title: Identification and trajectory of growth of concerning SARS-CoV-2 variants in Houston, Texas, January through April 2021 based on 11,568 genome sequences

abstract: Genetic variants of the SARS-CoV-2 virus are of substantial concern because they can detrimentally alter the pandemic course and disease features in individual patients. Here we report SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist healthcare system diagnosed from January 1, 2021 through May 31, 2021. The SARS-CoV-2 variant designated U.K. B.1.1.7 increased rapidly and caused 63%-90% of all new cases in the Houston area in the latter half of May. Eleven of the 3,276 B.1.1.7 genomes had an E484K change in spike protein. Compared with non-B.1.1.7 patients, individuals with B.1.1.7 had a significantly lower cycle threshold value (a proxy for higher virus load) and significantly higher rate of hospitalization. Other variants (e.g., B.1.429, B.1.427, P.1, P.2, and R.1) also increased rapidly, although the magnitude was less than for B.1.1.7. We identified 22 patients infected with B.1.617 "India" variants; these patients had a high rate of hospitalization. Vaccine breakthrough cases (n=207) were caused by a heterogeneous array of virus genotypes, including many that are not variants of interest or concern. In the aggregate, our study delineates the trajectory of concerning SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, and heralds the arrival and spread of B.1.617 variants in the metroplex.


title: Trajectory of Growth of SARS-CoV-2 Variants in Houston, Texas, January through May 2021 Based on 12,476 Genome Sequences

category: pathology


title: Disease-specific contribution of pulvinar dysfunction to impaired emotion recognition in schizophrenia

abstract: One important aspect for managing social interactions is the ability to rapidly and accurately perceive and respond to facial expressions, which is highly dependent upon intact processing within both cortical and subcortical components of the early visual pathways. Social cognitive deficits, including face emotion recognition (FER) deficits, are characteristic of several neuropsychiatric disorders, including schizophrenia (Sz) and autism spectrum disorders (ASD). Here, we investigated potential visual sensory contributions to FER deficits in Sz (n=28) and adult ASD (n=20) participants compared to neurotypical (n=30) controls using task-based fMRI during an implicit static/dynamic FER task. Compared to neurotypical controls, both Sz and ASD participants had significantly lower FER scores which interrelated with diminished activation of the superior temporal sulcus (STS). In Sz, STS deficits were predicted by reduced activation of both early visual regions and the pulvinar nucleus of the thalamus, along with impaired cortico-pulvinar interaction. By contrast, ASD participants showed patterns of increased early visual cortical and pulvinar activation. Large effect-size structural and histological abnormalities of pulvinar have previously been documented in Sz. Moreover, we have recently demonstrated impaired pulvinar activation to simple visual stimuli in Sz. Here, we provide the first demonstration of a disease-specific contribution of impaired pulvinar activation to social cognitive impairment in Sz.

category: psychiatry and clinical psychology


title: Independent and combined effects of nutrition and sanitation interventions on child growth in rural Cambodia: a factorial cluster-randomized controlled trial

abstract:
BackgroundChildhood exposure to fecal pathogens contributes to growth faltering, which is linked with adverse side effects later in life. The prevalence of stunting remains high in rural Cambodia, despite rapid economic development over the last two decades. This study aimed to assess the independent and combined effects of nutrition and sanitation programming on child growth outcomes in rural Cambodia.

MethodsWe conducted a factorial cluster-randomized controlled trial of 4,015 households with 4,124 children (1-28 months of age) across rural Cambodia. Fifty-five communes (clusters) were randomly assigned to a control arm or one of three treatments: a nutrition-only arm, a sanitation-only arm, and a combined nutrition and sanitation arm receiving both treatments. The primary outcome was length-for-age Z-score (LAZ). Secondary outcomes were weight-for-age Z-score (WAZ), weight-for-height Z-score (WHZ), stunting, wasting, underweight, and caregiver-reported diarrhea. Analysis was by intention-to-treat. The trial was pre-registered with ISRCTN Registry (ISRCTN77820875).

FindingsCompliance in the arms receiving the nutrition intervention was high, but compliance in the arms receiving the sanitation intervention was low. Compared with a mean LAZ of -1.04 (SD 1.2) in the control arm, children in the nutrition-only arm (LAZ +0.08, 95% CI: -0.01-0.18) and combined nutrition and sanitation arm (LAZ +0.10, 95% CI: 0.01-0.20) experienced greater linear growth; there were no measurable differences in LAZ in the sanitation-only arm. Similarly, compared with a mean WAZ of -1.05 (SD 1.1) in the control arm, children in the nutrition-only arm (WAZ +0.10, 95% CI 0.00-0.19) and combined-intervention arm (WAZ +0.11, 95% CI 0.03-0.20) were heavier for their age; there was no measurable difference in WAZ in the sanitation-only arm. There were no differences between arms in prevalence of stunting, wasting, underweight status, or one week period prevalence of diarrhea.

InterpretationImprovements in child growth in nutrition and combined nutrition and sanitation arms are consistent with other recent trials but we found no evidence that this sanitation intervention improved child growth. The sanitation intervention achieved only modest changes in sanitation access and use suggesting that more effective approaches are needed to reduce open defecation in this setting.

FundingUnited States Agency for International Development (USAID). The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.

category: public and global health


title: Dynamic magnetic resonance imaging of muscle contraction in facioscapulohumeral muscular dystrophy

abstract:
BackgroundQuantitative muscle MRI (water-T2 and fat mapping) is being increasingly used to assess disease involvement in muscle disorders, while imaging techniques for assessment of the dynamic and elastic muscle properties have not been translated yet into clinics.

MethodsHere, we quantitatively characterized muscle deformation (strain) in patients affected by facioscapulohumeral muscular dystrophy (FSHD), a prevalent muscular dystrophy, by applying dynamic MRI synchronized with neuromuscular electrical stimulation (NMES). We evaluated the quadriceps muscles in 34 ambulatory patients and 12 healthy controls, at 6 month intervals.

ResultsWe found that while a subgroup of patients behaved similarly to controls, for another subgroup the strain significantly decreased over time (50% over 1.5 years). Dynamic MRI parameters did not correlate with quantitative MRI.

ConclusionsIn conclusion, our results suggest that the evaluation of muscle ability to contract by NMES-MRI could be used to explore the elastic properties and monitor muscle involvement in FSHD and other neuromuscular disorders.

category: radiology and imaging


title: Domiciliary high-flow nasal cannula oxygen therapy for stable hypercapnic COPD patients: a prospective, multicenter, open-label, randomized controlled trial

abstract:
BackgroundThe effectiveness of the domiciliary use of high-flow nasal cannula oxygen therapy (HFNC) in patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease (COPD) remains controversial.

ObjectivesTo investigate the efficacy and safety of domiciliary HFNC use in stable hypercapnic COPD patients.

MethodsThis multicenter, open-label, randomized controlled trial enrolled patients with stable hypercapnic COPD. Over 52 weeks, we compared long-term oxygen therapy (LTOT) alone versus domiciliary HFNC plus LTOT (HFNC/LTOT). The primary endpoint was the frequency of moderate/severe COPD exacerbations. We also compared changes from baseline levels in arterial blood gas, SpO2, pulmonary function, health-related quality of life (HRQOL), and a six-minute walk test.

ResultsWe enrolled 104 patients in total; from these, we removed mismatching patients and then assigned 49 and 50 patients to HFNC/LTOT and LTOT groups, respectively, for safety analysis; 47 and 46 patients for HFNC/LTOT and LTOT groups, respectively, for efficacy analysis. Thirty-seven (79%) and 41 patients (89%) in HFNC/LTOT and LTOT, respectively, completed the final evaluation. HFNC significantly reduced the frequency of COPD exacerbations and prolonged the duration without moderate or severe COPD exacerbations over the 52-week study period (p = 0.002, p = 0.032, respectively). The adjusted odds ratios (95% confidence intervals [CIs]) of the frequency of COPD exacerbations in LTOT against HFNC/LTOT was 2.85 (1.48, 5.47). The median survival time (95% CI) to the first COPD exacerbation with moderate or severe for the LTOT group was 25 weeks (14.1, 47.4); however, the HFNC/LTOT group did not reach the median survival time. HFNC also caused statistically significant differences (p < 0.05) in the SpO2, FVC (%FVC), and FEV1 (%FEV1); however, these improvements were transient. There were no other improvements in arterial blood gas, pulmonary function, HRQOL, or six-minute walk test parameters. In addition, no safety concerns were identified for HFNC.

ConclusionsHFNC may be a reasonable therapeutic choice in stable hypercapnic COPD patients with a history of exacerbations.

Trial registration number: UMIN000028581, NCT03282019 (http://www.umin/ac.jp, https://clinicaltrials.gov/)

category: respiratory medicine


title: Unawareness for chronic kidney disease is high in all stages, age groups and comorbidities and higher in women than in men

abstract:
BackgroundChronic kidney disease (CKD) is associated with an increased risk for cardiovascular events, hospitalizations or mortality. In populations aged [≥]40 years, CKD is as prevalent as diabetes or coronary heart disease. Awareness for CKD though is generally low in public, patients and physicians, which hinders early diagnosis and treatment to decelerate disease progress.

MethodWe analyzed baseline data collected in 2010 from 3,334 participants with CKD stages 1-5 from German CKD cohorts and registries. CKD unawareness and 95%-confidence intervals (CI) was estimated according to patients answer to the question whether they had ever been told to suffer from a CKD. Prevalence ratios (PR) with 95%-CI were estimated in categories of age, sex, CKD stages, BMI, hypertension, diabetes and other relevant comorbidities.

ResultsCKD unawareness was high, reaching 82% (95% CI: 80%-84%) for CKD stages 1 or 2, 71% (68%-73%) in CKD 3a, 49% (45%-54%) in CKD 3b and still 30% (24%-36%) in CKD4, in each stage increasing with age. CKD unawareness was similarly high in patients with hypertension, diabetes or cardiovascular comorbidities. Women were more often unaware than men (PR=1.07 (1.02;1.12)), this sex difference increased with increasing CKD stage. Macroalbuminuria (PR=0.90 (0.82; 1.00)), anemia (PR=0.78 (0.73; 0.83)) and BMI [≥]40 (PR=0.88 (0.77; 1.00)) were associated with higher CKD awareness.

ConclusionEven in older patients or in patients with comorbidities, CKD unawareness was high. Sex differences were largest in later stages. Guideline oriented treatment of patients with hypertension or diabetes could increase awareness. Patient-physician communication about CKD might be amendable.

category: nephrology


title: Heterozygous variants in KCNC2 cause a broad spectrum of epilepsy phenotypes associated with characteristic functional alterations

abstract:
BackgroundKCNC2 encodes a member of the shaw-related voltage-gated potassium channel family (KV3.2), which are important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain.

MethodsIndividuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic and functional analysis. The cases were referred through clinical and research collaborations in our study. Four de novo variants were examined electrophysiologically in Xenopus laevis oocytes.

ResultsWe identified novel KCNC2 variants in 27 patients with various forms of epilepsy. Functional analysis demonstrated gain-of-function in severe and loss-of-function in milder phenotypes as the underlying pathomechanisms with specific response to valproic acid.

ConclusionThese findings implicate KCNC2 as a novel causative gene for epilepsy emphasizing the critical role of KV3.2 in the regulation of brain excitability with an interesting genotype-phenotype correlation and a potential concept for precision medicine.

category: neurology


title: Dose-dependent effect of nuts on blood pressure: a systematic review and meta-analysis of randomized controlled trials

abstract:
ObjectiveTraditional pairwise meta-analyses indicated that nuts consumption can improve blood pressure. We iamed to determine the dose-dependent effect of nuts on systolic (SBP) and diastolic blood pressure (DBP) in adults.

MethodsA systematic search was undertaken in PubMed, Scopus, and ISI Web of Science till March 2021. Randomized controlled trials (RCT) evaluating the effects of nuts on SBP and DBP in adults were included. We estimated change in blood pressure for each 20 g/d increment in nut consumption in each trial and then, calculated mean difference (MD) and 95%CI using a random-effects model. We estimated dose-dependent effect using a dose-response meta-analysis of differences in means. The certainty of evidence was rated using the GRADE instrument, with the minimal clinically important difference being considered 2 mmHg.

ResultsA total of 31 RCTs with 2784 participants were included. Each 20 g/d increase in nut consumption reduced SBP (MD: -0.50 mmHg, 95%CI: -0.79, -0.21; I2 = 12%, n = 31; GRADE = moderate certainty) and DBP (MD: -0.23 mmHg, 95%CI: -0.38, -0.08; I2 = 0%, n = 31; GRADE = moderate certainty). The effect of nuts on SBP was more evident in patients with type 2 diabetes (MD: -1.31, 95%CI: -2.55, -0.05; I2 = 31%, n = 6). The results were robust in the subgroup of trials with low risk of bias. Levels of SBP decreased proportionally with the increase in nuts consumption up to 40 g/d (MD40g/d: -1.60, 95%CI: -2.63, -0.58), and then appeared to plateau with a slight upward curve. A linear dose-dependent reduction was seen for DBP, with the greatest reduction at 80 g/d (MD80g/d: -0.80, 95%CI: -1.55, -0.04).

ConclusionsThe available evidence provides a good indication that nut consumption can result in a small improvement in blood pressure in adults. Well-designed trials are needed to confirm the findings in long term follow-up.

category: nutrition


title: Multi-trait GWAS of atherosclerosis detects novel pleiotropic loci

abstract:
RationaleAlthough affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. Analysis of their shared genetic architecture, along with that of common risk factors, may identify novel common biology.

ObjectiveTo identify novel pleiotropic genetic loci associated with atherosclerosis and provide a better understanding of biological pathways underlying atherosclerosis.

Methods and ResultsSummary statistics from genome wide association studies (GWAS) of nine known atherosclerotic (CAD, PAD) or atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein (LDL), high density lipoprotein, total cholesterol, and triglycerides) were combined to perform 15 separate multi-trait genetic association scans which resulted in 31 unique novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified 34 candidate causal genes across 14 of the detected signals. Notably, the signal between PAD and CAD at the VDAC2 locus (rs7088974) colocalized with VDAC2 expression in aorta and tibial artery tissues. Additionally, the signal between PAD and LDL at the PCSK6 locus (rs1531817) affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte like cells.

ConclusionsJoint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. VDAC2 and PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.

category: genetic and genomic medicine


title: M-DATA: A Statistical Approach to Jointly Analyzing De Novo Mutations for Multiple Traits

abstract:
Recent studies have demonstrated that multiple early-onset diseases have shared risk genes, based on findings from de novo mutations (DNMs). Therefore, we may leverage information from one trait to improve statistical power to identify genes for another trait. However, there are few methods that can jointly analyze DNMs from multiple traits. In this study, we develop a framework called M-DATA (Multi-trait framework for De novo mutation Association Test with Annotations) to increase the statistical power of association analysis by integrating data from multiple correlated traits and their functional annotations. Using the number of DNMs from multiple diseases, we develop a method based on an Expectation-Maximization algorithm to both infer the degree of association between two diseases as well as to estimate the gene association probability for each disease. We apply our method to a case study of jointly analyzing data from congenital heart disease (CHD) and autism. Our method was able to identify 23 genes for CHD from joint analysis, including 12 novel genes, which is substantially more than single-trait analysis, leading to novel insights into CHD disease etiology.

Author SummaryCongenital heart disease (CHD) is the most common birth defect. With the development of new generation sequencing technology, germline mutations such as de novo mutations (DNMs) with deleterious effects can be identified to aid in discovering the genetic causes for early on-set diseases such as CHD. However, the statistical power is still limited by the small sample size of DNM studies due to the high cost of recruiting and sequencing samples, and the low occurrence of DNMs given its rarity. Compared to DNM analysis for other diseases, it is even more challenging for CHD given its genetic heterogeneity. Recent research has suggested shared disease mechanisms between early-onset neurodevelopmental diseases and CHD based on findings from DNMs. Currently, there are few methods that can jointly analyze DNM data on multiple traits. Therefore, we develop a framework to identify risk genes for multiple traits simultaneously for DNM data. The new method is applied to CHD and autism as a case study to demonstrate its improved power in identifying risk genes compared with single-trait analysis. Our results lead to new insights on the disease etiology of CHD, and the shared etiological mechanisms between CHD and autism.


title: Clinical, immunological and genomic characterization of asymptomatic and symptomatic cases with SARS-CoV-2 infection, India

abstract:
BackgroundThe current global pandemic of Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 led to the investigation with clinical, biochemical, immunological and genomic characterization from the patients to understand the pathophysiology of viral infection.

MethodsSamples were collected from six asymptomatic and six symptomatic SARS-CoV-2 confirmed hospitalized patients in Bhubaneswar, Odisha, India. Clinical details, biochemical parameters, treatment regime were collected from hospital, viral load was determined by RT-PCR, levels of cytokines and circulating antibodies in plasma were assessed by Bioplex and isotyping respectively. In addition, the whole genome sequencing of viral strains and mutational analysis were carried out.

FindingsAnalysis of the biochemical parameters highlighted the increased levels of C-Reactive protein (CRP), lactate dehydrogenase (LDH), serum SGPT, serum SGOT and ferritin in symptomatic patients indicating that patients with higher levels of few biochemical parameters might experience severe pathophysiological complications after SARS-CoV-2 infection. This was also observed that symptomatic patients were mostly with one or more comorbidities, especially diabetes (66.6%). Surprisingly the virological estimation revealed that there was no significant difference in viral load of oropharyngeal (OP) samples between the two groups. This suggests that the viral load in OP sample does not correlate with the disease severity and both asymptomatic and symptomatic patients are equally capable of transmitting the virus. Whereas, viral load was higher in plasma and serum samples of symptomatic patients suggesting that the development of clinical complications is mostly associated to high viral load in plasma and serum. This also demonstrated that the patients with high viral load in plasma and serum samples were found to develop sufficient amounts of antibodies (IgG, IgM and IgA). Interestingly, the levels of 7 cytokines (IL-6, IL-.1, IP-10, IL-8, IL-10, IFN-2, IL-15) were found to be highly elevated in symptomatic patients, while three cytokines (soluble CD40L, GRO and MDC) were remarkably higher in asymptomatic patients. Therefore, this data suggest that cytokines and chemokines may serve as "predictive indicator" of SARS-CoV-2 infection and contribute to understand the pathogenesis of COVID-19. The whole genome sequence analysis revealed that the current isolates were clustered with 19B, 20A and 20B clades, however acquired 11 additional changes in Orf1ab, spike, Orf3a, Orf8 and nucleocapsid proteins. The data also confirmed that the D614G mutation in spike protein is mostly linked with higher virus replication efficiency and severe SARS-CoV-2 infection as three patients had higher viral load and among them two patients with this mutation passed away.

InterpretationThis is the first comprehensive study of SARS CoV-2 patients from India. This will contribute to a better understanding of the pathophysiology of SARS-CoV-2 infection and advance in the implementation of effective disease control strategies.

FundingThis study was supported by the core funding of Institute of Life Sciences, Bhubaneswar, Dept of Biotechnology, India.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAsymptomatic patients are a source of concern as measures taken to control the spread of the virus are severely impacted by their undetectability. Presently, there is an inadequate information about the characteristics of the asymptomatic and symptomatic patients. The association between SARS-CoV-2 viral load, cytokines and risk of disease progression remains unclear in COVID-19 in Indian scenario. PubMed was searched for articles published up to May, 2021, using the keywords "SARS CoV-2 patients in India", or "2019 novel coronavirus patients in India". No published work about the patients data on SARS CoV-2 in Indian scenario could be identified.

Added value of this studyThis investigation highlights the ability of both asymptomatic and symptomatic patients to transmit the virus equally. This study also demonstrates that the D614G mutation in the spike protein is associated with severe SARS-CoV-2 infection and enhance levels of inflammatory markers such as CRP and ferritin which can be predictive biomarkers for critical condition of patients. This is the first comprehensive study of SARS CoV-2 patients from India and will contribute to a better understanding of the pathophysiology of SARS-CoV-2 infection by advancing the implementation of effective disease control strategies.

Implications of all the available evidenceThe current global pandemic of Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 led to the investigation with clinical, biochemical, immunological and viral genome sequencing to understand the pathophysiology of this virus infection. Samples were collected from six asymptomatic and six symptomatic SARS-CoV-2 confirmed hospitalized patients in Bhubaneswar, Odisha, India. This investigation highlights the ability of both asymptomatic and symptomatic patients to transmit the virus equally. This also demonstrated that the D614G mutation is mostly associated with higher virus replication capacity and severe SARS-CoV-2 infection and enhanced levels of inflammatory markers such as CRP and ferritin which are associated with critical conditions of patients. This is the first comprehensive study of SARS CoV-2 patients from India and will contribute to a better understanding of the pathophysiology of SARS-CoV-2 infection by advancing the implementation of competent disease control strategies.

category: infectious diseases


title: Measurement of multiple SARS-CoV-2 antibody titer after vaccination represents individual vaccine response and contributes to individually appropriate vaccination schedules

abstract: The SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer-BioNTech) has become a game-changer in the COVID-19 crisis. Faster and wider coverage of vaccine supply is urgently needed, although vaccine supply is far from abundant in many countries and regions. There is no denying that Japan is vaccinating at a slower pace than in many other countries. At the end of April 2021, it had administered less than 2% of the population, according to the statistics website Our World in Data.1 Single-dose vaccination may be considered to induce an adequate antibody response in individuals with prior infection,2-5 which can lead to more effective vaccine distribution to people in serious need. However, multiple antibody responses in populations with various backgrounds, including prior COVID-19 infection, underlying diseases, and age, have not been investigated sufficiently. Due to the lack of antibody measurement data, antibody follow-up measurement recommendations have yet to be suggested. Accumulation of available data regarding quantitative antibody titer will lead to the establishment of personally customized schedules, including antibody follow-up, and will balance both faster delivery of vaccines and confirmation of effective vaccination.


title: T-cell and antibody immunity after COVID-19 mRNA vaccines in healthy and immunocompromised subjects-An exploratory study.

abstract:
BackgroundIn recent studies, up to half of immunocompromised (IC) subject populations fail to develop antibodies after COVID-19 vaccination.

Purpose and MethodsHere, we explore whether T-cells which respond to the spike (S) antigenic sequence and its less conserved S1, and the conserved S2 component are present in serial samples before and after each dose of mRNA1273 or BNT162b2 vaccines in 20 healthy immunocompetent subjects. Single samples from 7 vaccinated IC subjects were also tested. Simultaneously, we measured IgG antibodies to the receptor binding domain (RBD) of S1, and anti-S IgG, and frequencies of monocytic CD14+HLA-DR-(M-MDSC) and polymorphonuclear CD14-CD15+CD11b+ (PMN-MDSC) myeloid-derived suppressor cells.

ResultsIn healthy subjects, S1-, S2-, and S-reactive CD4 and CD8 T-cell frequencies showed a numeric but not statistically significant decrease after the first vaccine dose and were accompanied by increased MDSC frequencies (p<0.05). After the second dose, S2-and S-reactive CD4 and CD8 cells and MDSC approached pre-vaccination levels. In healthy subjects, a) S1-reactive CD8 frequencies were significantly higher after the second dose compared with pre-vaccination levels (p=0.015), b) anti-RBD and anti-S IgG were present in all after the second dose. Among seven IC subjects, anti-RBD and anti-S IgG were absent in 4 and 3 subjects, respectively. S1-reactive CD8 cells were identified in 2 of 4 anti-RBD negative subjects. S-reactive CD4 or CD8 cells were identified in all three anti-S negative subjects.

ConclusionsIn healthy immunocompetent subjects, mRNA vaccines induce antibodies to the spike antigenic sequences and augment CD8 cells reactive to the S1 spike sequence, which is more specific for the SARS-CoV-2 virus. In this exploratory cohort of vaccinated immunocompromised subjects, S1-reactive CD8 cells can be detected in some who are negative for RBD antibody, and S-reactive T-cells are present in all who are negative for spike antibody.

category: emergency medicine


title: Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation.

abstract:
Alloreactivity forms the basis of allogeneic hematopoietic cell transplantation (HCT), with donor derived T cell response to recipient antigens mediating clinical responses either in part or entirely. These encompass the different manifestations of graft vs. host disease (GVHD), infection risk as well as disease response. Whilst the latter is contingent upon disease biology and thus may be less predictable, the former two are more likely to be directly proportional to the magnitude of donor derived T cell recovery. Herein we explore the quantitative aspects of immune cell recovery following allogeneic HCT and clinical outcomes in two cohorts of HLA matched allograft recipients who received rabbit anti-thymocyte globulin (ATG) on different schedules (days -9 to -7 vs. -3 to -1). Monocyte as well as donor derived T cell (ddCD3) recovery was superior in those given ATG early in their course (days -9/-7). This difference was related to a more rapid rate of ddCD3 recovery, largely driven by CD3+/8+ cells in the first month following transplantation. Early monocyte recovery was associated with later T cell recovery, improved survival, and less chronic GVHD. In contrast rapid and early ddCD3 expansion out of proportion to monocyte recovery was associated with a high likelihood of acute GVHD and poor survival. This analytic methodology demonstrates that modelling  early-term immune reconstitution following HCT yields insights that may be useful in management of post-transplant immunosuppression and adaptive cellular therapy to optimize clinical outcomes.

HighlightsATG given early (day -9 to -7) prior to HCT leads to improved survival and non-relapse mortality. Improved monocyte counts as well as donor-derived T cell counts are seen in recipients of early ATG. Improved clinical outcomes are observed in patients with enhanced monocyte and T cell recovery after HCT.

category: oncology


title: Are we allowed to visit now? Concerns and issues surrounding vaccination and infection risks in UK care homes during COVID-19

abstract:
BackgroundVaccination uptake in the UK and increased care home testing are likely affecting care home visitation. With scant scientific evidence to date, the aim of this longitudinal qualitative study was to explore the impact of both (vaccination and testing) on the conduct and experiences of care home visits.

MethodsFamily carers of care home residents with dementia and care home staff from across the UK took part in baseline (October/November 2020) and follow-up interviews (March 2021). Public advisers were involved in all elements of the research. Data were analysed using thematic analysis.

ResultsAcross 62 baseline and follow-up interviews with family carers (n=26; 11) and care home staff (n=16; 9), five core themes were developed: Delayed and inconsistent offers of face-to-face visits; Procedures and facilitation of visits; Frustration and anger among family carers; Variable uptake of the COVID-19 vaccine; Misinformation, education, and free choice. The variable uptake in staff, compared to family carers, was a key factor seemingly influencing visitation, with a lack of clear guidance leading care homes to implement infection control measures and visitation rights differently.

ConclusionsWe make five recommendations in this paper to enable improved care home visitation in the ongoing, and in future, pandemics. Visits need to be enabled and any changes to visiting rights must be used as a last resort, reviewed regularly in consultation with residents and carers and restored as soon as possible as a top priority, whilst more education needs to be provided surrounding vaccination for care home staff.

category: geriatric medicine


title: Aerosol transport measurements and assessment of risk from infectious aerosols: a case study of two German cash-and-carry hardware/DIY stores

abstract: We report experimental results on aerosol dispersion in two large German cash- and-carry hardware/DIY stores to better understand the factors contributing to disease transmission by infectious human aerosols in large indoor environments. We examined the transport of aerosols similar in size to human respiratory aerosols (0.3 {micro}m-10 {micro}m) in representative locations, such as high-traffic areas and restrooms. In restrooms, the observed decay of aerosol concentrations was consistent with well-mixed air exchange. In all other locations, fast decay times were measured, which were found to be independent of aerosol size (typically a few minutes). From this, we conclude that in the main retail areas, including at checkouts, rapid turbulent mixing and advection is the dominant feature in aerosol dynamics. With this, the upper bound of risk for airborne disease transmission to a susceptible is determined by direct exposure to the exhalation cloud of an infectious. For the example of the SARS-CoV-2 virus, we find when speaking without a face mask and aerosol sizes up to an exhalation (wet) diameter of 50 {micro}m, a distance of 1.5 m to be unsafe. However, at the smallest distance between an infectious and a susceptible, while wearing typical surgical masks and for all sizes of exhaled aerosol, the upper bound of infection risk is only [~]5% and decreases further by a factor of 100 ([~]0.05%) for typical FFP2 masks for a duration of 20 min. This upper bound is very conservative and we expect the actual risk for typical encounters to be much lower. The risks found here are comparable to what might be expected in calm outdoor weather.

category: health policy


title: RT-qPCR detection of SARS-CoV-2 mutations S 69-70 del, S N501Y and N D3L associated with variants of concern in Canadian wastewater samples

abstract:
SARS-CoV-2 variants of concern (VoC) have been increasingly detected in clinical surveillance in Canada and internationally. These VoC are associated with higher transmissibility rates and in some cases, increased mortality. In this work we present a national wastewater survey of the distribution of three SARS-CoV-2 mutations found in the B.1.1.7, B.1.351, and P.1 VoC, namely the S-gene 69-70 deletion, N501Y mutation, and N-gene D3L. RT-qPCR allelic discrimination assays were sufficiently sensitive and specific for detection and relative quantitation of SARS-CoV-2 variants in wastewater to allow for rapid population-level screening and surveillance. We tested 261 samples collected from 5 Canadian cities (Vancouver, Edmonton, Toronto, Montreal, and Halifax) and 6 communities in the Northwest Territories from February 16th to March 28th, 2021. VoC were not detected in the Territorial communities, suggesting the absence of VoC SARS-CoV-2 cases in those communities. Percentage of variant remained low throughout the study period in the majority of the sites tested, however the Toronto sites showed a marked increase from ~25% to ~75% over the study period.

The results of this study highlight the utility of population level molecular surveillance of SARS-CoV-2 VoC using wastewater. Wastewater monitoring for VoC can be a powerful tool in informing public health responses, including monitoring trends independent of clinical surveillance and providing early warning to communities.


title: Emergence of SARS-CoV-2 variants of concern in the pediatric population of the United States

abstract: The evolution of SARS-CoV2 virus has led to the emergence of variants of concern (VOC). Children, particularly <12 years old not yet eligible for vaccines, continue to be important reservoirs of SARS-CoV-2 yet VOC prevalence data in this population is lacking. We report data from a genomic surveillance program that includes 9 U.S. childrens hospitals. Analysis of SARS-CoV-2 genomes from 2119 patients <19 years old between 03/20 to 04/21 identified 252 VOCs and 560 VOC signature mutations, most from 10/20 onwards. From 02/21 to 04/21, B.1.1.7 prevalence increased from 3.85% to 72.22% corresponding with the decline of B.1.429/B.1.427 from 51.82% to 16.67% at one institution. 71.74% of the VOC signature mutations detected were in children <12 years old, including 33 cases of B.1.1.7 and 119 of B.1.429/B.1.427. There continues to be a need for ongoing genomic surveillance, particularly among young children who will be the last groups to be vaccinated.


title: COVID-19 Associated Pulmonary Aspergillosis: Systematic Review and Patient-Level Meta-Analysis

abstract:
RationalePulmonary aspergillosis may complicate COVID-19 and contribute to excess mortality in intensive care unit (ICU) patients. The incidence is unclear because of discordant definitions across studies.

ObjectiveWe sought to review the incidence, diagnosis, treatment, and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA), and compare research definitions.

MethodsWe systematically reviewed the literature for ICU cohort studies and case series including [≥] patients with CAPA. We calculated pooled incidence. Patients with sufficient clinical details were reclassified according to 4 standardized definitions (Verweij, White, Koehler, and Bassetti).

MeasurementsCorrelations between definitions were assessed with Spearmans rank test. Associations between antifungals and outcome were assessed with Fishers Exact test.

Main Results38 studies (35 cohort studies and 3 case series) were included. Among 3,297 COVID-19 patients in ICU cohort studies, 313 were diagnosed with CAPA (pooled incidence 9.5%). 197 patients had patient-level data allowing reclassification. Definitions had limited correlation with one another ({rho}=0.330 to 0.621, p<0.001). 38.6% of patients reported to have CAPA did not fulfil any research definitions. Patients were diagnosed after a median of 9 days (interquartile range 5-14) in ICUs. Tracheobronchitis occured in 5.3% of patients examined with bronchoscopy. The mortality rate (50.0%) was high, irrespective of antifungal use (p=0.28); this remained true even when the analysis was restricted to patients meeting standardized definitions for CAPA.

ConclusionsThe reported incidence of CAPA is exaggerated by use of non-standard definitions. Further research should focus on identifying patients likely to benefit from antifungals.

category: intensive care and critical care medicine


title: Genomic epidemiology reveals geographical clustering of multidrug-resistant Escherichia coli sequence type (ST)131 associated with bacteraemia in Wales, United Kingdom

abstract:
2.Increasing resistance to third-generation cephalosporins (3GCs) threatens public health, as these antimicrobials are prescribed as empirical therapies for systemic infections caused by Gram-negative bacteria. Resistance to 3GCs in urinary tract infections (UTIs) and bacteraemia is associated with the globally disseminated, multidrug-resistant, uropathogenic Escherichia coli sequence type (ST)131. This study combines the epidemiology of E.coli blood culture surveillance with whole-genome sequencing (WGS) to investigate ST131 associated with bacteraemia in Wales between 2013 and 2014. This population-based prospective genomic analysis investigated temporal, geographic, and genomic risk factors. To identify spatial clusters and lineage diversity, we contextualised 142 genomes collected from twenty hospitals, against a global ST131 population (n=181). All three major ST131 clades are represented across Wales, with clade C/H30 predominant (n=102/142, 71.8%). Consistent with global findings, Welsh strains of clade C/H30 contain {beta}-lactamase genes from the blaCTX-M-1 group (n=65/102, 63.7%), which confers resistance to 3GCs. In Wales, the majority of clade C/H30 strains belonged to sub-clade C2/H30Rx (n=88/151, 58.3%), whereas sub-clade C1/H30R strains were less common (n=14/67, 20.9%). A sub-lineage unique to Wales was identified within the C2/H30Rx sub-clade (named GB-WLS.C2/H30Rx) and is defined by six non-recombinogenic single-nucleotide polymorphisms (SNPs), including a missense variant in febE (ferric enterobactin transport protein) and fryC (fructose-like permease IIC component), and the loss of the capsular biosynthesis genes encoding the K5 antigen. Bayesian analysis predicted that GB-WLS.C2/H30Rx diverged from a common ancestor (CA) most closely related to a Canadian strain between 1998 and 1999. Further, our analysis suggests a descendent of GB-WLS.C2/H30Rx arrived through an introduction to North Wales circa 2002, spread and persists in the geographic region, causing a cluster of cases (CA emerged circa 2009) with a maximum pair-wise distance of 30 non-recombinogenic SNPs. This limited genomic diversity likely depicts local transmission within the community in North Wales. This investigation emphasises the value of genomic epidemiology, allowing detection of suspected transmission clusters and the spread of genetically similar/identical strains in local areas. These analyses will enable targeted and timely public health interventions.

3. Impact statementUropathogenic Escherichia coli (UPEC) is a leading cause of bacteraemia, resulting in substantial mortality and morbidity, with rates of E. coli bacteraemia (ECB) becoming a particular concern in Wales(1). Previous genomic and multilocus sequence typing (MLST) studies have identified that ECB cases are disproportionately caused by specific groups [sequence types (ST)] of related E. coli. Previous work reports ST131 as a globally disseminated lineage associated with bacteraemia and antimicrobial resistance (AMR). Despite widespread study of ECB, the temporal and geographic patterns of key ECB clones remain an important area of study. Moreover, by gaining a detailed understanding of the population structure of key ECB clones, it should be possible to develop and improve public health measures to reduce the risk of ECB and act to combat the rise of AMR. Using whole-genome sequencing, we describe the temporal and spatial relationship of a collection of E. coli ST131 bacteraemia cases sampled across Wales. High-resolution analyses of genetic variants identified a local (North Wales) cluster of strains within the highly antimicrobial-resistant sub-clade C2/H30Rx, which are characterised by resistance to nitrofurantoin and the loss of the K5 capsule. Notably, AMR stewardship guidelines in Wales recently changed to include nitrofurantoin as a first-line treatment for uncomplicated UTIs. This local cluster likely represents environmentally-mediated community transmission, environmentally mediated, from the strains common ancestor that existed circa 2009, highlighting the need for national genomic surveillance, close to real-time, to track and understand the evolution of AMR in communities.

4. Data summaryThe study sequences are available in the National Center for Biotechnology Information (NCBI) under BioProject accession number PRJNA729115. Raw Illumina sequence read data have been deposited to the NCBI sequence read archive [SRA (https://www.ncbi.nlm.nih.gov/sra)] under the accession numbers SRR14519411 to SRR14519567. A complete list of SRA accession numbers is available in Table S1 (available in the online version of this article). The high-quality draft assemblies have been deposited to GenBank under the accession numbers JAHBGJ000000000 to JAHBMG000000000, and JAHBRR000000000 to JAHBRT000000000. The programs used to analyse raw sequence reads for polymorphism discovery and whole-genome sequencing based phylogenetic reconstruction are available as described in the materials and methods. The authors confirm all supporting data, code, and protocols have been provided within the article or through supplementary data files.

category: epidemiology


title: COVID-19 Fatality Rate Classification using Synthetic Minority Oversampling Technique (SMOTE) for Imbalance Class

abstract: SARS-Cov-2 is not to be introduced anymore. The global pandemic that originated more than a year ago in Wuhan, China has claimed thousands of lives. Since the arrival of this plague, face mask has become part of our dressing code. The focus of this study is to design, develop and evaluate a COVID-19 fatality rate classifier at the county level. The proposed model predicts fatality rate as low, moderate, or high. This will help government and decision makers to improve mitigation strategy and provide measures to reduce the spread of the disease. Tourists and travelers will also find the work useful in planning of trips. Dataset used in the experiment contained imbalanced fatality levels. Therefore, class imbalance was offset using SMOTE. Evaluation of the proposed model was based on precision, F1 score, accuracy, and ROC curve. Five learning algorithms were trained and evaluated. Experimental results showed the Bagging model has the best performance.


title: Lockdown babies- Birth and new parenting experiences during the 2020 Covid-19 lockdown in South Africa

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSPerceived birth experiences of parents can have a lasting impact on children. We explored the birth and new parenting experiences of South African parents during the Covid-19 lockdown.

MethodsWe conducted an online cross-sectional survey with consenting parents of babies born in South Africa during 2020. Factors associated with negative birth emotions and probable depression were estimated using logistic regression.

ResultsMost of the 520 respondents were females (n= 496, 95%) who gave birth at private hospitals (n=426, 86%). Mothers reported having overall positive birth emotions (n= 399, 80%). Multivariable analysis showed that having the baby during lockdown (adjusted odds ratio (aOR) 5.02; CI 1.28 - 19.66); being diagnosed with Covid-19 (aOR 3.17; CI 1.07 - 9.42); having negative new parenting emotions (aOR 6.07; CI 3.27 - 11.29); a preterm baby (aOR 3.02; CI 1.36 - 6.70) and lockdown related barring of preferred in hospital support (aOR 2.45; CI 1.35 - 4.43) were associated with mothers reporting predominately negative emotions about the birth. Having their chosen delivery method reduced the odds of negative birth emotions (aOR 0.4; CI 0.22 - 0.72). Multivariable analysis showed that having predominantly negative new parenting emotions (aOR 10.75; CI 5.41-21.37), breastfeeding struggles (aOR 2.16; CI 1.36 - 3.46); lockdown preventing health care access (aOR 2.06; CI 1.20 - 3.54) and creating financial strain (aOR 2.58; CI 1.08 - 6.18) were associated with probable minor depression

ConclusionsLockdown exacerbated many birth and parenting challenges including mental health and health care access. However, overall experiences were positive and there was a strong sense of resilience amongst parents.


title: BODY MASS INDEX TRAJECTORY BEFORE DEATH IN COMMUNITY-DWELLING OLDER ADULTS. POPULATION-BASED COHORT STUDY

abstract:
Background and objectiveBoth low and high body mass index (BMI) have been associated with greater mortality in older adults. This study evaluated the trajectory of BMI in the final years of life.

DesignPopulation-based cohort study.

SettingCommunity-dwelling adults in the English Longitudinal Study of Ageing between 1998 and 2012.

MeasurementsBody mass index, years before death and all-cause mortality. Analyses were adjusted for age, gender, educational level, housing tenure and social class.

ResultsData were analysed for 16,924 participants with 31,857 BMI records; mean age at study start, 61.6 (SD 10.9) years; mean BMI, 27.5 (4.7) Kg/m2. There were 3,686 participants (4,794 BMI records) who died and 13,238 participants (27,063 BMI records) who were alive at last follow-up. Mean BMI increased with age to 60-69 years but then declined, but the age-related decline was more rapid in decedents. At ages 80-89 years, mean BMI in decedents was 26.1 (4.7) compared with 27.1 (4.4) Kg/m2 in survivors. After adjusting for age and covariates, mean BMI declined in the five years before death. From 9 to 5 years before death or end of study, adjusted mean BMI was 0.51 (95% confidence interval 0.24 to 0.78) Kg/m2 lower for decedents than survivors; and from four to zero years before death, 1.55 (1.26 to 1.84) Kg/m2 lower in decedents.

ConclusionsIn community-dwelling older adults, mean body mass index enters an accelerating decline during five years before death. Reverse causation may account for the association of lower BMI with mortality.


title: Feasibility of Rapid Case Ascertainment for Cancer in East Africa: An Investigation of Community-Representative Kaposi Sarcoma in the Era of Antiretroviral Therapy.

abstract:
BACKGROUNDRapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa.

METHODSTo determine the feasibility of RCA of KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements.

RESULTSWe identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%).

CONCLUSIONSWe found that RCA -- an important tool for cancer research in resource-rich settings -- is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa.


title: Combining serological assays and official statistics to describe the trajectory of the COVID-19 pandemic: results from the EPICOVID19-RS study in Rio Grande do Sul (Southern Brazil)

abstract:
BackgroundThe EPICOVID19-RS study conducted 10 population-based surveys in Rio Grande do Sul (Southern Brazil), starting early in the epidemic. The sensitivity of the rapid point-of-care test used in the first eight surveys has been shown to decrease over time after some phases of the study were concluded. The 9th survey used both the rapid test and an enzyme-linked immunosorbent assay (ELISA) test, which has a higher and stable sensitivity.

MethodsWe provide a theoretical justification for a correction procedure of the rapid test estimates, assess its performance in a simulated dataset and apply it to empirical data from the EPICOVID19-RS study. COVID-19 deaths from official statistics were used as an indicator of the temporal distribution of the epidemic, under the assumption that fatality is constant over time. Both the indicator and results from the 9th survey were used to calibrate the temporal decay function of the rapid tests sensitivity from a previous validation study, which was used to estimate the true sensitivity in each survey and adjust the rapid test estimates accordingly.

ResultsSimulations corroborated the procedure is valid. Corrected seroprevalence estimates were substantially larger than uncorrected estimates, which were substantially smaller than respective estimates from confirmed cases and therefore clearly underestimate the true infection prevalence.

ConclusionCorrecting biased estimates requires a combination of data and modelling assumptions. This work illustrates the practical utility of analytical procedures, but also the critical need for good quality, populationally-representative data for tracking the progress of the epidemic and substantiate both projection models and policy making.


title: Perceptions of and obstacles to SARS-CoV-2 vaccination among adults in Lebanon: a cross-sectional online survey

abstract: The COVID-19 pandemic is an additional burden on Lebanons stressed population, fragmented healthcare system, and political, economic, and refugee crises. Understanding the populations intentions to vaccinate, and perceptions of and obstacles to SARS-CoV-2 vaccination, can inform Lebanons vaccination efforts. We performed a cross-sectional study from 29 Jan 2021 to 11 Mar 2021 using an online questionnaire in Arabic via convenience "snowball" sampling to assess the perceptions of adults residing in Lebanon. 1,185 adults participated in the survey. % [95% CI: 43.2%-49.0%] of survey participants intended to take the SARS-CoV-2 vaccine when available to them, 19.0% [16.8%-21.4%] indicated that they would not, and 34.0% [31.3%-36.8%] were unsure. The most common reasons for hesitancy were concerns about safety, limited testing, side effects, and efficacy. Vaccine hesitancy appears to be high in Lebanon. Disseminating clear, consistent, evidence-based safety and efficacy information on vaccines may help reduce vaccine hesitancy, especially among the large proportion of adults who appear to be unsure about (rather than opposed to) vaccination.


title: The maladaptive vascular response in COVID-19 acute respiratory distress syndrome and recovery

abstract: Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development ("at risk", N=59), an intensive care unit cohort with ARDS ("ARDS", N=31), and a cohort recovering from ARDS ("recovery", N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.


title: Research priorities for lower limb amputation in patients with vascular disease

abstract:
IntroductionLower limb amputation is a life-changing event for patients and can be associated with high mortality and morbidity rates. Research into this critical part of vascular surgery is limited. The Vascular Society of Great Britain and Ireland (VSGBI) in partnership with the James Lind Alliance (JLA) process, aimed to identify and develop key research priorities for amputation.

MethodsA modified JLA Priority Setting Partnership was undertaken, encompassing all vascular practice. Two separate Delphi processes to identify research topics were undertaken with healthcare professionals, patients and carers, led by the VSGBI. The priorities were then ranked by the same participants and amalgamated to produce a list for final prioritisation. The final consensus meeting was attended by patients, carers and healthcare professionals from a variety of backgrounds involved in the care of people with amputation. Using a nominal group technique, the top ten research priorities were identified.

ResultsA total of 481 clinicians submitted 1231 research questions relating to vascular surgery in general. 63 amputation-specific research questions were combined into 5 final clinical questions. 373 patients or carers submitted 582 research questions related to vascular surgery in general. Nine amputation-specific research questions were identified after combining similar questions. Amalgamating both the clinician and patient questions, 12 questions were discussed at the final prioritisation meeting and the top 10 identified. These related to amputation prevention, supporting rehabilitation, improving clinical outcomes following amputation (preventing/treating pain including phantom limb pain and improving wound healing) and research into information provision for patients undergoing amputation.

ConclusionThe top 10 research priority areas in vascular amputation provide guidance for researchers, clinicians, and funders on the direction of future research questions that are important to both healthcare professionals and patients.

category: surgery


title: T Cell Positive B Cell Negative Flow Cytometry Crossmatch (FCXM): Frequency, HLA-Locus Specificity, and Mechanisms Among 3073 Clinical FCXM Tests

abstract:
BackgroundA T cell positive and B cell negative (T+B-) flow cytometry crossmatch (FCXM) result remains a conundrum since HLA-class I antigens are expressed on both T and B cells. We investigated the frequency, HLA specificity of the antibodies and mechanisms for the T+B- FCXM result.

MethodsWe analyzed 3073 clinical FCXM tests performed in an American Society of Histocompatibility and Immunogenetics accredited histocompatibility laboratory. The sera associated with the T+B- FCXM were also tested for donor HLA IgG antibodies using LABScreen single antigen assays.

ResultsAmong the 3073 FCXM tests, 1963 were T-B-, 811 were T-B+, 274 were T+B+, and 25 were T+B-. IgG antibodies directed at donor HLA-A, B, or Cw locus determined antigens (DSA) were identified in all 25 sera and the summed mean fluorescence intensity (MFI) of DSA ranged from 212 to 53,187. Correlational analyses identified a significant association between the summed MFI of class I DSA, and the median channel fluorescence (MCF) of T cells treated with the recipient serum (Spearman rank correlation, rs=0.34, P=0.05) but not with the MCF of B cells (rs=0.23, P=0.24). We identified that differential binding of anti-HLA antibodies to T cells and B cells and the B cell channel shift threshold used to classify a B cell FCXM are potential contributors to a T+B- FCXM result.

ConclusionsOur analysis of 3073 FCXM, in addition to demonstrating that HLA antibodies directed at HLA-A, B or Cw locus are associated with a T+B- result, identified mechanisms for the surprising T+B- FCXM result.

category: transplantation


title: Prioritizing disease-causing metabolic genes by integrating metabolomics with whole exome sequencing data

abstract: The integration of metabolomics data with sequencing data is a key step towards improving the diagnostic process for finding the disease-causing gene(s) in patients suspected of having an inborn error of metabolism (IEM). The measured metabolite levels could provide additional phenotypical evidence to elucidate the degree of pathogenicity for variants found in metabolic genes. We present a computational approach, called Reafect, that calculates for each reaction in a metabolic pathway a score indicating whether that reaction is being deficient or not. When calculating this score, Reafect takes multiple factors into account: the magnitude and sign of alterations in the metabolite levels, the reaction distances between metabolites and reactions in the pathway, and the biochemical directionality of the reactions. We applied Reafect to untargeted metabolomics data of 72 patient samples with a known IEM and found that in 80% of the cases the correct deficient enzyme was ranked within the top 5% of all considered enzyme deficiencies. Next, we integrated Reafect with CADD scores (a measure for variant deleteriousness) and ranked the potential disease-causing genes of 27 IEM patients. We observed that this integrated approach significantly improved the prioritization of the disease-causing genes when compared with the two approaches individually. For 15/27 IEM patients the correct disease-causing gene was ranked within the top 0.2% of the set of potential disease-causing genes. Together, our findings suggest that metabolomics data improves the identification of disease-causing genetic variants in patients suffering from IEM.


title: Efficacy and safety of novel probiotic formulation in adult Covid19 outpatients: a randomized, placebo-controlled clinical trial

abstract:
BackgroundProbiotics have been proposed as adjuvants for Coronavirus Disease 2019 (Covid19) but randomized controlled trials (RCT) are lacking.

MethodsSingle-center, quadruple-blinded RCT. Symptomatic Covid 19 outpatients (aged 18 to 60 years) with positive SARS-CoV2 nucleic acids test were randomized to active (n=150; [≥]2x109 colony-forming units (CFU) of probiotic strains Lactiplantibacillus plantarum KABP022, KABP023 and KAPB033, plus strain Pediococcus acidilactici KABP021) or placebo (n=150), take orally once daily for 30 days. Oral acetaminophen was allowed and controlled as co-intervention. Primary endpoint included: i) proportion of patients in complete remission (both symptoms and nucleic acids test) or progressing to moderate or severe disease with hospitalization; ii) death rate and duration on Intensive Care Unit (ICU). Safety was assessed in all patients. This study is registered at ClinicalTrials.gov (NCT04517422).

Findings300 subjects were randomized (median age 37.0 years [range 18 to 60], 161 [53.7%] women, 126 [42.0%] having known metabolic risk factors), and 293 completed the study (97.7%). Remission was achieved by 78 of 147 (53.1%) in the active group compared to 41 of 146 (28.1%) in placebo (P<0.0001; ARR=25.0% [95%CI 14.1-35.9%]), still significant after multiplicity correction for the primary endpoint. No hospitalizations or deaths occurred during the study, precluding the assessment of efficacy on these endpoints. No serious adverse events occurred during the study. Replication studies with this probiotic formula are warranted.


title: ACTIVATE-2: A DOUBLE-BLIND RANDOMIZED TRIAL OF BCG VACCINATION AGAINST COVID19 IN INDIVIDUALS AT RISK

abstract: BCG vaccination induces heterologous protection against respiratory tract infections, and in children improves survival independently of tuberculosis prevention. The phase III ACTIVATE-2 study assessed whether BCG could also protect against COVID19 in the elderly. In this double-blind, randomized trial, elderly Greek patients were randomized (1:1) to receive either BCG revaccination or placebo at hospital discharge, followed by 6 months observation for incidence of COVID19 infection. BCG revaccination resulted in 68% risk reduction for total COVID19 clinical and microbiological diagnoses (OR 0.32, 95% CI 0.13-0.79). Five patients in the placebo group and one in the BCG-vaccinated group had severe COVID19 that necessitated hospitalization. 3 months after BCG vaccination 1.3% of placebo and 4.7% of BCG-vaccinated volunteers had anti-SARS-CoV-2 antibodies. These data argue that BCG revaccination is safe and protects the elderly against COVID19. BCG revaccination may represent a viable preventive measure against COVID19.


title: Retrospective screening for SARS-CoV-2 among 5,800 hospitalizations related to influenza-like illness during the 2018-19 pre-pandemic and 2019-2020 pandemic influenza seasons in the VAHNSI network, Spain.

abstract: On March 9 2020 the WHO Global Influenza Program (GIP) asked participant sites on the Global Influenza Hospital Surveillance Network (GIHSN) to contribute to data collection concerning severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We re-analysed 5,833 viral RNA archived samples collected prospectively from hospital admissions for influenza-like illness (ILI) in the Valencia Region of Spain by the VAHNSI network (4 hospitals, catchment area population 1,118,732) during the prepandemic 2018/2019 (n=4,010) and pandemic 2019/2020 (n=1,823) influenza seasons, for the presence of SARS-CoV-2. We did not find evidence for community-acquired SARS-CoV-2 infection in hospital admissions for ILI in our region before early March 2020.


title: EVALUATION OF A RAPID ANTIGEN TEST FOR SARS-COV-2 IN SYMPTOMATIC PATIENTS AND THEIR CONTACTS: A MULTICENTER STUDY

abstract:
BACKGROUNDPoint-of-care rapid tests to identify SARS-CoV-2 can be of great help because, in principle, they allow decisions to be made at the site of care for treatment, or for the separation of cohorts avoiding cross-infection, especially in emergency situations.

METHODSA cross sectional study in adults requesting care in Emergency Rooms (ER), or the outpatient clinics of referral hospitals for COVID-19, to define the diagnostic characteristics of a rapid antigen test for SARS-CoV-2 (the Abbott Panbio) having as a gold standard the RT-PCR for SARS-CoV-2. Health personnel in a routine situation within an active pandemic in several cities of Mexico performed the tests.

RESULTSA total of 1,069 participants with a mean age of 47 years (SD 16 years), 47% with a self-reported comorbidity, and an overall prevalence of a positive RT-PCR test of 45%, were recruited from eight hospitals in Mexico. Overall sensitivity of the Panbio test was 54.4% (95%CI 51-57) with a positive likelihood ratio of 35.7, a negative likelihood ratio of 0.46 and a Receiver-Operating Characteristics curve area of 0.77.

Positivity for the rapid test depended strongly on an estimate of the viral load (Cycle threshold of RT-PCR, Ct), and the days of symptoms. With a Ct[≤]25, sensitivity of the rapid test was 0.82 (95%CI, 0.76-0.87). For patients during the first week of symptoms sensitivity was 69.6% (95%CI 66-73). On the other hand, specificity of the rapid test was above 97.8% in all groups.

CONCLUSIONSThe Panbio rapid antigen test for SARS-CoV-2 has a good specificity, but due to low and heterogeneous sensitivity in real life, a negative test in a person with suggestive symptoms at a time of community transmission of SARS-CoV-2 requires confirmation with RT-PCR, and after the first week of symptoms, sensitivity decreases considerably.


title: Leveraging Northern European population history; novel low frequency variants for polycystic ovary syndrome

abstract:
BackgroundPolycystic ovary syndrome (PCOS) is a common, complex disorder, which should be recognized as a prominent health concern also outside the context of fertility. Although PCOS affects up to 18% of women worldwide, its etiology remains poorly understood. It is likely that a combination of genetic and environmental factors contributes to the risk of PCOS development. Whilst previous genome-wide association studies have mapped several loci associated with PCOS, analysis of populations with unique population history and genetic makeup has the potential to uncover new low frequency variants with larger effects. In this study, we leverage genetic information of two neighboring and well-characterized populations in Europe - Finnish and Estonian - to provide a basis for a new understanding of the genetic determinants of PCOS.

Methods and FindingsWe conducted a three-stage case-control genome-wide association study (GWAS). In the discovery phase, we performed a GWAS comprising of a total of 797 cases and 140,558 controls from the FinnGen study. For validation, we used an independent dataset from the Estonian Biobank, including 2,812 cases and 89,230 controls. Finally, we conducted a joint meta-analysis of 3,609 cases and 229,788 controls from both cohorts.

In total, we identified three novel genome-wide significant variants associating with PCOS. Two of these novel variants, rs145598156 (p=3.6 x 10-8, OR=3.01 [2.02-4.50] MAF=0.005) and rs182075939 (p=1.9 x 10-16, OR= 1.69 [1.49-1.91], MAF=0.04), were found to be enriched in the Finnish and Estonian populations and are tightly linked to a deletion c.1100delC (r2= 0.95) and a missense I157T (r2=0.83) in CHEK2. The third novel association is a common variant near MYO10 (rs9312937, p= 1.7 x 10-8, OR=1.16 (1.10-1.23), MAF=0.44). We also replicated four previous reported associations near the genes ERBB4, DENND1A, FSHB and ZBTB16.

ConclusionsWe identified three novel variants for PCOS in a Finnish-Estonian GWAS. Using isolated populations to perform genetic association studies provides a useful resource to identify rare variants contributing to the genetic landscape of complex diseases such as PCOS.


title: The COVID in the Context of Pregnancy, Infancy and Parenting (CoCoPIP) Study: protocol for a longitudinal study of parental mental health, social interactions, physical growth, and cognitive development of infants during the pandemic.

abstract:
IntroductionWhile the secondary impact of the COVID pandemic on the psychological wellbeing of pregnant women and parents has become apparent over the past year, the impact of these changes on early social interactions, physical growth and cognitive development of their infants is unknown, as is the way in which a range of COVID related changes have mediated this impact. This study (CoCoPIP) will investigate: i) how parents experiences of the social, medical, and financial changes during the pandemic have impacted pre and postnatal parental mental health and parent-infant social interaction; and (ii) the extent to which these COVID-related changes in parental pre and postnatal mental health and social interaction are associated with fetal and infant development.

Methods and analysisThe CoCoPIP study is a national online survey initiated in July 2020. This ongoing study (n = 1700 families currently enrolled as of 6th May 2021) involves both quantitative and qualitative data being collected across pregnancy and infancy. It is designed to identify the longitudinal impact of the pandemic from pregnancy to two years of age, with the aim of identifying if stress-associated moderators (i.e., loss of income, COVID-19 illness, access to ante/postnatal support) impact parental mental health, and in turn, infant development. In addition, we aim to document individual differences in social and cognitive development in toddlers who were born during restrictions intended to mitigate COVID-19 spread (e.g., social distancing, national lockdowns).

Ethics and disseminationEthical approval was given by the University of Cambridge, Psychology Research Ethics Committee (PREC) (PRE.2020.077). Findings will be made available via community engagement, public forums (e.g., social media,) and to national (e.g., NHS England) and local (Cambridge Universities Hospitals NHS Foundation Trust) healthcare partners. Results will be submitted for publication in peer-reviews journals.

Strengths and Limitations of this study- This is a new cohort of families being followed from prenatal to postnatal (up to 18 months) during the COVID-19 pandemic.
- The study involves the collection of quantifiable data to identify the short- and long-term influences of the pandemic on key aspects of infant development.
- The study also has a range of open-ended questions for qualitative analysis aimed at exploring familial experiences in more detail.
- The data is being collected online and is therefore limited to self- and parent-report measures, with no direct assessment of child development and parental mental health.
- Although the sample of families being recruited are diverse in their indices of multiple deprivation (IMD) and geographic location, they may not be fully representative of the wider population.


title: Attitudes Toward The COVID-19 Vaccine Among North Carolina Participants In The COVID-19 Community Research Partnership

abstract: Willingness to receive the newly developed Coronavirus Disease-2019 (COVID-19) vaccines is highly variable. To assess the receptiveness of a select sample of North Carolinians to COVID-19 vaccination, a brief survey was conducted among participants in the COVID-19 Community Research Partnership (CCRP) affiliated with five medical centers in North Carolina. A total of 20,232 CCRP participants completed a multiple choice, mini survey electronically between December 17, 2020 and January 13, 2021. Of the 20,232 survey respondents, 15,422 (76.2%) were receptive to vaccination. Vaccine receptiveness increased incrementally with age with those >70 years being the most willing to be vaccinated compared to all other age groups. Respondents with no previous COVID-19 diagnosis were more likely to accept the vaccine compared to those that have a previous COVID-19 diagnosis (76.6% vs 60.9%). Comparative analysis of gender, race/ethnicity, and residence locale revealed that women, African Americans, and suburban participants were less willing to get a COVID-19 vaccine. There was no difference in vaccine intent based on healthcare worker status. Of those unwilling to get the vaccine, 82% indicated that the reason was uncertainty about the safety and efficacy of the vaccine.


title: Effectiveness of COVID-19 vaccines against the B.1.617.2 variant

abstract:
BackgroundThe B.1.617.2 COVID-19 variant has contributed to the surge in cases in India and has now been detected across the globe, including a notable increase in cases in the UK. We estimate the effectiveness of the BNT162b2 and ChAdOx1 COVID-19 vaccines against this variant.

MethodsA test negative case control design was used to estimate the effectiveness of vaccination against symptomatic disease with both variants over the period that B.1.617.2 began circulating with cases identified based on sequencing and S-gene target status. Data on all symptomatic sequenced cases of COVID-19 in England was used to estimate the proportion of cases with B.1.617.2 compared to the predominant strain (B.1.1.7) by vaccination status.

ResultsEffectiveness was notably lower after 1 dose of vaccine with B.1.617.2 cases 33.5% (95%CI: 20.6 to 44.3) compared to B.1.1.7 cases 51.1% (95%CI: 47.3 to 54.7) with similar results for both vaccines. With BNT162b2 2 dose effectiveness reduced from 93.4% (95%CI: 90.4 to 95.5) with B.1.1.7 to 87.9% (95%CI: 78.2 to 93.2) with B.1.617.2. With ChAdOx1 2 dose effectiveness reduced from 66.1% (95% CI: 54.0 to 75.0) with B.1.1.7 to 59.8% (95%CI: 28.9 to 77.3) with B.1.617.2. Sequenced cases detected after 1 or 2 doses of vaccination had a higher odds of infection with B.1.617.2 compared to unvaccinated cases (OR 1.40; 95%CI: 1.13-1.75).

ConclusionsAfter 2 doses of either vaccine there were only modest differences in vaccine effectiveness with the B.1.617.2 variant. Absolute differences in vaccine effectiveness were more marked with dose 1. This would support maximising vaccine uptake with two doses among vulnerable groups.


title: Conflicts of Interest of Pediatric Journal Authors

abstract: The Physician Payments Sunshine Act requires disclosure of payments made by drug and medical device manufacturers to physicians or teaching hospitals. Academic literature extensively documents gender disparities in the medical profession with regard to salary, promotion, and government funded research. This investigation sought to quantify potential conflicts of interest (CoIs) in pediatric medical journals, specifically examining sex differences. To identify potential CoIs, we examined manuscripts published prior to 2019 in six pediatric journals (JAMA Pediatrics, Pediatrics, The Journal of Pediatrics, Pediatric Blood and Cancer, Pediatric Critical Care Medicine, and The Pediatric Infectious Disease Journal). We collected physician demographics and specialty from the National Plan and Provider Enumeration System National Provider Identifier Registry and compensation data from both ProPublicas Dollars for Docs (PDD) and Centers for Medicare and Medicaid Services Open Payments (CMSOP). Data was collected on 2,747 authors from 929 manuscripts. Of the 1,088 authors based in the United States with medical degrees (40.5% female), 510 (46.9%) had entries in PDD and CMSOP. Overall, 11,791 payments to these physician-authors totaled $9,586,089.97. Males were 19.6% more likely to receive payments (RR = 1.20, 95% CI [1.05, 1.37], p = 0.008). The mean amount received by males was $23,250.71 while that received by females was $10,970.78 (mean difference = 12,279.92, 95% CI = (2036.31, 22,523.54), p = 0.019). A comprehensive understanding of these CoIs can inform the disclosure policies of journals to promote transparency of authors.

category: pediatrics


title: Fine-scale heterogeneity in population density predicts wave dynamics in dengue epidemics

abstract: The spread of dengue and other arboviruses constitutes an expanding global health threat. The daunting heterogeneity in population distribution and movement in megacities of the developing world frustrates predictive modeling, even as its importance to disease spread is clearer than ever. Using surveillance data at fine resolution from Rio de Janeiro, we document a scale-invariant pattern in the size of successive epidemics following DENV4 emergence. This pattern emerges from the combined effect of herd immunity and seasonal transmission, and is strongly driven by variation in population density at sub-kilometer scales. It is apparent only when the landscape is stratified by population density and not by spatial proximity as has been common practice. Models that exploit this emergent simplicity should afford improved predictions of epidemic waves.


title: Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain

abstract: Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimers disease (AD). Using whole-genome sequencing, we assessed mitochondrial DNA (mtDNA) heteroplasmy levels and mtDNA copy number (mtDNAcn) in 1,361 human brain samples of five brain regions from three studies. Multivariable analysis of ten common brain pathologies identified tau pathology in the dorsolateral prefrontal cortex and TDP-43 pathology in the posterior cingulate cortex as primary drivers of reduced mtDNAcn in the aged human brain. Amyloid-{beta} pathology, age, and sex were not associated with mtDNAcn. Further, there is evidence for a direct effect of mitochondrial health on cognition. In contrast, while mtDNA heteroplasmy levels increase by about 1.5% per year of life in the cortical regions, we found little evidence for an association with brain pathologies or cognitive functioning. Thus, our data indicates that mtDNA heteroplasmy burden is unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.


title: Atlas of functional connectivity relationships across rare and common genetic variants, traits, and psychiatric conditions

abstract:
Polygenicity and pleiotropy are key properties of the genomic architecture of psychiatric disorders. An optimistic interpretation of polygenicity is that genomic variants converge on a limited set of mechanisms at some level from genes to behavior. Alternatively, convergence may be minimal or absent.

We took advantage of brain connectivity, measured by resting-state functional MRI (rs- fMRI), as well as rare and common genomic variants to understand the effects of polygenicity and pleiotropy on large-scale brain networks, a distal step from genes to behavior. We processed ten rs-fMRI datasets including 32,988 individuals, to examine connectome-wide effects of 16 copy number variants (CNVs), 10 polygenic scores, 6 cognitive and brain morphometry traits, and 4 idiopathic psychiatric conditions.

Although effect sizes of CNVs on connectivity were correlated to cognition and number of genes, increasing polygenicity was associated with decreasing effect sizes on connectivity. Accordingly, the effect sizes of polygenic scores on connectivity were 6-fold lower compared to CNVs. Despite this heterogeneity of connectivity profiles, multivariate analysis identified convergence of genetic risks and psychiatric disorders on the thalamus and the somatomotor network. Based on spatial correlations with transcriptomic data, we hypothesize that excitatory thalamic neurons may be primary contributors to brain alteration profiles shared across genetic risks and conditions. Finally, pleiotropy measured by genetic and transcriptomic correlations between 38 pairs of conditions/traits showed significant concordance with connectomic correlations, suggesting a substantial causal genetic component for shared connectivity.

Such findings open avenues to delineate general mechanisms - amenable to intervention - across conditions and genetic risks.

One sentence summaryEffects of rare and common genomic variants on brain functional connectivity shed light on the impact of polygenicity and pleiotropy in psychiatry.


title: Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials

abstract:
BackgroundWe systematically assessed benefits and harms of the use of ivermectin (IVM) in COVID-19 patients.

MethodsPublished and preprint randomized controlled trials (RCTs) assessing IVM effects on COVID-19 adult patients were searched until March 15, 2021 in five engines. Primary outcomes were all-cause mortality, length of stay (LOS), and adverse events (AE). Secondary outcomes included viral clearance and severe AEs. We evaluated risk of bias (RoB) using the Cochrane RoB 2{middle dot}0 tool. Inverse variance random effect meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology. Subgroup analyses by severity of disease and RoB, and sensitivity analyses by time of follow-up were conducted.

ResultsTen RCTs (n=1173) were included. Controls were standard of care [SOC] in five RCTs and placebo in five RCTs. RCTs sample size ranged from 24 to 398 patients, mean age from 26 to 56 years-old, and severity of COVID-19 disease was mild in 8 RCTs, moderate in one RCT, and mild and moderate in one RCT. IVM did not reduce all-cause mortality vs. controls (RR 1.11, 95%CI 0.16-7.65, very low QoE). IVM did not reduce LOS vs. controls (MD 0.72 days, 95%CI -0.86 to 2.29, very low QoE). AEs, severe AE and viral clearance were similar between IVM and controls (low QoE for these three outcomes). Subgroup analyses by severity of COVID-19 disease or RoB were consistent with main analyses. Sensitivity analyses excluding RCTs with follow up <21 days showed no difference in all-cause mortality but diminished heterogeneity (I2=0%).

ConclusionsIn comparison to SOC or placebo, IVM did not reduce all-cause mortality, length of stay or viral clearance in RCTs in COVID-19 patients with mostly mild disease. IVM did not have effect on AEs or SAEs. IVM is not a viable option to treat COVID-19 patients.


title: Surveillance of colistin-resistance and mcr genes in multi-drug resistant Enterobacteriaceae

abstract:
BackgroundThe plasmid-mediated bacterial colistin-resistant (mcr) gene is a global concern in clinical health care. This study aimed to clarify the prevalence of colistin resistance through nine mcr genes in ESBL-producing and CRE isolated Enterobacteriaceae in Japan.

MethodsWe collected strains from August 2016 to March 2017 from five tertiary hospitals. MICs were measured using the microdilution method. PCR was performed to detect mcr-1 to mcr-9 genes in all strains. Additionally, we performed whole-genome sequencing of the mcr gene-positive strain.

ResultsThe rate of colistin resistance was 7.7%. The mcr-5 and mcr-9 gene were detected in one ESBL-producing E. coli strain (0.37%) and three CRE strains (1.1%), respectively. Since the ESBL-producing E. coli strain was the first clinical strain with mcr-5 in Japan, whole-genome sequencing analysis was performed for the strain. The sequenece type of the mcr-5 positive strain was ST1642 and it carried two distinct plasmids, ESBL gene-carrying pN-ES-6-1 and mcr-5.1-carrying pN-ES-6-2.

ConclusionsWe showed that the frequency of colistin resistance and mcr-positive strains is not high in Japan. Since the MIC for colistin was low in the mcr-5.1 and mcr-9 gene-positive strain, continuous monitoring of mcr genes is necessary.


title: Automatic Electrocardiogram Detection of Suspected Hypertrophic Cardiomyopathy: Application to Wearable Heart Monitors

abstract: In this work, an automatic detection algorithm for hypertrophic cardiomyopathy (HCM) is presented. Of particular interest is the algorithms ability to differentiate HCM subjects and healthy volunteers from a single lead ECG dataset. Suspected HCM subjects are identified by the primary clinical abnormality associated with HCM, left ventricular hypertrophy (LVH). In total, n=43 human subjects ECG datasets are investigated: n=21 healthy volunteers and n=22 left ventricular hypertrophy (LVH) patients. Significant differences of p-value 0.01 and 0.04 were found for the respective ECG parameters, S-wave amplitude and ST-segment, when differentiating between the LVH patients and healthy human volunteers.

category: cardiovascular medicine


title: Umbilical Cord Blood DNA Methylation in Children Who Later Develop Type 1 Diabetes

abstract: Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine, whether perinatal DNA methylation could be associated with later progression to type 1 diabetes. Reduced representation bisulfite sequencing (RRBS) analysis was performed on umbilical cord blood samples collected within the Type 1 Diabetes Prediction and Prevention (DIPP) study. Children later diagnosed with type 1 diabetes and/or testing positive for multiple islet autoantibodies (N=43) were compared to control individuals (N=79), who remained autoantibody-negative throughout the DIPP follow-up until 15 years of age. Potential confounding factors related to the pregnancy and the mother were included in the analysis. No differences in the cord blood methylation patterns were observed between these cases and controls.

category: endocrinology


title: COVID-19 County Level Severity Classification with Class Imbalance: A NearMiss Under-sampling Approach

abstract: COVID-19 pandemic that broke out in the late 2019 has spread across the globe. The disease has infected millions of people. Thousands of lives have been lost. The momentum of the disease has been slowed by the introduction of vaccine; however, some countries are still recording high number of casualties. The focus of this work is to design, develop and evaluate a machine learning county level COVID-19 severity classifier. The proposed model will predict severity of the pandemic in a county into low, moderate, or high. Policy makers will find the work useful in the distribution of vaccines. Four learning algorithms (two ensembles and two non-ensembles) were trained and evaluated. Class imbalance was addressed using NearMiss under-sampling of the majority classes. The result of our experiment shows that the ensemble models outperformed the non-ensemble models by a considerable margin.


title: COVID-19 County Level Severity Classification with Cl Imbalanced Class: A NearMiss Under-sampling Approach


title: COVID-19 County Level Severity Classification with Imbalanced Class: A NearMiss Under-sampling Approach


title: A Geospatial Analysis of salmonellosis and its with socioeconomic status in Texas

abstract:
ObjectiveThe studys objective was to find the association between salmonellosis and socioeconomic status (SES) in hot spot areas and statewide counties.

DesignA retrospective cohort study.

SettingThe data was recorded regarding salmonellosis in 2017 from the Texas surveillance database. It included assessment of hot spot analysis and SES association with salmonellosis at the county level.

ParticipantsPatients with salmonellosis of all age groups in Texas.

ResultsThere were a total of 5113 salmonelloses from 254 counties with an unadjusted crude rate of 18 per 100,000 Person-year. Nine SES risk factors in the hot spot counties were as follows: low values of the severe housing problem, unemployment, African American, and high values of college education, social association rate, fast food/full-service restaurant use, Hispanic, and senior low access-to-store (P < 0.05). A 12% difference existed between local health departments in hot (25%) and cold spot (37%) counties ({chi}2 [1, n = 108] = 0.5, P = 0.81). Statewide independent risk factors were severe housing problem (IRR = 1.1; CI:1.05-1.14), social association rate (IRR = 0.89; CI:0.87-0.92), college education (IRR = 1.05; CI: 1.04-1.07), and non-Hispanic senior local access-to-store (IRR = 1.98; CI: 1.26-3.11). The severe housing problem predicted zero occurrences of infection in a county (OR = 0.51; CI: 0.28-0.95).

ConclusionsDisparity exists in salmonellosis and socioeconomic status. Attention to unmet needs will decrease salmonellosis. Severe housing problem is a notable risk.


title: A Geospatial Analysis of salmonellosis and its association with socioeconomic status in Texas


title: A Phenomenological Analysis of COVID-19

abstract: A phenomenological analysis of the time evolution of some COVID-19 data in terms of a Fermi-Dirac function is presented. In spite of its simplicity, the approach appears to describe the data well and allows to correlate the information in a universal plot in terms of non-dimensional or reduced variables Nr = N (t)/Nmax, and tr = t/{Delta}T, with N (t) being the total number of cases as a function of time, Nmax the number of total infected cases, and {Delta}T the diffuseness of the Fermi/Dirac function associated with the rate of infection. The analysis of the reported data for the first outbreak in some selected countries and the results are presented and discussed. The approach is also applicable to subsequent waves. Support of our framework is provided by the SIS limit of the SIR model, and simulations carried out with the SEICRD extension.


title: Biologic Therapies for the Treatment of Post Ileal Pouch Anal Anastomosis Surgery Chronic Inflammatory Disorders: Systematic Review and Meta-analysis

abstract:
BackgroundChronic inflammatory disorders after ileal pouch-anal anastomosis (IPAA) surgery are common. These include chronic pouchitis, Crohns disease of the pouch, prepouch ileitis, and rectal cuff inflammation. The aim of this study was to evaluate the efficacy of biologic therapies in treating these disorders.

MethodSystematic review of all published studies from inception to April 1st, 2021 was performed to investigate the efficacy of biologic therapies for post IPAA chronic inflammatory disorders. The primary outcome was the efficacy of biologic therapies in achieving complete response or remission. A subgroup analysis was performed for each disorder separately.

ResultsA total of 24 studies were identified including 682 patients. Using a random effect model, the overall pooled efficacy of biologic therapies in achieving complete response or remission in patients with post IPAA surgery chronic inflammatory disorders was 60% (95% Confidence Interval (CI), 56 - 64). Specifically, the pooled efficacy of ustekinumab was 75% (95% CI, 64 - 85, p = 0.007), whereas the efficacy of vedolizumab was 60% (95% CI, 52 - 68, p = 0.172). In addition, the efficacy infliximab and adalimumab were 59% (95% CI, 53 - 64, p <0.01) and 51% (95% CI, 42 - 60, p = 0.452) respectively.

ConclusionUstekinumab, infliximab, vedolizumab and adalimumab are effective in achieving complete response or remission in post IPAA surgery chronic inflammatory disorders. There is also a clear trend toward higher efficacy in patients with Crohns disease of the pouch compared to chronic pouchitis. More studies are needed to determine the efficacy of biologics in cuffitis.

SummaryChronic inflammatory disorders after ileal pouch-anal anastomosis surgery are common. These include chronic pouchitis, Crohns disease of the pouch, prepouch ileitis, and rectal cuff inflammation. This study aimed to evaluate the efficacy of biologic therapies in achieving complete response or remission in these disorders.

category: gastroenterology


title: Infection control, occupational and public health measures including mRNA-based vaccination against SARS-CoV-2 infections to protect healthcare workers from variants of concern: a 14-month observational study using surveillance data

abstract:
BackgroundWe evaluated measures to protect healthcare workers (HCWs) in Vancouver, Canada, where variants of concern (VOC) went from <1% in February 2021 to >92% in mid-May. Canada has amongst the longest periods between vaccine doses worldwide, despite Vancouver having the highest P.1 variant rate outside Brazil.

MethodsWith surveillance data since the pandemic began, we tracked laboratory-confirmed SARS-CoV-2 infections, positivity rates, and vaccine uptake in all 25,558 HCWs in Vancouver Coastal Health, by occupation and subsector, and compared to the general population. We employed Cox regression modelling adjusted for age and calendar-time to calculate vaccine effectiveness (VE) against SARS-CoV-2 in fully vaccinated ([≥] 7 days post-second dose), partially vaccinated (14 days post vaccine) and unvaccinated HCWs; we also compared with unvaccinated community members of the same age-range.

FindingsOnly 3.3% of our HCWs became infected, mirroring community rates, with peak positivity of 9.1%, compared to 11.8% in the community. As vaccine coverage increased, SARS-CoV-2 infections declined significantly in HCWs, despite a surge with predominantly VOC; unvaccinated HCWs had an infection rate of 1.3/10,000 person-days compared to 0.89 for HCWs post first dose, and 0.30 for fully vaccinated HCWs. VE compared to unvaccinated HCWs was 37.2% (95% CI: 16.6-52.7%) 14 days post-first dose, 79.2% (CI: 64.6-87.8%) 7 days post-second dose; one dose provided significant protection against infection until at least day 42. Compared with community infection rates, VE after one dose was 54.7% (CI: 44.8-62.9%); and 84.8% (CI: 75.2-90.7%) when fully vaccinated.

InterpretationPredominantly droplet-contact precautions, with N95s required for aerosol generating medical procedures and available as needed according to point-of-care risk assessment, has been a highly effective approach to preventing occupational infection in HCWs, with one dose of mRNA vaccination further reducing infection risk despite VOC and transmissibility concerns. Delaying second doses to allow more widespread vaccination against severe disease, with strict public health, occupational health and infection control measures, has been effective in protecting the healthcare workforce.

category: public and global health


title: Deep Covid - Coronavirus Diagnosis Using Deep Neural Networks and Transfer Learning

abstract: Coronavirus is a global emergency as of May 2021. If not acted upon by drugs at the right time, coronavirus may result in the death of individuals. Hence early diagnosis is very important along the progress of the disease. This paper focuses on coronavirus detection using x-ray images, for automating the diagnosis pipeline using convolutional neural networks and transfer learning. This could be deployed in places where radiologists are not easily available in order to detect the disease at very early stages. In this study we propose our deep learning architecture for the classification task, which is trained with modified images, through multiple steps of preprocessing. Our classification method uses convolutional neural networks and transfer learning architecture for classifying the images. Our findings yield an accuracy value of 91.03%, precision of 89.76 %, recall value of 96.67% and F1 score of 93.09%.

category: radiology and imaging


title: Deep Covid -Covid Diagnosis Using Deep Neural Networks and Transfer Learning


title: A feasibility study to test a novel approach to dietary weight loss with a focus on assisting informed decision making in food selection

abstract:
Obesity is a significant contributor to the development of chronic diseases, some of which can be prevented or reversed by weight loss. However, dietary weight loss programs have shortcomings in the success rate, magnitude, or sustainability of weight loss. The Individualized Diet Improvement Programs (iDip) objective was to test the feasibility of a novel approach that helps individuals self-select a sustainable diet for weight loss and maintenance instead of providing weight loss products or rigid diet instructions to follow.

The iDip study consisted of 22 dietary improvement sessions over 12 months with six months of follow-up. Daily weights were collected, and a chart summarizing progress was provided weekly. Six 24-hour dietary records were collected, and dietary feedback was provided in the form of a protein-fiber plot, in which protein/energy and fiber/energy of foods were plotted two-dimensionally together with a target box specific to weight loss or maintenance. An exit survey was conducted at 12 months.

Twelve (nine female, 46.3{+/-}3.1 years (mean{+/-}SE)) of the initial 14 participants (BMI>28 kg/m2) completed all sessions. Mean percent weight loss (n=12) at six and 12 months was -4.9%{+/-}1.1 (p=0.001) and -5.4%{+/-}1.7 (p=0.007), respectively. Weight loss varied among individuals at 12 months; top and bottom halves (n=6 each) achieved -9.7%{+/-}1.7 (p=0.0008) and -1.0%{+/-}1.4 weight loss, respectively. The 24-hour records showed a significant increase in protein density from baseline to final (4.1g/100kcal{+/-}0.3 vs. 5.7g/100kcal{+/-}0.5; p=0.008). Although mean fiber density showed no significant change from the first month (1.3g/100kcal{+/-}0.1), the top half had significantly higher fiber/energy intake than the bottom half group. The survey suggested that all participants valued the program and its self-guided diet approach.

In conclusion, half of the participants successfully lost >5% and maintained the lost weight for 12 months without strict diet instructions, showing the feasibility of the informed decision-making approach.

category: nutrition