title: Different HMGCR-inhibiting statins vary in their association with increased survival in patients with COVID-19

abstract:
BackgroundIn response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. Here we explored the possibility that different statins might differ in their ability to exert protective effects based on computational predictions.

MethodsA Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2, with a total of 2,436 drugs investigated. Top drug predictions included statins, which were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. A database containing over 4,000 COVID-19 patients on statins was also analyzed to determine mortality risk in patients prescribed specific statins versus untreated matched controls.

FindingsSimvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins were predicted to be active in > 50% of analyses. In vitro testing of SARS- CoV-2 infected cells revealed simvastatin to be a potent inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin.

InterpretationDifferent statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and validate non-obvious mechanisms and drug repurposing opportunities.

FundingDARPA, Wyss Institute, Hess Research Fund, UCSF Program for Breakthrough Biomedical Research, and NIH


title: Slight increase in fomite route transmission risk of SARS-CoV-2 Omicron variant compared with the ancestral strain in households

abstract: The Omicron SARS-CoV-2 variant has become the dominant lineage worldwide, and experimental study had shown that SARS-CoV-2 Omicron variant was more stable on various environmental surfaces than ancestral strain. However, how the changes of stability on surfaces would influence the role of fomite route in SARS-CoV-2 transmission is still unknown. In this study, we modeled the Omicron and ancestral strain SARS-CoV-2 transmission within a household over 1-day period from multiple pathways, i.e., airborne, droplet and contact route. We assumed there were 2 adults and 1 child in the household, and one of the adults was infected with SARS-CoV-2. We assume a scenario of pre-/asymptomatic infection, i.e., SARS-CoV-2 was emitted by breathing and talking, and symptomatic infection, i.e., SARS-CoV-2 was emitted by breathing, talking, and coughing. In pre-/asymptomatic infection, all three routes contributed a role, contact route contribute most (37%-45%), followed by airborne route (34%-38%) and droplet route (21%-28%). In symptomatic infection, droplet route was the dominant pathway (48%-71%), followed by contact route (25%-42%), airborne route played a negligible role (<10%). In the contact route, indirect contact (fomite) route dominated (contributed more than 97%). Compared with ancestral strain, though the contribution of contact route increased in Omicron variant transmission, the increase was slight, from 25%-41% to 30%-45%.

category: infectious diseases


title: Health behaviours the month prior to COVID-19 infection and the development of self-reported long COVID and specific long COVID symptoms: A longitudinal analysis of 1,811 UK adults

abstract:
BackgroundDemographic and infection-related characteristics have been identified as risk factors for long COVID, but research on the influence of health behaviours (e.g., exercise, smoking) immediately preceding the index infection is lacking.

Methods1,811 UK adults from the UCL COVID-19 Social Study and who had previously been infected with COVID-19 were analysed. Health behaviours in the month before infection were weekly exercise frequency, days of fresh air per week, sleep quality, smoking, consuming more than the number of recommended alcoholic drinks per week (>14), and the number of mental health care behaviours (e.g., online mental health programme). Logistic regressions controlling for covariates (e.g., COVID-19 infection severity and pre-existing health conditions) examined the impact of health behaviours on long COVID and three long COVID symptoms (difficulty with mobility, cognition, and self-care).

ResultsIn the month before infection with COVID-19, poor quality sleep increased the odds of long COVID (odds ratio [OR]: 3.53; (95% confidence interval [CI]: 2.01 to 6.21), as did average quality sleep (OR: 2.44; 95% CI: 1.44 to 4.12). Having smoked (OR: 8.39; 95% CI: 1.86 to 37.91) increased and meeting recommended weekly physical activity guidelines (3+ hours) (OR: 0.05; 95% CI: 0.01 to 0.39) reduced the likelihood of difficulty with self-care (e.g., washing all over or dressing) amongst those with long COVID.

ConclusionResults point to the importance of sleep quality for long COVID, potentially helping to explain previously demonstrated links between stress and long COVID. Results also suggest that exercise and smoking may be modifiable risk factors for preventing the development of difficulty with self-care.

FundingThe Nuffield Foundation [WEL/FR-000022583], the MARCH Mental Health Network funded by the Cross-Disciplinary Mental Health Network Plus initiative supported by UK Research and Innovation [ES/S002588/1], and the Wellcome Trust [221400/Z/20/Z and 205407/Z/16/Z].

What is already known on the topicLong COVID is rapidly becoming a public health concern. Although existing evidence to date has identified health characteristics such as obesity as risk factors, hardly any research on modifiable risk factors such as health behaviours has been conducted.

What this study addsThis study adds to the dearth of evidence on modifiable risk factors occurring before COVID-19 infection. Findings suggest a role of poor sleep quality for the development of long COVID, and for meeting physical activity guidelines (3+ hours per week) and not smoking as modifiable risk factors for self-care difficulties amongst those with long COVID.

category: epidemiology


title: Multiplex RT-qPCR assay (N200) to detect and estimate prevalence of multiple SARS-CoV-2 Variants of Concern in wastewater

abstract: Wastewater-based surveillance (WBS) has become an effective tool around the globe for indirect monitoring of COVID-19 in communities. Quantities of viral fragments of SARS-CoV-2 in wastewater are related to numbers of clinical cases of COVID-19 reported within the corresponding sewershed. Variants of Concern (VOCs) have been detected in wastewater by use of reverse transcription quantitative polymerase chain reaction (RT-qPCR) or sequencing. A multiplex RT-qPCR assay to detect and estimate the prevalence of multiple VOCs, including Omicron/Alpha, Beta, Gamma, and Delta, in wastewater RNA extracts was developed and validated. The probe-based multiplex assay, named "N200" focuses on amino acids 199-202, a region of the N gene that contains several mutations that are associated with variants of SARS- CoV-2 within a single amplicon. Each of the probes in the N200 assay are specific to the targeted mutations and worked equally well in single- and multi-plex modes. To estimate prevalence of each VOC, the abundance of the targeted mutation was compared with a non- mutated region within the same amplified region. The N200 assay was applied to monitor frequencies of VOCs in wastewater extracts from six sewersheds in Ontario, Canada collected between December 1, 2021, and January 4, 2022. Using the N200 assay, the replacement of the Delta variant along with the introduction and rapid dominance of the Omicron variant were monitored in near real-time, as they occurred nearly simultaneously at all six locations. The N200 assay is robust and efficient for wastewater surveillance can be adopted into VOC monitoring programs or replace more laborious assays currently being used to monitor SARS- CoV-2 and its VOCs.


title: Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study

abstract:
BackgroundA major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021.

MethodsWe conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged [≥]18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models.

ResultsWe included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%-94%) [≥]84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%-99%) [≥]112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%-94%) [≥]56 days after a first dose, increasing to 97% (95%CI: 91%-99%) [≥]56 days after a second dose. Lower one-dose effectiveness was observed for adults aged [≥]80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants.

ConclusionsTwo doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.

category: public and global health


title: A Systematic Approach to Identify Neuroprotective Interventions for Motor Neuron Disease

abstract:
BackgroundMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial.

ObjectivesHere we detail a systematic, structured, and unbiased evidence-based approach to guide selection of drugs for clinical evaluation in the Motor Neuron Disease - Systematic Multi-arm Adaptive Randomised Trial (MND-SMART, clinicaltrials.gov registration number: NCT04302870), an adaptive platform trial.

MethodsWe conducted a two-stage systematic review and meta-analysis to identify potential neuroprotective interventions. In stage one, we identified drugs from the clinical literature tested in at least one study in MND or in two or more cognate diseases with potential shared pivotal pathways (Alzheimers disease, Huntingtons disease, Parkinsons disease, or multiple sclerosis). We scored and ranked 66 drugs thus identified using a predefined framework evaluating safety, efficacy, study size and quality of studies. In stage two, we conducted a systematic review of the MND preclinical literature describing efficacy of these drugs in animal models, multicellular eukaryotic models and human induced pluripotent stem cell studies; 17 of these drugs were reported to improve survival in at least one preclinical study. An expert panel then shortlisted and ranked 22 drugs considering stage one and stage two findings, mechanistic plausibility, safety and tolerability, findings from previous clinical trials in MND, and feasibility for use in clinical trials.

ResultsBased on this process, the panel selected memantine and trazodone for testing in MND-SMART.

DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human induced pluripotent stem cells.

STRENGTHS AND LIMITATIONS OF THIS STUDYO_LIWe described a systematic, evidence-based approach towards drug repurposing in motor neuron disease (MND), specifically for Motor Neuron Disease - Systematic Multi-arm Adaptive Randomised Trial (MND-SMART), a phase III multi-arm multi-stage clinical trial in MND.
C_LIO_LISystematic reviews of clinical studies in neurodegenerative diseases and MND preclinical studies provided a robust evidence base to inform expert panel decisions on drug selection for clinical trials.
C_LIO_LIProviding a contemporary evidence base using traditional systematic reviews is challenging given their time-consuming and labour-intensive nature.
C_LIO_LIIncorporation of machine learning and automation tools for systematic reviews, and data from experimental drug screening can be helpful for future drug selection.
C_LI

category: neurology


title: Non-intuitive trends of fetal fraction development related to gestational age and fetal gender, and their practical implications for non-invasive prenatal testing

abstract:
ObjectiveDiscovery of fetal cell-free DNA fragments in maternal blood revolutionized prenatal diagnostics. Although non-invasive prenatal testing (NIPT) is already a matured screening test with high specificity and sensitivity, the accurate estimation of the proportion of fetal fragments, called fetal fraction, is crucial to avoid false-negative results.

MethodsWe collected 6999 samples from women undergoing NIPT testing with a single male fetus to demonstrate the influence of fetal fraction by the maternal and fetal characteristics.

ResultsWe show several fetal fraction discrepancies that contradict the generally presented conventional view. At first, the fetal fraction is not consistently rising with the maturity of the fetus due to a drop in 15 weeks of maturation. Secondly, the male samples have a lower fetal fraction than female fetuses, arguably due to the smaller gonosomal chromosomes. Finally, we discuss not only the possible reasons why this inconsistency exists but we also outline why these differences have not yet been identified and published.

ConclusionWe demonstrate two non-intuitive trends to better comprehend the fetal fraction development and more precise selection of patients with sufficient fetal fraction for accurate testing.

Bulleted statementsO_ST_ABSWhat is already known about this topic?C_ST_ABSO_LINon-invasive prenatal testing has become a well-known mature screening test, and the fetal fraction is studied in detail by research teams worldwide.
C_LI

What does this study add?O_LIHere we demonstrate two non-intuitive trends to better comprehend fetal fraction development that can further increase the sensitivity of routine testing by proper selection of blood sampling according to gestational age and fetus gender.
C_LI

category: obstetrics and gynecology


title: Associations of genetic and infectious risk factors with coronary heart disease

abstract:
Background and PurposeCoronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD.

Participants and MethodsStudy participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every five years. We analyzed a subgroup of 3459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multivariable stepwise Cox proportional hazards regression analyses.

ResultsOf the 3459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status and statin intake, revealed that high polygenic risk (hazard ratio (HR) 1.31, 95% CI 1.10-156, P = 2.64e-03) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, P = 1.99e-02) were independently associated with incident CHD.

ConclusionIn a prospective, population-based cohort, high polygenic risk and infection with Fusobacterium nucleatum have a small, yet independent impact on CHD risk.

category: genetic and genomic medicine


title: Localization of Abnormal Brain Regions in Parkinsonian Disorders: An ALE Meta-Analysis

abstract: Parkinsonism is a feature of several neurodegenerative disorders, including Parkinsons disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration syndrome (CBS) and multiple system atrophy (MSA). Neuroimaging studies have yielded insights into parkinsonism; however it remains unclear whether there is a common neural substrate amongst disorders. The aim of the present meta-analysis was to identify consistent brain alterations in parkinsonian disorders (PD, PSP, CBS, MSA) both individually, and combined, to elucidate the shared substrate of parkinsonism. 33,505 studies were systematically screened following searches of MEDLINE Complete and Embase databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 126 neuroimaging studies (64 PD; 25 PSP; 18 CBS; 19 MSA) utilizing anatomical MRI, perfusion or metabolism positron emission tomography and single photon emission computed tomography. Abnormality of the caudate, thalamus, middle frontal and temporal gyri was common to all parkinsonian disorders. Localizations of commonly affected brain regions in individual disorders aligned with current diagnostic imaging markers, localizing the midbrain in PSP, putamen in MSA-parkinsonian variant and brainstem in MSA-cerebellar variant. Regions of the basal ganglia and precuneus were most commonly affected in PD, while CBS was characterized by caudate abnormality. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders. Findings support the notion that parkinsonism may share a common neural substrate, independent of the underlying disease process, while also highlighting characteristic patterns of brain abnormality in each disorder.


title: Low Intensity Vibration Protects the Weight Bearing Skeleton and Suppresses Fracture Incidence in Boys with Duchenne Muscular Dystrophy

abstract:
Introduction/AimsThe ability of low intensity vibration (LIV) to combat skeletal decline in Duchenne Muscular Dystrophy (DMD) was evaluated in a randomized controlled trial.

MethodsTwenty DMD boys were enrolled, all ambulant and treated with glucocorticoids (mean age 7.6, height-adjusted Z-scores (HAZ) of hip BMD -2.3). Ten DMD boys were assigned to stand for 10min/d on an Active LIV platform (0.4g @ 30Hz), while 10 stood on a Placebo device. Baseline and 14-month BMC and BMD of spine, hip and total body were measured with DXA, and trabecular bone density (TBD) of tibia with QCT.

ResultsAll children tolerated the LIV intervention well, with daily compliance averaging 78%. At 14 months, TBD in the proximal and distal tibia remained unchanged in Placebo (-0.7% & -0.8%), while rising 4.1% and 4.5% in LIV. HAZ for hip BMD and BMC in Placebo declined 22% and 13% respectively, contrasting with no change from baseline (0.9% and 1.4%) in LIV. Fat mass in the leg increased 33% in Placebo, contrasting with 20% in LIV subjects. Across the 14-month study, there were four incident fractures in three placebo patients (30%), with no new fractures identified in LIV subjects.

ConclusionsThese data suggest that non-invasive LIV can help protect the skeleton of DMD children against the disease progression, the consequences of diminished load bearing, and the complications of chronic steroid use.


title: The effect of population migration on the diffusion of cholera outbreaks in metapopulations

abstract:
In this study, an improved Susceptible-Infected-Recovered (SIR) epidemic diffusion model for cholera is extended by including migration for susceptible people. This model is applied to a metapopulation that consists of two isolated cities where just susceptible individuals can migrate between the cities. The disease-free equilibrium, the endemic equilibrium points, and the basic reproductive number with unequal migration rates are analyzed for this metapopulation. Firstly, the study showed that the basic reproductive number depends on the migration rates between the cities. Then, showed that when the epidemic SIR system is stable, then the infected cases for cholera outbreak can reach zero in one city, but the infected cases in the other city still can stay positive. Finally, discussed three scenarios that depend on population sizes and migration rates of susceptible people between the cities and showed how important the migration rates are in the diffusion of the cholera outbreak by visualizing these three scenarios.

Mathematics Subject ClassificationPrimary: 92B05; Secondary: 92D40


title: Genetic and potential antigenic evolution of influenza A(H1N1)pdm09 viruses circulating in Kenya during 2009-2018 influenza seasons

abstract:
BackgroundInfluenza viruses undergo rapid evolutionary changes, which requires continuous surveillance to monitor for genetic and potential antigenic changes in circulating viruses that can guide control and prevention decision making.

MethodsWe sequenced and phylogenetically analyzed A(H1N1)pdm09 virus genome sequences obtained from specimens collected from hospitalized patients of all ages with or without pneumonia between 2009 and 2018 from seven sentinel surveillance sites across Kenya. We compared these sequences with recommended vaccine strains during the study period to infer genetic and potential antigenic changes in circulating viruses and determinants of clinical outcome.

ResultsWe generated and analyzed a total of 383 A(H1N1)pdm09 virus genome sequences. Phylogenetic analyses revealed that multiple genetic groups (clades, subclades, and subgroups) of A(H1N1)pdm09 virus circulated in Kenya over the study period; these evolved away from their vaccine strain, forming clades 7 and 6, subclades 6C, 6B, and 6B.1, and subgroups 6B.1A and 6B.1A1. Several amino acid substitutions among circulating viruses were associated with continued evolution of the viruses, especially in antigenic epitopes and receptor binding sites (RBS) of circulating viruses. Disease severity reduced with increase in age among children aged <5 years.

ConclusionOur study highlights the utility of genomic surveillance to monitor the evolutionary changes of influenza viruses. Routine influenza surveillance with broad geographic representation and whole genome sequencing capacity to inform on the severity of circulating strains could improve selection of influenza strains for inclusion in vaccines.


title: Real-time RT-PCR for Venezuelan equine encephalitis complex, Madariaga and Eastern equine encephalitis viruses: application in clinical diagnostic and mosquito surveillance

abstract:
BackgroundVenezuelan equine encephalitis (VEE) complex, eastern equine encephalitis virus (EEEV), and Maradiaga virus (MADV), are associated with severe neurological disease in human and equine hosts. We aimed to overcome the lack of available molecular diagnostics for these pathogens by designing and clinically evaluating real-time reverse transcription PCRs (rRT-PCRs) for 1) VEE complex and 2) MADV/EEEV.

Methodology/Principal FindingsPrimers and probes were designed from alignments of all publicly available complete genome sequences for VEE complex, EEEV and MADV. Linear range for the VEE complex and MADV/EEEV rRT-PCRs extended from 2.0 to 8.0 log10 copies/{micro}L with exclusive detection of the respective viruses. Fifteen serum samples from febrile patients collected from 2015 and 2017 outbreaks in Panama were tested to evaluate the new assays. Ten samples (66.7%) samples were positive for VEEV, and in one of these ten samples, rRT-PCR detected both VEEV and MADV. The remaining five samples were negative for both MADV and VEEV. Three acute samples ([≤] 3 days since onset) with coincidental anti-VEEV IgM and IgG antibodies were also found positive for VEEV viral RNA. Of 150 mosquito pools, 3 tested positive for VEEV by rRT-PCR. Two of these yielded VEEV isolates.

ConclusionsThe VEE complex and MADV/EEEV rRT-PCRs provide accurate detection while yielding significant benefits over currently available molecular methods. Outcomes from the clinical evaluation provide further evidence for VEE complex and MADV co-infections and suggest that re-infection with VEE complex viruses is possible.

Author SummaryThe alphavirus encephalitis viruses include species of the Venezuelan equine encephalitis (VEE) complex, Maradiaga virus (MADV), and Eastern equine encephalitis virus (EEEV). They persist in sylvatic-enzootic cycles throughout the Americas and are transmitted to humans by Culex spp. mosquitoes. Human and equine outbreaks are reported sporadically in endemic regions. Detection of VEE complex, MADV and EEEV infections in the acute phase is complicated by their non-specific clinical manifestations and lack of widely available diagnostic tools. Current molecular tests lack optimal performance metrics characteristics necessary for routine diagnostic testing. Here we design two real-time RT-PCRs for VEE complex and MADV/EEEV, which were then evaluated by testing a set of clinical and mosquito samples collected during two outbreaks of VEEV and MADV in Panama. The VEE complex and MADV/EEEV rRT-PCRs provide accurate detection while yielding significant benefits over currently available molecular methods.


title: Quantitative longitudinal natural history of eight gangliosidoses - conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis.

abstract:
PurposeGangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay and regression, leading to significant morbidity, and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies.

MethodsSingle disease registry of eight gangliosidoses (NCT04624789).

Cross-sectional analysis of baseline data in N= 26 patients.

Primary endpoint: disease severity assessed by the 8-in-1 score.

Secondary endpoints: first neurological sign or symptom observed a. by parents and b. by physicians, diagnostic delay, as well as phenotypical characterization.

Tertiary endpoints: Neurological outcomes (development, ataxia, dexterity) and disability.

ResultsThe 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 [IQR 0.69 ... 6.25] years. Eight patients presented with late-infantile phenotypes.

ConclusionData in this registry raise awareness of these rare and fatal conditions in order to accelerate diagnosis, inform counselling of afflicted families, define quantitative endpoints for clinical trials, and can serve as historical controls for future therapeutic studies. The characterization of a late-infantile phenotype is novel. Longitudinal follow-up is planned.


title: The Co-Production of the Roots Framework: A Reflective Framework for Mapping the Implementation Journey of Trauma-Informed Care

abstract:
BackgroundThe trauma-informed care programme at the Tees, Esk and Wear Valleys Foundation NHS Trust identified a need to evaluate the ongoing service-wide trauma-informed care implementation effort. An absence of staff, service user and system-related outcomes specific to trauma-informed care presented barriers to monitoring the adoption of trauma-informed approaches and progress over time across the Tees, Esk and Wear Valleys Foundation NHS Trust. This paper describes the co-production of a new self-assessment tool, Roots, a discussion-based framework that facilitates learning and improvement by reflecting on positive or negative examples of trauma-informed services.

MethodsUsing secondary data obtained from an affiliated national trauma summit and instruments found in literature, domains and items were co-produced with the help of trauma-informed care leads, NHS staff and service users. The research design consisted of community-based co-production methods such as surveys, focus groups, and expert consultations.

ResultsAdopting trauma-informed care requires enthusiasm and commitment from all members of the organisation. Services must adapt to meet the dynamic needs of staff and service users to ensure they remain trauma-informed; this must be done as a community.

ConclusionsFollowing an extensive co-production process, the Roots framework was published open-access and accompanied by a user manual. Roots can provide both qualitative and quantitative insights on trauma-informed care implementation by provoking the sharing of experience across services.

category: health systems and quality improvement


title: Understanding community level influences on COVID-19 prevalence in England: New insights from comparison over time and space

abstract:
The COVID-19 pandemic has impacted communities far and wide and put tremendous pressure on healthcare systems of countries across the globe. Understanding and monitoring the major influences on COVID-19 prevalence is essential to inform policy making and device appropriate packages of non-pharmaceutical interventions (NPIs).

This study evaluates community level influences on COVID-19 incidence in England and their variations over time with specific focus on understanding the impact of working in so called high-risk industries such as care homes and warehouses. Analysis at community level allows accounting for interrelations between socioeconomic and demographic profile, land use, and mobility patterns including residents self-selection and spatial sorting (where residents choose their residential locations based on their travel attitudes and preferences or social structure and inequality); this also helps understand the impact of policy interventions on distinct communities and areas given potential variations in their mobility, vaccination rates, behavioural responses, and health inequalities. Moreover, community level analysis can feed into more detailed epidemiological and individual models through tailoring and directing policy questions for further investigation.

We have assembled a large set of static (socioeconomic and demographic profile and land use characteristics) and dynamic (mobility indicators, COVID-19 cases and COVID-19 vaccination uptake in real time) data for small area statistical geographies (Lower Layer Super Output Areas, LSOA) in England making the dataset, arguably, the most comprehensive set assembled in the UK for community level analysis of COVID-19 infection. The data are integrated from a wider range of sources including telecommunications companies, test and trace data, national travel survey, Census and Mid-Year estimates.

To tackle methodological challenges specifically accounting for highly interrelated influences, we have augmented different statistical and machine learning techniques. We have adopted a two-stage modelling framework: a) Latent Cluster Analysis (LCA) to classify the country into distinct land use and travel patterns, and b) multivariate linear regression to evaluate influences at each distinct travel cluster. We have also segmented our data into different time periods based on changes in policies and evolvement in the course of pandemic (such as the emergence of a new variant of the virus). By segmenting and comparing influences across spaces and time, we examine more homogeneous behaviour and uniform distribution of infection risks which in turn increase the potential to make causal inferences and help understand variations across communities and over time. Our findings suggest that there exist significant spatial variations in risk influences with some being more consistent and persistent over time. Specifically, the analysis of industrial sectors shows that communities of workers in care homes and warehouses and to a lesser extent textile and ready meal industries tend to carry a higher risk of infection across all spatial clusters and over the whole period we modelled in this study. This demonstrates the key role that workplace risk has to play in COVID-19 risk of outbreak after accounting for the characteristics of workers residential area (including socioeconomic and demographic profile and land use features), vaccination rate, and mobility patterns.

category: health informatics


title: EMS responses to hospice patients: a qualitative study

abstract:
1In the palliative care community, multiple emergency department visits and hospitalizations are considered an indicator of poor-quality end of life care. There is substantial research on the events surrounding ED visits, and subsequent hospitalizatons, by hospice patients. It is important however to understand that these hospital arrivals often begin with an ambulance response to the home. Emergency medical services (EMS) responses to hospice patients have been less well-studied. We conducted a retrospective study of 170 consecutive electronic patient care reports produced contemporaneously by EMS providers in several US counties during the normal course of their responses to hospice patients. We summarized descriptive epidemiology of the patients and of the incidents, and we explored the provider narratives for recurring themes. To our knowledge this is the first study to explore the contemporaneously-documented on-scene circumstances of pre-hospital care for patients enrolled in a hospice program.

The median patient age was 76. Cancer, chronic lung disease, and heart failure were the most common hospice-qualifying diagnoses. Transportation of the patient from the scene occurred in 111 cases (65.3%). Consistent with previous studies based on interviews of EMS providers, the most common chief complaints included pain, dyspnea, and altered mental status. EMS was frequently called for confirmation of death, a finding not previously reported.

Transitions of care, such as from curative medical care to hospice care, and from hospital to home, were a recurring theme. Gaps in care around these transitions were often evident, with EMS being called upon to fill them. Care transitions around weekends were prominent. Also emerging from the narratives was the concept that hospice enrollment is not a single event but rather a step-wise process; we developed a preliminary coding taxonomy to classify those enrollment stages.

The hospice-EMS interface can be complex. Although all care by EMS providers is with the literal or implied consent of the patient, the arrival of an ambulance to a scene where emotions are running high carries a certain momentum and could lead to a cascade of interventions that, in retrospect and given other options, the patient may not have wanted. A better understanding of the hospice-EMS interface might illuminate changes that could be made to improve it, with a goal of ensuring that hospice patients and their families receive emergency medical services when they need and can benefit from them but receive other, non-EMS, services when those are more suitable to their needs. It might also improve the efficiency of an already overburdened EMS system.

category: emergency medicine


title: Ambient Temperature and Dengue Hospitalisation in Brazil over a 10-year period, 2010-2019: a times series analysis

abstract:
BackgroundClimate factors are known to influence seasonal patterns of dengue transmission. However, little is known about the effect of extreme heat on the severity of dengue infection, such as hospital admission. We aimed to quantify the effect of ambient temperature on dengue hospitalisation risk in Brazil.

MethodsWe retrieved daily dengue hospitalisation counts by each of 5,570 municipalities across the 27 states of Brazil from 1st of January 2010 to 31st of December 2019, from the Brazilian Public Hospital Admission System ("SIH"). We obtained average daily ambient temperature for each municipality from the ERA5-land product reanalysis. We combined distributed lag non-linear models with time stratified design model framework to pool an estimate for dose-response and lag-response structures for the association of Dengue hospitalisation relative risk (RR) and temperature. We estimated the overall dengue hospitalisation RR for the whole country as well as for each of the five macro-regions by meta-analysing state level estimates.

Findings579,703 hospital admissions due to dengue occurred over the 10 years period of 2010 to 2019. We observed a positive association between high temperatures and high risk of hospitalisation for Brazil and each of the five macro-regions. The overall RR for dengue hospitalisation was at the 50th percentile of temperature distribution 1{middle dot}40 (95% IC 1{middle dot}27-1{middle dot}54) and at 95th percentile of temperature the RR was 1{middle dot}50 (1{middle dot}38-1{middle dot}66) for Brazil, relative to the minimum temperature, which was the one with the lowest risk. We also found lagged effects of heat on hospitalisation, particularly observed on the same day (lag 0) both at the 50th percentile and 95th.

InterpretationHigh temperatures are associated with an increase in the risk of hospitalisation by dengue infection. These findings may guide preparedness and mitigation policies during dengue season outbreaks, particularly on the health-care demand.

FundingConselho Nacional de Pesquisa, Coordenacao Nacional de Aperfeicoamento de Pessoal, Institut de Salud Carlos III.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTemperature can have an effect of aggravating a dengue infection progressing to severe disease requiring hospitalisation. On February 12, 2022, we searched PudMed for the terms "dengue", "severe or hospital" and "temperature or heat". Although there is extensive literature on the association of temperature and number of dengue cases, we did not find any study quantifying the association of ambient temperature and hospitalisation by dengue. Quantitative evidence on this association, and how the extreme high temperature augments the risk of hospitalisation by dengue is needed to guide plans of mitigation and preparedness.

Added value of this studyOur findings show that heat can aggravate an on-going infection of Dengue virus leading to hospitalisation. Average temperatures above 23.96{degrees} Celsius degrees, the 50th percentile of temperature distribution over Brazil, represents a risk of over 1.3x to the Minimum Hospitalisation Temperature. An average temperature of 28.68{degrees} Celsius degrees, the 95th percentile of temperature distribution, represents a risk of hospitalisation of over 1.4x to the Minimum Hospitalisation Temperature. The South region, which does not have a high incidence of Dengue cases and a colder climate compared to other regions, has a temperature-related risk of hospitalisation of greater magnitude compared to other regions.

Implications of all the available evidenceHeat exposure plays an important role to the public health policy for mitigating dengue virus burden on the population. Hospitalisation is costly to any health system and can be more impacting on fragile or unprepared health systems as frequently found in countries affected by dengue. Due to its hyperendemicity and its seasonality, dengue can be predicted in mid to long term allowing for better designed early-warnings systems to mitigation measures.


title: Estimation of the morbidity and mortality of congenital Chagas disease: a systematic review and meta-analysis

abstract:
Chagas disease is caused by the parasite Trypanosoma cruzi which can be transmitted from mother to baby during pregnancy. There is no consensus on the proportion of infected infants that become symptomatic for congenital Chagas disease (cCD). The objective of this systematic review is to determine the burden of cCD.

Articles from journal inception to 2020 reporting morbidity and mortality associated with cCD were retrieved from academic search databases. Observational studies, randomized-control trials, and studies of babies diagnosed with cCD were included. Studies were excluded if they were case reports or series, without original data, case-control without cCD incidence estimates, and/or did not report number of participants. Two reviewers screened articles for inclusion. To determine pooled proportion of symptomatic infants with cCD, individual symptoms, and case-fatality, random effects meta-analysis was performed.

We identified 4,531 records and reviewed 4,301, including 47 articles in the narrative summary and analysis. 28.3% (95% confidence interval (CI) = 19.0%, 38.5%); of cCD infants were symptomatic and 2.2% of infants died (95% CI = 1.3%, 3.5%). The proportion of infected infants with hepatosplenomegaly was 12.5%, preterm birth 6.0%, low birth weight 5.8%, anemia 4.9%, and jaundice 4.7%. Although most studies did not include a comparison group of non-infected infants, the proportion of infants with cCD symptomatic at birth are comparable to those with congenital toxoplasmosis (10.0%-30.0%) and congenital cytomegalovirus (10.0%-15.0%).

We conclude that cCD burden appears significant, but more studies comparing infected mother-infant dyads to non-infected ones are needed to determine an association of this burden to cCD infection.

Author summaryChagas disease is caused by the parasite Trypanosoma cruzi, which can be passed from mother to infant. It is estimated that one million women of reproductive age are infected with T. cruzi. Prior to our work, the proportion of infants infected with T. cruzi congenitally presenting with clinical symptoms was unknown. After systematically searching for and identifying studies that collected information on infants with congenital Chagas disease, we summarized and analyzed 47 studies. Our pooled analysis of these studies estimated that 28.3% of infants with congenital Chagas disease were symptomatic and 2.2% died. Prior work has shown that transmission of T. cruzi from mother to child occurs in 5% of cases. Other studies have shown that this transmission is preventable through treatment of women prior to conception, and infants can be cured if shown to be infected at birth. Our estimated proportion of 28.3% of infants diagnosed with cCD at birth presenting with clinical symptoms are comparable to infants diagnosed with congenital toxoplasmosis presenting with clinical symptoms (10.0%-30.0%) and congenital cytomegalovirus (10.0%-15.0%). More studies comparing infected mother-infant dyads to non-infected mother-infant dyads are needed to determine an association of this burden to cCD infection.


title: Alpha-1 adrenoreceptor antagonism mitigates extracellular mitochondrial DNA accumulation in lung fibrosis models and in patients with IPF

abstract: Idiopathic Pulmonary Fibrosis is increasingly associated with adrenergic innervation and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here we report that noradrenaline (NA) derived from the lungs adrenergic nerve supply drives the accumulation of SMA-expressing fibroblasts via a mechanism involving 1 adrenoreceptors and mtDNA. Using the bleomycin model of lung fibrosis we compared the effect of lung specific adrenergic denervation achieved via the inhalational administration of the sympathetic neurotoxin 6-hydroxydopamine to surgically mediated adrenal ablation and found that NA derived from local but not adrenal sources drives lung fibrosis. Bleomycin induced the appearance of a SMA+ fibroblast population co-expressing the adrenoreceptor alpha-1D (ADRA1D). Therapeutic delivery of the 1 adrenoreceptor antagonist terazosin reversed these changes and suppressed the accumulation of extracellular mtDNA. TGF{beta}1-stimulated normal human lung fibroblasts treated with TGF{beta}1 and Noradrenaline expressed ADRA1D and developed reduced SMA expression and extracellular mtDNA concentrations when treated with terazosin. IPF patients prescribed 1 adrenoreceptor antagonists for non-pulmonary indications showed improved survival and reduced concentrations of plasma mtDNA. These findings link nerve-derived NA and 1 adrenoreceptor antagonism with mtDNA accumulation and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuro-innate connection may yield new avenues for investigation in the clinical and basic science realms.

category: respiratory medicine


title: Beyond Common Outcomes: Clients' Perspectives on the Benefits of Prenatal Care Coordination

abstract: Prenatal Care Coordination (PNCC) is a fee-for-service Medicaid benefit available in Wisconsin and several other states. It provides for home visiting, health education, care coordination and other supportive services to high-risk mothers. However, PNCC is not supported by an evidence-based model, its impact is not systematically evaluated, and the benefit is not currently reaching all eligible mothers. The purpose of this qualitative descriptive study was to describe PNCC clients perspectives on the experience of receiving the PNCC benefit and the value and impact of PNCC in the context of their own lives. We interviewed recent clients of PNCC programs in two PNCC sites that varied by racial/ethnic community makeup, rural/urban geography, and health department size. PNCC clients identified two major benefits of PNCC: 1) social and emotional support from the PNCC nurse; and 2) assistance with obtaining or getting connected to other resources they needed. These two program benefits were especially meaningful to PNCC clients in the context of difficult life events and circumstances. Findings from this study highlight the impact of PNCC services on social and emotional health through trusting and supportive nurse-client relationships. Our findings also suggest that a longer program period and the development of standards to assess program effectiveness would improve PNCC client outcomes and reduce disparities in maternal health.

category: nursing


title: The Influence of Pregnancy on PrEP uptake and Adherence Amongst HIV-Negative High-Risk Young Women in Kampala, Uganda: A Qualitative Assessment

abstract:
BackgroundPregnant young women who engage in high-risk sexual activity are at elevated biological and social risk for HIV acquisition. PrEP serves as an effective means of HIV prevention, including during pregnancy. This study aimed to explore attitudes, experiences and challenges with PrEP to understand what motivates or limits PrEP uptake and adherence during pregnancy among this population of young women.

MethodsSemi-structured interviews were conducted with 23 participants, recruited from the Prevention on PrEP (POPPi) study in the Good Health for Women Project clinic in Kampala, Uganda. POPPis inclusion criteria comprised of HIV-uninfected women, aged 15-24, who engaged in high-risk sexual activity. Interviews focused on experience with PrEP and pregnancy. Data were analyzed utilizing a framework analysis approach.

FindingsKey themes were comprised of participant barriers to and facilitators of PrEP uptake and adherence. Reasons for PrEP initiation included desire for autonomy and agency, mistrust of partners, and social support. Participants expressed challenges with initiating or sustaining their use of PrEP, including PrEP access and perceived or felt stigma. During pregnancy, participants primary motivators for altering PrEP use were either understanding of PrEP safety for their baby or changes in perceptions of their HIV risk. Many of these factors were similar across participants who had experience with pregnancy and those who did not.

InterpretationThis study highlights the importance of addressing barriers to and facilitators of PrEP adherence, especially during pregnancy where risk is elevated, with a multi-level approach. Community-oriented education, stigma reduction activities alongside access to PrEP, can serve as means for adherence. The development of robust PrEP adherence support guidelines regarding PrEP use during pregnancy among high-risk women, and strategies for their implementation, are of utmost importance for the control of HIV in key populations and the elimination of mother-to-child transmission of HIV.

category: hiv aids


title: Anti-inflammatory therapy with nebulised dornase alfa in patients with severe COVID-19 pneumonia

abstract:
BackgroundSARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) DNA is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-DNA clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia.

MethodsIn this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation ([≥]94%) on supplementary oxygen and a C-reactive protein (CRP) level [≥]30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA.

ResultsWe screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96g/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported.

ConclusionsIn this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials.


title: Anti-inflammatory therapy with nebulised dornase alfa in patients with severe COVID-19 pneumonia. A Randomised Clinical Trial.


title: A Sepsis Treatment Algorithm to Improve Early Antibiotic De-escalation While Maintaining Adequacy of Coverage (Early-IDEAS): A Prospective Observational Study

abstract:
BackgroundEmpiric antibiotic treatment selection should provide adequate coverage for potential pathogens while minimizing unnecessary broad-spectrum antibiotic use. We sought to pilot a rule- and model-based early sepsis treatment algorithm (Early-IDEAS) to make optimal individualized antibiotic recommendations.

MethodsThe Early-IDEAS decision support algorithm was derived from previous Gram-negative and Gram-positive prediction rules and models. The Gram-negative prediction consists of multiple parametric regression models which predict the likelihood of susceptibility for each commonly used antibiotic for Gram-negative pathogens, based on epidemiologic predictors and prior culture results and recommends the narrowest spectrum agent that exceeds a predefined threshold of adequate coverage. The Gram-positive rules direct the addition or cessation of vancomycin based on prior culture results. We applied the algorithm to prospectively identified consecutive adults within 24-hours of suspected sepsis. The primary outcome was the proportion of patients for whom the algorithm recommended de-escalation of the primary antibiotic regimen. Secondary outcomes included: (1) the proportion of patients for whom escalation was recommended; (2) the number of recommended de-escalation steps along a pre-specified antibiotic cascade; and (3) the adequacy of therapy in the subset of patients with culture-confirmed infection.

ResultsWe screened 578 patients, of whom 107 eligible patients with sepsis were included. The Early-IDEAS treatment recommendation was informed by Gram-negative models in 76 (71%) of patients, Gram-positive rules in 66 (61.7%), and local guidelines in 27 (25%). Antibiotic de-escalation was recommended by the algorithm in almost half of all patients (n=50, 47%), no treatment change was recommended in 48 patients (45%), and escalation was recommended in 9 patients (8%). Amongst the patients where de-escalation was recommended, the median number of steps down the a priori antibiotic treatment cascade was 2. Among the 17 patients with relevant culture-positive blood stream infection, the clinician prescribed regimen provided adequate coverage in 14 (82%) and the algorithm recommendation would have provided adequate coverage in 13 (76%), p=1. Among the 25 patients with positive relevant (non-blood) cultures, the clinician prescribed regimen provided adequate coverage in 22 (88%) and the algorithm recommendation would have provided adequate coverage in 21 (84%), p=1.

ConclusionsAn individualized decision support algorithm in early sepsis could lead to substantial antibiotic de-escalation without compromising adequate antibiotic coverage.


title: Evaluation of machine learning for predicting COVID-19 outcomes from a national electronic medical records database

abstract:
ObjectiveWhen novel diseases such as COVID-19 emerge, predictors of clinical outcomes might be unknown. Using data from electronic medical records (EMR) allows evaluation of potential predictors without selecting specific features a priori for a model. We evaluated different machine learning models for predicting outcomes among COVID-19 inpatients using raw EMR data.

Materials and MethodsIn Premier Healthcare Data Special Release: COVID-19 Edition (PHD-SR COVID-19, release date March, 24 2021), we included patients admitted with COVID-19 during February 2020 through April 2021 and built time-ordered medical histories. Setting the prediction horizon at 24 hours into the first COVID-19 inpatient visit, we aimed to predict intensive care unit (ICU) admission, hyperinflammatory syndrome (HS), and death. We evaluated the following models: L2-penalized logistic regression, random forest, gradient boosting classifier, deep averaging network, and recurrent neural network with a long short-term memory cell.

ResultsThere were 57,355 COVID-19 patients identified in PHD-SR COVID-19. ICU admission was the easiest outcome to predict (best AUC=79%), and HS was the hardest to predict (best AUC=70%). Models performed similarly within each outcome.

DiscussionAlthough the models learned to attend to meaningful clinical information, they performed similarly, suggesting performance limitations are inherent to the data.

ConclusionPredictive models using raw EMR data are promising because they can use many observations and encompass a large feature space; however, traditional and deep learning models may perform similarly when few features are available at the individual patient level.


title: Level and duration of IgG and neutralizing antibodies to SARS-CoV-2 in children with symptomatic or asymptomatic SARS-CoV-2 infection

abstract:
BackgroundThere are presently conflicting data about level and duration of antibodies to SARS-CoV-2 in children after symptomatic or asymptomatic infection.

MethodsWe enrolled adults and children in a prospective 6-month study in the following categories: 1) symptomatic, SARS-CoV-2 PCR+ (SP+; children, n=8; adults, n=16), 2) symptomatic, PCR- or untested (children, n=27), 3) asymptomatic exposed (children, n=13) and 4) asymptomatic, no known exposure (children, n=19). Neutralizing and IgG antibodies to SARS-CoV-2 antigens and Spike protein variants were measured by multiplex serological assays.

ResultsAll SP+ children developed nAb, whereas 81% of SP+ adults developed nAb. Decline in the presence of nAb over 6 months was not significant in symptomatic children (100% to 87.5%, p=0.32) in contrast to adults (81.3 to 50.0%, p=0.03). Among all children with nAb (n=22), nAb titers and change in titers over 6 months were similar in symptomatic and asymptomatic children. Levels of IgG antibodies in children to the SARS-CoV-2 Spike, RBD-1 and -2, nucleocapsid and N-terminal domain antigens and to Spike protein variants were similar to those in adults. IgG levels to primary antigens decreased over time in both children and adults, but levels to three of six Spike variants decreased only in children.

ConclusionsChildren with asymptomatic or symptomatic SARS-CoV-2 infection develop robust neutralizing antibodies that remain present longer than in adults but wane in titer over time, and broad IgG antibodies that also wane in level over time.

Key PointsChildren have robust neutralizing and IgG antibody responses to SARS-CoV-2 infection after symptomatic or asymptomatic disease that are at least as strong as in adults. Neutralizing antibodies in children last longer than in adults but wane over time.


title: Development of highly specific singleplex and multiplex real-time reverse transcription PCR assays for the identification of SARS-CoV-2 Omicron BA.1, BA.2 and Delta variants

abstract: The Omicron variant of SARS-CoV-2 (B.1.1.529), first identified during November 2021, is rapidly spreading throughout the world, replacing the previously dominant Delta variant. Omicron has a high number of mutations in the spike gene, some of which are associated with greatly increased transmissibility and immune evasion. The BA.1 sublineage has been most prevalent but there is recent evidence that the BA.2 sublineage is increasing in proportion in many countries. Genome sequencing is the gold standard for Omicron identification but is relatively slow, resource intensive, of limited capacity and often unavailable. We therefore developed a simple, rapid reverse transcription PCR (RT-PCR) method for sensitive and specific detection of the Omicron variant, including both the BA.1 and BA.2 sublineages. The assay targets a total of 5 nucleotide mutations in the receptor binding domain of the spike gene that give rise to 4 amino acid substitutions at G339D, S371L, S373P and S375F. The forward primer was designed as a double-mismatch allele specific primer (DMAS) with an additional artificial mismatch located four nucleotides from the 3 end to enhance binding specificity. Assay specificity was confirmed by testing a wide range of previously-sequenced culture-derived viral isolates and clinical samples including the Alpha, Beta and Delta variants and  wild type SARS-CoV-2. Respiratory syncytial virus and influenza A were also tested. The assay can be run in singleplex format, or alternatively as a multiplex RT-PCR to enable Omicron and Delta variants to be detected and distinguished within the same reaction by means of probes labelled with different fluorescent dyes. Sublineages BA.1 and BA.2 can be differentiated if required. The methods presented here can readily be established in any PCR laboratory and should provide valuable support for epidemiologic surveillance of Omicron infections, particularly in those regions that lack extensive sequencing facilities.


title: Epidemiology of infections with SARS-CoV-2 Omicron BA.2 variant in Hong Kong, January-March 2022

abstract: Hong Kong reported 12,631 confirmed COVID-19 cases and 213 deaths in the first two years of the pandemic but experienced a major wave predominantly of Omicron BA.2.2 in early 2022 with over 1.1 million reported SARS-CoV-2 infections and more than 7900 deaths. Our data indicated a shorter incubation period, serial interval, and generation time of infections with Omicron than other SARS-CoV-2 variants. Omicron BA.2.2 cases without a complete primary vaccination series appeared to face a similar fatality risk to those infected in earlier waves with the ancestral strain.


title: Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition

abstract:
BackgroundEpidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.

MethodsWe analyzed targeted metabolomics data available for 5,828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites, and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data shared lasso penalty.

ResultsOut of the 50 studied metabolites, (i) six were inversely associated with risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2 and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk, and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk.

ConclusionsThese results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.


title: Unique Metabolic Profiles in South Asian Women Characterizes Gestational Diabetes in Low and High-Risk Women

abstract:
BackgroundGestational Diabetes Mellitus (GDM) is the most common pregnancy complication to occur worldwide, however prevalence varies substantially between ethnicities with South Asians experiencing up to 3-times the risk of the disease compared to white Europeans (WEs). Factors driving this discrepancy in prevalence and the pathogenesis of GDM are unclear, although the metabolome is of great importance due to the metabolic dysregulation characterised GDM.

ObjectiveTo characterise and distinguish the metabolic profiles of GDM in two distinct ethnic populations at < 28 weeks gestation.

Design146 fasting serum metabolite values, quantified by nuclear magnetic resonance, from 2668 pregnant WE and 2671 pregnant Pakistani (PK) women from the Born in Bradford (BIB) cohort, were analysed using partial least squares discriminatory analyses (PLSDA). The presence of a linear relationships between metabolite values and post-oral glucose tolerance test measures of dysglycemia (fasting glucose and 2-hour post glucose) were also examined.

ResultsSeven metabolites were associated with GDM status in both ethnicities, while 6 additional metabolites associated with GDM only in WE women. Unique metabolic profiles were observed in healthy weight women who later developed GDM, with distinct metabolite patterns identified by ethnicity and BMI status. Of the 146 metabolite values analysed in relation to dysglycemia, quantities of lactate, histidine, apolipoprotein A1, HDL cholesterol, HDL2 cholesterol, and DHA, as well as the diameter of very low density lipoprotein particles (nm) were associated with dysglycemia in WE women; while in PK women albumin alone associated with dysglycemia.

ConclusionThis is the first study to show that the metabolic risk profile for GDM differs between ethnicities and highlights a need for ethnically appropriate GDM prevention strategies.


title: Racial differences in white matter hyperintensity burden in aging, MCI, and AD

abstract: White matter hyperintensities may be one of the earliest pathological changes in aging and may potentially accelerate cognitive decline. Whether race influences WMH burden has been conflicting. The goal of this study was to examine if race differences exist in WMH burden and whether these differences are influenced by vascular factors [i.e., diabetes, hypertension, body mass index (BMI)]. Participants from the Alzheimers Disease Neuroimaging Initiative were included if they had a baseline MRI, diagnosis, and WMH measurements. Ninety-one Black and 1937 White individuals were included. Using bootstrap re-sampling, 91 Whites were randomly sampled and matched to Black participants based on age, sex, education, and diagnosis 1000 times. Linear regression models examined the influence of race on baseline WMHs with and without vascular factors: WMH [~] Race + Age + Sex + Education + BMI + Hypertension + Diabetes and WMH [~] Race + Age + Sex + Education. The 95% confidence limits of the t-statistics distributions for the 1000 samples were examined to determine statistical significance. All vascular risk factors had significantly higher prevalence in Black than White individuals. When not including vascular risk factors, Black individuals had greater WMH volume overall as well as in frontal and parietal regions, compared to White individuals. After controlling for vascular risk factors, no WMH group differences remained significant. These findings suggest that vascular risk factors are a major contributor to racial group differences observed in WMHs.

category: geriatric medicine


title: Pre-Pandemic COVID-19 in New York City: A descriptive analysis of COVID-19 illness prior to February 29, 2020

abstract:
BackgroundOn January 30, 2020 the COVID-19 pandemic was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization. Almost a month later on February 29, 2020, the first case in New York City (NYC) was diagnosed.

MethodsThree-hundred-sixty persons with COVID-like illness was reported to the NYC Department of Health and Mental Hygiene (DOHMH) before February 29, but 37 of these tested negative and 237 were never tested for SARS-COV-2. Records of 86 persons with confirmed COVID-19 and symptom onset prior to February 29, 2020 were reviewed by four physician-epidemiologists. Case-patients were classified as likely early onset COVID-19, or insufficient evidence to determine onset. Clinical and epidemiological factors collected by DOHMH and supplemented with emergency department records were analyzed.

ResultsThirty-nine likely early onset COVID-19 cases were identified. The majority had severe disease with 69% presenting to an ED visit within 2 weeks of symptom onset. The first likely COVID-19 case on record had symptom onset on January 28, 2020. Only 7 of the 39 cases (18%) had traveled internationally within 14 days of onset (none to China).

ConclusionsSARS-CoV-2 and COVID-19 was in NYC before being classified as a PHEIC, and eluded surveillance for another month. The delay in recognition limited mitigation effort and by the time that city and state-wide mandates were enacted 16 and 22 days later there was already community transmission.

Key PointsRecords of 86 persons with confirmed COVID-19 and symptom onset prior to February 29, 2020 were reviewed for likelihood of early onset COVID-19. Thirty-nine likely early onset COVID-19 cases were identified, suggesting that early COVID-19 transmission in NYC went undetected.


title: Beta infection combined with Pfizer BNT162b2 vaccination leads to broadened neutralizing immunity against Omicron

abstract: Omicron (B.1.1.529) shows extensive escape from vaccine immunity, although vaccination reduces severe disease and death1. Boosting with vaccines incorporating variant spike sequences could possibly broaden immunity2. One approach to choose the variant may be to measure immunity elicited by vaccination combined with variant infection. Here we investigated Omicron neutralization in people infected with the Beta (B.1.351) variant and subsequently vaccinated with Pfizer BNT162b2. We observed that Beta infection alone elicited poor Omicron cross-neutralization, similar to what we previously found3 with BNT162b2 vaccination alone or in combination with ancestral or Delta virus infection. In contrast, Beta infection combined with BNT162b2 vaccination elicited neutralization with substantially lower Omicron escape.


title: Immediate effect of osteopathic techniques on human resting muscle tone in healthy subjects using myotonometry: A factorial randomized trial

abstract:
BackgroundMusculoskeletal disorders (MSDs) are highly prevalent, burdensome, and putatively associated with an altered human resting muscle tone (HRMT). Osteopathic manipulative treatment (OMT) is commonly and effectively applied to treat MSDs and reputedly influences the HRMT. Arguably, OMT may modulate alterations in HRMT underlying MSDs. However, there is sparse evidence even for the effect of OMT on HRMT in healthy subjects.

MethodsA 3x3 factorial randomised trial was performed to investigate the immediate-term effect of myofascial release (MRT), muscle energy (MET), and soft tissue techniques (STT) on the HRMT of the corrugator supercilii (CS), superficial masseter (SM), and upper trapezius muscles (UT) in healthy subjects in Hamburg, Germany. Participants were randomised into three groups (1:1:1 allocation ratio) receiving treatment, according to different muscle-technique pairings, over the course of three sessions with one-week washout periods. Primarily, we assessed the effect of osteopathic techniques on muscle tone (F), biomechanical (S, D), and viscoelastic properties (R, C) from baseline to follow-up (main effect) and tested if specific muscle-technique pairs modulate the effect pre- to post-intervention (interaction effect) using the MyotonPRO (at rest). Data were analysed using descriptive (mean, standard deviation, quantiles, and simple effect) and inductive statistics (Bayesian ANOVA).

Results59 healthy participants were randomised into three groups and two subjects dropped out from one group (n=20; n=20; n=19 and n=17, respectively). The CS produced frequent measurement errors and was excluded from analysis. The main effect changed significantly for F (-0.163 [0.060]; p=0.008), S (-3.060 [1.563]; p=0.048), R (0.594 [0.141]; p<0.001), and C (0.038 [0.017]; p=0.028) but not for D (0.011 [0.017]; p=0.527). The interaction effect did not change significantly (p>0.05). No adverse events were reported.

ConclusionOMT modified the HRMT in healthy subjects which may inform future research on MSDs. In detail, MRT, MET, and STT reduced the muscle tone (F), decreased biomechanical (S not D), and increased viscoelastic properties (R and C) of the SM and UT (CS was not measurable) at immediate term. However, the effect on HRMT was not modulated by muscle-technique interaction.

Trial registrationGerman Clinical Trial Register (DRKS00020393).

category: primary care research


title: Investigating direct and indirect genetic effects in attention deficit hyperactivity disorder (ADHD) using parent-offspring trios

abstract:
BackgroundAttention deficit hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e. direct) and non-transmitted (i.e. indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is over-transmitted to ADHD probands. We also tested for indirect or  genetic nurture effects, by examining whether non-transmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative.

MethodsPolygenic risk scores (PRS) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder (OCD), schizophrenia, Tourettes syndrome, and cognitive ability were calculated in UK controls (N=5,081), UK probands with ADHD (N=857), and, where available, their biological parents (N=328 trios), and also a replication sample of 844 ADHD trios.

ResultsADHD PRS were over-transmitted and cognitive ability and OCD PRS were under-transmitted to probands. These results were independently replicated. Over-transmission of polygenic liability was not observed for other disorders. Non-transmitted alleles were not enriched for ADHD liability compared to controls. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status.

ConclusionsThe results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that non-transmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be non-random, in terms of demographic and clinical factors.

category: psychiatry and clinical psychology


title: Prioritisation of Informed Health Choices (IHC) Key Concepts to be included in lower-secondary school resources: a consensus study

abstract:
BackgroundThe Informed Health Choices Key Concepts are principles for thinking critically about healthcare claims and deciding what to do. The Key Concepts provide a framework for designing curricula, learning resources, and evaluation tools.

ObjectivesTo prioritise which of the 49 Key Concepts to include in resources for lower-secondary schools in East Africa.

MethodsTwelve judges used an iterative process to reach a consensus. The judges were curriculum specialists, teachers, and researchers from Kenya, Uganda, and Rwanda. After familiarising themselves with the concepts, they pilot tested draft criteria for selecting and ordering the concepts. After agreeing on the criteria, nine judges independently assessed all 49 concepts and reached an initial consensus. We sought feedback on the draft consensus from teachers and other stakeholders. After considering the feedback, nine judges independently reassessed the prioritised concepts and reached a consensus. The final set of concepts was determined after user-testing prototypes and pilot-testing the resources.

ResultsThe first panel prioritised 29 concepts. Based on feedback from teachers, students, curriculum developers, and other members of the research team, two concepts were dropped. A second panel of nine judges prioritised 17 of the 27 concepts. Due to the Covid-19 pandemic and school closures, we have only been able to develop one set of resources instead of two, as originally planned. Based on feedback on prototypes of lessons and pilot-testing a set of 10 lessons, we determined that it was possible to introduce nine concepts in 10 single-period (40 minute) lessons. We included eight of the 17 prioritised concepts and one additional concept.

ConclusionUsing an iterative process with explicit criteria, we prioritised nine concepts as a starting point for students to learn to think critically about healthcare claims and choices.


title: Epidural stimulation of the cervical spinal cord improves voluntary motor control in post-stroke upper limb paresis

abstract: A large proportion of cerebral strokes disrupt descending commands from motor cortical areas to the spinal cord which can results in permanent motor deficits of the arm and hand1,2. However, below the lesion, the spinal circuits that control movement5 remain intact and could be targeted by neurotechnologies to restore movement6-9. Here we demonstrate that by engaging spinal circuits with targeted electrical stimulation we immediately improved voluntary motor control in two participants with chronic post-stroke hemiparesis. We implanted a pair of 8-contact percutaneous epidural leads on the lateral aspect of the cervical spinal cord to selectively target the dorsal roots that provide excitatory inputs to motoneurons controlling the arm and hand10,11. With this strategy, we obtained independent activation of shoulder, elbow and hand muscles. Continuous stimulation through selected contacts at specific frequencies enabled participants to perform movements that they had been unable to perform for many years. Overall, stimulation improved strength, kinematics, and functional performance. Unexpectedly, both participants retained some of these improvements even without stimulation, suggesting that spinal cord stimulation could be a restorative as well as an assistive approach for upper limb recovery after stroke.

category: rehabilitation medicine and physical therapy


title: The "Trauma Pitch": How stigma emerges for Iraq and Afghanistan veterans seeking disability compensation

abstract: Posttraumatic Stress Disorder continues to be a highly stigmatized disease for the veteran population and stigma continues to be identified as the main deterrent in treatment seeking. Little attention has been paid to how the process of obtaining service-connected disability status can amplify veterans perceptions of being stigmatized. The following ethnographic study identified how combat veterans experienced stigma in processing through Veterans Affairs care and the effects of linking a Posttraumatic Stress Disorder diagnosis with disability compensation to perceived stigmas. Stigma was identified in two inter-related areas: 1) the structural level in the Veterans Affairs disability claims process and 2) the individual level in interactions with Veterans Affairs service providers. Results based on veterans narratives suggest that the disability claims process, requiring multiple repetitions of personal trauma, coupled with perceptions of institutional stigmas of malingering, created bureaugenic effects: a worsening of symptoms caused by bureaucratic protocols intended to help veterans. This process influenced first time treatment users of the Veterans Affairs by deterring treatment-seeking behavior but was not found to affect veterans who had already initiated treatment. Despite the experience of stigma and commodification of their suffering through disability and diagnostic screening, veterans still sought disability compensation. Veterans viewed this compensation as acknowledgment of their loss and validation of their sacrifice.

category: medical ethics


title: Significance and clinical suggestions for the Somatosensory Evoked Potentials increased in amplitude revealed by a large sample of neurological patients

abstract:
ObjectivesTo investigate the relationship between N20-P25 peak-to-peak amplitude (N20p-P25p) of Somatosensory Evoked Potentials (SEPs) and the occurrence of abnormalities of the peripheral and/or central sensory pathways and of myoclonus/epilepsy, in 308 patients with increased SEPs amplitude from upper limbs stimulation

MethodsWe compared cortical response (N20p-P25p) in different groups of patients identified by demographic, clinical and neurophysiological factors and performed a cluster analysis for classifying the natural occurrence of subgroups of patients.

ResultsNo significant differences of N20p-P25p were found among different age-dependent groups, and in patients with or without PNS/CNS abnormalities of sensory pathways, while myoclonic/epileptic patients showed higher N20p-P25p than other groups. Cluster analysis identified four clusters including patients with myoclonus/epilepsy, patients with central sensory abnormalities, patients with peripheral sensory abnormalities, patients with neither myoclonus nor sensory abnormalities.

ConclusionsIncreased N20p-P25p correlated to different pathophysiological conditions: strong cortical hyperexcitability in patients with cortical myoclonus and/or epilepsy and enlarged N20p-P25p, while milder increase of N20p-P25p could be underpinned by plastic cortical changes following abnormalities of sensory pathways, or degenerative process involving the cortex. SEPs increased in amplitude cannot be considered a specific correlated for myoclonus/epilepsy, but it in several neurological disorders may represent a sign of adaptive, plastic and/or degenerative cortical changes.


title: Elevated plasma phosphorylated tau in amyotrophic lateral sclerosis relates to lower motor neuron dysfunction

abstract:
ObjectivePlasma phosphorylated tau (p-tau181) is reliably elevated in Alzheimers disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau181 is elevated in amytrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed clinical evaluation to unravel the potential source of this unexpected observation.

MethodsPatients were clinically or pathologically diagnosed with ALS (n=130) or AD (n=82), or were healthy non-impaired controls (n=33). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron (UMN) and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss.

ResultsA Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W=3297, p=0.0000020), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC=0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W=827, p=0.0072), thoracic (W=469, p=0.00025), and lumbosacral regions (W=851, p=0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho=0.46, p=0.017), but not in the motor cortex (p=0.41). CSF p-tau181 and plasma neurofilament light chain (NfL) were included as reference analytes, and demonstrate specificity of findings.

InterpretationWe found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction.


title: Characteristics of Patients with Hematologic Malignancies Without Seroconversion Post-COVID19 Third Vaccine Dosing

abstract: Patients with hematologic malignancies (HM) are at greater risk of severe morbidity and mortality caused by COVID19 and show a lower response to a two-dose COVID19 mRNA vaccine series. The primary objective of this retrospective cohort study is to explore the characteristics of the subset of patients with HM who had little to no change in SARS-CoV-2 spike antibody titer levels after a 3rd vaccine dose (3V) (-/-). As a secondary objective, we seek to compare the cohorts of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. A total of 625 patients with HM had two titer results at least 21 days apart pre- and post- the 3V dose. Among the participants who were seronegative prior to 3V (268), 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. HM diagnosis was significantly associated with seroconversion status (P = .0003) with patients non-Hodgkin lymphoma 6 times the odds of not seroconverting compared to multiple myeloma patients (P = .0010). Among the cohort of patients who remained seronegative post-3V, 107 (90.0%) patients showed no reaction to 3V as indicated by pre- and post- 3V index values. This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V, providing much needed data for clinicians to target and counsel this subset of patients.

category: oncology


title: The contribution of genetic risk to the comorbidity of depression and anxiety: a multi-site electronic health records study

abstract:
ImportanceDepression and anxiety are common and highly comorbid, posing a clinical and public health concern because such comorbidity is associated with poorer outcomes.

ObjectiveTo evaluate association of genetic risk scores with depression and anxiety diagnosis either in isolation or comorbid with each other.

DesignInternational Classification of Diseases (ICD) ninth and tenth edition codes were extracted from longitudinal electronic health records (EHR) from four EHR-linked biobanks with genetic data available. Data analysis was performed between February 2021 to October 2021.

SettingEHR-linked biorepository study.

ParticipantsAcross the four biobanks, 140947 patients (80601 female [57.2%] including 109592 European ancestry [77.8%], 22321 African ancestry [15.8%], and 9034 Hispanic [6.4%]) were included in the study.

Main outcomes and measuresPolygenic risk scores (PRS) for depression and anxiety were computed for all participants. They were assessed for diagnosis of depression and anxiety using ICD9/10 codes. The primary outcome was a four-level depression/anxiety diagnosis group variable: neither, depression-only, anxiety-only, and comorbid. Estimated effect measures include odds ratios and the proportion of variance on the liability scale explained by the PRS.

Results95992 patients had neither diagnosis (68.1%), 14918 depression-only (10.6%), 12682 anxiety-only (9.0%), and 17355 comorbid (12.3%). PRS for depression and anxiety predicted their respective diagnoses within each biobank and each ancestry with the exception of anxiety-PRS not predicting anxiety in any ancestral group from one biobank. In the meta-analysis across participants of European ancestries, both PRSs for depression and anxiety were higher in each diagnosis group compared to controls. Notably, depression-PRS (OR=1.20 per SD increase in PRS; 95% CI= 1.18-1.23) and anxiety-PRS (OR=1.07; 95% CI=1.05-1.09) had the largest effect size for the comorbid group when compared to controls. The confidence interval for the depression-PRS effect did not overlap across groups demonstrating a gradient of genetic risk across the four diagnosis groups.

Conclusions and RelevanceThe genetic risk of depression and anxiety make distinct contributions to the risk of comorbid depression and anxiety, supporting the hypothesis that the correlated disorders represent distinct nosological entities.

Key PointsO_ST_ABSQuestionC_ST_ABSIs the genetic risk of depression and anxiety associated with comorbidity of depression and anxiety?

FindingsUsing electronic health records from four academic medical centers, this study found that genetic risk of depression and anxiety are jointly associated with clinical depression and anxiety diagnoses with better prediction occurring for a diagnosis of depression.

MeaningThe genetic risk of depression and anxiety make distinct contributions to comorbid depression and anxiety, which supports the hypothesis that the correlated disorders represent distinct nosological entities.


title: Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

abstract:
BackgroundThe 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive.

MethodsWe analyzed gene expression using blood from 3 individuals with 15q13.3 microdeletion and brain cortex tissue from 10 mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein-protein interaction (PPI) functional modules, and gene expression in brain developmental stages.

ResultsThe deleted genes haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a singular critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development.

ConclusionsWe show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.


title: Allelic expression imbalance in articular cartilage and subchondral bone refined genome-wide association signals in osteoarthritis.

abstract: Osteoarthritis (OA) is an age-related joint disease with a strong and complex genetic component. Genome-wide association studies (GWAS) discovered a large number of genomic regions associated with OA. Nevertheless, to link associated genetic variants affecting the expression of OA-risk genes in relevant tissues remains a challenge. Here, we showed an unbiased approach to identify transcript single nucleotide polymorphisms (SNPs) of OA risk loci by allelic expression imbalance (AEI). We used RNA sequencing of articular cartilage (N = 65) and subchondral bone (N= 24) from OA patients. AEI was determined for all genes present in the 100 regions reported by GWAS catalog. The count fraction of the alternative allele ({varphi}) was calculated for each heterozygous individual with the risk-SNP or with the SNP in linkage disequilibrium (LD) with it. Furthermore, a meta-analysis was performed to generate a meta-{varphi} (null hypothesis median {varphi}=0.49) and P-value for each SNP. We identified 30 transcript SNPs subject to AEI (28 in cartilage and 2 in subchondral bone). Notably, 10 transcript SNPs were located in genes not previously reported in the GWAS catalogue, including two long intergenic non-coding RNAs (lincRNAs), MALAT1 (meta-{varphi}=0.54, FDR=1.7x10-4) and ILF3-DT (meta-{varphi}=0.6, FDR=1.75x10-5). Moreover, 14 drugs were interacting with 7 genes displaying AEI, of which 7 drugs has been already approved. By prioritizing proxy transcript SNPs that mark AEI in cartilage and/or subchondral bone at loci harboring GWAS signals, we present an unbiased approach to identify the most likely functional OA risk-SNP and gene. We identified 10 new potential OA risk genes ready for further, translation towards underlying biological mechanisms.


title: Art therapy as treatment modality for persons living with dementia- a protocol for a scoping review of systematic reviews

abstract:
ObjectiveTo establish a robust understanding of the state of the evidence on the effectiveness and/or efficacy of art therapy (AT) as a non-pharmacological treatment (NPT) modality for persons living with dementia (PLWD).

BackgroundOver the past decade, AT has received increased attention from health care professionals and researchers as having a potential role to play within treatment plans for PLWD.(1-4)

Inclusion criteriaThis scoping review will include systematic reviews from health-related disciplines conducted within the last 20 years that report the effectiveness and/or efficacy of AT as an NPT modality for PLWD and Mild Cognitive Impairment (MCI). Study outcomes must include cognition, quality of life, emotional and psychological well-being, and/or neuropsychiatric symptoms (NPS).

MethodsA scoping review of systematic reviews was selected to outline different types of evidence and to identify gaps in the literature. The proposed review will be guided by the methodological framework proposed by the Joanna Briggs Institute. We will therefore specify the research question, identify relevant studies, select eligible studies, extract, collate, and summarize our results. We will not conduct a quality appraisal of the included studies as this review aims to explore the general scope of research conducted that assesses AT effectiveness and efficacy in PLWD.


title: Using Facebook groups to support families: midwives perceptions and experiences of professional social media use

abstract:
Seeking support from Facebook groups during pregnancy is now widespread and social media has been widely used by maternity services during the COVID-19 pandemic. Despite this, little is currently known about midwives attitudes towards, and experiences of social media in practice. Research is needed to understand barriers and solutions to meeting mothers expectations of online support and to improve services.

This study explored midwife involvement in Facebook groups, exploring experiences and perceptions of its use to communicate with and support mothers. 719 midwives and student midwives completed an online survey during August-September 2020 and their numerical and free-text responses analysed descriptively.

Few participants were involved in providing Facebook support, and most of these were unpaid. There was a consensus on a range of benefits for mothers, but widespread concern that engaging with mothers online was a personal and professional risk, underpinned by a lack of support. Experience of being involved in midwife moderation increased belief in its benefits and reduced fear of engaging online, despite a lack of renumeration and resources. Midwives and students felt they were discouraged from offering Facebook support and sought further training, guidance and support.

Although limited, experiences of providing Facebook group support are positive. Perceptions of risk and a lack of support are significant barriers to midwives involvement in using Facebook groups to support mothers. Midwives seek support and training to safely and effectively engage with mothers using Facebook.

Engaging with mothers via social media is embedded in national policy and digital strategy, and progress is needed to fulfil these, to improve services and meet mothers expectations. Midwives experiences suggest extending opportunities to provide Facebook support would benefit midwives, services and families. Consultation to revise local policy to support midwives and students in line with strategic goals is recommended.

Author SummarySocial media use continues to grow and we know that use among pregnant and new parents for peer support and accessing information is widespread. Previous research suggests however that they can find it difficult to know which information to trust, and would like to engage with their midwives online. However, little was known about how many midwives are supporting families via social media, or what their experiences of this are. Nor did we know what the perceptions of developing this service are amongst the workforce. Here, we used an online survey to explore these attitudes and perceptions. We found that although few midwives are engaging with families on social media, those that do have positive experiences. Many fear that a lack of support and guidance presents risks to themselves and to families, but recognised the potential benefits to developing the service. We also found that midwives would like to receive more training to deliver services online and engage safely on social media. Our study provides new insights that can be used to improve support for midwives and to realise the potential of social media in midwifery care.