


title: Stronger Microstructural Damage Revealed in Multiple Sclerosis Lesions with Central Vein Sign by Quantitative Gradient Echo MRI

abstract:
BackgroundMultiple sclerosis (MS) lesions typically form around a central vein that can be visualized with FLAIR* MRI, creating the central vein sign (CVS) which may reflect lesion pathophysiology. Herein we used Gradient Echo Plural Contrast Imaging (GEPCI) MRI to simultaneously visualize CVS and measure tissue damage in MS lesions. We examined CVS in relation to tissue integrity in white matter (WM) lesions and among MS subtypes.

Subjects and MethodsThirty relapsing-remitting MS (RRMS) subjects and 38 progressive MS (PMS) subjects were scanned with GEPCI protocol. GEPCI T2*-SWI images were generated to visualize CVS. Two investigators independently evaluated WM lesions for CVS and measured lesion volumes. To estimate tissue damage severity, total lesion volume, mean lesion volume, R2t*-based tissue damage score (TDS) of individual lesions and tissue damage load (TDL) were measured for CVS+, CVS-, and confluent lesions. Spearman correlations were made between MRI and clinical data. A paired t-test was used to compare measurements of CVS+ versus CVS- lesions in each individual.

Results398 of 548 lesions meeting inclusion criteria showed CVS. Most patients had [≥] 40% CVS+ lesions. CVS+ lesions were present in similar proportion among MS subtypes. Interobserver agreement was high for CVS detection. CVS+ and confluent lesions had higher average and total volumes versus CVS- lesions. CVS+ and confluent lesions had more tissue damage than CVS- lesions based on TDL and mean TDS.

ConclusionCVS occurred in RRMS and PMS in similar proportions. CVS+ lesions had greater tissue damage and larger size than CVS- lesions.

category: neurology


title: Phase I single center trial of Ketogenic Diet for Adults with Traumatic Brain Injury

abstract:
BackgroundTraumatic Brain injury (TBI) is a major cause of mortality and morbidity in the United States. Ketogenic diet (KD) has been shown to have neuroprotective effects in acute brain injury, but limited data about its use in adult TBI patients is available. The objective of this study is to investigate the feasibility and safety of ketogenic diet (KD) for adult TBI patients in the Neuroscience Intensive Care Unit (NSICU).

MethodsTBI patients admitted to NSICU between June 2019 to March 2021 were enrolled in this single-center, open label, single-arm prospective intervention study. The primary feasibility outcome was achievement of ketosis (detection and maintenance of serum beta-hydroxybutyrate (BOB) levels above normal); secondary outcomes included laboratory and clinical adverse effects related to KD.

Results10 adults with TBI with Abbreviated Injury Score (AIS)-Head of at least 3 and ventriculostomy tube inserted met inclusion/exclusion criteria and were considered for KD. Mean age was47 years, and all patients were male. Eight out of 10 patients achieved ketosis within mean 2.2 days. KD was initiated within 8-33 hours (average 23 hours) of hospital admission. No clinical adverse effects were noted, 2 patients developed hypertriglyceridemia and 1 patient developed hypoglycemia. Serum glucose showed a decreasing trend in most patients.

ConclusionsThis pilot study shows that KD is feasible and safe in the management of TBI patients. A randomized controlled trial (RCT) is justified to further understand the optimal serum BOB levels, dose and duration of KD in TBI and its effect on the outcome.

ClinicalTrials.gov Identifier: NCT03982602, Registered 06/11/2019, https://clinicaltrials.gov/ct2/show/NCT03982602?term=brain+injury&cond=ketogenic+diet&draw=2&rank=3.


title: Nutritional risk assessment using Malnutrition Universal Screening Tool (MUST) in COVID-19 patients: An observational study in a tertiary care hospital in Eastern India

abstract:
AimsTo diagnose malnutrition, the nutritional status of each infected patient should be evaluated before starting general treatment. The role of Malnutrition Universal Screening Tool (MUST) in evaluating nutritional status of COVID-19 patients is still unknown. The aim of this study was to evaluate the use of MUST in assessment of nutritional status of COVID-19 patients.

MethodsWe retrospectively analyzed the data of hospitalized COVID-19 patients above 18 years of age from July 25th to September 25th, 2020. All COVID-19 patients with a length of hospital stay greater than 24 hours underwent malnutrition screening and nutritional assessment based upon MUST. Demographic data, laboratory parameters and MUST score were retrieved from case files.

ResultsOut of 106 COVID-19 patients included in the study, 68 (64%) were male and 38 (36%) were female. Number of deaths due to COVID-19 was 17 (16.03%). A total of 22 (20.75%) patients had MUST score of 2 and above. Analysis between MUST score and age group showed statistically significant result (p=0.012). MUST score according to clinical outcome at the end of hospitalization was also statistically significant (p<0.001).

ConclusionOur results highlight a possible role of MUST as screening tool for malnutrition in COVID-19 patients.

category: nutrition


title: Intentions to participate in cervical and colorectal cancer screening during the COVID-19 pandemic: a mixed-methods study

abstract:
Worldwide, cancer screening faced significant disruption in 2020 due to the COVID-19 pandemic. If this has led to changes in public attitudes towards screening and reduced intention to participate, there is a risk of long-term adverse impact on cancer outcomes. In this study, we examined previous participation and future intentions to take part in cervical and colorectal cancer (CRC) screening following the first national lockdown in the UK.

Overall, 7543 adults were recruited to a cross-sectional online survey in August-September 2020. Logistic regression analyses were used to identify correlates of strong screening intentions among 2,319 participants eligible for cervical screening and 2,502 eligible for home-based CRC screening. Qualitative interviews were conducted with a sub-sample of 30 participants. Verbatim transcripts were analysed thematically.

Of those eligible, 74% of survey participants intended to attend cervical screening and 84% intended to complete home-based CRC screening when next invited. Thirty percent and 19% of the cervical and CRC samples respectively said they were less likely to attend a cancer screening appointment now than before the pandemic. Previous non-participation was the strongest predictor of low intentions for cervical (aOR 26.31, 95% CI: 17.61-39.30) and CRC (aOR 67.68, 95% CI: 33.91-135.06) screening. Interview participants expressed concerns about visiting healthcare settings but were keen to participate when screening programmes resumed.

Intentions to participate in future screening were high and strongly associated with previous engagement in both programmes. As screening services recover, it will be important to monitor participation and to ensure people feel safe to attend.

category: oncology


title: Restored Hematopoietic Stem Cell Transcriptional Program in Fanconi Anemia Patients Following Gene Therapy

abstract: SUMMARY PARAGRAPHFanconi anemia (FA) is a monogenic inherited disease associated with mutations in genes that encode for proteins participating in the FA/BRCA DNA repair pathway. Mutations in FA genes result in chromosomal instability and cell death, leading to cancer risks and progressive cell mortality, most notably in hematopoietic stem and progenitor cells (HSPC). Recently, we showed the first clinical evidence that gene therapy confers engraftment and proliferative advantage of gene-corrected HSPCs in FA patients1. Despite this and many other gene therapy advances, the question of whether the molecular pathways affected in monogenic diseases can be reverted by lentiviral-mediated gene therapy has never been addressed. This is even more challenging in DNA repair syndromes such as FA since in these cases, transcriptional defects in affected cells might not be restored due to DNA damage accumulated prior to gene therapy. Using single-cell RNA sequencing in HSPCs from FA-A patients previously treated by ex vivo gene therapy, we demonstrate that lentiviral-mediated gene therapy prior to severe bone marrow failure not only restores the expression of the defective gene, but also induces a long-term correction of the transcriptional program in FA HSPCs, which then acquire a signature characteristic of healthy HSPCs. Our results reveal new molecular evidence showing the potential of gene therapy to fully rescue phenotypic defects in FA, a devastating HSPC disease characterized by defective DNA repair.

category: genetic and genomic medicine


title: Plasma cell-free DNA promise disease monitoring and tissue injury assessment of COVID-19

abstract: COVID-19 is a huge threat to global health. Due to the lack of definitive etiological therapeutics currently, effective disease monitoring is of high clinical value for better healthcare and management of the large number of COVID-19 patients. In this study, we recruited 37 COVID-19 patients, collected 176 blood samples upon diagnosis and during treatment, and analyzed cell-free DNA (cfDNA) in these samples. We report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA characteristics reflect patient-specific physiological conditions during treatment. Further analysis on tissue origin tracing of cfDNA reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, we demonstrate the translational merit of cfDNA as valuable analyte for effective disease monitoring, as well as tissue injury assessment in COVID-19 patients.


title: The efficacy of vaccines in the context of COVID-19 and its variants: Role of Spatio-temporal boundary

abstract: The preference for a COVID-19 vaccine, among many available, may be difficult for common people and normally relies on efficacy values reported from clinical trials. Vaccine efficacy depends on statistical data from primary and secondary endpoints of a trial. This study provides a time-varying mathematical framework that compares two vaccines of contrasting efficacy (Pfizer-BioNTech and AstraZeneca-Oxford) using hypothetical trials with real-world data. Modeling shows that efficacies can fluctuate depending on the prevailing infection rate and demographics. The efficacy of AstraZeneca-Oxford can become comparable and even better than Pfizer-BioNTech, depending on the region and time of the clinical trials. We also introduce an idea of composite efficacy considering multi-variants and show that the efficacy of various vaccines shows differential sensitivity to the delta variant rampant in India.

category: health policy


title: Impact of health system strengthening on delivery strategies to improve child immunization coverage and inequalities in rural Madagascar

abstract:
To reach global immunization goals, national programs need to balance routine immunization at health facilities with vaccination campaigns and other outreach activities (e.g. vaccination weeks), which boost coverage at particular times and help reduce geographic inequalities. However, where routine immunization is weak, an overreliance on vaccination campaigns may lead to heterogeneous coverage. Here, we assessed the impact of a health system strengthening (HSS) intervention on the relative contribution of routine immunization and outreach activities to reach immunization goals in rural Madagascar.We obtained data from health centers in Ifanadiana district on the monthly number of recommended vaccines (BCG, measles, DTP and Polio) delivered to children, during 2014-2018. We also analyzed data from a district-representative cohort carried out every two years in over 1500 households in 2014-2018. We compared changes inside and outside the HSS catchment in the delivery of recommended vaccines, population-level vaccination coverage, geographic and economic inequalities in coverage, and timeliness of vaccination. The impact of HSS was quantified via mixed-effects logistic regressions. The HSS intervention was associated with a significant increase in immunization rates (Odds Ratio between 1.22 for measles and 1.49 for DTP), which diminished over time. Outreach activities were associated with a doubling in immunization rates, but their effect was smaller in the HSS catchment. Analysis of cohort data revealed that HSS was associated with higher vaccination coverage (Odds Ratio between 1.18 per year of HSS for measles and 1.43 for BCG), a reduction in economic inequality, and a higher proportion of timely vaccinations. Yet, the lower contribution of outreach activities in the HSS catchment was associated with persistent inequalities in geographic coverage, which prevented achieving international coverage targets. Investment in stronger primary care systems can improve vaccination coverage, reduce inequalities and improve the timeliness of vaccination via increases in routine immunizations.

Key questionsO_ST_ABSWhat is already known?C_ST_ABS- Reaching the minimum recommended vaccination coverage of 90% for childhood illnesses remains a substantial challenge for low and middle income countries (LMICs).
- Understanding how vaccine delivery strategies can be improved to achieve coverage targets in rural areas of LMICs is essential due to the fragility of health systems and associated health budgets.
- While evidence exists on the impact of outreach activities and other targeted interventions aimed at improving immunization coverage, it is unclear how strengthening local health systems can help improve key indicators of vaccination coverage, via its different impacts on routine and outreach immunizations.

What are the new findings?- A health systems strengthening (HSS) intervention in a rural district of Madagascar improved overall vaccination coverage, reduced economic inequalities in vaccination coverage, and increased the proportion of timely vaccinations via an increase in routine immunizations.
- The contribution of outreach activities was lower in the HSS catchment area than in the rest of the district, which was associated with a persistence of geographic inequalities in vaccination coverage.

What do the new findings imply?- Strengthening local health systems can help improve key indicators of vaccination coverage in rural, low resource settings, even when those interventions do not target specifically vaccine improvements themselves.
- Explicit efforts are still necessary in areas undergoing HSS to vaccinate children in remote areas so that immunization goals can be reached.

category: health systems and quality improvement


title: Antibody titers measured by commercial assays are correlated with neutralizing antibody titers calibrated by international standards

abstract: The World Health Organization (WHO) has highlighted the importance of an international standard (IS) for SARS-CoV-2 neutralizing antibody titer detection, with the aim of calibrating different diagnostic techniques. In this study, IS was applied to calibrate neutralizing antibody titers (IU/mL) and binding antibody titers (BAU/mL) in response to SARS-CoV-2 vaccines. Serum samples were collected from participants receiving the Moderna (n = 20) and Pfizer (n = 20) vaccines at three time points: pre-vaccination, after one dose, and after two doses. We obtained geometric mean titers of 1404.16 and 928.75 IU/mL for neutralizing antibodies after two doses of the Moderna and Pfizer vaccines, respectively. These values provide an important baseline for vaccine development and the implementation of non-inferiority trials. We also compared three commercially available kits from Roche, Abbott, and MeDiPro for the detection of COVID-19 antibodies based on binding affinity to S1 and/or RBD. Our results demonstrated that antibody titers measured by commercial assays are highly correlated with neutralizing antibody titers calibrated by IS.


title: Integrative Metabolomic and Proteomic Signatures Define Clinical Outcomes in Severe COVID-19

abstract: The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identified. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a novel network of protein-metabolite interactions in COVID-19 patients through targeted metabolomic and proteomic profiling of serum samples in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity, such as acute kidney injury. Finally, we developed a novel composite outcome measure for COVID-19 disease severity and created a clinical prediction model based on the metabolomics data. The model predicts severe disease with a concordance index of around 0.69, and furthermore shows high predictive power of 0.83-0.93 in two previously published, independent datasets.


title: Re-estimating prevalence of hepatitis B virus immunity among adults in the United States: self-reported vaccination, immunologic markers, and bias correction

abstract:
BackgroundTwo instruments used to measure adult hepatitis B vaccination coverage in the United States are self-report and antibody to hepatitis B surface antigen (anti-HBs). Estimates based on either of these measures are subject to misclassification when used to determine immunity to hepatitis B. This study presents misclassification-corrected estimates of hepatitis B immune prevalence in the US and compares them to self-report- and antibody-based estimates.

MethodsWe used cross-sectional data from the 2015-2016 NHANES cycle on 5,151 adults in the US age 18 and older. Existing literature on long-term immunity after vaccination informed anti-HBs sensitivity as a measure of immunity. Our model incorporated literature-based distributions for sensitivity and specificity using a Bayesian approach to correct for misclassification of true immune status by anti-HBs.

ResultsAfter correcting for misclassification, overall adult immune prevalence was estimated at 31.0% (95% credible interval, 27.9% to 34.1%). Anti-HBs prevalence was 6.4 (3.9 to 8.8) and self-report prevalence 2.6 (-0.6 to 5.8) percentage points lower than overall immune prevalence. Among Asian Americans, anti-HBs and self-report underestimated immune prevalence by 15.8% (11.5% to 20.9%) and 25.1% (17.3% to 33.2%), respectively. Among 19 to 25-year-olds, anti-HBs and self-report underestimated immune prevalence by 26.5% (20.7% to 32.5%) and 21.0% (12.6% to 28.9%).

ConclusionsBoth self-reported vaccination and antibody-based measures underestimate hepatitis B immunity among adults. This underestimation was especially large among younger adults and Asian Americans. The consequences of treating these surrogates as unbiased measures of vaccination or immunity may only increase as more vaccinated children age into adulthood.


title: Typically asymptomatic but with robust antibody formation: Childrens unique humoral immune response to SARS-CoV-2

abstract:
BackgroundLong-term persistence of antibodies against SARS-CoV-2, particularly the SARS-CoV-2 Spike Trimer, determines individual protection against infection and potentially viral spread. The quality of childrens natural humoral immune response following SARS-CoV-2 infection is yet incompletely understood but crucial to guide pediatric SARS-CoV-2 vaccination programs.

MethodsIn this prospective observational multi-center cohort study, we followed 328 households, consisting of 548 children and 717 adults, with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. The serological response was assessed at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays.

ResultsOverall, 33.76% of SARS-CoV-2 exposed children and 57.88% adults were seropositive. Children were five times more likely to have seroconverted without symptoms compared to adults. Despite the frequently asymptomatic course of infection, children had higher specific antibody levels, and their antibodies persisted longer than in adults (96.22% versus 82.89% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induced similar humoral responses in all age groups. In symptomatic children, only dysgeusia was found as diagnostic indicator of COVID-19. SARS-CoV-2 infections occurred independent of HCoV serostatus. Antibody binding responses to VOCs were similar in children and adults, with reduced binding for the Beta variant in both groups.

ConclusionsThe long-term humoral immune response to SARS-CoV-2 infection in children is robust and may provide long-term protection even after asymptomatic infection.

(Study ID at German Clinical Trials Register: 00021521)

category: pediatrics


title: Subgrouping School-Aged Children with Autism Spectrum Disorder Based on Co-Occurring Psychopathology

abstract:
BackgroundPhenotypic heterogeneity along the autism spectrum is compounded by co-occurring psychiatric conditions. Deriving subgroups of autistic individuals based on symptoms of these conditions could better our understanding of psychiatric symptom patterns existing within this population. This studys goals were to derive subgroups of school-aged autistic children based on co-occurring psychiatric symptoms while controlling for age and sex and to examine correlates of subgroup membership while controlling for the degree of ASD-related diagnostic features.

MethodLatent class models were estimated in a sample from the Simons Simplex Collection (n = 2,087) using "borderline/clinical" versus "normative" range data from five of the DSM-Oriented Scales from the CBCL/6-18 as indicator variables. We evaluated the predictive value of NVIQ < 70, atypical sleep duration, allergies/autoimmune conditions, gastrointestinal conditions, and neurological conditions on subgroup membership using multinomial logistic regression.

ResultsFour subgroups emerged: Low Psychiatric Symptoms (41.02%), Externalizing Symptoms (12.36%), Internalizing Symptoms (31.58%), and High Psychiatric Symptoms (15.05%). Key findings were that NVIQ < 70 was associated with decreased odds of belonging to the Internalizing Symptoms and High Psychiatric Symptoms subgroups over the Low Psychiatric Symptoms subgroup, while atypical sleep duration and gastrointestinal conditions were associated with increased odds of belonging to the Externalizing Symptoms and High Psychiatric Symptoms subgroups. Neurological conditions were also associated with increased odds of belonging to the Externalizing Symptoms subgroup.

ConclusionDistinct patterns of psychiatric symptoms exist within school-aged autistic children and are correlated with NVIQ < 70, atypical sleep duration, and medical conditions, providing insights for clinical practice and etiology-driven research.


title: Subgrouping School-Aged Children on the Autism Spectrum Based on Co-Occurring Psychiatric Symptoms


title: Does COVID-19 vaccination improve mental health? A difference-in-difference analysis of the UnderstandingCoronavirus in America study

abstract:
BackgroundMental health problems increased during the COVID-19 pandemic. Knowledge that one is less at risk after being vaccinated may alleviate distress, but this hypothesis remains unexplored. Here we test whether psychological distress declined in those vaccinated against COVID-19 in the US and whether changes in perceived risk mediated any association.

MethodsA nationally-representative cohort of U.S. adults (N=5,792) in the Understanding America Study were interviewed every two weeks from March 2020 to June 2021 (28 waves). Difference-in-difference regression tested whether getting vaccinated reduced distress (PHQ-4 scores), with mediation analysis used to identify potential mechanisms, including perceived risks of infection, hospitalization, and death.

ResultsVaccination was associated with a 0.09 decline in distress scores (95% CI:-0.15 to -0.04) (0-12 scale), a 5.7% relative decrease compared to mean scores in the wave prior to vaccination. Vaccination was also associated with an 8.44 percentage point reduction in perceived risk of infection (95% CI:-9.15% to -7.73%), a 7.44-point reduction in perceived risk of hospitalization (95% CI:-8.07% to -6.82%), and a 5.03-point reduction in perceived risk of death (95% CI:-5.57% to -4.49%). Adjusting for risk perceptions decreased the vaccination-distress association by two-thirds. Event study models suggest vaccinated and never vaccinated respondents followed similar PHQ-4 trends pre-vaccination, diverging significantly post-vaccination. Analyses were robust to individual and wave fixed effects, time-varying controls, and several alternative modelling strategies. Results were similar across sociodemographic groups.

ConclusionReceiving a COVID-19 vaccination was associated with declines in distress and perceived risks of infection, hospitalization, and death. Vaccination campaigns could promote these additional benefits of being vaccinated.


title: Does COVID-19 vaccination improve mental health? A difference-in-difference analysis of the Understanding Coronavirus in America study


title: Cultural Adaptation of a Brief Intervention to Reduce Alcohol Use Among Injury Patients in Tanzania

abstract:
BackgroundHarmful alcohol use is a leading risk factor for injury-related death and disability in low- and middle-income countries (LMICs). Brief negotiational interventions (BNIs) administered in emergency departments (EDs) to injury patients with alcohol use disorders (AUDs) are effective in reducing post-hospital alcohol intake and re-injury rates. However, most BNIs to date have been developed and implemented in high-income countries. The efficacy of BNIs in LMICs is largely unknown as few studies have undertaken the rigorous task of culturally adapting these interventions to new settings. Given the high prevalence of alcohol-related injury in the Kilimanjaro region of Tanzania, we culturally adapted a BNI to reduce post-injury alcohol use for implementation in this patient population.

MethodsWe used an iterative, multiphase process to culturally adapt a high-income country standard of care BNI to the Tanzanian setting using the Intervention Mapping ADAPT framework. Our team consisted of local healthcare professionals with extensive experience in counseling patients who use alcohol, as well as an international team of academic and clinical professionals. Focus groups were used to inform culturally appropriate changes to the standard of care BNI protocol. Objective assessment of BNI delivery was performed to ensure adherence to the FRAMES model of motivational interviewing.

ResultsWe developed the Punguza Pombe Kwa Afya Yako (PPKAY); a one-time, 15-minute nurse-led BNI that encourages safe alcohol use and motivates change in alcohol use behaviors among injury patients in the Kilimanjaro region of Tanzania. Adaptations to the original intervention protocol include changes regarding the interventionist, how a patient is greeted, how the topic of alcohol use is raised, how a patient is informed of their harmful alcohol use, how graphics are visualized within the intervention protocol, how behavior change is motivated, and which behavior changes are encouraged.

ConclusionsThe PPKAY intervention is the first BNI to be culturally adapted for delivery to injury patients in an LMIC population. Our study demonstrates a unique approach to adapting substance use interventions for use in LMICs, and shows that cultural adaptation of alcohol use interventions is feasible even in settings where community knowledge regarding harmful alcohol use is limited. Our study prompts the need for further research and cultural adaptation of BNIs for other low-income communities at increased risk of alcohol-related harm.


title: Apathy: an underestimated feature in GBA and LRRK2 non-manifesting mutation carriers.

abstract:
BackgroundHigher prevalence of motor and non-motor features has been observed in non-manifesting mutation carriers of Parkinsons Disease (PD) compared to Healthy Controls (HC).

ObjectivesThe aim was to detect the differences between GBA and LRRK2 mutation carriers without PD and HC on neuropsychiatric symptoms.

MethodsThis is a cross-sectional retrospective study of non-manifesting GBA and LRRK2 mutation carriers and HC enrolled into Parkinsons Progression Markers Initiative (PPMI). Data extracted from the PPMI database contained: demographics and performance in MoCA scale and MDS-UPDRS scale part 1A (neuropsychiatric symptoms). All six features were treated as both continuous (MDS-UPDRS individual scores) and categorical variables (MDS-UPDRS individual score>0 and MDS-UPDRS individual score=0). Logistic regression analyses were applied to evaluate the association between mutation carrying status and neuropsychiatric symptoms.

ResultsWe found that non-manifesting mutation carriers as a whole (total N=654, GBA: n=285, LRRK2: n=369) were 2.3 times more likely to present apathy compared to HC, even after adjustment for covariates (adjusted OR=2.3, 95% CI=1.1-5.0, p-value=0.027). The effect was mainly driven by GBA mutation carriers (adjusted OR= 2.6, 95% CI=1.1-6.3, p=0.031), while the higher percentage of apathy for LRRK2 carriers compared to HC was marginally non-significant. Other neuropsychiatric symptoms, such as psychotic or depressive manifestations, did not differ between groups.

ConclusionsSymptoms of apathy could be present in the premotor period of LRRK2 and, especially, GBA mutation carriers. Longitudinal data, including detailed neuropsychiatric evaluation and neuroimaging, would be essential to further investigate the pathophysiological basis of this finding.


title: Dissecting Biological Pathways of Psychopathology using Cognitive Genomics

abstract: Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identified collective segments of the genome, which we call "meta-loci", that showed differential pleiotropic patterns for psychopathology relative to either General Cognitive Ability (GCA) or Non-Cognitive Skills (NCS). We observed that neurodevelopmental gene sets expressed during the prenatal-early childhood predominated in GCA-relevant meta-loci, while post-natal synaptic gene sets were more involved in NCS-relevant meta-loci. Notably, we found that GABA-ergic, cholinergic, and glutamatergic genes drove pleiotropic relationships within dissociable NCS meta-loci.


title: Preventable deaths from SARS-CoV-2 in England and Wales: a systematic analysis of coroners case reports from the COVID-19 pandemic

abstract:
ObjectivesTo examine coroners Prevention of Future Deaths reports (PFDs) to identify deaths involving SARS-CoV-2 that coroners deemed preventable.

DesignConsecutive case series.

SettingEngland and Wales.

ParticipantsPatients reported in 510 PFDs dated between 01 January 2020 and 28 June 2021, collected from the UKs Courts and Tribunals Judiciary website using web scraping to create an openly available database, https://preventabledeathstracker.net/.

Main outcome measuresConcerns reported by coroners.

Public and Patient InvolvementPatients and members of the public were not involved in this study.

ResultsSARS-CoV-2 was involved in 23 deaths reported by coroners in PFDs. Twelve deaths were indirectly related to the COVID-19 pandemic, defined as those that were not medically caused by SARS-CoV-2, but were associated with mitigation measures. In 11 cases the coroner explicitly reported that COVID-19 had directly caused death. There was geographical variation in the reporting of PFDs; most (39%) were written by coroners in the North-West of England. The coroners raised 56 concerns, problems in communication being the most common (30%), followed by failure to follow protocols (23%). Organizations in the National Health Service (NHS) were sent the most PFDs (51%), followed by the Government (26%), but responses to PFDs by these organizations were poor.

ConclusionsPFDs contain a rich source of information on preventable deaths that has previously been difficult to examine systematically. Our openly available tool (https://preventabledeathstracker.net/) streamlines this process and has identified many concerns raised by coroners that should be addressed during the Governments inquiry into the handling of the COVID-19 pandemic, so that mistakes made are less likely to be repeated.

Study protocol pre-registrationhttps://osf.io/bfypc/

Summary boxO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThe UK Government has stated that there will be a public inquiry into the handling of the COVID-19 pandemic, to learn lessons for future pandemics.
C_LIO_LICoroners in England and Wales have a duty to report and communicate information about the deaths they investigate when the coroner believes that action should be taken to prevent future deaths.
C_LIO_LIThese reports, called Prevention of Future Death reports (PFDs), had not yet been systematically analysed to identify deaths that occurred during the COVID-19 pandemic.
C_LI

What are the new findings?O_LIWe created the Preventable Deaths Database (https://preventabledeathstracker.net/) using web scraping to systematically assess PFDs published on the Courts and Tribunal Judiciary website.
C_LIO_LIBetween 01 January 2020 and 28 June 2021, one in 20 (4.5%, n=23) PFDs that were published by coroners involved SARS-CoV-2.
C_LIO_LICoroners raised many concerns about the care of patients in hospitals, care homes, and people in the community during the COVID-19 pandemic, which require action to prevent future deaths.
C_LI

How might it affect clinical practice in the foreseeable future?O_LIPreventable deaths that occurred during the COVID-19 pandemic should be referred to the coroner so that an inquest can be performed and a PFD issued, highlightng actions that could be avoided in improving the handling of future pandemics in both the UK and elsewhere.
C_LIO_LIOur tool, https://preventabledeathstracker.net/, can be used by others to examine preventable deaths in England and Wales, and to identify signals for quality improvement to reduce avoidable harms in clinical practice.
C_LI


title: Preventable deaths from SARS-CoV-2 in England and Wales: a systematic case series of coroners reports during the COVID-19 pandemic


title: Interaction-based feature selection algorithm outperforms polygenic risk score in predicting Parkinson's Disease status

abstract: Polygenic risk scores (PRS) aggregating results from genome-wide association studies are state of the art to predict the susceptibility to complex traits or diseases. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions. We applied our approach to the Parkinsons Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])). Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinsons Disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25. These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.


title: Beyond poverty as a proxy: reducing inequality in infant mortality by identifying and targeting higher risk births

abstract: Infant mortality remains high and uneven in much of sub-Saharan Africa. Given finite resources, reducing premature mortality requires effective tools to identifying left-behind populations at greatest risk. While countries routinely use income- or poverty-based thresholds to target policies, we examine whether models that consider other factors can substantially improve our ability to target policies to higher-risk births. Using machine learning methods, and 25 commonly available variables that can be observed prior to birth, we construct child-level risk scores for births in 22 sub-Saharan African countries. We find that targeting based on poverty, proxied by income, is only slightly better than random targeting, with the poorest 10 percent of the population experiencing approximately 10 percent of total infant mortality burden. By contrast the 10 percent of the population at highest risk according to our model accounts for 15-30% of infants deaths, depending on country. A hypothetical intervention that can be administered to 10% of the population and prevents just 5% of the deaths that would otherwise occur, for example, would save roughly 841,000 lives if targeted to the poorest decile, but over 1.6 million if targeted using our approach.


title: Exploring predictive frameworks for malaria in Burundi

abstract: Malaria is a major public health concern in Burundi. The infection has been increasing in the last decade despite efforts to increase access to health services, and the deployment of several intervention programs. The use of different data sources can help to build predictive models of malaria cases in different sub-populations. We built predictive frameworks using generalized linear model (GLM), and artificial neural network to predict malaria cases in four sub-populations (pregnant women and children under 5 years, pregnant women, children between 0 and 11 months, children between 12 and 59 months), and the overall general population. The results showed that almost half malaria infections are observed in pregnant women and children under 5 years, but children between 12 and 59 months carry the highest burden. Neural network model performed better in predicting total cases compared to GLM. But the latter provided information on the effect of predictors, which is an important source of information to mainstream target interventions. Early prediction of cases can provide timely information needed to be proactive for intervention strategies, and it can help to mitigate the epidemics and reduce its impact on populations and the economy.


title: BNT162b2 Vaccination efficacy is marginally affected by the SARS-CoV-2 B.1.351 variant in fully vaccinated individuals.

abstract:
BackgroundIsraeli has vaccinated over 80% of its adult population, with two doses of the Pfizer BNT162b2 vaccine. This intervention has been highly successful in curtailing the coronavirus 2 outbreak. One major concern is the ability of the virus to mutate which potentially can cause SARS-CoV-2 to partially escape from the immune system. Here we evaluate the efficacy of the Pfizer vaccine against the B.1.351 variant.

MethodsThe Ministry of Health, initiated sequencing of selected positive swab samples identified as being of interest. We used logistic regression, with variant type as the dependent variable, vaccination status as the main explanatory variable, controlling for age, sex, subpopulation, place of residence and time of sample, to estimate the odds ratio for a vaccinated case to have the B. 1.351 versus the B.1.1.7 variant, within vaccinated and unvaccinated persons who tested positive.

FindingsThere were 19 cases of B.1.351 variant (3.2%) among those vaccinated more than 14 days before the positive sample and 88 (3.5%) among the unvaccinated. The estimated odds ratio was 1.29 [95% CI: 0.66-2.50]. From this result, assuming the efficacy against the B.1.1.7 variant to be 95%, the estimated efficacy against the B.1.351 variant was 94% [95% CI: 87-97%].

InterpretationDespite the concerns caused by the B.1.351 variant, the BNT162b2 vaccine seems to provide substantial immunity against both that variant and the B.1.1.7. Our results suggest that from 14 days following the second vaccine dose the efficacy of BNT162b2 vaccine is at most marginally affected by the B.1.351 variant.

FundingNo funding


title: Recruitment of highly functional SARS-CoV-2-specific CD8+ T cell receptors mediating cytotoxicity of virus-infected target cells in non-severe COVID-19

abstract: T cell immunity is crucial for the control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and has been widely characterized on a quantitative level. In contrast, the quality of such T cell responses has been poorly investigated, in particular in the case of CD8+ T cells. Here, we explored the quality of SARS-CoV-2-specific CD8+ T cell responses in individuals who recovered from mild symptomatic infections, through which protective immunity should develop, by functional characterization of their T cell receptor (TCR) repertoire. CD8+ T cell responses specific for SARS-CoV-2-derived epitopes were low in frequency but could be detected robustly early as well as late - up to twelve months - after infection. A pool of immunodominant epitopes, which accurately identified previous SARS-CoV-2 infections, was used to isolate TCRs specific for epitopes restricted by common HLA class I molecules. TCR-engineered T cells showed heterogeneous functional avidity and cytotoxicity towards virus-infected target cells. High TCR functionality correlated with gene signatures of T cell function and activation that, remarkably, could be retrieved for each epitope:HLA combination and patient analyzed. Overall, our data demonstrate that highly functional HLA class I TCRs are recruited and maintained upon mild SARS-CoV-2 infection. Such validated epitopes and TCRs could become valuable tools for the development of diagnostic tests determining the quality of SARS-CoV-2-specific CD8+ T cell immunity, and thereby investigating correlates of protection, as well as to restore functional immunity through therapeutic transfer of TCR-engineered T cells.


title: Comparative profiles of SARS-CoV-2 Spike-specific milk antibodies elicited by COVID-19 vaccines currently authorized in the USA

abstract: Numerous COVID-19 vaccines are authorized globally. To date, [~]71% of doses are comprised of the Pfizer/BioNTech vaccine, and [~]17% the Moderna/NIH vaccine, both of which are mRNA-based. The chimpanzee Ad-based Oxford/AstraZeneca (AZ) vaccine comprises [~]9%, while the Johnson & Johnson/Janssen (J&J) human adenovirus (Ad26) vaccine ranks 4th at [~]2% [1]. No COVID-19 vaccines are yet available for children 0-4. One method to protect this population may be passive immunization via antibodies (Abs) provided in the milk of a lactating vaccinated person. Our early work [2] and other reports [3-5] have demonstrated that unlike the post-SARS-CoV-2 infection milk Ab profile, which is rich in specific secretory (s)IgA, the vaccine response is highly IgG-dominant. In this report, we present a comparative assessment of the milk Ab response elicited by Pfizer, Moderna, J&J, and AZ vaccines. This analysis revealed 86% -100% of mRNA vaccine recipient milk exhibited Spike-specific IgG endpoint titers, which were 12 - 28-fold higher than those measured for Ad vaccine recipient milk. Ad-based vaccines elicited Spike-specific milk IgG in only 33%-38% of recipients. Specific IgA was measured in 52%-71% of mRNA vaccine recipient milk and 17%-23% of Ad vaccine recipient milk. J&J recipient milk exhibited significantly lower IgA than Moderna recipients, and AZ recipients exhibited significantly lower IgA titers than Moderna and Pfizer. <50% of milk of any group exhibited specific secretory Ab, with Moderna recipient IgA titers measuring significantly higher than AZ. Moderna appeared to most frequently elicit >2-fold increases in specific secretory Ab titer relative to pre-vaccine sample. These data indicate that current Ad-based COVID-19 vaccines poorly elicit Spike-specific Ab in milk compared to mRNA-based vaccines and that mRNA vaccines are preferred for immunizing the lactating population. This study highlights the need to design vaccines better aimed at eliciting an optimal milk Ab response.

category: allergy and immunology


title: Comparative profiles of SARS-CoV-2 Spike-specific human milk antibodies elicited by mRNA- and adenovirus-based COVID-19 vaccines


title: Change in age distribution of COVID-19 deaths with the introduction of COVID-19 vaccination

abstract:
BackgroundMost countries initially deployed COVID-19 vaccines preferentially in elderly populations. Population-level vaccine effectiveness may be heralded by an increase in the proportion of deaths among non-elderly populations that were less covered by vaccination programs.

MethodsWe collected data from 40 countries on age-stratified COVID-19 deaths during the vaccination period (1/14/2021-5/31/2021) and two control periods (entire pre-vaccination period and excluding the first wave). We meta-analyzed the proportion of deaths in different age groups in vaccination versus control periods in countries with low vaccination rates; (2) countries with age-independent vaccination policies; and (3) countries with standard age-dependent vaccination policies.

FindingsCountries that prioritized vaccination among older people saw an increasing share of deaths among 0-69 year old people in the vaccination versus the two control periods (summary prevalence ratio 1{middle dot}32 [95 CI% 1{middle dot}24-1{middle dot}41] and 1{middle dot}35 [95 CI% 1{middle dot}26-1{middle dot}44)]. No such change was seen on average in countries with age-independent vaccination policies (1{middle dot}05 [95 CI% 0{middle dot}78-1{middle dot}41 and 0{middle dot}97 [95 CI% 0{middle dot}95-1{middle dot}00], respectively) and limited vaccination (0{middle dot}93 [95 CI% 0{middle dot}85-1{middle dot}01] and 0{middle dot}95 [95 CI% 0{middle dot}87-1{middle dot}03], respectively). Prevalence ratios were associated with the difference of vaccination rates in elderly versus non-elderly people. No significant changes occurred in the share of deaths in age 0-49 among all 0-69 deaths in the vaccination versus pre-vaccination periods.

InterpretationThe substantial shift in the age distribution of COVID-19 deaths in countries that rapidly implemented vaccination predominantly among elderly may herald the population level-effectiveness of COVID-19 vaccination and a favorable evolution of the pandemic towards endemicity with fewer elderly deaths.

FundingThis study received no specific funding.


title: The devil is in the details: Reporting and transparent research practices in sports medicine and orthopedic clinical trials

abstract:
IntroductionWhile transparent reporting of clinical trials is essential to assess the risk of bias and translate research findings into clinical practice, earlier studies have shown that deficiencies are common. This study examined current clinical trial reporting and transparent research practices in sports medicine and orthopedics.

MethodsThe sample included clinical trials published in the top 25% of sports medicine and orthopedics journals over nine months. Two independent reviewers assessed pre-registration, open data and criteria related to scientific rigor, the study sample, and data analysis.

ResultsThe sample included 163 clinical trials from 27 journals. While the majority of trials mentioned rigor criteria, essential details were often missing. Sixty percent (confidence interval [CI] 53-68%) of trials reported sample size calculations, but only 32% (CI 25-39%) justified the expected effect size. Few trials indicated the blinding status of all main stakeholders (4%; CI 1-7%). Only 18% (CI 12-24%) included information on randomization type, method, and concealed allocation. Most trials reported participants sex/gender (95%; CI 92-98%) and information on inclusion and exclusion criteria (78%; CI 72-84%). Only 20% (CI 14-26%) of trials were pre-registered. No trials deposited data in open repositories.

ConclusionsThese results will aid the sports medicine and orthopedics community in developing tailored interventions to improve reporting. While authors typically mention blinding, randomization and other factors, essential details are often missing. Greater acceptance of open science practices, like pre-registration and open data, is needed. These practices have been widely encouraged, we discuss systemic interventions that may improve clinical trial reporting.

Registrationhttps://doi.org/10.17605/OSF.IO/9648H

category: sports medicine


title: Present knowledge, attitude, practice, and fear level of Bangladeshi people towards covid-19 after one year of the pandemic situation: a web-based cross-sectional study.

abstract: In the earlier phase of the pandemic situation, the governments of Bangladesh badly suffered to adhere their people to preventive measures probably due to less knowledge and attitude towards covid-19. To tackle the second wave of coronavirus, the governments again enforced an array of preventive measures, but still encountering the same problem after a year of the pandemic situation. In an attempt to find out the reasons behind this, our study aimed to assess the present knowledge, attitude, practice, and fear level of the people. A cross-sectional study was conducted from 15th to 25th April 2021. A total of 402 participants met all the inclusion criteria and were considered for performing all statistical analyses (Descriptive statistics, Mann-Whitney U test, Kruskal-Wallis H test, Multiple logistic regression, Spearman rank-order correlation). Out of 402 participants, more than 90% participants were students and all were adults aged 16 to 30. 84.6%, 65.7%, 54%, and 21.6% participants had more adequate knowledge, more positive attitude, more frequent practice, and moderate to high fear towards covid-19, respectively. Knowledge, attitude, practice, and fear were interrelated directly or indirectly. It was found knowledgeable participants were more likely to have more positive attitude (OR = 2.12, 95% CI = 1.14-3.95, P < 0.05) and very less fear (OR = 1.98, 95% CI = 1.02-3.82, P < 0.05). More positive attitude was found as a good predictor of more frequent practice (OR = 4.33, 95% CI = 2.66-7.04, P < 0.001), and very less fear had same negative impact on both attitude (OR = 0.48, 95% CI = 0.25-0.91, P < 0.05) and practice (OR = 0.48, 95% CI = 0.27-0.85, P < 0.05). Our findings reflect that knowledge level has elevated but attitude level subsided, and practice level stayed same as was in the earlier phase of pandemic and people are no longer panicked.


title: Early, intensive rehabilitation improves gross motor function after perinatal stroke: results of a randomized controlled trial

abstract:
BackgroundPerinatal stroke injures motor regions of the brain, compromising movement for life. Early, intensive, active interventions for the upper extremity are efficacious, but interventions for the lower extremity (LE) remain infrequent and understudied.

ObjectiveTo determine the efficacy of ELEVATE - Engaging the Lower Extremity Via Active Therapy Early - on gross motor function, as compared to usual care.

MethodWe conducted a single-blind, two-arm, randomized controlled trial (RCT), with the Immediate Group receiving the intervention while the Delay Group served as a three-month waitlist-control. A separate cohort living beyond commuting distance was trained by their parents with guidance from physical therapists. Participants were 8 months to 3 years old, with MRI-confirmed perinatal ischemic stroke and early signs of hemiparesis. The intervention was play-based, focused on weight-bearing, balance and walking for 1 hour/day, 4 days/week for 12 weeks. The primary outcome was the Gross Motor Function Measure-66 (GMFM-66). Secondary outcomes included steps and gait analyses. Final follow-up occurred at age four.

ResultsThirty-four children participated (25 RCT, 9 Parent-trained). The improvement in GMFM-66 over 12 weeks was greater for the Immediate than the Delay Group (average change 3.4 units higher) and greater in younger children. Average step counts reached 1370-3750 steps/session in the last week of training for all children. Parent-trained children also improved but with greater variability.

ConclusionsEarly, activity-intensive LE therapy for young children with perinatal stroke is feasible and improves gross motor function in the short term. Longer term improvement may require additional bouts of intervention.

Clinical trial registratioThis study was registered at ClinicalTrials.gov (NCT01773369).

category: rehabilitation medicine and physical therapy


title: New susceptibility loci for severe COVID-19 by detailed GWAS analysis in European populations

abstract: Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic [~]0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.


title: Reduced neutralizing activity of post-SARS-CoV-2 vaccination serum against variants B.1.617.2, B.1.351, B.1.1.7+E484K and a sub-variant of C.37

abstract: Highly efficacious vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed.1 However, the emergence of viral variants that are more infectious than the earlier SARS-CoV-2 strains is concerning.2 Several of these viral variants have the potential to partially escape neutralizing antibody responses warranting continued immune-monitoring. Here, we tested a number of currently circulating viral variants of concern/interest, including B.1.526 (Iota), B.1.1.7+E484K (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and C.37 (Lambda) in neutralization assays using a panel of post-mRNA vaccination sera. The assays were performed with authentic SARS-CoV-2 clinical isolates in an assay that mimics physiological conditions. We found only small decreases in neutralization against B.1.526 and an intermediate phenotype for B.617.2. The reduction was stronger against a sub-variant of C.37, followed by B.1.351 and B.1.1.7+E484K. C.37 is currently circulating in parts of Latin America3 and was detected in Germany, the US and Israel. Of note, reduction in a binding assay that also included P.1, B.1.617.1 (Kappa) and A.23.1 was negligible. Taken together, these findings suggest that mRNA SARS-CoV-2 vaccines may remain effective against these viral variants of concern/interest and that spike binding antibody tests likely retain specificity in the face of evolving SARS-CoV-2 diversity.


title: Cell-Mediated and Humoral Immune Response to 2-Dose SARS-CoV2 mRNA vaccination in Immunocompromised patient population

abstract: Characterization of cell-mediated and humoral immune responses to SARS-CoV2 mRNA vaccine has implications for protective immunity in immunocompromised patients. However, studies have demonstrated poor humoral response to SARS-CoV2 mRNA vaccine in immunocompromised patients and data on cellular immune response are currently lacking. Here we compared immune response after 2-dose vaccination in 100 immunocompromised patients (solid organ transplant recipients, hematologic malignancy, autoimmune condition, and primary immunodeficiency) and 16 immunocompetent healthy healthcare workers. We find that 100% (CI=80.6-100%) of immunocompetent individuals show positive cell-mediated and humoral immune response post vaccination while only 50% (CI=40.4-59.6%) of immunocompromised patients show humoral immune response and 69% (CI=59.4-77.2%) have a positive cell-mediated immune response. 21% of immunocompromised patients have no humoral immune response or cell-mediated immune response and thus are likely vulnerable to SARS-CoV2 infection. Monitoring of immune response in immunocompromised populations, particularly in high-risk immunocompromised patients (solid organ transplant recipients, patients with severe autoimmunity, and those [≥]50 years), with clinical IGRA and serological assay after vaccination may identify patients who may benefit from revaccination or prophylactic monoclonal antibody therapy to prevent COVID-19 in this patient population


title: Health Related Quality of Life and Hospitalizations In Chronic Thromboembolic Pulmonary Hypertension Versus Idiopathic Pulmonary Arterial Hypertension: An Analysis from the Pulmonary Hypertension Association (PHAR)

abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, morbid, potentially curable subtype of pulmonary hypertension that negatively impacts health-related quality of life (HRQoL). Little is known about differences in HRQoL and hospitalization between CTEPH patients and idiopathic pulmonary arterial hypertension (IPAH) patients. Using multivariable linear regression and mixed effects models, we examined differences in HRQoL assessed by emPHasis-10 (E10) and SF-12 between CTEPH and IPAH patients in the Pulmonary Hypertension Association Registry, a prospective multicenter cohort of patients newly evaluated at a Pulmonary Hypertension Care Center. Multivariable negative binomial regression models were used to estimate incidence rate ratios (IRR) for hospitalization amongst the two groups. We included 461 IPAH and 169 CTEPH patients. 21% of CTEPH patients underwent pulmonary thrombendarterectomy (PTE) before the end of follow-up. At baseline, patients with CTEPH had significantly worse HRQoL (higher E10 scores) ({beta} 2.83, SE 1.11, p=0.01); however, differences did not persist over time. CTEPH patients had higher rates of hospitalization (excluding the hospitalization for PTE) compared to IPAH after adjusting for age, sex, body mass index, WHO functional class and six-minute walk distance (IRR 1.66, 95%CI 1.04 - 2.65, p=0.03). CTEPH patients who underwent PTE had improved HRQoL as compared to those that were medically managed, but patients who underwent PTE were younger, had higher cardiac outputs and greater six-minute walk distances. In this large, prospective, multicenter cohort, CTEPH patients had significantly worse baseline HRQoL and higher rates of hospitalizations than those with IPAH. CTEPH patients who underwent PTE had significant improvements in HRQoL.

category: respiratory medicine


title: Low adherence to existing model reporting guidelines by commonly used clinical prediction models

abstract:
ObjectiveTo assess whether the documentation available for commonly used machine learning models developed by an electronic health record (EHR) vendor provides information requested by model reporting guidelines.

Materials and MethodsWe identified items requested for reporting from model reporting guidelines published in computer science, biomedical informatics, and clinical journals, and merged similar items into representative "atoms". Four independent reviewers and one adjudicator assessed the degree to which model documentation for 12 models developed by Epic Systems reported the details requested in each atom. We present summary statistics of consensus, interrater agreement, and reporting rates of all atoms for the 12 models.

ResultsWe identified 220 unique atoms across 15 model reporting guidelines. After examining the documentation for the 12 most commonly used Epic models, the independent reviewers had an interrater agreement of 76%. After adjudication, the model documentations median completion rate of applicable atoms was 39% (range: 31%-47%). Most of the commonly requested atoms had reporting rates of 90% or above, including atoms concerning outcome definition, preprocessing, AUROC, internal validation and intended clinical use. For individual reporting guidelines, the median adherence rate for an entire guideline was 54% (range: 15%-71%). Atoms reported half the time or less included those relating to fairness (summary statistics and subgroup analyses, including for age, race/ethnicity, or sex), usefulness (net benefit, prediction time, warnings on out-of-scope use and when to stop use), and transparency (model coefficients).

Atoms relating to reliability also had low reporting, including those related to missingness (missing data statistics, missingness strategy), validation (calibration plot, external validation), and monitoring (how models are updated/tuned, prediction monitoring).

ConclusionThere are many recommendations about what should be reported about predictive models used to guide care. Existing model documentation examined in this study provides less than half of applicable atoms, and entire reporting guidelines have low adherence rates. Half or less of the reviewed documentation reported information related to usefulness, reliability, transparency and fairness of models. There is a need for better operationalization of reporting recommendations for predictive models in healthcare.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow often does documentation for commonly deployed clinical predictive models report the information requested by model reporting guidelines?

FindingCombining the recommendations from 15 model reporting guidelines, we identified 220 unique requested items. We reviewed the documentation of 12 commonly deployed Epic models and assessed the completion rate of applicable items. The median completion rate was 39%. While the most commonly requested items were highly reported, information on usefulness, reliability, transparency and fairness was missing from at least half of documentation.

MeaningThere is incomplete documentation for model users to ensure that deployed models are useful, reliable, transparent and fair.

category: health informatics


title: Intestinal fungal dynamics and linkage to hematopoietic cell transplantation outcomes.

abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) induces profound shifts in the intestinal bacterial microbiota. The dynamics of intestinal fungi and their impact on clinical outcomes have not yet been integrated into a model of microbiota function during allo-HCT. Here, we combined parallel high-throughput fungal ITS1 amplicon sequencing, bacterial 16S amplicon sequencing, and fungal cultures to reveal striking trans-kingdom dynamics and their association with patient outcomes. We saw that the overall density and the biodiversity of intestinal fungi were stable during allo-HCT, but the species composition changed drastically from day to day. We identified a subset of patients with fungal dysbiosis characterized by culture positivity, stable expansion of Candida parapsilosis complex species, and distinct trans-kingdom microbiota profiles. These patients had worse overall survival and higher transplant-related mortality independent of candidemia. Our data expand the clinical significance of the mycobiota and suggest that targeting fungal dysbiosis may help to improve long-term patient survival.

category: hematology


title: On dynamics of fractional incommensurate model of Covid-19 with nonlinear saturated incidence rate

abstract: In December 2019, a new virus belonging to the coronavirus strain has been discovered in Wuhan, China, this virus has attracted world-wide attention and it spread rapidly in the world, reaching nearly 216 countries in the world in November 2020. In this chapter, we study the fractional incommensurate SIQR (susceptible, infections,quarantined and removed) COVID-19 model with nonlinear saturated incidence rate using Atangana-Baleanu fractional derivatives. The existence and uniqueness of the solutions for the fractional model is proved using fixed point theorem, the model are shown to have two equilibrium point (disease-free and an endemic equilibrium). Some numerical simulations using Euler method are also carried out to support our theoretical results. We estimated the value of the fractional orders and the parameters of the proposed model using the least squares method.. Further, the sensitivity analysis of the parameter is performed as a result, our incommensurate model gives a good approximation to real data of COVID-19.

category: epidemiology


title: Parsing Genetically Influenced Risk Pathways: Genetic Loci Impact Problematic Alcohol Use Via Externalizing and Specific Risk

abstract:
ImportanceCharacterizing whether genetic variants for psychiatric outcomes operate via specific versus general pathways provides more informative measures of genetic risk, and, potentially, allows us to design more targeted prevention and interventions.

ObjectiveEmploy multivariate methods to tease apart variants associated with problematic alcohol use through either general or specific pathways and compare results to standard univariate genetic analysis of problematic alcohol use.

DesignWe compared results from a univariate genome wide association study (GWAS) of problematic alcohol use to those from a previous multivariate GWAS of externalizing phenotypes. We identified genetic variants associated with problematic alcohol use through a broad liability to externalizing, and those that remain after removing shared variance with externalizing. We compared these results across SNP overlap, bioannotations, genetic correlations, and polygenic scores.

SettingWe included GWAS summary statistics from existing GWAS, and two US based hold out samples: The National Longitudinal Study of Adolescent to Adult Health (Add Health) and the Collaborative Study on the Genetics of Alcoholism (COGA).

ParticipantsPublicly available GWAS of externalizing behaviors and participants in Add Health (N=5,107) and COGA (N=7,483), limited to individuals of European ancestries.

Exposure(s)N/A

Main Outcome(s) and Measure(s)Outcomes included problematic alcohol use (ALCP-O), shared risk for externalizing (EXT), and problematic alcohol use-specific risk (ALCP-S) for the GWASs; a preregistered list of 99 available phenotypes for genetic correlations; and substance use, substance use disorder criteria, and alcohol misuse in the polygenic score analyses.

ResultsThe analysis differentiated SNPs operating through common versus specific risk pathways. While ALCP-O was associated with multiple phenotypes, ALCP-S was predominantly associated with alcohol use and other forms of psychopathology. Polygenic scores for ALCP-O were associated with a variety of other forms of substance use and substance use disorders, polygenic scores for ALCP-S were only associated with alcohol phenotypes. Polygenic scores for both ALCP-S and EXT show differential patterns of associations with alcohol misuse across development.

Conclusions and RelevanceFocusing on the differential impacts of shared and specific risk can better characterize pathways of risk for alcohol use disorders. Multivariate methods can be a useful tool for studying many psychiatric conditions. Parsing risk pathways will become increasingly relevant as genetic information is incorporated into clinical practice for psychiatric outcomes.

category: psychiatry and clinical psychology


title: Trait Mindful Nonreactivity and Nonjudgment Prospectively Predict of COVID-19 Health Protective Behaviors Across a Two-Month Interval in a USA Sample

abstract: The COVID-19 pandemic has prompted a growing recommendation for social distancing and using personal protective equipment (PPE) to help mitigate the virus transmission. Previous studies have shown promising relationships between perceived susceptibility to COVID-19, mindfulness-related variables, and COVID-19 health protective behaviors (social distancing and PPE use). In this longitudinal study, the variables were measured across a two-month interval during the earlier phase of the pandemic in June (Time 1) and August (Time 2), 2020. The results from 151 matched USA MTurk participants indicated that the perceived susceptibility to COVID-19 did not significantly predict the health protective behaviors. For mindfulness, nonreactivity was positively related to PPE use while nonjudgement was negatively related to PPE use. Accordingly, mindfulness promotion messages could be a way to increase the likelihood of people performing health protective behaviors to better constrain the COVID-19 outbreak.

category: public and global health


title: Sensitivity of excess mortality due to the COVID-19 pandemic to the choice of the mortality index, method, reference period, and the time unit of the death series

abstract: Estimating excess mortality is challenging. The metric depends on the expected mortality level, which can differ based on given choices, such as the method and the time series length used to estimate the baseline. However, these choices are often arbitrary, and are not subject to any sensitivity analysis. We bring to light the importance of carefully choosing the inputs and methods used to estimate excess mortality. Drawing on data from 26 countries, we investigate how sensitive excess mortality is to the choice of the mortality index, the number of years included in the reference period, the method, and the time unit of the death series. We employ two mortality indices, three reference periods, two data time units, and four methods for estimating the baseline. We show that excess mortality estimates can vary substantially when these factors are changed, and that the largest variations stem from the choice of the mortality index and the method. We also find that the magnitude of the variation in excess mortality can change markedly within countries, resulting in different cross-country rankings. We conclude that the inputs and method used to estimate excess mortality should be chosen carefully based on the specific research question.


title: Simple, Accurate Calculation of Mechanical Power in Pressure Controlled Ventilation (PCV)

abstract: Power is a promising new metric to assess energy transfer from a ventilator to a patient, as it combines the effects of multiple different parameters into a single comprehensive value. For volume-controlled ventilation (VCV), excellent equations exist for calculating power from basic ventilator parameters, but for pressure-controlled ventilation (PCV), an accurate, easy-to-use equation has been elusive. Here, we present a new power equation and evaluate its accuracy compared to the three published PCV power equations. When applied to a sample of 50 patients on PCV with a non-zero rise time, we found that our equation estimated power within an average of 8.4% {+/-} 5.9% (mean {+/-} standard deviation) of the reference value. This new equation is accurate and simple to use, making it an attractive option to estimate power in PCV cases at the bedside.


title: Systematic Review and Meta-analysis of Eculizumab, Inebilizumab, Tocilizumab, and Satralizumab for Neuromyelitis Optica

abstract: Neuromyelitis optica is rare, autoimmune-mediated inflammation and demyelination of the central nervous system with a prevalence of 1-2 persons per 100,000 populations. We aim to generate a head-to-head comparison of these drugs with appropriate evidence to guide future trials and treatment guidelines in a patient with recurrent attacks of NMO. We searched the databases like PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase for studies published prior to April 2021 using the keywords. Over all 929 patients from 11 different publications were included in the study. Five studies were included for quantitative synthesis. Pooling of studies showed significant mean reduction of ARR in the monoclonal antibody group (-0.26 [-0.35, -0.17], P <0.00001, I2=0%) and the mean difference in EDSS score from baseline in monoclonal antibodies was - 0.23(95% CI [-0.43, -0.03], P=0.02, I2=0%). There was no significant difference in frequency of total reported adverse events between monoclonal antibody and the comparator arm (RR: 1.01 [0.95, 1.07], P=0.74, I2=14%). Our findings, particularly seen from the context of a few RCTs, support the pursuit of larger, multi-center RCTs that evaluate the effectiveness of each of the currently available monoclonal antibodies and better describe their adverse risk profile.


title: Protocol for a prospective, hospital-based registry of pregnant women with SARS-CoV-2 infection in India: PregCovid Registry study

abstract:
IntroductionPregnant women are at increased risk of contracting coronavirus disease 2019 (COVID-19) due to several factors and therefore require special attention. However, the consequences of the COVID-19 pandemic on pregnant women and their newborns remain uncharted. The PregCovid registry aims to document the impact of SARS-CoV-2 infection on pregnant, post-partum women and their newborns. The aim of the registry is also to determine mother-to-child transmission of SARS-CoV-2 infection in India.

Methods and analysisPregCovid is a hospital-based registry for capturing information of pregnant, post-partum women with COVID-19 and their newborns in India. Medical case records of pregnant and post-partum women with laboratory-confirmed diagnoses of COVID-19 will be captured in real-time using an online electronic patient record (EPR) software. The frequency of each symptom will be calculated. The laboratory data will be analyzed for calculating the frequency of laboratory parameters consistently higher in women with COVID- The adverse pregnancy and neonatal outcomes will be analyzed and their frequency will be calculated. Response to treatment will be analyzed for frequency calculation (number of women treated with different treatment regimens). The mother-to-child transmission data will be analyzed from the RT-PCR and/ antibody data of neonatal and maternal samples tested wherever the information is available. The registry data will be crucial for developing strategies for reducing the adverse impact of COVID-19 on pregnant women and their new-born.

Ethics and disseminationThe study is approved by the Institutional Ethics Committee of ICMR-National Institute for Research in Reproductive Health (#55/2020), BYL Nair Hospital, Mumbai, India (# 63/2020); and all the 18 participating study sites under Medical Education and Drugs Department of Government of Maharashtra. The Institutional Ethics Committees granted a waiver of consent as the data is collected from the medical case records.

Trial registration numberCTRI/2020/05/025423

Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThe PregCovid registry is a hospital-based registry at dedicated COVID-19 hospitals in India. The registry will help to identify new epidemiological, clinical characteristics, obstetrics outcomes associated with pregnant women and/post-partum women with COVID-19 in India. The study will also generate information on clinical presentations and outcomes of neonatal born to mothers with COVID-19 in India.
C_LIO_LIPregCovid registry will provide evidence of mother to child transmission of SARS-CoV-2 infection in Indian women
C_LIO_LIThe evidence on unusual presentations of COVID-19 in pregnant and post-partum women will be generated.
C_LIO_LIThe follow-up of participants is only till the discharge from the hospital. Long-term follow-up is not included in the study.
C_LI

category: obstetrics and gynecology


title: Associations between forensic loci and neighboring gene expression levels may compromise medical privacy

abstract: A set of 20 short tandem repeats (STRs) is used by the United States criminal justice system to identify suspects, and to maintain a database of genetic profiles for individuals who have been previously convicted or arrested. Some of these STRs were identified in the 1990s, with a preference for markers in putative gene deserts to avoid forensic profiles revealing protected medical information. We revisit that assumption, investigating whether forensic genetic profiles reveal information about gene expression variation, or potential medical information. We find six significant correlations (FDR = 0.23) between the forensic STRs and the expression levels of neighboring genes in lymphoblastoid cell lines. We explore possible mechanisms for these associations, with evidence compatible with forensic STRs causing expression variation, or being in LD with a causal locus in three cases, and weaker or potentially spurious associations in the other three cases. Together, these results suggest that forensic genetic loci may reveal expression level and, perhaps, medical information.