title: Kinetics of immune responses to the AZD1222/Covishield vaccine with varying dose intervals in Sri Lankan individuals

abstract:
BackgroundTo understand the kinetics of immune responses with different dosing gaps of the AZD1222 vaccine, we compared antibody and T cell responses in two cohorts with two different dosing gaps.

MethodsAntibodies to the SARS-CoV-2 virus were assessed in 297 individuals with a dosing gap of 12 weeks, sampled at 12 weeks post second dose (cohort 1) and in 77 individuals with a median dosing gap of 21.4 weeks (cohort 2) sampled 6 weeks post second dose. ACE2 receptor blocking antibodies (ACE2R-Abs), antibodies to the receptor binding domain (RBD) of the virus and variants of concern (VOC) and ex vivo T cell responses were assessed in a sub cohort.

ResultsAll individuals (100%) had SARS-CoV-2 specific total antibodies and 94.2% of cohort 1 and 97.1% of cohort 2 had ACE2R-blocking Abs. There was no difference in antibody titres or positivity rates in different age groups in both cohorts. The ACE2R-blocking Abs (p<0.0001) and antibodies to the RBD of the VOCs were significantly higher in cohort 2, compared to cohort 1. 41.2% to 65.8% of different age groups gave a positive response by the haemagglutination assay to the RBD of the ancestral virus and VOCs in cohort 1, while 53.6% to 90% gave a positive response in cohort 2. 17/57 (29.8%) of cohort 1 and 17/29 (58.6%) of cohort 2 had ex vivo IFN{gamma} ELISpot responses above the positive threshold. The ACE2R-blocking antibodies and ex vivo IFN{gamma} ELISpot responses at 12 weeks post-first dose, significantly correlated with levels 12 weeks post second dose (Spearmans r=0.46, p=0.008) and (Spearmans r=0.71, p<0.0001) respectively.

ConclusionsBoth dosing schedules resulted in high levels of antibody and T cell responses post vaccination, although those with a longer dosing gap had a higher magnitude of responses, possibly as immune responses were measured 6 weeks post second dose compared to 12 weeks post second dose.

category: allergy and immunology


title: Boosting of the SARS-CoV-2-specific immune response after vaccination with single-dose Sputnik Light vaccine

abstract: Despite the measures taken worldwide, COVID-19 pandemic still progresses. While efficient antiviral drugs are not yet widely available, vaccination is the best option to control the infection rate. Although this option is obvious in case of COVID-19-naive individuals, it is still unclear when individuals who have recovered from a previous SARS-CoV-2 infection should be vaccinated and whether the vaccination raises immune responses against the coronavirus and its novel variants. Here we measured the dynamics of the antibody and T-cell responses, as well as virus neutralizing activity (VNA) in serum against two SARS-CoV-2 variants, B.1.1.1 and B.1.617.2, among 84 individuals with different COVID-19 status who were vaccinated with Sputnik Light vaccine. We showed that vaccination of individuals previously exposed to the virus considerably boosts the existing immune response. In these individuals, RBD-specific IgG titers and VNA in serum were already elevated on the 7th day after vaccination, while COVID-19-naive individuals developed the antibody response and VNA mainly 21 days post-vaccination. Additionally, we found a strong correlation between RBD-specific IgG titers and VNA in serum, and according to these data vaccination may be recommended if the RBD-specific IgG titers drop to 142.7 BAU/mL or below. In summary, the results of the study demonstrate that vaccination is beneficial both for COVID-19-naive and recovered individuals, especially since it raises serum VNA against the B.1.617.2 variant - one of four the SARS-CoV-2 variants of concern.

category: epidemiology


title: Mobility network reveals the impact of geographic vaccination heterogeneity on COVID-19

abstract:
Mass vaccination is one of the most effective epidemic control measures. Because ones vaccination decision is shaped by social processes, the pattern of vaccine uptake tends to show strong social and spatial heterogeneity, such as urban-rural divide and clustering. Examining through network perspectives, we develop a framework for quantifying the impact of spatial vaccination heterogeneity on epidemic outbreaks. Leveraging fine-grained mobility data and computational models, we investigate two network effects--the "hub effect" (vaccinating mobility hubs reduces transmission) and the "homophily effect" (stronger homophily in vaccination rates increases transmission). Applying Bayesian deep learning and fine-grained epidemic simulations, we show a negative effect of homophily and a positive effect of highly vaccinated hubs on reducing case counts for both the synthetic network and the U.S. mobility network. Our framework enables us to evaluate the outcome of various hypothetical spatial vaccine distributions and propose a vaccination campaign strategy that targets a small number of regions with the largest gain in protective power, given the state of the COVID-19 as of January 2022. Our simulation shows that our strategy can prevent about 2.5 times more cases than a uniform strategy with an additional 1% of the population vaccinated. Our study suggests that we must examine the interplay between vaccination patterns and mobility networks beyond the overall vaccination rate, and that accurate location-based targeting can be just as important as improving the overall vaccination rate.

One sentence summaryWe examine network effects of heterogeneous vaccine uptake on epidemic outcomes and show a location-based vaccination may be a potent strategy.


title: Mobility network reveals the impact of spatial vaccination heterogeneity on COVID-19


title: A systematic review of enteric pathogens and antibiotic resistance genes in extramural urban aerosols

abstract:
Aerosol transport of enteric microbiota including fecal pathogens and antimicrobial resistance genes (ARGs) has been documented in a range of settings but remains poorly understood outside indoor environments. We conducted a systematic review of the peer-reviewed literature to summarize evidence on specific enteric microbiota including enteric pathogens and ARGs that have been measured in aerosol samples in urban settings where the risks of outdoor exposure and antibiotic resistance (AR) spread may be highest. Following PRISMA guidelines, we conducted a key word search for articles published within the years 1990-2020 using relevant data sources. Two authors independently conducted the keyword searches of databases and conducted primary and secondary screenings before merging results. To be included, studies contained extractable data on enteric microbes and AR in outdoor aerosols regardless of source confirmation and reported on qualitative, quantitative, or viability data on enteric microbes or AR. Qualitative analyses and metric summaries revealed that enteric microbes and AR have been consistently reported in outdoor aerosols, generally via relative abundance measures, though gaps remain preventing full understanding of the role of the aeromicrobiological pathway in the fate and transport of enteric associated outdoor aerosols. We identified remaining gaps in the evidence base including a need for broad characterization of enteric pathogens in bioaerosols beyond bacterial genera, a need for greater sampling in locations of high enteric disease risk, and a need for quantitative estimation of microbial and nucleic acid densities that may be applied to fate and transport models and in quantitative microbial risk assessment.

FUNDINGThis study was funded by the National Science Foundation under grant number 1653226. This funding source had no role in the design of this study and had no role during its execution, analyses, interpretation of the data, or decision to submit results.

category: public and global health


title: A systematic review of enteric pathogens and antibiotic resistance genes in outdoor urban aerosols


title: Combining Navigator and Optical Prospective Motion Correction for High-Quality 500 μm Resolution Quantitative Multi-Parameter Mapping at 7T

abstract:
PURPOSEHigh-resolution quantitative multi-parameter mapping shows promise for non-invasively characterizing human brain microstructure but is limited by physiological artifacts. We implemented corrections for rigid head movement and respiration-related B0-fluctuations and evaluated them in healthy volunteers and dementia patients.

METHODSCamera-based optical prospective motion correction (PMC) and free-induction decay (FID) navigator correction were implemented in a gradient and RF-spoiled multi-echo 3D gradient echo sequence for mapping proton density (PD), longitudinal relaxation rate (R1) and effective transverse relaxation rate (R2*). We studied their effectiveness separately and in concert in young volunteers and then evaluated the navigator correction (NAVcor) with PMC in a group of elderly volunteers and dementia patients. We used spatial homogeneity within white matter (WM) and gray matter (GM) and scan-rescan measures as quality metrics.

RESULTSNAVcor and PMC reduced artifacts and improved the homogeneity and reproducibility of parameter maps. In elderly participants, NAVcor improved scan-rescan reproducibility of parameter maps (coefficient of variation decreased by 14.7% and 11.9% within WM and GM respectively). Spurious inhomogeneities within WM were reduced more in the elderly than in the young cohort (by 9% vs 2%). PMC increased regional GM/WM contrast and was especially important in the elderly cohort, which moved twice as much as the young cohort. We did not find a significant interaction between the two corrections.

CONCLUSIONNavigator correction and PMC significantly improved the quality of PD, R1 and R2* maps, particularly in less compliant elderly volunteers and dementia patients.

category: neurology


title: Sample Size Analysis for Machine Learning Clinical Validation Studies

abstract:
OBJECTIVEBefore integrating new machine learning (ML) into clinical practice, algorithms must undergo validation. Validation studies require sample size estimates. Unlike hypothesis testing studies seeking a p-value, the goal of validating predictive models is obtaining estimates of model performance. Our aim was to provide a standardized, data distribution- and model-agnostic approach to sample size calculations for validation studies of predictive ML models.

MATERIALS AND METHODSSample Size Analysis for Machine Learning (SSAML) was tested in three previously published models: brain age to predict mortality (Cox Proportional Hazard), COVID hospitalization risk prediction (ordinal regression), and seizure risk forecasting (deep learning). The SSAML steps are: 1) Specify performance metrics for model discrimination and calibration. For discrimination, we use area under the receiver operating curve (AUC) for classification and Harrells C-statistic for survival models. For calibration, we employ calibration slope and calibration-in-the-large. 2) Specify the required precision and accuracy ([≤]0.5 normalized confidence interval width and {+/-}5% accuracy). 3) Specify the required coverage probability (95%). 4) For increasing sample sizes, calculate the expected precision and bias that is achievable. 5) Choose the minimum sample size that meets all requirements.

RESULTSMinimum sample sizes were obtained in each dataset using standardized criteria.

DISCUSSIONSSAML provides a formal expectation of precision and accuracy at a desired confidence level.

CONCLUSIONSSAML is open-source and agnostics to data type and ML model. It can be used for clinical validation studies of ML models.

category: health informatics


title: Dampening of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early COVID-19

abstract:
Vaccinations against SARS-CoV-2 are effective in COVID-19. However, with limited vaccine access, vaccine hesitancy and variant breakthroughs, there is still a need for effective and safe early treatments. Two community-based clinical trials of the inhaled corticosteroid, budesonide, have recently been published showing and improvement in patients with COVID-19 treated early with budesonide1,2. To understand mechanistically how budesonide was beneficial, inflammatory mediators were assessed in the nasal mucosa of patients recruited to the Steroids in COVID (STOIC1) trial and a cohort of SARS-CoV-2 negative individuals. Here we show that in early COVID-19, elevation in viral response proteins and Th1 and Th2 inflammation occurs. Longitudinal sampling in the natural course of COVID-19 showed persistently high interferon levels and elevated concentrations of the eosinophil chemokine, CCL11. In patients who deteriorate, the initial nasal mucosal signal is characterised by a marked suppression of the early inflammatory response, with reduced concentrations of interferon and inflammatory cytokines, but elevated eosinophil chemokines. Systemic inflammation remained altered in COVID-19 patients, implying that even after symptom resolution, changes in immunological mediators do not resolve. Budesonide treatment decreased IL-33 and IFN-{gamma}, implying a reduction in epithelial damage and dampening of the interferon response. Budesonide treatment also increased CCL17 concentrations, suggesting an improved T-cell response; and significantly alters inflammatory pathways giving further insight into how this treatment can accelerate patient recovery.

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category: infectious diseases


title: The Persistence of Neutralising Antibodies up to 11 months after SARS-CoV-2 Infection in the Southern Region of New Zealand

abstract: During the first wave of SARS-CoV-2 infection in New Zealand a cohort of 78 PCR-confirmed COVID-19 cases was recruited in the Southern District Health Board region. Here we report on this unique cohort nearly 1-year after infection. There was no known community transmission in the region over the study period due to New Zealands elimination status at the time, nor had any participants received a COVID-19 vaccine. In the absence of re-exposure, antibody reactivity to the viral spike protein, as well as neutralising antibodies to both the ancestral strain and the delta variant remained relatively stable between 8 and 11 months post-infection. This suggests long-lived antibody responses can be generated from a single natural infection event. However, given the risks of serious disease associated with SARS-CoV-2 infection, vaccination is still strongly recommended.


title: Protocol for 18F-PSMA PET imaging in staging and management of prostate cancer - a retrospective cohort study

abstract:
BackgroundMRI, bone scan, and CT staging is recommended in the staging of prostate cancer. However, prostate-specific membrane antigen positron emission tomography (PSMA PET) could be superior in detection of local and distant prostate cancer cells. Most PSMA PET scans for prostate cancer are performed with a Gallium-68 ligand, with the Fluorine-18 (18F) ligand being introduced more recently. Methods: We will conduct a retrospective review of electronic patient records for all consecutive patients who underwent preoperative 18F-PSMA PET scan for prostate cancer from its introduction at our centre in 2019. We will compare PET scans with other imaging modalities and evaluate its use in diagnosis and management decisions for prostate cancer.

ConclusionsUnderstanding the role of 18F-PSMA PET in diagnosis and management could influence the diagnostic pathway of primary and secondary prostate cancer.

Trial registrationNot applicable.

category: urology


title: PREPRINT: Mechanisms of Motoric Cognitive Risk: hypotheses based on a systematic review and meta-analysis of longitudinal cohort studies of older adults

abstract:
We aimed to refine the hypothesis that Motoric Cognitive Risk (MCR), a syndrome combining measured slow gait speed and self-reported cognitive complaints, is prognostic of incident dementia and other major causes of morbidity in older age. We propose mechanisms on the relationship between motor and cognitive function and describe a roadmap to validate these hypotheses. We systematically searched major electronic databases from inception to August 2021 for original longitudinal cohort studies of adults aged [≥]60 years that compared an MCR group to a non-MCR group with any health outcome. Fifteen cohorts were combined by meta-analysis. Participants with MCR were at an increased risk of cognitive impairment (adjusted hazard ratio [aHR] 1.76, 95%CI 1.49-2.08; I2=24.9%), dementia (aHR 2.12, 1.85-2.42; 33.1%), falls (adjusted Relative Risk 1.38, 1.15-1.66; 62.1%), and mortality (aHR 1.49, 1.16-1.91; 79.2%). The prognostic value of MCR is considerable and mechanisms underlying the syndrome are proposed.

Systematic review registrationPROSPERO CRD42020225183.

category: geriatric medicine


title: Safety Monitoring of mRNA Vaccines Administered During the Initial 6 Months of the U.S. COVID-19 Vaccination Program: Reports to Vaccine Adverse Events Reporting System (VAERS) and v-safe

abstract:
BackgroundIn December 2020, two mRNA-based COVID-19 vaccines were authorized for use in the United States. Vaccine safety was monitored using the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system, and v-safe, an active surveillance system.

MethodsVAERS and v-safe data during December 14, 2020--June 14, 2021 were analyzed. VAERS reports were categorized as non-serious, serious, or death; reporting rates were calculated. Rates of reported deaths were compared to expected mortality rates by age. Proportions of v-safe participants reporting local and systemic reactions or health impacts the week following doses 1 and 2 were determined.

FindingsDuring the analytic period, 298,792,852 doses of mRNA vaccines were administered in the United States. VAERS processed 340,522 reports; 92{middle dot}1% were non-serious; 6{middle dot}6%, serious, non-death; and 1{middle dot}3%, death. Over half of 7,914,583 v-safe participants self-reported local and systemic reactogenicity, more frequently after dose 2. Injection-site pain, fatigue, and headache were commonly reported during days 0-7 following vaccination. Reactogenicity was reported most frequently one day after vaccination; most reactions were mild. More reports of being unable to work or do normal activities occurred after dose 2 (32{middle dot}1%) than dose 1 (11{middle dot}9%); <1% of participants reported seeking medical care after vaccination. Rates of deaths reported to VAERS were lower than expected background rates by age group.

InterpretationSafety data from >298 million doses of mRNA COVID-19 vaccine administered in the first 6 months of the U.S. vaccination program show the majority of reported adverse events were mild and short in duration.


title: Regional probabilistic situational awareness and forecasting of COVID-19

abstract:
Mathematical models and statistical inference are fundamental for surveillance and control of the COVID-19 pandemic. Several aspects cause regional heterogeneity in disease spread. Individual behaviour, mobility, viral variants and transmission vary locally, temporally and with season, and interventions and vaccination are often implemented regionally. Therefore, we developed a new regional changepoint stochastic SEIR metapopulation model. The model is informed by real-time mobility estimates from mobile phone data, laboratory-confirmed cases, and hospitalisation incidence. To estimate locally and time-varying transmissibility, case detection probabilities, and missed imported cases, we present a new sequential Approximate Bayesian Computation method allowing inference in useful time, despite the high parametric dimension. We test our approach on Norway and find that three-week-ahead predictions are precise and well-calibrated, suitable for real-time surveillance.

SignificanceWe developed a regional infectious disease spread model focussing on operational usefulness in real time. The model is informed by near real-time mobile phone mobility data, laboratory-confirmed cases, and hospitalisation incidence. The model is used to estimate reproduction numbers and provide regional predictions of future hospital beds. Regional reproduction numbers are important due spatio-temporal heterogeneity due to for example local interventions. We assume different regional reproduction numbers for different periods of the epidemic. We propose a new calibration method to estimate the reproduction numbers and other parameters of the model, tailored to handle the increasingly high dimension of parameters over time. The model has been successfully used for local situational awareness and forecasting for the Norwegian health authorities during COVID-19.


title: Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

abstract:
Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the {beta}-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.

Graphical Abstract

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C_FIG


title: The association between lymphocyte mitochondrial DNA abundance and Stroke: a combination of multivariable-adjusted survival and mendelian randomization analyses

abstract:
Background and PurposeMitochondrial dysfunction is associated with increased Reactive Oxygen Species that are thought to drive risk of disease, including stroke. We investigated the association between mtDNA abundance, as a proxy for mitochondrial function, and incident stroke using multivariable-adjusted survival and Mendelian Randomization (MR) analyses.

MethodsCox-proportional hazard model analyses were conducted to assess the association between lymphocyte mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-years follow-up in unrelated European-ancestry participants from UK Biobank. MR was conducted using independent (R2<0.001) lead variants for lymphocyte mtDNA abundance (p < 5x10-8) as instrumental variables. Single-Nucleotide Polymorphism (SNP)- ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/controls): MEGASTROKE (60,341/454,450), UK Biobank (2,404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed.

ResultsA total of 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between mtDNA abundance and ischemic or hemorrhagic stroke (lowest 20% versus highest 20%: ischemic stroke, hazard ratio, 1.06 [95% confidence interval 0.95, 1.18]; hemorrhagic stroke, hazard ratio 0.97 [95% confidence interval, 0.82, 1.15]). In line, in the MR analyses, we found no evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.04; confidence interval, 0.95, 1.15).

ConclusionsFrom the multivariable-adjusted survival analyses and the MR analyses, we did not find support for low lymphocyte mtDNA abundance as a causal risk factor in the development of stroke.

category: cardiovascular medicine


title: Detection of SARS-CoV-2 RNA Throughout Wastewater Treatment Plants and A Modeling Approach to Understand COVID-19 Infection Dynamics in Winnipeg, Canada

abstract: Although numerous studies have detected SARS-CoV-2 in wastewater and attempted to find correlations between the concentration of SARS-CoV-2 and the number of cases, no consensus has been reached on sample collection and processing, and data analysis. Moreover, the fate of SARS-CoV-2 in wastewater treatment plants is another issue, specifically regarding the discharge of the virus into environmental settings and the water cycle. The current study monitored SARS-CoV-2 in influent and effluent wastewater samples with three different concentration methods and sludge samples over six months (July to December 2020) to compare different virus concentration methods, assess the fate of SARS-CoV-2 in wastewater treatment plants, and describe the potential relationship between SARS-CoV-2 concentrations in influent and infection dynamics. Skimmed milk flocculation (SMF) resulted in higher recoveries (15.27% {+/-} 3.32%) of an internal positive control, Armored RNA, and higher positivity rate of SARS-CoV-2 in samples compared to ultrafiltration methods employing a prefiltration step to eliminate solids. Our results suggested that SARS-CoV-2 may predominate in solids and therefore, concentration methods focusing on both supernatant and solid fractions may result in better recovery. SARS-CoV-2 was detected in influent and primary sludge samples but not in secondary and final effluent samples, indicating a significant reduction during primary and secondary treatments. SARS-CoV-2 was first detected in influent on September 30th, 2020. A decay-rate formula was applied to estimate initial concentrations of late-processed samples with SMF. A model based on shedding rate and new cases was applied to estimate SARS-CoV-2 concentrations and the number of active shedders. Inferred sensitivity of observed and modeled concentrations to the fluctuations in new cases and test-positivity rates indicated a potential contribution of newly infected individuals to SARS-CoV-2 loads in wastewater.


title: Geo-epidemiology of Malaria in Burkina Faso, 2013-2018: a recent re-increase.

abstract:
BackgroundAfter a global decline, malaria cases re-increases have been shown recently.

The aim of this analysis was to update the epidemiological facies of malaria in Burkina Faso (around 4% of malaria cases worldwide) by estimating weekly malaria incidences at health district levels, from 2013 to 2018, associated to environmental and meteorological factors.

MethodsMalaria cases and deaths weekly reports were extracted from the National Malaria Control Program for each health district from 2013 to 2018. Population data were extracted from the reports of the national statistics council. Environmental data were collected through remote sensing.

After estimating incidence through time and space, trend was assessed by an additive decomposition of the incidence and malaria seasons of transmission was estimated by change point analysis (PELT algorithm).

Incidence maps for each year of the study period were assessed to highlight spatial variability through years. Maps of rainfall, temperature, and vegetation (NDVI) were produced to characterize the health district environmental variability.

ResultsIn 2013, 775 cases /100,000 inhab.week were observed in average, and remain roughly constant until 2015. Malaria re-increased from 2016, reaching 2428 cases /100,000 inhab.week in 2018.

From 2013 to 2016, two transmission periods were observed: low from January to July (included) and high from August to December (included).

From 2017 to 2018, an intermediate transmission period from mid-November to early January intercalated between the low transmission period from mid-February to early June and the high transmission period from July to late December

From 2013 to 2015, the most affected districts were located in the center and central-eastern part of the country. From 2016 to 2018 all health districts, except those in the Sahel region, were affected with at least 45,000 cases per 100,000 persons/year. This south-to-north gradient was also observed with rainfall, temperature and NDVI.

ConclusionMalaria incidences re-increased through years and across the country since 2016. But no modification of the environmental factor variability was observed during the same period, in time or space. The re-increase of malaria in Burkina Faso could be due to a real increase of the disease, or to a better access to diagnostic and cure, together with the development of the epidemiological information system.


title: Deficient butyrate-producing capacity in the gut microbiome of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients is associated with fatigue symptoms

abstract:
BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease of unknown cause for which there is no specific therapy. Patients suffering from ME/CFS commonly experience persistent fatigue, post-exertional malaise, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever and irritable bowel syndrome (IBS). Recent evidence implicates gut microbiome dysbiosis in ME/CFS. However, most prior studies are limited by small sample size, differences in clinical criteria used to define cases, limited geographic sampling, reliance on bacterial culture or 16S rRNA gene sequencing, or insufficient consideration of confounding factors that may influence microbiome composition. In the present study, we evaluated the fecal microbiome in the largest prospective, case-control study to date (n=106 cases, n=91 healthy controls), involving subjects from geographically diverse communities across the United States.

ResultsUsing shotgun metagenomics and qPCR and rigorous statistical analyses that controlled for important covariates, we identified decreased relative abundance and quantity of Faecalibacterium, Roseburia, and Eubacterium species and increased bacterial load in feces of subjects with ME/CFS. These bacterial taxa play an important role in the production of butyrate, a multifunctional bacterial metabolite that promotes human health by regulating energy metabolism, inflammation, and intestinal barrier function. Functional metagenomic and qPCR analyses were consistent with a deficient microbial capacity to produce butyrate along the acetyl-CoA pathway in ME/CFS. Metabolomic analyses of short-chain fatty acids (SCFAs) confirmed that fecal butyrate concentration was significantly reduced in ME/CFS. Further, we found that the degree of deficiency in butyrate-producing bacteria correlated with fatigue symptom severity among ME/CFS subjects. Finally, we provide evidence that IBS comorbidity is an important covariate to consider in studies investigating the microbiome of ME/CFS subjects, as differences in microbiota alpha diversity, some bacterial taxa, and propionate were uniquely associated with self-reported IBS diagnosis.

ConclusionsOur findings indicate that there is a core deficit in the butyrate-producing capacity of the gut microbiome in ME/CFS subjects compared to healthy controls. The relationships we observed among symptom severity and these gut microbiome disturbances may be suggestive of a pathomechanistic linkage, however, additional research is warranted to establish any causal relationship. These findings provide support for clinical trials that explore the utility of dietary, probiotic and prebiotic interventions to boost colonic butyrate production in ME/CFS.


title: The Effect of Bilingual Exposure on Language and Cognitive Development in Children Following Ischemic Stroke

abstract:
AIMWhile many children who experience ischemic stroke come from bilingual backgrounds, it is unclear whether bilingual exposure affects post-stroke development. Our research evaluates the effects of bilingual vs. monolingual exposure on linguistic/cognitive development post-stroke.

METHODAn institutional stroke registry and medical charts were used to gather data on 237 children across 3 stroke-onset groups: neonatal - <28 days, first-year - 28 days to 12 months and childhood - 13 months to 18 years. The Pediatric Stroke Outcome Measure (PSOM) was administered at several times post-stroke, to evaluate cognition and linguistic development.

RESULTSBilingual children had better post-stroke performance on the language subscales, compared to monolinguals. An interaction with stroke-onset group was also observed, with monolinguals in the first-year group having worse outcomes.

INTERPRETATIONOverall, no detrimental effects of bilingualism were found on childrens post-stroke cognition and linguistic development. Our study suggests that a bilingual environment may facilitate language development in children post-stroke.

category: pediatrics


title: Using machine learning to improve diagnostic assessment of ASD in the light of specific differential diagnosis

abstract:
BackgroundDiagnostic assessment of ASD requires substantial clinical experience and is particular difficult in the context of other disorders with behavioral symptoms in the domain of social interaction and communication. Observation measures such as the Autism Diagnostic Observation Schedule (ADOS) do not take into account such comorbid and differential disorders.

MethodWe used a well-characterized clinical sample of individuals (n=1262) that had received detailed outpatient evaluation for the presence of an ASD diagnosis (n=481) and covered a range of additional differential or overlapping diagnoses, including anxiety related disorders (ANX, n=100), ADHD (n=440), and conduct disorder (CD, n=192). We focused on ADOS module 3, covering the age range with particular high prevalence of such differential diagnoses. We used machine learning (ML) and trained random forest models on ADOS single item scores to predict a clinical best estimate diagnosis of ASD in the context of these differential diagnoses (ASD vs. ANX, ASD vs. ADHD, ASD vs. CD) and an unspecific model using all available data. We employed nested cross-validation for an unbiased estimate of classification performance (ASD vs. non-ASD).

ResultsWe obtained very good overall sensitivity (0.89-0.94) and specificity (0.87-0.89) for the classification of ASD vs. non-ASD. In particular for individuals with less severe symptoms (around the ADOS cut-off) our models showed increases of up to 20% in sensitivity or specificity. Furthermore, we analyzed item importance profiles of the ANX-, ADHD- and CD-models in comparison to the unspecific model. These analyses revealed distinct patterns of importance for specific ADOS-items with respect to differential diagnoses.

ConclusionUsing ML-based diagnostic classification may improve clinical decisions by utilizing the full range of information from comprehensive and detailed diagnostic observation such as the ADOS. Importantly, this strategy might be of particular relevance for individuals with less severe symptoms that typically present a very difficult decision for the clinician.

category: psychiatry and clinical psychology


title: COVCOG 2: Cognitive and Memory Deficits in Long COVID: A Second Publication from the COVID and Cognition Study.

abstract: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been often characterized as a respiratory disease. However, it is increasingly being understood as an infection that impacts multiple systems, and many patients report neurological symptoms. Indeed, there is accumulating evidence for neural damage in some individuals, with recent studies suggesting loss of gray matter in multiple regions particularly in the left hemisphere. There are a number of mechanisms by which COVID-19 infection may lead to neurological symptoms and structural and functional changes in the brain, and cognitive problems are one of the most commonly reported symptoms in those suffering from Long COVID--the chronic illness following COVID-19 infection that affects between 10-25% of sufferers. However, there is as yet little research testing cognition in Long COVID. The COVID and Cognition Study is a cross-sectional/longitudinal study aiming to understand cognitive problems in Long COVID. The first paper from the study explored the characteristics of our sample of 181 individuals who had suffered COVID-19 infection, and 185 who had not, and the factors that predicted ongoing symptoms and self-reported cognitive deficits. In this second paper from the study, we assess this sample on tests of memory, language and executive function. We hypothesize that performance on "objective" cognitive tests will reflect self-reported cognitive symptoms. We further hypothesize that some symptom profiles may be more predictive of cognitive performance than others, perhaps giving some information as to mechanism. We found a consistent pattern of memory deficits in those that had suffered COVID-19 infection, with deficit increasing with severity of self-reported ongoing symptoms. Fatigue/Systemic symptoms during the initial illness and ongoing neurological symptoms were predictive of cognitive performance.


title: Water, Sanitation, and Women's Empowerment: A systematic review and qualitative metasynthesis

abstract:
BackgroundWater and sanitation programs historically have focused on womens instrumental value in improving effectiveness and impact of programs, though focus is shifting to consider how programming and conditions may contribute to womens empowerment an gender equality. To date no systematic review has comprehensively assessed and synthesized evidence on water and sanitation and women and girls empowerment. The primary aims of this review were to: a) identify empirical water and sanitation research that engaged empowerment and/or empowerment-related domains from a pre-specified conceptual model; b) tabulate and report how empowerment-related terminology was used, where and when research was conducted, what methods were leveraged, and if water and/or sanitation was the primary focus; c) synthesize findings by empowerment domain and water and/or sanitation focus.

Methods and FindingsThe conceptual model of womens and girls empowerment developed by van Eerdewijk et.al (2017) informed our search strategy and analysis. The model presents three interrelated domains (agency, resources, institutional structures) and 13 sub-domains of empowerment. We searched MEDLINE, EMBASE, CABI Global Health, PsycINFO, CINAHL and AGRICOLA for any peer-reviewed sources presenting research related to water and/or sanitation and either empowerment and/or related terms from the conceptual model (4 May 2020). Systematic and ancestry and decendency searching identified 12,616 publications, of which 257 were included following screening, representing 1,600,348 participants. We assessed all studies using the Mixed-Method Appraisal Tool (MMAT). We followed the  best-fit framework synthesis approach for analysis, using the domains and sub-domains of the conceptual model as codes to assess all included sources. During coding, we inductively identified two additional sub-domains relevant to water and sanitation: privacy and freedom of movement. Thematic analysis guided synthesis of coded text by domain and sub-domain. The majority of research took place in Asia (46%; 117) or Africa (40%; 102), engaged adults (69%; 177), and were published since 2010; (82%; 211). A greater proportion of studies focused on water (45%; 115) than sanitation (22%; 57) or both (33%; 85). Over half of articles use the term empowerment yet only 7% (17) provided a clear definition or conceptualization. Agency was the least commonly engaged domain (47%; 122) while the Resources domain was dominant (94%; 241). Measures for assessing empowerment and related domains is limited. This review was limited by only including sources in English and only includes menstruation-focused research in the context of water and sanitation.

ConclusionsWater and sanitation research specifically engaging womens and girls empowerment in a well-defined or conceptualized manner is limited. A substantial body of research examining domains and sub-domains of empowerment exists, as does research that illuminates myriad negative impacts of water and sanitation conditions and circumstances womens and girls well-being. Available research should be used to develop and evaluate programs focused on improving the life outcomes of women and girls, which has only been minimally conducted to date. A more comprehensive  transformative WASH that includes gender-transformative approaches to challenge and reduce systemic constraints on womens and girls resources and agency is not only warranted but long overdue.


title: Impact of non-pharmacological interventions on COVID-19 boosting vaccine prioritization and vaccine-induced herd immunity: a population-stratified modelling study

abstract:
BackgroundWhile the COVID-19 pandemic seemed far from the end, the booster vaccine project was proposed to further reduce the transmission risk and infections. However, handful studies have focused on questions that with limited vaccine capacity ether boosting high-risk workers first or prioritizing susceptible normal individuals is optimal, and vaccinating how many people can lead us to the goal of herd immunity. In this study we aimed to explore the conclusions of such two problems with consideration of non-pharmacological interventions including mandatory quarantine for international entrants, keeping social distance and wearing masks.

MethodsBy implementing the corresponding proportion of individuals who remain infectious after four lengths of quarantine strategies to the novel population-stratified model, we quantified the impact of such measures on optimizing vaccine prioritization between high-risk workers and normal populations. Furthermore, by setting the hypothetical COVID-19 transmission severity (reproduction number, R0) to the level of the most contagious COVID-19 variant (B.1.617.2, delta variant, R0 = 5.0), we separately estimated the threshold vaccine coverage of five countries (China, United States, India, South Africa and Brazil) to reach herd immunity, with and without the consideration of interventions including wearings masks and keeping social distance. At last, the sensitive analysis of essential parameter settings was performed to examine the robustness of conclusions.

ResultsFor Chinese scenarios considered with moderate hypothetical transmission rate (R0 = 1.15-1.8), prioritizing high-risk workers the booster dose reached lower cumulative infections and deaths if at least 7-days of quarantine for international travelers is maintained, and the required screening time to remain such vaccinating strategy as optimal increased from 7-days to 21-days with the transmission severity. Although simply maintaining at least 7-days quarantine can lead to over 69.12% reduction in total infections, the improvement of longer quarantine strategies was becoming minimum and the least one was 2.28% between the 21 and the 28-days of quarantine. Besides, without the vaccination program, the impact of such measures on transmission control dropped significantly when R0 exceeded 1.5 and reached its minimal level when R0 equal to 2.5. On the other hand, when we combat the delta variant, the threshold vaccine coverage of total population to reach herd immunity lay within 74%-89% (corresponding to the vaccine efficiency from 70% to 50%), and such range decreased to 71%-84% if interventions including wearing mask and keeping social distance were implemented. Furthermore, Results of other countries with 85% vaccine efficiency were estimated at 79%, 91%, 94% and 96% for South Africa, Brazil, India and United States respectively.

ConclusionsNon-pharmacological interventions can substantially affect booster vaccination prioritization and the threshold condition to reach herd immunity. To combat the delta variant, restrictions need to be integrated with mass vaccination so that can reduce the transmission to the minimum level, and the 21-days might be the suggested maximum quarantine duration according to the cost-effectiveness. Besides, by implementing interventions, the requirement to reach herd immunity can be lower in all countries. Lastly, the following surveillance after vaccination can help ensure the real-time proportion of vaccinated individuals with sufficient protection.


title: Spatial covariance analysis of FDG-PET and HMPAO-SPECT for the differential diagnosis of dementia with Lewy bodies and Alzheimer's disease.

abstract: We investigated diagnostic characteristics of spatial covariance analysis (SCA) of FDG-PET and HMPAO-SPECT scans in the differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimers disease (AD), in comparison with visual ratings and region of interest (ROI) analysis. Sixty-seven patients (DLB 29, AD 38) had both HMPAO-SPECT and FDG-PET scans. Spatial covariance patterns were used to separate AD and DLB in an initial derivation group (DLB n=15, AD n=19), before being forward applied to an independent group (DLB n=14, AD n=19). Visual ratings were by consensus, with ROI analysis utilising medial occipital/medial temporal uptake ratios. SCA of HMPAO-SPECT performed poorly (AUC 0.59{+/-}0.10), whilst SCA of FDG-PET (AUC 0.83{+/-}0.07) was significantly better. For FDG-PET, SCA showed similar diagnostic performance to ROI analysis (AUC 0.84{+/-}0.08) and visual rating (AUC 0.82{+/-}0.08). In contrast to ROI analysis, there was little concordance between SCA and visual ratings of FDG-PET scans. We conclude that SCA of FDG-PET outperforms that of HMPAO-SPECT and performed similarly to other analytical approaches, with the potential to improve with larger derivation groups. Compared to visual rating, SCA of FDG-PET relies on different sources of group variance to separate DLB from AD.

category: radiology and imaging


title: Processing of slow-global auditory regularities causes larger neural responses to heartbeats in patients under minimal consciousness state, compared to unresponsive wakefulness syndrome

abstract:
ObjectivesDetermine if contextual processing of auditory regularities (local-global paradigm) modulate the heartbeat-evoked responses (HERs), and if these modulations may provide complementary information to the auditory related potentials to facilitate the diagnose of patients with disorders of consciousness (DOC).

MethodsDOC patients underwent the local-global paradigm to evaluate the cognitive processing of short/long term-auditory regularities. High-density EEG was recorded to evaluate HERs in local, global and overall conditions.

ResultsThe global effect triggers higher HERs, as well as overall higher HER variance appears in minimally conscious patients. The variance and amplitude effects were uncorrelated, indicating different cognitive processes.

DiscussionOur results corroborate previous findings on HER variance, a marker able to separate DOC without specific stimulations. HER modulations in response to global auditory irregularities represents a novel neural signature of consciousness access, which may facilitate the bedside diagnosis of state of consciousness with more affordable options to neuroimaging methods.


title: Signal Intensity Normalization of Multispectal Magnetic Resonance Images Obtained with Clinical Sequences

abstract: Assessment of intrinsic tissue integrity is commonly accomplished via quantitative relaxometry or other specialized imaging, which requires sequences and analysis procedures not routinely available in clinical settings. We detail an alternative technique for extraction of quantitative tissue biomarkers based on intensity normalization of T1- and T2-weighted images. We develop the theoretical underpinnings of this approach and demonstrate its utility in imaging of multiple sclerosis.


title: White matter microstructure in Parkinson's disease with and without elevated REM sleep muscle tone

abstract: People with Parkinsons disease who have elevated muscle activity during rapid eye movement sleep (REM sleep without atonia) typically have worse motor and cognitive impairment compared to those with normal muscle atonia during REM sleep. This study used tract-based spatial statistics to compare diffusion MRI measures of fractional anisotropy, radial, mean and axial diffusivity (measures of axonal microstructure based on the directionality of water diffusion) in white matter tracts between people with Parkinsons disease with and without REM sleep without atonia and controls and their relationship to measures of motor and cognitive function. Thirty-eight individuals with mild-to-moderate Parkinsons disease and twenty-one matched control subjects underwent ultra-high-field MRI (7Tesla), quantitative motor assessments of gait and bradykinesia, and neuropsychological testing. The Parkinsons disease cohort was separated post-hoc into those with and without elevated chin or leg muscle activity during REM sleep based on polysomnography findings. Fractional anisotropy was significantly higher, and diffusivity significantly lower, in regions of the corpus callosum, projection, and association white matter pathways in the Parkinsons group with normal REM sleep muscle tone compared to controls, and in a subset of pathways relative to the Parkinsons disease group with REM sleep without atonia. The Parkinsons disease group with elevated REM sleep muscle tone showed significant impairments in gait and upper arm speed compared to controls and significantly worse scores in specific cognitive domains (executive function, visuospatial memory) compared to the Parkinsons disease group with normal REM sleep muscle tone. Regression analyses showed that gait speed and step length in the Parkinsons disease cohort were predicted by measures of fractional anisotropy of the anterior corona radiata, whereas elbow flexion velocity was predicted by fractional anisotropy of the superior corona radiata. Visuospatial memory task performance was predicted by the radial diffusivity of the posterior corona radiata. These findings show that people with mild-to-moderate severity of Parkinsons disease who have normal muscle tone during REM sleep demonstrate compensatory-like adaptations in axonal microstructure that are associated with preserved motor and cognitive function, but these adaptations are reduced or absent in those with increased REM sleep motor tone.


title: Characterising severe traumatic brain injury from fresh cerebral biopsy in living patients

abstract:
Traumatic brain injury (TBI) is one of the most complex disorder in the most complex organ in the body and current classifications of mild, moderate and severe often fail to capture this complexity. Although the mainstay of prognosis involves several clinical classification systems, these systems are confined to macroscopic analysis. Therefore, we aim to use immunohistochemical examination of fresh brain biopsy samples to study the cellular and molecular changes caused by severe TBI.

Twenty-five adult patients suffering severe TBI were recruited into the Severe Head Injury Brain Analysis (SHIBA) study. Fresh brain biopsies obtained prior intracranial pressure (ICP) monitor insertion or during craniotomy underwent immunohistochemical analysis using the neuronal marker (NeuN), dendritic marker (MAP2), vascular markers (claudin-5 and vWF), and neuroinflammation markers (Iba1 and P2Y12) to investigate the injury severity at microscopic level.

Obtaining brain biopsy from the twenty-five patients in the study did not cause any additional burden to patients standard care and there were no adverse effects. The mean ({+/-} SD) Glasgow Outcome Scale-Extended (GOS-E) 3-months after injury was 4.0 ({+/-} 2.7), consisting of 64% unfavourable outcomes and 36% favourable outcomes. Immunostaining of brain tissue revealed various qualitative changes resulting in neuronal injury, dendritic injury, neurovascular injury, and neuroinflammation, which we classified into 4 subgroups for each injury type using the newly devised Yip, Hasan and Uff (YHU) grading system. Using this grading scale, patients with a total YHU grade of [≥] 11, 100% (n=11) had a GOS-E of [≤] 4, including death (54.5%), vegetative state (18.2%) and severe disability (27.3%) 3-months post injury. In contrast, those with a YHU grade of [≤] 8, 100% (n=8) had a GOS-E of 5 or higher, indicating a favourable outcome. Linear regression showed a significant negative correlation between the GOS-E and neuronal injury (R2 =0.240, p= 0.0129), dendritic injury (R2 =0.430, p= 0.0004), neurovascular injury (R2 =0.538, p<0.0001), and neuroinflammation (R2 =0.361, p= 0.0015).

Brain biopsy in severe TBI is a simple and safe procedure. Furthermore, immunofluorescence staining enables classification of this heterogeneous patient population into various categories of injury severity based on the cellular and molecular pathophysiology according to the YHU grading system. This new grading scale should facilitate a more precise diagnosis, similar to what is currently standard in oncology, allowing earlier and more accurate prognosis than current grading systems, thereby adding to the arsenal of resources available to guide clinical decision making in treating patients with severe TBI.


title: Collaborative Federated Learning behind Hospitals' Firewalls for Predicting Histological Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

abstract: 1Triple-Negative Breast Cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options compared to other breast cancers. The current standard of care in non-metastatic settings is neoadjuvant chemotherapy (NACT), with the goal of breast-conserving surgery and for an in vivo assessment of chemosensitivity. However, the efficacy of this treatment varies significantly across patients, and this histological response heterogeneity is still poorly understood partly due to the paucity of available curated TNBC data. Motivated by this problem, we investigate the use of machine learning (ML) to predict at diagnosis the histological response to NACT for early TNBC patients. To overcome the known biases of related small scale studies while respecting data privacy, we conduct, for the first time, a TNBC study in a multi-centric fashion behind hospitals firewalls using collaborative Federated Learning (FL). Thereby allowing access to enough TNBC data to sustain a complete response heterogeneity investigation. We show evidence that local ML models relying on Whole-Slide Images (WSIs) at diagnosis are able to predict the histological response to NACT as accurately as current clinical approaches, which rely on time-consuming expert annotations. We demonstrate that collaborative training further improves performance over single-center training outperforming clinical methods. Our ML model is interpretable by design, and we show that it is sensitive to specific histological patterns. While we identify known predictive biomarkers among them, this proof of concept for real-world collaborative FL paves the way for future biomarker discovery using unprecedently large datasets.

category: oncology


title: Implementation and extended evaluation of the Euroimmun Anti-SARS-CoV-2 IgG assay and its contribution to the United Kingdom's COVID-19 public health response

abstract: 1.In March 2020, the Rare and Imported Pathogens Laboratory at Public Health England, Porton Down, was tasked by the Department of Health and Social Care with setting up a national surveillance laboratory facility to study SARS-CoV-2 antibody responses and population-level sero-surveillance in response to the growing SARS-CoV-2 outbreak. In the following 12 months, the laboratory tested more than 160,000 samples, facilitating a wide range of research and informing PHE, DHSC and UK government policy. Here we describe the implementation and use of the Euroimmun anti-SARS-CoV-2 IgG assay and provide an extended evaluation of its performance. We present a markedly improved sensitivity of 91.39% ([≥]14 days 92.74%, [≥]21 days 93.59%) compared to our small-scale early study, and a specificity of 98.56%. In addition, we detail extended characteristics of the Euroimmun assay: intra- and inter-assay precision, correlation to neutralisation and assay linearity.


title: The effects of maternal pre-pregnancy BMI, pregnancy smoking and alcohol consumption on molar-incisor hypomineralisation: A negative control study

abstract:
ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
C_LI

MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH.

category: dentistry and oral medicine


title: The effects of modifiable maternal pregnancy risk factors on molar-incisor hypomineralisation: A negative control study


title: The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study


title: seqr: a web-based analysis and collaboration tool for rare disease genomics

abstract: Exome and genome sequencing have become the tools of choice for rare disease diagnosis, leading to large amounts of data available for analyses. To identify causal variants in these datasets, powerful filtering and decision support tools that can be efficiently used by clinicians and researchers are required. To address this need, we developed seqr - an open source, web-based tool for family-based monogenic disease analysis that allows researchers to work collaboratively to search and annotate genomic callsets. To date, seqr is being used in several research pipelines and one clinical diagnostic lab. In our own experience through the Broad Institute Center for Mendelian Genomics, seqr has enabled analyses of over 10,000 families, supporting the diagnosis of more than 3,800 individuals with rare disease and discovery of over 300 novel disease genes. Here we describe a framework for genomic analysis in rare disease that leverages seqrs capabilities for variant filtration, annotation, and causal variant identification, as well as support for research collaboration and data sharing. The seqr platform is available as open source software, allowing low-cost participation in rare disease research, and a community effort to support diagnosis and gene discovery in rare disease.

category: genetic and genomic medicine


title: Guillain-Barre syndrome following Zika virus infection is associated with a diverse spectrum of peripheral nerve reactive antibodies

abstract:
IntroductionRecent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurological side effects. Concurrence with the inflammatory neuropathy Guillain-Barre syndrome (GBS) is observed in 1:4000 ZIKV cases. Whether the neurological symptoms of ZIKV infection are a consequence of autoimmunity or direct neurotoxicity is unclear.

MethodsWe employed rat dorsal root ganglion (DRG) neurons, Schwann cells (SCs), and human stem cell-derived sensory neurons myelinated with rat SCs as cellular models to screen for IgG and IgM autoantibodies reactive to peripheral nerve in sera of ZIKV patients with and without GBS. In this study, 52 ZIKV-GBS patients were compared with 134 ZIKV-infected patients, and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array.

ResultsOverall, IgG antibody reactivity to rat SCs (6.5%) and myelinated co-cultures (9.6%) were significantly higher, albeit infrequently, in the ZIKV-GBS group compared to all controls. IgM antibody immunoreactivity to DRGs (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared to other controls, while IgM reactivity to co-cultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from one patient were confirmed to react with neurofascin-155 and 186. Serum from a ZIKV non-GBS patient displayed strong myelin-binding and anti-lipid antigen reaction characteristics. There was no significant association of ZIKV-GBS with any anti-glycolipid antibodies.

ConclusionAutoantibodies in ZIKV associated GBS patients sera target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection.


title: Integrated patient network and genomic plasmid analysis reveal a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes

abstract:
The incidence of carbapenemase-producing Enterobacterales (CPE) is rising globally, yet Imipenemase (IMP) carbapenemases remain relatively rare. This study describes an investigation of the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network.

A network analysis approach to patient pathways, using routinely collected electronic health records, identified previously unrecognised contacts between patients who were IMP CPE positive on screening, implying potential bacterial transmission events. Whole genome sequencing of 85 Enterobacterales isolates from these patients revealed that 86% (73/85) were diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli) and harboured an IncHI2 plasmid, which carried both blaIMP and the putative mobile colistin resistance gene mcr-9. Detailed phylogenetic analysis identified two distinct IncHI2 plasmid lineages, A and B, both of which showed significant association with patient movements between four hospital sites and across medical specialities.

Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard microbiology and infection control investigations. With whole genome sequencing (WGS) technologies and large-data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Analysing outbreaks at the plasmid level reveals that resistance may be wider spread than suspected, allowing more targetted interventions to stop the transmission of resistance within hospital networks.


title: How many lives do COVID vaccines save? Evidence from Israel.

abstract:
BackgroundIn December 2020, Israel began a mass vaccination program with the rapid rollout of the Pfizer-BioNTech COVID-19 BNT162b2 vaccine for adults in Israel. The campaign vaccinated fewer people than necessary for herd immunity. However, at the same time, government stringency measures in terms of closing public life were decreased. Real-world observational data were used to examine the effect of mass vaccination on Covid-19 mortality.

MethodsThe study period to examine the effect of vaccination on mortality was chosen to capture when at least 90% of the population over age 70 were vaccinated for less than seven months. Projected deaths as expected from vaccine efficacy and actual mortality data were compared for the study population with examination of potential confounding effects of government stringency. Average government stringency (Oxford Stringency Index) was calculated in the study period and the preceding period of the pandemic. Potential confounding effects of an age shift in the distribution of deaths were examined by analyzing the distributions of deaths and cases before and after the study period.

ResultsConfirmed deaths from COVID-19 in the population over 70 after mass vaccination were recorded as 370, versus 408 expected from applying person-days of vaccine efficacy, and 5,120 estimated without vaccinations.

ConclusionsVaccines against COVID-19 saved more lives than expected by simply applying individual vaccine efficacy to the vaccinated population in Israel, despite a loosening of government stringency.


title: Racial identity and mental health stigma among Black adults in the United States

abstract:
ObjectivesMental illness stigma is a barrier to engagement in mental health services. This study assesses our hypothesis that specific racial identity dimensions influences mental health behavior including stigma.

MethodsWe performed an online cross sectional observational study among Black adults (n = 248, ages 18-65). We examined the relationship between an individuals approach to their racial identity in the community and stigma behavior towards mental health; generalized linear models were performed. We assessed demographic characteristics as moderators of the primary association.

ResultsBlack adults with higher centrality reported lower past stigma behavior (RR=1.57, CI: 1.11-2.21, p=0.01), but higher future intended stigma behavior (RR=0.93, CI: 0.88-0.99, p=0.02). Majority of respondents reported high centrality and high assimilation; however, assimilation did not appear to correlate with mental health stigma behavior. Age, education and ethnicity appeared to have a limited moderating effect on the association between centrality and stigma behavior.

ConclusionsCentrality was associated with mental health stigma behavior. By understanding the intersecting characteristics that may increase the likelihood for mental illness stigma, we will be better able to reduce mental illness stigma and optimize engagement in mental health services.


title: Evaluation of peripheral enhancement on contrast-enhanced CT and corresponding pathological findings in colorectal liver metastases after preoperative chemotherapy

abstract:
ObjectiveTo correlate peripheral enhancement on contrast-enhanced computed tomography (CE-CT) of post-chemotherapy colorectal liver metastases (CRLM) patients with the pathological findings.

MethodsForty-four patients with CRLM who underwent hepatic resection after preoperative chemotherapy between 2008 and 2013 were included. Two radiologists blinded to the histopathology findings performed a consensus categorization of the marginal contrast effects of CRLM on CE-CT as follows: Group 1, smooth margin without enhancement; Group 2, smooth margin with an enhanced rim; and Group 3, fuzzy margin with/without an enhanced rim. The Kruskal-Wallis test was used to compare the imaging findings with the histological findings.

ResultsThe percentage of infarct-like necrosis was significantly higher in CRLM with smooth margins than in those with fuzzy margins (p<0.001, r=0.62). The percentage of viable cells was lowest in CRLM with smooth margins without enhancement (p<0.001, r=0.60).

ConclusionsOur findings suggest that the type of necrosis is related to the nature of the margins, and the presence of residual cells are related to peripheral enhancement.

Advances in knowledgeIn CRLM, following chemotherapy, the presence of residual cells and dangerous haloes is related to the contrast effect of the tumor margins, suggesting that tumor angiogenesis affects the contrast effect.


title: Rapid health evaluation in migrant peoples in transit through Darien, Panama: Protocol for a multi-method qualitative and quantitative study

abstract:
BackgroundThe world is currently unprepared to deal with a the drastic increase in global migration. There is an urgent need to develop programs to protect the well being and health of migrant peoples. Increased population movement is already evident throughout the Americas as exemplified by the rising number of migrant peoples that pass through the Darien neotropical moist broadleaf forest along the border region between Panama and Colombia. The transit of migrant peoples through this area has an increase in the last years. In 2021 an average of 9,400 people entered the region per month compared to 2,000-3,500 people monthly in 2019. Along this trail, there is no access to healthcare, food provision, potable water, or housing. To date, much of what is known about health needs and barriers to healthcare within this population is based on journalistic reports and anecdotes. There is a need for a comprehensive approach to assess the healthcare needs migrant peoples in transit. This study aims to describe demographic characteristics, mental and physical health status and needs, and experiences of host communities, and to identify opportunities to improve healthcare provision to migrant peoples in transit in Panama.

Study design and methodsThis multi-method study will include qualitative (n=70) and quantitative (n=520) components. The qualitative component includes interviews with migrant peoples in transit, national and international non-governmental organizations and agencies based in Panama. The quantitative component is a rapid epidemiological study which includes a questionnaire and four clinical screenings: mental health, sexual and reproductive health, general and tropical medicine, and nutrition.

ConclusionThis study will contribute to a better understanding of the health status and needs of migrant peoples in transit through the region. Findings will be used to allocate resources and provide targeted healthcare interventions for migrant peoples in transit through Darien, Panama.


title: Predictors of quality of life among Brazilian medical students during second coronavirus wave

abstract:
ObjectiveTo assess the impact of COVID-19 second wave on quality of life (QoL) of Brazilian medical students.

MethodsThe data from 210 medical students were collected through a web-based survey between February and March 2021. We assessed information about sociodemographic characteristics, health conditions, electronics tools-related to physical activity (PA-eTool), and health-associated QoL. Multiple linear regression was performed to identify the potential QoL predictors.

ResultsThe psychological domain was the most affected, showing lower score during COVID-19 second wave. Being male was a positive predictor in the physical health domain. Spending too much time indoors and sexual minority-group membership were associated with lower perception on psychological well-being. Personal benefit from having PA-eTool accessed and higher income were positively associated with psychological and environmental domains, respectively, and in the overall QoL.

ConclusionsPsychological well-being impairment is a long-term negative impact among Brazilian medical students during COVID-19. By evidencing that students QoL has been worsened in this global crisis, supportive interventions provided by community and universities are required to aid those vulnerable students facing mental health or QoL impairment.

category: medical education


title: Prostate-specific membrane antigen is a biomarker for residual disease following neoadjuvant intense androgen deprivation therapy in prostate cancer

abstract: Neoadjuvant intense androgen deprivation therapy can exert a wide range of histologic responses, which in turn are reflected in the final prostatectomy specimen. Accurate identification and measurement of residual tumor volumes are critical for tracking and stratifying patient outcomes. The goal of this current study was to evaluate the ability of antibodies against prostate-specific membrane antigen (PSMA) to detect residual tumor in a cohort of 35 patients treated with androgen deprivation therapy plus enzalutamide for six months prior to radical prostatectomy. Residual carcinoma was detected in 31 patients, and PSMA reacted positively with tumor in all cases. PSMA staining was 95.5% sensitive for tumor, with approximately 81.6% of benign regions showing no reactivity. By contrast, PSMA positively reacted with 72.2% of benign regions in a control cohort of 37 untreated cases, resulting in 27.8% specificity for tumor. PSMA further identified highly dedifferentiated prostate carcinomas including tumors with evidence of neuroendocrine differentiation. We propose that anti-PSMA immunostaining be a standardized marker for identifying residual cancer in the setting of neoadjuvant intense androgen deprivation therapy.


title: Altered Neurotransmitter Ratio in the Prefrontal Cortex is Associated with Pain in Fibromyalgia Syndrome

abstract: The central mechanisms underlying fibromyalgia syndrome (FMS) remain undetermined. The dorsolateral prefrontal cortex (DLPFC) is particularly relevant to FMS because it is implicated in cognitive, affective, and top-down pain regulation. Imbalances in excitatory (Glutamate) and inhibitory (Gamma aminobutyric acid; GABA) neurochemicals may play a critical role in the pathophysiology of the condition and more generally in homeostatic function within cortical circuits. Although the balance of excitation and inhibition are intrinsically linked no investigations to date have investigated the E/I ratio in FMS. Thus, the primary objective of this study was to determine whether the E/I ratio in the DLPFC is altered in participants with FMS compared to healthy controls using magnetic resonance spectroscopy. Additionally, we examined the relationship between E/I ratio and pain metrics. We hypothesized that the E/I ratio within the DLPFC would be altered in participants with FMS compared to controls and, secondly, that E/I ratio would be associated with both clinical pain and thermal pain sensitivity. The Brief Pain Inventory (BPI) self-assessment was used to evaluate pain severity and impact on physical functioning and acute pain sensitivity was determined via quantitative sensory testing to define thermal (heat) pain threshold and tolerance. Our results revealed an elevation in the E/I ratio in FMS compared to controls. A positive relationship between E/I ratio and thermal pain sensitivity measures was identified in the FMS cohort. Collapsing across groups, there was a positive relationship between E/I ratio and BPI score. These findings suggest that dysfunction in the balance between excitation and inhibition within cognitive brain circuitry may play a role in pain processing in FMS.

category: pain medicine


title: Loss-of-Function FLNC Variants are Associated with Arrhythmogenic Cardiomyopathy Phenotypes when Identified through Exome Sequencing of a General Clinical Population

abstract:
BackgroundThe FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy (ACM), which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for ACM-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort.

MethodsWe identified rare, putative FLNCLOF among 171,948 individuals with exome sequencing linked to health records. Associations with ACM phenotypes from available diagnoses and cardiac evaluations were investigated.

ResultsSixty individuals (0.03%; median age 58 years [47-70 IQR], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios (OR) for dilated cardiomyopathy (OR:4.9, [95% confidence interval: 2.6-7.6]; p<0.001), supraventricular tachycardia (OR:3.2, [1.1-5.6]; p=0.01), defibrillator implantation (OR:4.6, [1.9-8.4]; p<0.001), and left-dominant ACM (OR:4.2, [1.4-7.9]; p=0.003). Echocardiography revealed reduced left ventricular ejection fraction (52{+/-}13% vs. 57{+/-}9%; p=0.001) associated with FLNCLOF. Overall, at least 9% of FLNCLOF carriers demonstrated evidence of penetrant disease.

ConclusionsFLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.


title: Parent-of-origin effects in the life-course evolution of cardio-metabolic traits

abstract:
ObjectiveHuman traits are heritable, and some of these including metabolic and lipid phenotypes show preferential parental transmissions, or parent-of-origin effects. These have been mostly studied in populations comprising adults. We aimed to investigate heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in a birth-cohort with serial measurements to assess if these effects manifested at an early age.

Research design and methodsWe investigated heritability and parent-of-origin effects on cardiometabolic and anthropometric traits in the Pune Maternal Nutrition Study (PMNS) wherein offspring and parents were studied from birth and followed-up for 18 years. Heritability was estimated by calculating association between mid-parental phenotypes and offspring. Maternal and paternal effects on offspring phenotype were modelled by regression after adjusting for age, sex and BMI. Parent-of-origin effects were calculated by the difference between maternal and paternal effects.

ResultsAnthropomorphic traits and cardiometabolic traits were robustly heritable. Parent-of-origin effects were observed for glycemic traits at both 6- and 12-years, with a paternal effect at 6-years which transitioned to a maternal effect at 12-years. For insulin and HOMA-S, a negative maternal effect transitioned to a positive one at 12-years. For HOMA-B, a paternal effect at 6-years transitioned to a maternal one at 12-years. Lipid traits consistently showed stronger maternal influence while anthropometric traits did not show any parental biases.

ConclusionsOur study highlights that parental programming of cardiometabolic traits is evident from early childhood and can transition during puberty. Further studies are needed to determine the mechanisms of underlying such effects.


title: Seizure Onset Zone Identification Using Phase-Amplitude Coupling and Multiple Machine Learning Approaches for Interictal Electrocorticogram

abstract: Automatic seizure onset zone (SOZ) localization using interictal electrocorticogram (ECoG) improves the diagnosis and treatment of patients with medically refractory epilepsy. This study aimed to investigate the characteristics of phase-amplitude coupling (PAC) extracted from interictal ECoG and the feasibility of PAC served as a promising biomarker for SOZ identification. We employed the mean vector length modulation index approach on the 20-s ECoG window to calculate PAC features between low-frequency rhythms (0.5-24 Hz) and high frequency oscillations (HFOs) (80-560 Hz). We used statistical measures to test the significant difference in PAC between SOZ and non-seizure onset zone (NSOZ). To overcome the drawback of handcraft feature engineering, we established novel machine learning models to automatically learn the characteristics of PAC features obtained and classify them to identify SOZ. Besides, to conquer the imbalance of datasets, we introduced novel feature-wise/class-wise re-weighting strategies in conjunction with classifiers. In addition, we proposed the time-series nest cross-validation to provide more accurate and unbiased evaluations for this model. Seven patients with focal cortical dysplasia were included in this study. The experiment results not only illustrate that the significant coupling at band pairs of slow waves and HFOs exists in the SOZ when compared with the NSOZ but also indicate the effectiveness of PAC features and the proposed models with better classification performance.


title: Personalized survival probabilities for SARS-CoV-2 positive patients by explainable machine learning

abstract: Interpretable risk assessment of SARS-CoV-2 positive patients can aid clinicians to implement precision medicine. Here we trained a machine learning model to predict mortality within 12 weeks of a first positive SARS-CoV-2 test. By leveraging data on 33,928 confirmed SARS-CoV-2 cases in eastern Denmark, we considered 2,723 variables extracted from electronic health records (EHR) including demographics, diagnoses, medications, laboratory test results and vital parameters. A discrete-time framework for survival modelling enabled us to predict personalized survival curves and explain individual risk factors. Performances of weighted concordance index 0.95 and precision-recall area under the curve 0.71 were measured on the test set. Age, sex, number of medications, previous hospitalizations and lymphocyte counts were identified as top mortality risk factors. Our explainable survival model developed on EHR data also revealed temporal dynamics of the 22 selected risk factors. Upon further validation, this model may allow direct reporting of personalized survival probabilities in routine care.


title: Intrahost-diversity of influenza A virus in upper and lower respiratory tract derived samples from a college community

abstract:
MotivationInfluenza is a rapidly mutating RNA virus responsible for annual epidemics causing substantial morbidity, mortality, and economic loss. Characterizing influenza virus mutational diversity and evolutionary processes within and between human hosts can provide tools to help track and understand transmission events. In this study we investigated possible differences between the intrahost genomic content of influenza virus in upper respiratory swabs and exhaled aerosols thought to be enriched for virus from the lower respiratory tract.

ResultsWe examined the sequences of specimens collected from influenza A virus (IAV) infected college community members from December 2012 through May 2013. We analyzed four types of IAV samples (fine [≤]5 {micro}m aerosols (N=38), coarse >5{micro}m aerosols (N=27), nasopharyngeal (N=53), and oropharyngeal swabs (N=47)) collected from 42 study participants with 60 sampling instances. Eighteen (42.9%) participants had data from four sample types (nasopharyngeal swab, oropharyngeal swab, coarse aerosol, fine aerosol) included in the analysis, 10 (23.8%) had data from 3 sample types, 10 (23.8%) had data from 2 sample types, and 4 (9.5%) had data from one type of sample included in the analysis. We found that 481 (53.3%) consensus single nucleotide polymorphisms are shared by all sample types and 600 (66.5%) are shared by at least three different sample types. We observed that within a single patient consensus and non-consensus single nucleotide variants are shared across all sample types. Finally, we inferred a phylogenetic tree using consensus sequences and found that samples derived from a single patient are monophyletic.

ConclusionsSingle nucleotide polymorphisms did not differentiate between samples with varying origin along the respiratory tree. We found that signatures of variation in non-consensus intrahost single nucleotide variants are host and sample, but not site specific. We conclude that the genomic information available does not allow us to discern a transmission route. Future investigation into whether any site-specific mutational signatures emerge over a longer period of infection, for example in immunocompromised hosts, can be interesting from the virus evolution perspective.


title: Time of day of vaccination affects SARS-CoV-2 antibody responses in an observational study of healthcare workers

abstract: The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis with unprecedented challenges for public health. Vaccinations against SARS-CoV-2 have slowed the incidence of new infections and reduced disease severity. As the time-of-day of vaccination has been reported to influence host immune responses to multiple pathogens, we quantified the influence of SARS-CoV-2 vaccination time, vaccine type, age, sex, and days post-vaccination on anti-Spike antibody responses in healthcare workers. The magnitude of the anti-Spike antibody response associated with the time-of-day of vaccination, vaccine type, participant age, sex, and days post vaccination. These results may be relevant for optimizing SARS-CoV-2 vaccine efficacy.


title: In vitro characterisation and clinical evaluation of the diagnostic accuracy of a new antigen test for SARS-CoV-2 detection.

abstract: Background and aimsQuick, user-friendly and sensitive diagnostic tools are the key to controlling the spread of the SARS-CoV-2 pandemic in the new epidemiologic landscape. The aim of this work is to characterise a new Covid-19 antigen test that uses an innovative chromatographic Affimer(R)-based technology designed for the qualitative detection of SARS-CoV-2 antigen. As rapid technology to detect Covid-19, the test was extensively characterised in vitro. Once the analytical parameters of performance were set, the test system was challenged in a test field study. The aim of this study was to evaluate its diagnostic accuracy, as compared by the gold standard RT-PCR and other existing lateral flow tests.


title: COVID-19 Patients Symptoms: Gastrointestinal Presentations, Comorbidities and Outcome in a Canadian Hospital setting

abstract:
BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has had significant global impact. While public health interventions and universal health insurance has been credited with minimizing transmission rates in Canada relative to neighboring countries, significant morbidity and mortality have occurred nationwide. We sought to determine factors associated with differences in gastrointestinal outcomes in COVID-19 patients at a Canadian hospital.

MethodsWe collected data from 192 hospital records of COVID-19 patients across seven Hamilton Health Sciences hospitals, a network of academic health centres serving one of the largest metropolitan areas in Canada. Statistical and correlative analysis of symptoms, comorbidities, and mortality were performed.

ResultsThere were 192 patients. The mean age was 57.6 years (SD=21.0). For patients who died (n=27, 14%), mean age was 79.2 years old (SD=10.6) versus 54 years for survivors (SD=20.1). There was a higher mortality among patients with older age (p=0.000), long hospital stay (p=0.004), male patients (p=0.032), and patients in nursing homes (p=0.000). Patients with dyspnea (p=0.028) and hypertension (p=0.004) were more likely to have a poor outcome. Laboratory test values that were significant in determining outcomes were an elevated INR (p=0.007) and elevated creatinine (p=0.000). Cough and hypertension were the most common symptom and comorbidity, respectively. Diarrhea was the most prevalent (14.5%) gastrointestinal symptom. Impaired liver function was related to negative outcome (LR 5.6; p=0.018).

ConclusionsIn a Canadian cohort, elevated liver enzymes, prolonged INR and elevated creatinine were associated with poor prognosis. Hypertension was also linked to a higher likelihood of negative outcome.

SUMMARY BOXO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIThe prevalence of gastrointestinal symptoms in COVID-19 patients across Canada is lacking
C_LIO_LIGastrointestinal manifestations of COVID-19 are well described, and longterm sequelae of gastrointestinal tract involvement are an ongoing concern
C_LI

What are the new findings?O_LIThere was a significant prevalence of gastrointestinal symptoms in patients with a confirmed diagnosis of COVID-19 at one of the largest metropolitan regions across Canada
C_LIO_LILiver enzyme abnormalities were common in patients at diagnosis
C_LIO_LIThis report, over an 8-month period, represents the largest cohort of COVID-19 patients reported in Canada
C_LI

How might these results impact on clinical practice in the foreseeable future?O_LIBaseline gastrointestinal symptoms and laboratory abnormalities correlate with patient outcome in Canadian COVID-19 patients
C_LIO_LIThese results enhance our knowledge of the prevalence of gastrointestinal symptoms and laboratory abnormalities in Canadian patients and offer important baseline data for longitudinal studies in these patients
C_LIO_LIOur findings increase our knowledge of the epidemiology of COVID-19 in Canada and allow future comparison with international data
C_LI


title: Impact of the COVID-19 pandemic on routine immunization coverage in children under 2 years old in Ontario, Canada: A retrospective cohort study

abstract:
BackgroundThe COVID-19 pandemic has caused a disruption in childhood immunization coverage around the world. This study aimed to determine the change in immunization coverage for children under 2 years old in Ontario, Canada, comparing time periods pre-pandemic to during the pandemic.

MethodsWe conducted an observational retrospective open cohort study, using primary care electronic medical record data from the University of Toronto Practice-Based Research Network (UTOPIAN) database, from January 2019 to December 2020. Children under 2 years old who had at least 2 visits recorded in UTOPIAN were included. We measured up-to-date (UTD) immunization coverage rates, overall and by type of vaccine (DTaP-IPV-Hib, Pneu-C-13, Rot, Men-C-C, MMR, Var), and on-time immunization coverage rates by age milestone (2, 4, 6, 12, 15 and 18 months). We compared average coverage rates over 3 periods of time: January 2019-March 2020 (T1); March-July 2020 (T2); and August-December 2020 (T3).

Results12,313 children were included. Overall UTD coverage for all children was 71.0% in T1, dropped by 5.7% (95% CI: -6.2, -5.1) in T2, slightly increased in T3 but remained lower than in T1. MMR vaccine UTD coverage slightly decreased in T2 and T3 by approximately 2%. The largest decreases were seen at ages 15-month and 18-month old, with drops in on-time coverage of 14.7% (95% CI: -18.7, -10.6) and 16.4% (95% CI: -20.0, -12.8) respectively during T2. When stratified by sociodemographic characteristics, no specific subgroup of children was found to have been differentially impacted by the pandemic.

ConclusionChildhood immunization coverage rates for children under 2 years in Ontario decreased significantly during the early period of the COVID-19 pandemic and only partially recovered during the rest of 2020. Public health and educational interventions for providers and parents are needed to ensure adequate catch-up of delayed/missed immunizations to prevent potential outbreaks of vaccine-preventable diseases.

category: primary care research


title: Descriptive analysis of social determinant of mental health factors in an ethnically diverse Black adult population

abstract:
BackgroundBlack adults are often treated as a homogeneous group in research and health care despite the diversity within the Black population across ethnicity. This study considers ethnicity in assessing the heterogeneity among Black adults across multiple social determinants of mental health. Understanding the diversity within the Black population will help close the gap in mental health disparities by offering a more streamlined approach to meeting unmet mental health needs.

MethodsA cross-sectional descriptive study and analysis was conducted among Black adults in the United States (n = 269, ages 18-65) from diverse ethnic backgrounds (African-Americans, African immigrants, Afro-Caribbean immigrants). We calculated mean differences according to ethnicity, citizenship status, age group, and gender in the areas of medical mistrust, use of mental health services, depression symptom severity, mental health knowledge and stigma behavior.

ResultsAfrican Americans with moderate to severe depression symptoms had greater stigma behavior (mean = 12.2, SD = 3.2), than African Americans who screened in the minimal to mild depression range (mean = 13.1, SD = 3.5). Black immigrants across the spectrum of depression scores had greater stigma than African Americans (p = 0.037). Participants who identified as male had a prevalence of mild depression (5-9) that was 1.7 times higher than those who identified as female. Whereas, those who identified as female had a prevalence that was 1.2 times higher for moderate to severe depression (10-19) and 4.7 times higher for severe depression (20-27) compared to males (p = 0.021). Non-United States citizens reported higher medical mistrust (mean value difference = 0.16) compared to United States citizens (p = 0.011). We found statistically significant differences in depression symptom severity based on gender, prevalence of depression, medical mistrust and stigma behavior across demographic factors within the sample.

ConclusionThis study shows key variations across social determinant of mental health factors within the Black adult population. There is a need to better understand the heterogeneity within the Black population in order to improve the effectiveness of programs that seek to reduce mental health disparities.


title: Transferability of Psychological Interventions from Disaster-Exposed Employees to Healthcare Workers Working during the COVID-19 Pandemic

abstract:
BackgroundThe COVID-19 Pandemic had a significant negative impact on the mental health of healthcare workers. Evidence-based interventions that could be used to mitigate this impact are lacking in the literature. This review aims to evaluate psychological interventions used for employees following previous disasters and assess the transferability of these interventions to a healthcare setting during the COVID-19 pandemic.

MethodsIntervention information from a previously published systematic review of the literature published up to 2015 was extracted, and an additional search of studies published from 2015-2020 was conducted. Studies were assessed for transferability using a checklist derived from the PIET-T process model.

ResultsInterventions from eighteen studies were assessed for transferability (including three studies identified in an updated literature search). Interventions established as most transferable included resilience training, meditation/mindfulness interventions, and cognitive behavioural therapy. Psychological debriefing was transferable but as it is contrary to current recommendations is not deemed appropriate for adoption.

ImplicationsSeveral existing interventions have the potential to be utilised within the COVID-19 context/pandemic. More research needs to be undertaken in this area to assess these interventions upon transfer.