title: A gene expression map of host immune response in human brucellosis

abstract: Brucellosis is a common zoonotic disease caused by intracellular pathogens of the genus Brucella. Brucella infects macrophages and evades clearance mechanisms, which results in chronic parasitism. Herein, we studied the molecular changes that take place in human brucellosis both in vitro and in vivo. RNA sequencing was performed in primary human macrophages (M{varphi}) and polymorphonuclear neutrophils (PMNs) infected with clinical strains of B. melitensis. We observed a downregulation in the expression of genes involved in host response, such as TNF signaling, IL-1{beta} production and phagosome formation in M{varphi}, and phosphatidylinositol signaling and TNF signaling in PMNs, being in line with the ability of the pathogen to survive within phagocytes. Further transcriptomic analysis of isolated peripheral blood mononuclear cells (PBMCs) and PMNs from patients with acute brucellosis before treatment initiation and after successful treatment revealed a positive correlation of the molecular signature of active disease with pathways associated with response to interferons (IFN). We identified 24 common genes that were significantly altered in both PMNs and PBMCs, including genes involved in IFN signaling that were downregulated after treatment in both cell populations, and IL1R1 that was upregulated. The levels of several inflammatory mediators were evaluated in the serum of these patients, and we observed increased levels of IFN-{gamma}, IL-1{beta} and IL-6 before the treatment of acute brucellosis. An independent cohort of patients with chronic brucellosis also revealed the increased levels of IFN-{gamma} during relapse compared to remissions. Taken together, this study provides for the first time an in-depth analysis of the molecular alterations that take place in human phagocytes upon infection, and in peripheral blood immune populations during active disease.


title: Predictive Model of Risk Factors of High Flow Nasal Cannula Using Machine Learning in COVID-19

abstract:
BackgroundWith the rapid increase in the number of COVID-19 patients in Japan, the number of patients receiving oxygen at home has also increased rapidly, and some of these patients have died. An efficient approach to identify high-risk patients with slowly progressing and rapidly worsening COVID-19, and to avoid missing the timing of therapeutic intervention will improve patient prognosis and prevent medical complications.

MethodsPatients admitted to medical institutions in Japan from November 14, 2020 to April 11, 2021 and registered in the COVID-19 Registry Japan were included. Risk factors for patients with High Flow Nasal Cannula invasive respiratory management or higher were comprehensively explored using machine learning. Age-specific cohorts were created, and severity prediction was performed for the patient surge period and normal times, respectively.

ResultsWe were able to obtain a model that was able to predict severe disease with a sensitivity of 57% when the specificity was set at 90% for those aged 40-59 years, and with a specificity of 50% and 43% when the sensitivity was set at 90% for those aged 60-79 years and 80 years and older, respectively. We were able to identify lactate dehydrogenase level (LDH) as an important factor in predicting the severity of illness in all age groups.

DiscussionUsing machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. Using machine learning, we were able to identify risk factors with high accuracy, and predict the severity of the disease. We plan to develop a tool that will be useful in determining the indications for hospitalisation for patients undergoing home care and early hospitalisation.

category: infectious diseases


title: COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults

abstract:
ImportanceOlder adults, at high-risk of developing complications from COVID-19, could benefit from nirmatrelvir-ritonavir, an oral antiviral treatment for outpatients at high risk of complications from COVID-19; however, due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).

ObjectivesIdentify how common DDIs are between nirmatrelvir-ritonavir, common medications, and PIMs in older adults with polypharmacy. Craft anticipatory deprescribing guidance for PIMs that interact with nirmatrelvir-ritonavir to help prioritize deprescribing resources, and increase the proportion of older adults potentially benefitting from treatment.

DesignIn this secondary analysis, we retrospectively analyzed all patients in the MedSafer cluster randomized deprescribing trial (N=5698 participants) to investigate the proportion of older adults (age >65) with polypharmacy ([≥]5 usual home medications) who would be ineligible for treatment with nirmatrelvir-ritonavir due to pre-existing DDIs.

SettingThe setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals.

ParticipantsHospitalized persons, age 65 years and older, on 5 or more daily home medications, with an expected survival of 3 months or longer were included in this secondary analysis.

Main outcomes and measuresWe identified the prevalence of (PIMs), as defined by the MedSafer software. We then developed deprescribing guidance, so clinicians could proactively deprescribe in an effort to increase the proportion of older adults eligible for safe treatment with nirmatrelvir-ritonavir in the event of a SARS-CoV-2 infection.

ResultsOf 5698 participants, a total of 3869 (68%) were taking a medication with a known nirmatrelvir-ritonavir DDI, and of these 823 (21%) had at least one PIM. Of 823 PIMs, 627 (76%) were medications with a known high risk DDI and 213 (26%) were considered moderate risk DDIs with nirmatrelvir-ritonavir. Many of the PIMs required "advanced deprescribing" and could not simply be stopped, held, or adjusted at the time of nirmatrelvir-ritonavir receipt.

Conclusions and relevanceOlder adults are at high risk of developing severe complications from COVID-19. Deprescribing PIMs in advance of a COVID-19 infection could increase the proportion of older adults who can safely receive nirmatrelvir-ritonavir, in addition to the usual benefits observed with medication management.

Impact StatementWe certify that this work is novel. This timely clinical investigation explores the unforeseen consequences of polypharmacy and the use of potentially inappropriate medication in older adults during the COVID-19 pandemic. This manuscript addresses the many drug-drug interactions between nirmatrelvir-ritonavir, an antiviral treatment for COVID-19, and potentially inappropriate medications in older adults with polypharmacy from the MedSafer cluster randomized trial. Our work highlights that the pandemic has created an even greater urgency to examine the medication lists of older adults and proactively deprescribe to improve the safety and tolerability of different COVID-19 treatments.

Key PointsO_LIQuestion: How does polypharmacy affect the eligibility of older adults to receive Nirmatrelvir-ritonavir?
C_LIO_LIFindings: 68% of older adults in the MedSafer cluster randomized trial had a DDI with nirmatrelvir-ritonavir, and 21% were taking at least 1 potentially inappropriate medication.
C_LIO_LIMeaning: Due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).
C_LI


title: Serum levels of the novel adipokine isthmin-1 are associated with obesity in pubertal boys

abstract:
PurposeThe aims of this study were; 1) to evaluate if there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children, 2) to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity.

MethodsThe study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls) and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity and insulin resistance (IR) status. They counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as ISM1 serum levels measured. This population was intended as a discovery population in which to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation allowing deepening into the obesity-ISM1 molecular relationship.

ResultsHigher serum levels of ISM1 were observed in boys with obesity when compared with normal-weight (P=0.004), and overweight (P=0.007). ISM1 serum levels were positively associated with BMI Z-score (P=0.005), and negatively with myeloperoxidase (MPO) (p=0.043) in boys. Nevertheless, we did not find associations between ISM1 serum levels and metabolic outcomes in girls, indicating a putative sexual dimorphism. DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children.

DiscussionWe report an unprecedented study that provides a major step forward showing that ISM1 is robustly associated with obesity in pubertal boys, elucidating how this protein might be of special relevance as a new biomarker of obesity in children.

category: endocrinology


title: Disparities in SARS-CoV-2 case rates by ethnicity, religion, measures of socio-economic position, English proficiency, and self-reported disability: cohort study of 39 million people in England during the Alpha and Delta waves

abstract:
ObjectiveTo examine socio-demographic disparities in SARS-CoV-2 case rates during the second (Alpha) and third (Delta) waves of the COVID-19 pandemic.

DesignRetrospective, population-based cohort study.

SettingResident population of England.

Participants39,006,194 people aged 10 years and over who were enumerated at the 2011 Census, registered with the National Health Service (NHS) and alive on 1 September 2020.

Main outcome measuresTesting positive for SARS-CoV-2 during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. We calculated age-standardised case rates by socio-demographic characteristics and used logistic regression models to estimate adjusted odds ratios (ORs).

ResultsDuring the study period, 5,767,584 individuals tested positive for SARS-CoV-2. In the second wave, the fully-adjusted odds of having a positive test, relative to the White British group, were highest for the Bangladeshi (OR: 1.88, 95% CI 1.86 to 1.90) and Pakistani (1.81, 1.79 to 1.82) ethnic groups. Relative to the Christian group, Muslim and Sikh religious groups had fully-adjusted ORs of 1.58 (1.57 to 1.59) and 1.74 (1.72 to 1.76), respectively. Greater area deprivation, disadvantaged socio-economic position, living in a care home and low English language proficiency were also associated with higher odds of having a positive test. However, the disparities between groups varied over time. Being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of testing positive during the third wave.

ConclusionThere are large socio-demographic disparities on SARS-CoV-2 cases which have varied between different waves of the pandemic. Research is now urgently needed to understand why these disparities exist to inform policy interventions in future waves or pandemics.

What is already known on this topicPeople with pre-existing health conditions or disability, ethnic minority groups, the elderly, some religious groups, people with low socio-economic status, and those living in deprived areas have been disproportionately affected by the COVID-19 pandemic in terms of risk of infection and adverse outcomes.

What this study addsUsing linked data on 39 million people in England, we found that during the second wave, COVID-19 case rates were highest among the Bangladeshi and Pakistani ethnic groups, the Muslim religious group, individuals from deprived areas and of low socio-economic position; during the third wave, being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of receiving a positive test

Adjusting for geographical factors, socio-demographic characteristics, and pre-pandemic health status explained some, but not all, of the excess risk

When stratifying the dataset by broad age groups, the odds of receiving a positive test remained higher among the Bangladeshi and Pakistani ethnic groups aged 65 years and over during the third wave, which may partly explain the continued elevated mortality rates in these groups

category: epidemiology


title: Estimating relative generation times and relative reproduction numbers of Omicron BA.1 and BA.2 with respect to Delta in Denmark

abstract: The Omicron variant is the most transmissible variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) we had so far. The BA.1 and BA.2 sublineages of Omicron are circulating in Europe and it is urgent to evaluate the transmissibility of these sub-lineages. Using a mathematical model describing trajectories of variant frequencies that assumes a constant ratio in generation times and a constant ratio in effective reproduction numbers among variants, trajectories of variant frequencies in Denmark from November 22, 2021 to February 26, 2022 were analyzed. We found that the generation times of Omicron BA.1 and BA.2 are 0.60 (95%CI: 0.59-0.62) and 0.51 (95%CI: 0.50-0.52) of the length of that of Delta, respectively. We also found that the effective reproduction number of Omicron BA.1 is 1.99 (95% CI: 1.98-2.02) times and that of Omicron BA.2 is 2.51 (95% CI: 2.48- 2.55) times larger than the effective reproduction number of Delta. The generation times of Omicron BA.2 is 0.85 (95% CI:0.84-0.86) the length of that of BA.1 and that the effective reproduction number of Omicron BA.2 is 1.26 (95% CI:1.25-1.26) times larger than that of Omicron BA.1. These estimates on the ratio of generation times and the ratio of effective reproduction numbers has epidemiologically important implications. The duration of quarantine for people who contacted with an Omicron BA.1 and BA.2 patient can be reduced to 60% and 51% of that for Delta, respectively. The control measures against Omicron BA.1 and BA.2 need to reduce contacts between infectious and susceptible people respectively by 50% (95% CI: 49-50%) and 60% (95% CI: 60-61%) compared to that against Delta to achieve the same effect on their control.


title: Introducing riskCommunicator: an R package to obtain interpretable effect estimates for public health

abstract:
Common statistical modeling methods do not necessarily produce the most relevant or interpretable effect estimates to communicate risk. Overreliance on the odds ratio and relative effect measures limit the potential impact of epidemiologic and public health research. We created a straightforward R package, called riskCommunicator, to facilitate the presentation of a variety of effect measures, including risk differences and ratios, number needed to treat, incidence rate differences and ratios, and mean differences. The riskCommunicator package uses g-computation with parametric regression models and bootstrapping for confidence intervals to estimate effect measures in time-fixed data. We demonstrate the utility of the package using data from the Framingham Heart Study to estimate the effect of prevalent diabetes on the 24-year risk of cardiovascular disease or death.

The absolute 24-year risk of cardiovascular disease or death was 30% (95% confidence interval (CI): 22, 38) higher among subjects with diabetes compared to subjects without diabetes at baseline. The relative 24-year risk was 55% (95% CI: 40, 70) higher. Because the outcome was common (41.8%), the odds ratio (4.55) is highly inflated compared to the risk ratio (1.55). An expected 4 additional persons would need to have diabetes at baseline to observe an increase in the number of cases of cardiovascular disease or death by 1 over 24 years of follow-up.

The package promotes the communication of public-health relevant effects and is accessible to a broad range of epidemiologists and health researchers with little to no expertise in causal inference methods or advanced coding.


title: A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

abstract:
AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated ion channels formed as different combinations of GluA1-4 subunits encoded by the genes GRIA1-4. Various pathogenic variants of these genes have been described in patients with developmental delay, intellectual disability, autistic spectrum disorder and seizures. Here we report a heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V) identified in a one-year-old male patient with seizures, developmental delay and failure to thrive. Electrophysiological investigation of heterologously expressed receptors showed GluA2 A643V to exhibit greatly slowed deactivation, and a markedly reduced extent of desensitization, compared with wild-type GluA2. When GluA2 A643V was coexpressed with the transmembrane AMPAR regulatory protein (TARP) {gamma}2, or with both GluA1 and {gamma}2 to generate TARPed heteromeric receptors, the slowed deactivation and decreased desensitization persisted. We found that the AMPAR negative allosteric modulator perampanel was able to fully block currents from GluA2 A643V/{gamma}2 receptors, albeit with reduced potency compared with wild-type GluA2/{gamma}2. The introduction of perampanel to the patients treatment regimen, alongside a modified Atkins diet, was associated with a marked reduction in seizure number, a resolution of failure to thrive, and clear developmental gains. Our study suggests that AMPAR gain-of-function (GoF) underlies the effect of the GRIA2 variant in our patient, and that perampanel may be beneficial in other patients with GRIA GoF variants.

Author summaryRapid communication between brain cells is mediated by the excitatory neurotransmitter glutamate. Mutations affecting genes that encode glutamate-gated ion channels can result in neurodevelopmental disorders and seizures. In a young male patient, we identified a mutation in the gene responsible for production of GluA2, a key subunit of AMPA-type glutamate receptors. We showed that receptors containing GluA2 produced by this GRIA2 A643V variant were more sensitive to glutamate and gave rise to unusually prolonged or sustained responses, thus causing  gain-of-function. We found that receptors affected by this mutation could, nonetheless, be inhibited by the AMPA receptor-targeting antiseizure medication, perampanel. Prompted by this finding we introduced perampanel alongside the patients ongoing antiseizure medication. This coincided with a decrease in the patients seizures and clear developmental gains. Taken together, our findings suggest that a GRIA2 gain-of-function mutation can cause neurological disease, that perampanel can be used to directly counteract the effect of the mutation, and that it may be beneficial in other GRIA gain-of-function patients.

category: pharmacology and therapeutics


title: Sex-specific genetic and transcriptomic liability to neuroticism

abstract:
BackgroundThe presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies (GWAS) of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.

MethodsNeuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. GWAS were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X-chromosomal variation. Two-sided Z-tests were used to test for sex-specific effects of discovered loci, genetic correlates (N=673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (BioVu, 39,692 females and 31,268 males).

ResultsThe SNP-heritability of neuroticism was not statistically different between males (h2=10.6%) and females (h2=11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and two male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with "mood disorders" (male OR=1.11, P=1.40x10-9; female OR=1.14, P=6.05x10-22). They also associated with sex-specific laboratory measures related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (males {beta}=0.026, P=0.002) and genetically-regulated transcriptomic changes highlighted the effect of RAB7L1, TEX26, and PLOT1.

ConclusionsThrough a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities.

category: psychiatry and clinical psychology


title: Analyzing county-wide trends in Tennessee Covid-19 rates, Median Household Income, and Presence of Hospital

abstract: The Covid-19 pandemic has caused millions of deaths and infections worldwide. Recent studies suggest that Covid-19 may be disproportionately affecting certain groups. The Tennessee Department of Health regularly publishes data on Covid infections and vaccinations. This data alongside data published from the 2010 census was used to analyze trends in Covid-19 rates for the State of Tennessee. The census data for the average household income of each county was cross-referenced with the covid data. A positive correlation between population of the county and the number of new cases reported on January 3rd, 2022, appeared when observing the data. A regression analysis (ANOVA) revealed that the data on population and covid rate was significant (P-value: 2.69E-10). The results from comparing the covid rates in a county with a hospital and a county without a hospital seemed to be the most significant. The data reported by the Sycamore institute on the Tennessee counties without a hospital was used to identify trends unique to these counties. The counties lacking a hospital were compared with counties with a similar population. 7 hospital-less counties were used for comparison, 6 counties (Fayette, Grainger, Haywood, Chester, Sequatchie, Clay) reported a greater number of cases than counties of a similar population. Of the 20 counties lacking a hospital, 16 fell within the bottom 50% of median household incomes, with 9 in the bottom 25% and 4 in the bottom 10%. Healthcare sites in rural areas may lack fundamental infrastructure. These areas may require unique interventions to address the healthcare concerns present.

category: public and global health


title: Predicting missed health care visits during the COVID-19 pandemic using machine learning methods: Evidence from 55,500 individuals from 28 European Countries

abstract:
BackgroundThe COVID-19 pandemic has led many individuals to miss essential care. Machine-learning models that predict which patients are at greatest risk of missing care visits can help health administrators prioritize retentions efforts towards patients with the most need. Such approaches may be especially useful for efficiently targeting interventions for health systems overburdened by the COVID-19 pandemic.

MethodsWe compare the performance of four machine learning algorithms to predict missed health care visits based on common patient characteristics available to most health care providers. We use data from 55,500 respondents of the Survey of Health, Ageing and Retirement in Europe (SHARE) COVID-19 survey (June - September 2020) in conjunction with longitudinal data from waves 1-8 (April 2004 - March 2020). We use stepwise selection, group lasso, random forest and neural network algorithms and employ 5-fold cross-validation to test the prediction accuracy, sensitivity, and specificity of the selected models.

FindingsWithin our sample, 15.5% of the respondents reported any missed essential health care visit due to the COVID-19 pandemic. All four machine learning methods perform similarly in their predictive power. When classifying all individuals with a predicted probability for missed care above 17% as at risk of a missed visit, they correctly identify between 41% and 53% of the respondents at risk, while correctly identifying between 74% and 64% of the individuals not at risk. We find that the sensitivity and specificity of the models are strongly related to the risk threshold used to classify individuals; thus, the models can be calibrated depending on users resource constraints and targeting approach. All models had an area under the curve around 0.62, indicating that they outperform random prediction.

InterpretationPandemics such as COVID-19 require rapid and efficient responses to reduce disruptions in health care. Based on characteristics available to health insurance providers, machine learning algorithms can be used to efficiently target efforts to reduce missed essential care.

FundingResearch in this article is a part of the European Unions H2020 SHARE-COVID19 project (Grant Agreement No. 101015924).


title: VALIDATION OF AN INSTRUMENTED MOUTHGUARD

abstract: The purpose of this study was to determine the validity of an raw and filtered acceleration time-series data from an instrumented mouthguard system against an anthropometric testing device. Testing was conducted in a laboratory using a standard impact protocol utilising the head-form of reference system and the mouthguard system. Testing occurred at 5 impact locations: facemask, front, oblique, side and back, and at four velocities (3.6, 5.5, 7.4, and 9.3 m/s) to attain a total of 55 impacts. A 160 Hz Low-pass 4th order Butterworth filter was applied to the time-series data, and was reported as raw and filtered. Peak linear acceleration, peak rotational velocity and peak rotational acceleration was statistically compared to the reference measurement system. Total concordance correlation coefficient was 90.7% and 96.9%, for raw and filtered data set. Raw and filtered had intraclass correlation coefficients of 0.85 and 0.95 for peak linear acceleration, 0.99 and 0.99 for peak rotational velocity and 0.94 and 0.95 peak rotational acceleration respectively. The instrumented mouthguard displayed high accuracy when measuring head impact kinematics in a laboratory setting. The results presented in this study provide the basis on which the instrumented mouthguard can be further developed for deployment and application within sport quantify head impact collision dynamics in order to optimise performance and brain health.

category: sports medicine


title: Personalised structural connectomics for moderate-to-severe traumatic brain injury

abstract: Graph theoretical analysis of the structural connectome has been employed successfully to characterise brain network alterations in patients with traumatic brain injury (TBI). However, heterogeneity in neuropathology is a well-known issue in the TBI population, such that group comparisons of patients against controls are confounded by within-group variability. Recently, novel single-subject profiling approaches have been developed to capture inter-patient heterogeneity. We present a personalised connectomics approach that examines structural brain alterations in six chronic patients with moderate-to-severe TBI who underwent anatomical and diffusion magnetic resonance imaging (MRI). We generated individualised profiles of lesion characteristics and network measures (including personalised graph metric  GraphMe plots, and nodal and edge-based brain network alterations) and compared them against healthy reference cases (N=12) to assess brain damage qualitatively and quantitatively at the individual level. Our findings revealed clinically significant alterations of brain networks with high variability between patients. Our profiling can be used by clinicians to formulate a neuroscience-guided integrative rehabilitation program for TBI patients, and for designing personalised rehabilitation protocols based on their unique lesion load and connectome.

category: neurology


title: Faster post-malnutrition weight gain during childhood is associated with risk of non-communicable disease in adult survivors of severe malnutrition

abstract:
BackgroundNutritional rehabilitation during severe malnutrition (SM) aims to rapidly restore body size and minimize poor short-term outcomes. We hypothesized that too rapid weight gain during and after treatment might however predispose to cardiometabolic risk in adult life.

MethodsWeight and height during hospitalization and one year post-hospitalization were abstracted from hospital records of children who survived SM. Six definitions of post-malnutrition weight gain/growth were analysed as continuous variables, quintiles and latent classes in age-sex and minimum weight-for-age z-scores-adjusted regression models against adult anthropometry, body composition (DEXA), blood pressure, blood glucose, insulin, and lipids.

Results60% of 278 participants were male, mean (SD) age 28.2 (7.7) years, mean (SD) BMI 23.6 (5.2) kg/m2. Mean admission age for SM was 10.9 months (range 0.3-36.3 months) and 207/270 (77%) were wasted (weight-for-height z-score<-2). During childhood, mean rehabilitation weight gain (SD) was 10.1(3.8) g/kg/day and 0.8(0.5) g/kg/day in the first year post-hospitalization. Rehabilitation weight gain >12.9 g/kg/day was associated with higher adult BMI (difference=0.5kg/m2, 95%CI: 0.1-0.9, p = 0.02), waist circumference (difference=1.4cm, 95%CI: 0.4-2.4, p=0.005), fat mass (difference = 1.1kg, 95%CI: 0.2-2, p=0.02), fat mass index (difference=0.32, 95%CI: -0.0001-0, p=0.05), and android fat mass (difference=0.09 kg, 95%CI: 0.01-0.2, p=0.03). Rehabilitation (g/month) and post-hospitalization (g/kg/month) weight gain were associated with greater lean mass (difference = 0.7 kg, 95% CI: 0.1, 1.3, p = 0.02) (difference=1.3kg, 95% CI: 0.3-2.4, p=0.015) respectively.

ConclusionRehabilitation weight gain exceeding 13g/kg/day was associated with adult adiposity in young, normal-weight adult SM survivors. This raises questions around existing malnutrition weight gain targets and warrants further studies exploring optimal post-malnutrition growth.

category: nutrition


title: A Systematic Review and Meta-Analysis of Digital Application use in Clinical Research in Pain Medicine

abstract:
ImportancePain is a silent global epidemic impacting approximately a third of the population. Pharmacological and surgical interventions are primary modes of treatment. Cognitive/behavioural management approaches and interventional pain management strategies are approaches that have been used to assist with the management of chronic pain. Accurate data collection and reporting treatment outcomes are vital to addressing the challenges faced. In light of this, we conducted a systematic evaluation of the current digital application landscape within chronic pain medicine.

ObjectiveThe primary objective was to consider the prevalence of digital application usage for chronic pain management. These digital applications included mobile apps, web apps, and chatbots.

Data SourcesWe conducted searches on PubMed and ScienceDirect for studies that were published between 1st January 1990 and 1st January 2021.

Study SelectionOur review included studies that involved the use of digital applications for chronic pain conditions. There were no restrictions on the country in which the study was conducted. Only studies that were peer-reviewed and published in English were included. Four reviewers had assessed the eligibility of each study against the inclusion/exclusion criteria. Out of the 84 studies that were initially identified, 38 were included in the systematic review.

Data Extraction and SynthesisThe AMSTAR guidelines were used to assess data quality. This assessment was carried out by 3 reviewers. The data were pooled using a random-effects model.

Main Outcome(s) and Measure(s)Before data collection began, the primary outcome was to report on the prevalence of digital application usage for chronic pain conditions. We also recorded the type of digital application studied (e.g. mobile application, web application) and, where the data was available, the prevalence of pain intensity, pain inferences, depression, anxiety, and fatigue.

Results38 studies were included in the systematic review and 22 studies were included in the meta-analysis.

The digital interventions were categorised to web and mobile applications and chatbots, with pooled prevalence of 0.22 (95% CI -0.16, 0.60), 0.30 (95% CI 0.00, 0.60) and -0.02 (95% CI -0.47, 0.42) respectively. Pooled standard mean differences for symptomatologies of pain intensity, depression, and anxiety symptoms were 0.25 (95% CI 0.03, 0.46), 0.30 (95% CI 0.17, 0.43) and 0.37 (95% CI 0.05, 0.69) respectively.

A sub-group analysis was conducted on pain intensity due to the heterogeneity of the results (I2=82.86%; p=0.02). After stratifying by country, we found that digital applications were more likely to be effective in some countries (e.g. USA, China) than others (e.g. Ireland, Norway).

Conclusions and RelevanceThe use of digital applications in improving pain-related symptoms shows promise, but further clinical studies would be needed to develop more robust applications.

category: pain medicine


title: Prescription opioid-related alterations to amygdalar and thalamic functional networks in chronic knee pain: A retrospective case control resting-state connectivity study.

abstract:
ObjectiveLong-term opioid use is associated with diminished pain relief, hyperalgesia, and addiction which is not well understood. This study aimed to characterise opioid-related brain network alterations in chronic pain, focused on the right amygdala, and left mediodorsal thalamic nuclei that play key roles in affective pain processing, and are particularly rich in mu opioid receptors (MOR).

SubjectsParticipants on opioid prescriptions with painful knee osteoarthritis and matched non-opioid using control pain participants.

Methods and designSeed-based functional connectivity (FC) maps from resting-state fMRI data were compared between groups.

ResultsWe found right amygdala hyperconnectivity with the posterior default mode network (pDMN) and the dorsomedial prefrontal cortex in opioid users in contrast to anti-correlations in controls. Conversely, opioid users showed predominant hypoconnectivity of the left dorsomedial thalamic seed with the cingulate cortex except for the subgenual part displaying an anti-correlation in opioid users and no association in non-users. Opioid users also showed higher negative affect in exploratory post-hoc tests suggesting a potential contribution of trait anxiety to amygdala-pDMN FC alteration.

ConclusionOpioid use related hyperconnectivity of the right amygdalar network likely reflects maladaptive mechanisms involving negative affect and network plasticity. Hypoconnectivity of the mediodorsal thalamic nuclei with the anterior and mid cingulate on the other hand may reflect impaired resilience in line with previously reported compensatory MOR upregulation. In conclusion, this study provides new insight into possible brain mechanisms underlying adverse effects of prolonged opioids in chronic pain and offer candidate network targets for novel interventions.


title: The role of alternative splicing in CEP290-related disease pathogenesis

abstract: Primary ciliopathies are a group of inherited developmental disorders resulting from defects in the primary cilium. Mutations in CEP290 (Centrosomal protein of 290kDa) are the most frequent cause of recessive ciliopathies (incidence up to 1:15,000). Pathogenic variants span the full length of this large (93.2kb) 54 exon gene, causing phenotypes ranging from isolated inherited retinal dystrophies (IRDs; Leber Congenital Amaurosis, LCA) to a pleiotropic range of severe syndromic multi-organ ciliopathies affecting retina, kidney and brain. Most pathogenic CEP290 variants are predicted null (37% nonsense, 42% frameshift), but there is no clear genotype-phenotype association. Almost half (26/53) of the coding exons in CEP290 are in-phase "skiptic" (or skippable) exons. Variants located in skiptic exons could be removed from CEP290 transcripts by skipping the exon, and nonsense-associated altered splicing (NAS) has been proposed as a mechanism that attenuates the pathogenicity of nonsense or frameshift CEP290 variants. Here, we have used in silico bioinformatic techniques to study the propensity of CEP290 skiptic exons for NAS. We then used CRISPR-Cas9 technology to model CEP290 frameshift mutations in induced pluripotent stem cells (iPSCs) and analysed their effects on splicing and ciliogenesis. We identified exon 36, a hotspot for LCA mutations, as a strong candidate for NAS that we confirmed in mutant iPSCs that exhibited sequence-specific exon skipping. Exon 36 skipping did not affect ciliogenesis, in contrast to a larger frameshift mutant that significantly decreased cilia size and incidence in iPSCs. We suggest that sequence-specific NAS provides the molecular basis of genetic pleiotropy for CEP290-related disorders.

category: genetic and genomic medicine


title: Association of clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults - a systematic review and meta-analysis

abstract:
IMPORTANCEThe predictive value of common performance-based outcome assessments of mobility capacity on incident disability in activities of daily living in community-dwelling older adults remains uncertain.

OBJECTIVETo synthesize all available research on the association between mobility capacity and incident disability in non-disabled older adults.

DATA SOURCESMEDLINE, EMBASE and CINAHL databases were searched without any limits or restrictions.

STUDY SELECTIONPublished reports of longitudinal cohort studies that estimated a direct association between baseline mobility capacity, assessed with a standardized outcome assessment, and subsequent development of disability, including initially non-disabled older adults.

DATA EXTRACTION AND SYNTHESISData extraction was completed by independent pairs of reviewers. The risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Random-effect models were used to explore the objective. The certainty of evidence was assessed using GRADE.

MAIN OUTCOME AND MEASURESThe main outcome measures were the pooled relative risks (RR) per one conventional unit per mobility assessment for incident disability in activities of daily living.

RESULTSA total of 40 reports were included, evaluating 85,515 and 78,379 participants at baseline and follow-up, respectively (median mean age: 74.6 years). The median disability rate at follow-up was 12.0% (IQR: 5.4%-23.3%). The overall risk of bias was judged as low, moderate and high in 6 (15%), 6 (15%), and 28 (70%) reports, respectively.

For usual and fast gait speed, the RR per -0.1 m/s was 1.23 (95% CI: 1.18-1.28; 26,638 participants) and 1.28 (95% CI: 1.19-1.38; 8,161 participants), respectively. Each point decrease in Short Physical Performance Battery score increased the risk of incident disability by 30% (RR = 1.30, 95% CI: 1.23- 1.38; 9,183 participants). The RR of incident disability by each second increase in Timed Up and Go test and Chair Rise Test performance was 1.15 (95% CI: 1.09-1.21; 30,426 participants) and 1.07 (95% CI: 1.04-1.10; 9,450 participants), respectively.

CONCLUSIONS AND RELEVANCEAmong community-dwelling non-disabled older adults, a poor mobility capacity is a potent modifiable risk factor for incident disability. Mobility impairment should be mandated as a quality indicator of health for older people.

Key PointsO_ST_ABSQUESTIONC_ST_ABSWhat are the associations between clinical outcome assessments of mobility capacity and incident disability in community-dwelling older adults?

FINDINGSIn this systematic review and meta-analysis that included 40 reports and data of 85,515 older adults, the risk ratios of incident disability on activities of daily living were 1.23, 1.30, 1.15, and 1.07 for usual gait speed, Short Physical Performance Battery, Timed Up and Go test, and Chair Rise Test, respectively, per one conventional unit.

MEANINGCommon assessments of mobility capacity may help identify older people at risk of incident disability and should be routinely established in regular health examinations.

category: geriatric medicine


title: Cost-effectiveness of the digital therapeutics for essential hypertension

abstract:
BackgroundHypertension increases the risk of cardiovascular and other diseases. Lifestyle modification is a significant component of nonpharmacological treatments for hypertension. We previously reported the clinical efficacy of digital therapeutics (DTx) in the HERB-DH1 pivotal trial. However, there is still a lack of cost-effectiveness assessments evaluating the impact of prescription DTx. This study aimed to analyze the cost-effectiveness of using prescription DTx in treating hypertension.

MethodsWe developed a monthly cycle Markov model and conducted Monte Carlo simulations using the HERB-DH1 trial data to investigate quality-adjusted life-years (QALYs) and the cost of DTx for hypertension plus guideline-based lifestyle modification consultation treatment as usual (TAU), comparing DTx+TAU and TAU-only groups with a lifetime horizon. The model inputs were obtained from published academic papers, publicly available data, and expert assumptions. The incremental cost-effectiveness ratio (ICER) per QALY was used as the benchmark for cost-effectiveness. We performed probabilistic sensitivity analyses (PSAs) using the Monte Carlo simulation with 2 million sets.

ResultsThe DTx+TAU strategy produced 18.778 QALY and was associated with {yen}3,924,075 ($34,122) expected costs, compared with 18.686 QALY and {yen}3,813,358 ($33,160) generated by the TAU-only strategy over a lifetime horizon, resulting in an ICER of {yen}1,199,880 ($10,434)/QALY gained for DTx+TAU. The monthly cost and attrition rate of DTx for hypertension have a significant impact on ICERs. In the PSA, the probability of the DTx arm being a cost-effective option was 87.8% at a threshold value of {yen}5 million ($43,478)/QALY gained.

ConclusionsThe DTx+TAU strategy was more cost-effective than the TAU-only strategy.

category: health economics


title: Acute and long-term impacts of COVID-19 on economic vulnerability: a population-based longitudinal study (COVIDENCE UK)

abstract:
BackgroundSocio-economic deprivation is well recognised as a risk factor for developing COVID-19. However, the impact of COVID-19 on economic vulnerability has not previously been characterised.

ObjectiveTo determine whether COVID-19 has a significant impact on adequacy of household income to meet basic needs (primary outcome) and work absence due to sickness (secondary outcome), both at the onset of illness (acutely) and subsequently (long-term).

DesignMultivariate mixed regression analysis of self-reported data from monthly on-line questionnaires, completed 1st May 2020 to 28th October 2021, adjusting for baseline characteristics including age, sex, socioeconomic status and self-rated health.

Setting and ParticipantsParticipants (n=16,910) were UK residents aged 16 years or over participating in a national longitudinal study of COVID-19 (COVIDENCE UK).

ResultsIncident COVID-19 was independently associated with increased odds of participants reporting household income as being inadequate to meet their basic needs, both acutely (adjusted odds ratio [aOR) 1.39, 95% confidence interval [CI] 1.12 to 1.73) and in the long-term (aOR 1.15, 95% CI 1.00 to 1.33). Exploratory analysis revealed the long-term association to be restricted to those who reported  long COVID, defined as the presence of symptoms lasting more than 4 weeks after the acute episode (aOR 1.39, 95% CI 1.10 to 1.77). Incident COVID-19 associated with increased odds of reporting sickness absence from work in the long-term (aOR 5.29, 95% CI 2.76 to 10.10) but not acutely (aOR 1.34, 95% CI 0.52 to 3.49).

ConclusionsWe demonstrate an independent association between COVID-19 and increased risk of economic vulnerability, both acutely and in the long-term. Taking these findings together with pre-existing research showing that socio-economic disadvantage increases the risk of developing COVID-19, this may generate a  vicious cycle of impaired health and poor economic outcomes.

Trial registrationNCT04330599

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISocioeconomic deprivation is recognised as a major risk factor for incidence and severity of COVID-19 disease, mediated via factors including increased occupational and household exposure to SARS-CoV-2 and greater physical vulnerability due to comorbidities
C_LIO_LIThe potential for COVID-19 to act as a cause, rather than a consequence, of economic vulnerability has not previously been characterised.
C_LI

What this study addsO_LIWe demonstrate an independent association between incident COVID-19 and subsequent self-report of household income being inadequate to meet basic needs, both acutely and in the long term
C_LIO_LIIncident COVID-19 was also associated with increased odds of subsequent self-report of sickness absence from work in the long-term.
C_LI


title: An observational study of the association between COVID-19 vaccination rates and participation in a vaccine lottery

abstract:
ObjectivesAre financial incentives from entry in a vaccine lottery associated with a higher probability of vaccination for COVID-19?

DesignA cross-sectional study with adjustment for covariates using logistic regression

SettingOctober and November 2021, Australia.

Participants2,375 respondents of the Taking the Pulse of the Nation Survey

InterventionsParticipation in the Million Dollar Vaccination Lottery

Primary and secondary outcome measuresThe proportion of respondents who had any vaccination, a first dose only, or second dose compared to all other respondents

ResultsThose who participated in the lottery were 2.27 times more likely to be vaccinated after the lottery opened on October 1st than those who did not. This was driven by those receiving second doses. Lottery participants were 1.38 times more likely to receive their first dose after October 1st and 2.31 times more likely to receive their second dose after October 1st.

ConclusionsLottery participation is associated with a higher vaccination rate, with this effect dominated by a higher rate of second doses. There is a smaller insignificant difference for those receiving a first dose, suggesting lotteries may not be as effective at reducing vaccine hesitancy, compared to  nudging people to get their second dose more quickly.

Strengths and limitations of this studyO_LIWe use a nationally representative sample of individuals.
C_LIO_LIWe distinguish between the association between lottery participation and first and second doses.
C_LIO_LIWe adjust for a rich set of individual characteristics associated with vaccination status
C_LIO_LIThe strong association for second dose vaccinations may reflect some individuals who had already had scheduled their second dose after the lottery opened, potentially leading to an overestimate of the association.
C_LI

Ethics statementThis study was approved by the University of Melbourne Faculty of Business and Economics & Melbourne Business School Human Ethics Advisory Group (Ref: 2056754.1).


title: An observational study of the association between COVID-19 vaccination rates and entry into the "Million Dollar Vax" competition


title: Prevalence of Bacterial Coinfection and Patterns of Antibiotics Prescribing in Patients with COVID-19: A Systematic review and Meta-Analysis

abstract:
BackgroundEvidence around prevalence of bacterial coinfection and pattern of antibiotic use in COVID-19 is controversial although high prevalence rates of bacterial coinfection have been reported in previous similar global viral respiratory pandemics. Early data on the prevalence of antibiotic prescribing in COVID-19 indicates conflicting low and high prevalence of antibiotic prescribing which challenges antimicrobial stewardship programmes and increases risk of antimicrobial resistance (AMR).

AimTo determine current prevalence of bacterial coinfection and antibiotic prescribing in COVID-19 patients

Data SourceOVID MEDLINE, OVID EMBASE, Cochrane and MedRxiv between January 2020 and June 2021.

Study EligibilityEnglish language studies of laboratory-confirmed COVID-19 patients which reported (a) prevalence of bacterial coinfection and/or (b) prevalence of antibiotic prescribing with no restrictions to study designs or healthcare setting

ParticipantsAdults (aged [≥] 18 years) with RT-PCR confirmed diagnosis of COVID-19, regardless of study setting.

MethodsSystematic review and meta-analysis. Proportion (prevalence) data was pooled using random effects meta-analysis approach; and stratified based on region and study design.

ResultsA total of 1058 studies were screened, of which 22, hospital-based studies were eligible, compromising 76,176 of COVID-19 patients. Pooled estimates for the prevalence of bacterial co-infection and antibiotic use were 5.62% (95% CI 2.26 - 10.31) and 61.77% (CI 50.95 - 70.90), respectively. Sub-group analysis by region demonstrated that bacterial co-infection was more prevalent in North American studies (7.89%, 95% CI 3.30-14.18).

ConclusionPrevalence of bacterial coinfection in COVID-19 is low, yet prevalence of antibiotic prescribing is high, indicating the need for targeted COVID-19 antimicrobial stewardship initiatives to reduce the global threat of AMR.


title: Morning SARS-CoV-2 testing yields better detection of infection due to higher viral loads in saliva and nasal swabs upon waking

abstract:
BackgroundThe analytical sensitivities of SARS-CoV-2 diagnostic tests span 6 orders of magnitude. Optimizing sample-collection methods to achieve the most reliable detection for a given sensitivity would increase the effectiveness of testing and minimize COVID-19 outbreaks.

MethodsFrom September 2020 to April 2021 we performed a household-transmission study in which participants self-collected samples every morning and evening throughout acute SARS-CoV-2 infection. Seventy mildly symptomatic participants collected saliva and, of those, 29 also collected nasal-swab samples. Viral load was quantified in 1194 saliva and 661 nasal-swab samples using a high-analytical-sensitivity RT-qPCR assay (LOD, 1,000 SARS-CoV-2 RNA copies/mL).

FindingsViral loads in both saliva and nasal-swab samples were significantly higher in morning-collected samples than evening-collected samples after symptom onset. We used these quantitative measurements to infer which diagnostic tests would have detected infection (based on sample type and test analytical sensitivity). We find that morning collection would have resulted in significantly improved detection and that this advantage would be most pronounced for tests with low to moderate analytical sensitivity, which would likely have missed infections if sampling in the evening.

InterpretationCollecting samples for COVID-19 testing in the morning offers a simple and low-cost improvement to clinical diagnostic sensitivity of low- to moderate-analytical-sensitivity tests. The phenomenon of higher viral loads in the morning may also have implications related to when transmission is more likely to occur.

FundingBill & Melinda Gates Foundation, Ronald and Maxine Linde Center for New Initiatives (Caltech), Jacobs Institute for Molecular Engineering for Medicine (Caltech)

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSReliable COVID-19 diagnostic testing is critical to reducing transmission of SARS-CoV-2 and reducing cases of severe or fatal disease, particularly in areas with limited vaccine access or uptake. Saliva and anterior-nares nasal swabs are common sample types; however, different diagnostic tests using these sample types have a range of analytical sensitivities spanning 6 orders of magnitude, with limits of detection (LODs) between 102 and 108 genomic copy equivalents of SARS-CoV-2 RNA (copies) per mL of sample. Due to limitations in clinical laboratory capacity, many low-resource settings rely on COVID-19 tests that fall on the moderate (LODs of 104 to 105 copies/mL) to lower (LODs of 105 to 108 copies/mL) end of this spectrum of analytical sensitivity. Alterations in sample collection methods, including time of sample collection, may improve the performance of these diagnostics.

Added value of this studyThis study quantifies viral loads from saliva and nasal-swab samples that were longitudinally self-collected by symptomatic patients in the morning immediately after waking and in the evening just prior to sleeping throughout the course of acute SARS-CoV-2 infection. The study cohort was composed of mildly or moderately symptomatic individuals (outpatients). This analysis demonstrates significantly higher viral loads in samples collected in the morning, relative to those collected in the evening. When using moderate to lower analytical sensitivity test methods, these loads are inferred to result in significantly better detection of infected individuals in the morning.

Implications of available evidenceThese findings suggest that samples collected in the morning immediately after waking will better detect SARS-CoV-2 infection in symptomatic individuals tested by moderate to lower analytical sensitivity COVID-19 diagnostic tests (LODs at or above 104 viral copies per mL of sample), such as many rapid antigen tests currently available.


title: Deep learning based electrocardiographic screening for chronic kidney disease

abstract:
BackgroundUndiagnosed chronic kidney disease (CKD) is a common and usually asymptomatic disorder that causes a high burden of morbidity and early mortality worldwide. We developed a deep learning model for CKD screening from routinely acquired ECGs.

MethodsWe collected data from a primary cohort with 111,370 patients which had 247,655 ECGs between 2005 and 2019. Using this data, we developed, trained, validated, and tested a deep learning model to predict whether an ECG was taken within one year of the patient receiving a CKD diagnosis. The model was additionally validated using an external cohort from another healthcare system which had 312,145 patients with 896,620 ECGs from between 2005 and 2018.

ResultsUsing 12-lead ECG waveforms, our deep learning algorithm achieved discrimination for CKD of any stage with an AUC of 0.77 (95% CI 0.76-0.77) in a held-out test set and an AUC of 0.71 (0.71-0.71) in the external cohort. Our 12-lead ECG-based model performance was consistent across the severity of CKD, with an AUC of 0.75 (0.0.74-0.77) for mild CKD, AUC of 0.76 (0.75-0.77) for moderate-severe CKD, and an AUC of 0.78 (0.77-0.79) for ESRD. In our internal health system with 1-lead ECG waveform data, our model achieved an AUC of 0.74 (0.74-0.75) in detecting any stage CKD. In the external cohort, our 1-lead ECG-based model achieved an AUC of 0.70 (0.70-0.70). In patients under 60 years old, our model achieved high performance in detecting any stage CKD with both 12-lead (AUC 0.84 [0.84-0.85]) and 1-lead ECG waveform (0.82 [0.81-0.83]).

ConclusionsOur deep learning algorithm was able to detect CKD using ECG waveforms, with particularly strong performance in younger patients and patients with more severe stages of CKD. Given the high global burden of undiagnosed CKD, further studies are warranted to evaluate the clinical utility of ECG-based CKD screening.

category: cardiovascular medicine


title: Stability of diagnostic coding of psychiatric outpatient visits across the transition from the second to the third version of the Danish National Patient Registry

abstract:
BackgroundIn Denmark, data on hospital contacts are reported to the Danish National Patient Registry (DNPR). The ICD-10 main diagnoses from the DNPR are often used as proxies for mental disorders in psychiatric research. With the transition from the second version of the DNPR (DNPR2) to the third (DNPR3) in February-March 2019, the way main diagnoses are coded in relation to outpatient treatment changed substantially. Specifically, in the DNPR2, each outpatient treatment course was labelled with only one main diagnosis. In the DNPR3, however, each visit during an outpatient treatment course is labelled with a main diagnosis. We assessed whether this change led to a break in the diagnostic time-series represented by the DNPR, which would pose a threat to the research relying on this source.

MethodsAll main diagnoses from outpatients attending the Psychiatric Services of the Central Denmark Region from 2013 to 2021 (n=100,501 unique patients) were included in the analyses. The stability of the DNPR diagnostic time-series at the ICD-10 subchapter level was examined by comparing means across the transition from the DNPR2 to the DNPR3.

ResultsWhile the proportion of psychiatric outpatients with diagnoses from some ICD-10 subchapters changed statistically significantly from the DNPR2 to the DNPR3, the changes were small in absolute terms (e.g., +0.9% for F2 - psychotic disorders and +0.1% for F3 - mood disorders).

ConclusionThe change from the DNPR2 to the DNPR3 is unlikely to pose a substantial threat to the validity of most psychiatric research at the diagnostic subchapter level.

Data availabilityDue to restrictions in Danish law for protecting patient privacy, the data used in this study is only available for research projects conducted by employees in the Central Denmark Region following approval from the Legal Office under the Central Denmark Region (in accordance with the Danish Health Care Act [§]46, Section 2). However, similar data can be accessed through Statistics Denmark. Danish institutions can apply for authorization to work with data within Statistics Denmark, and such organisations can provide access to affiliated researchers inside and outside of Denmark.

Significant OutcomesO_LIA significant administrative change in diagnostic coding of psychiatric outpatient treatment in Denmark did not induce marked destabilisation in the incidence of psychiatric diagnoses or the number of diagnoses received by each patient.
C_LIO_LIIn the DNPR3, most outpatient treatment courses are labelled with the same main diagnosis (subchapter level) at the first and last visit.
C_LI

LimitationsO_LIAnalyses were performed on data from the Central Denmark Region. While the administrative change was at the national level, and results should generalise, this is not testable from these data.
C_LIO_LIData was obtained from the Business Intelligence Office. While this source receives data from the same source as the National Patient Registry, and should be identical, this could not be tested.
C_LI


title: The Coronavirus Calendar (CoronaCal): a Simplified SARS-CoV-2 Test System for Sampling and Retrospective Analysis

abstract:
BackgroundThe testing of saliva samples for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA has become a useful and common method to diagnose coronavirus disease 2019 (Covid-19). However, there are limited examples of serial testing with correlated clinical metadata, especially in the outpatient setting.

MethodWe developed a method to collect serial saliva samples on ordinary white printer paper, which can be subsequently analyzed for the presence of SARS-CoV-2 RNA using established polymerase chain reaction (PCR) procedures. The collection systems consisted of a biological diary (CoronaCal) where subjects dab their saliva onto ovals printed onto paper. The dried samples are covered with a sticker that includes a symptom checklist to create a biological diary. Each sheet of letter paper can accommodate up to 14 serial samples.

ResultsIn a pilot study, ten subjects used CoronaCals for durations of nine to 44 days. SARS-CoV-2 RNA was extracted and detected in CoronaCals from nine of nine people with either Covid-19 symptoms or exposure to someone with Covid-19, and in zero of one asymptomatic person. The CoronaCals were stored for up to 70 days at room temperature during collection and then frozen for up to four months before analysis, suggesting that SARS-CoV-2 RNA is stable once dried onto paper. Interestingly, the temporal pattern of symptoms was not well correlated with SARS-CoV-2 RNA in serial daily collections for up to 44 days. In addition, SARS-CoV-2 positivity was discontinuous over time in most cases but persisted for up to 24 days.

ConclusionsWe conclude that sampling of saliva on simple paper CoronaCals may provide a useful method to study the natural history and epidemiology of Covid-19. The CoronaCal collection and testing method we developed is also easy to implement, inexpensive, non-invasive, and scalable. More broadly, the approach can be used to archive biological samples for retrospective analysis to deepen epidemiological understanding during viral disease outbreaks and to provide information about the natural history of emerging infections.


title: Quantifying the impact of association of environmental mixture in a type 1 and type 2 error balanced framework

abstract: In environmental epidemiology, analysis of environmental mixture in association to health effects is gaining popularity. Such models mostly focus on inferences of hypotheses or summarizing strength of association through regression coefficients and corresponding estimates of precision. Nonetheless, when a decision is made against alternative hypothesis, it becomes increasingly difficult to tease apart whether the decision is influenced by sample size or represents genuine absence of association and whether the result warrants further investigation. Similarly, in case of a decision made in favour of alternative hypothesis, a significant association may indicate influence of large sample and not a strong effect. Moreover, the disparate type 1 and type 2 errors, might render these inferences unreliable. Using Cohens f2 to evaluate the strength of explanatory associations in a more fundamental way, we herein propose a new concept, optimal impact, to quantify the maximum explanatory association solely contributed by an environmental-mixture after controlling for confounders and covariates such that the type 2 error remains at its minimum. optimal impact is built upon a novel hypothesis testing procedure in which the rejection region is determined in a way that type 1 and type 2 errors are balanced. Even when an association does not achieve statistical significance, its optimal impact might deem it meaningful and strong enough for further investigation. This idea was naturally extended to estimate sample size in designing studies by striking a balance between explanatory precision and utility. The properties of this framework are carefully studied and detailed results are established. A straightforward application of this procedure is illustrated using an exposure-mixture analysis of per-and-poly-fluoroalkyl substances and metals with serum cholesterols using data from 2017-2018 US National Health and Nutrition Examination Survey.


title: Effects of BA.1/BA.2 subvariant, vaccination, and prior infection on infectiousness of SARS-CoV-2 Omicron infections

abstract:
BACKGROUNDQatar experienced a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021 and peaked in mid-January, 2022. We investigated effects of Omicron subvariant (BA.1 and BA.2), previous vaccination, and prior infection on infectiousness of Omicron infections, between December 23, 2021 and February 20, 2022.

METHODSUnivariable and multivariable regression analyses were conducted to estimate the association between the RT-qPCR cycle threshold (Ct) value of PCR tests (a proxy for SARS-CoV-2 infectiousness) and each of the Omicron subvariants, mRNA vaccination, prior infection, reason for RT-qPCR testing, calendar week of RT-qPCR testing (to account for phases of the rapidly evolving Omicron wave), and demographic factors.

RESULTSCompared to BA.1, BA.2 was associated with 3.53 fewer cycles (95% CI: 3.46-3.60), signifying higher infectiousness. Ct value decreased with time since second and third vaccinations. Ct values were highest for those who received their boosters in the month preceding the RT-qPCR test--0.86 cycles (95% CI: 0.72-1.00) higher than for unvaccinated persons. Ct value was 1.30 (95% CI: 1.20-1.39) cycles higher for those with a prior infection compared to those without prior infection, signifying lower infectiousness. Ct value declined gradually with age. Ct value was lowest for those who were tested because of symptoms and was highest for those who were tested for travel-related purposes. Ct value was lowest during the exponential-growth phase of the Omicron wave and was highest after the wave peaked and was declining.

CONCLUSIONSThe BA.2 subvariant appears substantially more infectious than the BA.1 subvariant. This may reflect higher viral load and/or longer duration of infection, thereby explaining the rapid expansion of this subvariant in Qatar.


title: Process evaluation protocol for the SLEEP study: a hybrid digital CBT-I intervention for working people with insomnia

abstract: Introduction: The Supporting Employees with Insomnia and Emotional Regulation Problems (SLEEP) pilot uses hybrid digital Cognitive Behavioural Therapy for Insomnia (CBT-I) to help working people address their sleep and emotion regulation problems, using cognitive, behavioural, and psychoeducation techniques. A process evaluation within this trial will improve our understanding of how the intervention brought about change, including identifying barriers and facilitators to engagement and subsequent change, and the extent to which contextual factors played a role. Methods and analysis: This qualitative process evaluation will use semi-structured interviews, conducted via online videoconferencing, to explore participant experiences of the SLEEP intervention. Twenty-five participants who completed the SLEEP intervention (16 %) will be randomly sampled. Interviews will be analysed using a thematic and framework analytic approach. A codebook style thematic analysis will be used, and a framework focusing on the research questions will be applied to the codebook. The final report will present themes generated, alongside the finalised codebook. The report resulting from this research will adhere to CORE-Q quality guidelines. Ethics and dissemination: Full approval for the SLEEP study was given by the University of Warwick Biomedical and Research Ethics Committee (BSREC 45/20-21). All data collection adheres to data collection guidelines. Participants provided written informed consent for the main trial, and all interviewees provided additional written and verbal (audio-recorded) consent. The results of the process evaluation will be published in a peer-reviewed journal and presented at conferences. A lay report will be provided to all participants. Trial registration: ISRCTN13596153; Pre-results.


title: Investigating neurophysiological effects of a short course of tDCS for cognition in schizophrenia: a target engagement study.

abstract:
BackgroundCognitive impairment is highly prevalent in schizophrenia and treatment options are severely limited. Development of effective treatments will rely on successful engagement of biological targets. There is growing evidence that the cognitive impairments in schizophrenia are related to impairments in prefrontal cortical inhibition and dysfunctional cortical oscillations.

MethodsIn the current study we sought to investigate whether a short course of transcranial Direct Current Stimulation (tDCS) could modulate these pathophysiological targets. Thirty participants with schizophrenia were recruited and underwent neurobiological assessment (Transcranial Magnetic Stimulation combined with EEG [TMS-EEG] and task-related EEG) and assessment of cognitive functioning (n-back task and the MATRICS Consensus Cognitive Battery). Participants were then randomized to receive 5 sessions of either active or sham anodal tDCS to the left prefrontal cortex. Twenty-four hours after the last tDCS session participants repeated the neurobiological and cognitive assessments. Neurobiological outcome measures were TMS-evoked potentials (TEPs), TMS-related oscillations and oscillatory power during a 2-back task. Cognitive outcome measures were d prime and accurate reaction time on the 2-back and MATRICS scores.

ResultsFollowing active tDCS there was a significant reduction in the N40 TEP amplitude in the left parietal occipital region. There were no other significant changes.

ConclusionsFuture interrogation of evidence based therapeutic targets in large scale RCTs is required.


title: Predicting sex, age, general cognition and mental health with machine learning on brain structural connectomes

abstract: There is increasing expectation that advanced, computationally expensive machine learning techniques, when applied to large population-wide neuroimaging datasets, will help to uncover key differences in the human brain in health and disease. We take a comprehensive approach to explore how multiple aspects of brain structural connectivity can predict sex, age, general cognitive function and general psychopathology, testing different machine learning algorithms from deep learning model (BrainNetCNN) to classical machine learning methods. We modelled N = 8, 183 structural connectomes from UK Biobank using six different structural network weightings obtained from diffusion MRI. Streamline count generally provided highest prediction accuracies in all prediction tasks. Deep learning did not improve on prediction accuracies from simpler linear models. Further, high correlations between model coefficients from deep learning and linear models suggested similar decision mechanisms were used. This highlights that model complexity is unlikely to improve detection of associations between structural connectomes and complex phenotypes.


title: Determinants of COVID-19 vaccine acceptability in Mozambique: the role of institutional trust

abstract:
BackgroundVaccination plays an imperative role in protecting public health and preventing avoidable mortality. Yet, the reasons for vaccine hesitancy are not well understood. This study investigates the factors associated with the acceptability of COVID-19 vaccine in Mozambique.

MethodsThe data came from the three waves of the COVID-19 Knowledge, Attitudes and Practices (KAP) survey which followed a cohort of 1,371 adults in Mozambique over three months (N=3,809). Data collection was through a structured questionnaire using telephone interviewing (CAPI). Multilevel regression analysis was conducted to identify the trajectories of, and the factors associated with COVID-19 vaccine acceptability.

ResultsThere was great volatility in COVID-19 vaccine acceptability over time. Institutional trust was consistently and strongly correlated with different measures of vaccine acceptability. There was a greater decline in vaccine acceptability in people with lower institutional trust. The positive correlation between institutional trust and vaccine acceptability was stronger in younger than older adults. Vaccine acceptability also varied by gender and marital status.

ConclusionsVaccine acceptability is sensitive to news and information circulated in the public domain. Institutional trust is a central driver of vaccine acceptability and contributes to the resilience of the health system. Our study highlights the importance of health communication and building a trustful relationship between the general public and public institutions in the context of a global pandemic.


title: Deep Sequence Modeling for Pressure Controlled Mechanical Ventilation

abstract: This paper presents a deep neural network approach to simulate the pressure of a mechanical ventilator. The traditional mechanical ventilator has a control pressure monitored by a medical practitioner, which could behave inaccurately by missing the proper pressure. This paper exploits recent studies and provides a simulator based on a deep sequence model to predict the airway pressure in the respiratory circuit during the inspiratory phase of a breath given a time series of control parameters and lung attributes. This approach demonstrates the effectiveness of neural network-based controllers in tracking pressure waveforms significantly better than the current industry standard and provides insights to build effective and robust pressure-controlled mechanical ventilators.

category: respiratory medicine


title: Deep sequencing of early T stage colorectal cancers reveals disruption of homologous recombination repair in microsatellite stable tumours with high mutational burdens

abstract: Early T stage colorectal cancers (CRC) that invade lymph nodes (Stage IIIA) are greatly under-represented in large-scale genomic mapping projects such as TCGA datasets. We retrieved 10 Stage IIIA CRC cases, matched these to 16 Stage 1 CRC cases (T1 depth without lymph node metastasis) and carried out deep sequencing of 409 genes using the IonTorrent system. Tumour mutational burdens (TMB) ranged from 2.4-77.2/Mb sequenced. Using mean TMB as a cut-point to define groups, TMB-low (TMB-L) specimens showed higher frequency of KRAS and TP53 mutations in Stage IIIA compared to Stage I, consistent with TCGA data. TMB-High (TMB-H) specimens consisted of both microsatellite instable high (MSI-H) and microsatellite stable (MSS) genotypes. Comparison of TMB-H with TMB-L groups revealed clear differences in mutations of ATM, KDM5C, PIK3CA and APC. APC was less frequently mutated in the TMB-H group although variant composition was more diverse. Variants in ATM were restricted to the TMB-H group, and in four of five MSS specimens we observed the co-occurrence of mutations in homologous recombination repair (HRR) genes in either two of ATM, CDK12, PTEN or ATR, with at least one of these being a truncating mutation. No MSI-H specimens carried nonsense mutations in these genes. These findings add to our knowledge of early T stage CRC and highlight a potential therapeutic vulnerability in the HRR pathway of TMB-H MSS CRC.

category: oncology


title: Clonality and timing of relapsing colorectal cancer metastasis revealed through whole-genome single-cell sequencing

abstract:
BACKGROUNDRecurrence of tumor cells following local and systemic therapy is a significant hurdle in cancer. Most patients with metastatic colorectal cancer (mCRC) will relapse, despite resection of the metastatic lesions. A better understanding of the evolutionary history of recurrent lesions is thus required to identify the spatial and temporal patterns of metastatic progression and expose the genetic determinants of therapeutic resistance.

METHODSUtilizing a robust Bayesian phylogenetic approach, we analyzed a unique single-cell whole-genome sequencing dataset comprising 60 cells sampled from metastatic and recurrent hepatic lesions of a patient with a long-term disease course to investigate the origin, timing, and clonality of a colorectal metastatic relapse. We further tracked the changes in the size of the malignant cell population and evaluated the impact of the treatment strategy on the mutational landscape of this tumor.

RESULTSOur results suggest that the recurrent lesion originated from the clonal expansion of a single drug-resistant metastatic lineage, which began to expand around one year before surgical resection of the relapse. We additionally observed substantial variability in the substitution rates along the tumor cell phylogeny and found a large number of mutations specific to the ancestral lineage that gave rise to the relapse, including non-silent mutations in CRC genes. Moreover, our results point to a substantial contribution of chemotherapy exposure to the overall mutational burden.

CONCLUSIONSOur study suggests that resistant colorectal metastatic clones can quickly grow, even under strong drug-imposed pressure, highlighting the importance of profiling the genomic landscape of tumor lesions to identify mutations potentially contributing to treatment failure.


title: Identifying SARS-CoV-2 Variants of Concern through saliva-based RT-qPCR by targeting recurrent mutation sites

abstract:
SARS-CoV-2 variants of concern (VOCs) continue to pose a public health threat which necessitates a real-time monitoring strategy to compliment whole genome sequencing. Thus, we investigated the efficacy of competitive probe RT-qPCR assays for six mutation sites identified in SARS-CoV-2 VOCs and, after validating the assays with synthetic RNA, performed these assays on positive saliva samples. When compared with whole genome sequence results, the S{Delta}69-70 and ORF1a{Delta}3675-3677 assays demonstrated 93.60% and 68.00% accuracy, respectively. The SNP assays (K417T, E484K, E484Q, L452R) demonstrated 99.20%, 96.40%, 99.60%, and 96.80% accuracies, respectively. Lastly, we screened 345 positive saliva samples from December 7-22, 2021 using Omicron-specific mutation assays and were able to quickly identify rapid spread of Omicron in Upstate South Carolina. Our workflow demonstrates a novel approach for low-cost, real-time population screening of VOCs.

ImportanceSARS-CoV-2 variants of concern and their many sublineages can be characterized by mutations present within their genetic sequences. These mutations can provide selective advantages such as increased transmissibility and antibody evasion, which influences public health recommendations such as mask mandates, quarantine requirements, and treatment regimens. Our real-time RT-qPCR workflow allows for strain identification of SARS-CoV-2 positive saliva samples by targeting common mutation sites shared between VOCs and detecting single nucleotides present at the targeted location. This differential diagnostic system can quickly and effectively identify a wide array of SARS-CoV-2 strains, which can provide more informed public health surveillance strategies in the future.


title: Reverse Inflammaging: Long-term effects of HCV cure on biological age

abstract:
Background and AimsChronic hepatitis C virus (HCV) infection can be cured with direct-acting antiviral agents (DAA). However, not all sequelae of chronic hepatitis C appear to be completely reversible after sustained virologic response (SVR). Recently, chronic viral infections have been shown to be associated with biological age acceleration defined by the epigenetic clock. The aim of this study was to investigate whether chronic HCV infection is associated with epigenetic changes and biological age acceleration and whether this is reversible after SVR.

MethodsWe included 54 well-characterized patients with chronic hepatitis C at three time points: DAA treatment initiation, end of treatment, and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA methylation status from peripheral blood mononuclear cells (PBMC) was generated and used to calculate epigenetic age acceleration (EAA) using Horvaths clock.

ResultsHCV patients had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age-matched reference group (p<0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased to 1.37 years at long-term follow-up. The decrease in EAA was significant only between the end of treatment and follow-up (p=0.01). Interestingly, eight patients who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR.

ConclusionsOur data contribute to the understanding of the biological impact of HCV elimination after DAA and demonstrate that HCV elimination can lead to "reverse inflammaging". In addition, we provide new conceptual ideas for the use of biological age as a potential biomarker for HCV sequelae after SVR.

Lay SummaryChronic hepatitis C virus infection is now curable with direct acting antiviral agents (DAA), but are concomitant and sequelae also fully reversible after cure? Recent data demonstrate that chronic viral infections lead to an increase in biological age as measured by epigenetic DNA methylation status. Using a unique cohort of hepatitis C patients with and without cirrhosis as well as progression to HCC, we demonstrated that these epigenetic changes and concomitant increase in biological age are also observed in chronic HCV infection. Our data further suggest that this effect seems to be partially reversible in the long-term course after sustained virological response (SVR) by DAA therapy and that biological regeneration occurs. In this regard, the recovery effect appears to be dependent on disease course and was significantly lower in patients with progression to HCC. This suggests the use of biological age based on epigenetic state as a potential biomarker for HCV sequelae.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/22271777v1_ufig1.gif" ALT="Figure 1">
View larger version (33K):
org.highwire.dtl.DTLVardef@1095be4org.highwire.dtl.DTLVardef@16fdf7forg.highwire.dtl.DTLVardef@1ba318aorg.highwire.dtl.DTLVardef@10a6a45_HPS_FORMAT_FIGEXP  M_FIG C_FIG Highlights- Patients with chronic hepatitis C have accelerated epigenetic age compared with healthy controls.
- DAA treatment and HCV elimination partially reverse the accelerated epigenetic age in the long-term follow-up.
- Patients who developed hepatocellular carcinoma after HCV elimination did not show reversal of accelerated epigenetic aging during the follow-up.


title: Monitoring and understanding household clustering of SARS-CoV-2 cases using surveillance data in Fulton County, Georgia

abstract:
BackgroundHouseholds are important for SARS-CoV-2 transmission due to high intensity exposure in enclosed living spaces over prolonged durations. Using contact tracing, the secondary attack rate in households is estimated at 18-20%, yet no studies have examined COVID-19 clustering within households to inform testing and prevention strategies. We sought to quantify and characterize household clustering of COVID-19 cases in Fulton County, Georgia and further explore age-specific patterns in household clusters.

MethodsWe used state surveillance data to identify all PCR- or antigen-confirmed cases of COVID-19 in Fulton County, Georgia. Household clustered cases were defined as cases with matching residential address with positive sample collection dates within 28 days of one another. We described proportion of COVID-19 cases that were clustered, stratified by age and over time and explored trends in age of first diagnosed case within clusters and age patterns between first diagnosed case and subsequent household cases.

ResultsBetween 6/1/20-10/31/21, there were 106,233 COVID-19 cases with available address reported in Fulton County. Of these, 31,449 (37%) were from 12,955 household clusters. Children were more likely to be in household clusters than any other age group and children increasingly accounted for the first diagnosed household case, rising from 11% in February 2021 to a high of 31% in August 2021. Bubble plot density of age of first diagnosed case and subsequent household cases mirror age-specific patterns in household social mixing.

DiscussionOne-third of COVID-19 cases in Fulton County were part of a household cluster. High proportion of children in household clusters reflects higher probability of living in larger homes with caregivers or other children. Increasing probability of children as the first diagnosed case coincide with temporal trends in vaccine roll-out among the elderly in March 2021 and the return to in-person schooling for the Fall 2021 semester. While vaccination remains the most effective intervention at reducing household clustering, other household-level interventions should also be emphasized such as timely testing for household members to prevent ongoing transmission.


title: Laboratory verification of new commercial lateral flow assays for Cryptococcal antigen (CrAg) detection against the predicate IMMY CrAg LFA in a reference laboratory in South Africa

abstract:
BackgroundReflex Cryptococcal antigen (CrAg) testing in HIV-positive patients is done routinely at 47 laboratories in South Africa on samples with a confirmed CD4 count <100 cells/l, using the IMMY Lateral Flow Assay (LFA) as the standardized predicate method.

ObjectiveThis study aimed to verify the diagnostic performance of newer CrAg LFA assays against the predicate method.

MethodsRemnant CD4 samples collected between February and June 2019, with confirmed predicate LFA CrAg results, were retested on settled plasma with the (i) IMMY CrAg semi-quantitative (SQ) LFA; (ii) Bio-Rad RDT CryptoPS SQ; and (iii) Dynamiker CrAg SQ assays, within 24 hours of predicate testing. Sensitivity/ specificity analyses were conducted comparing predicate versus the newer assays, with McNemars tests p-values reported for comparative results (p values <0.05 significant). Positivity grading was noted for the IMMY SQ and Bio-Rad assays.

ResultsOf the 254 samples tested, 228 had comparative CrAg results across all assays. The predicate method reported 85 CrAg positive (37.2%), compared to between 35.08 and 37.28% for the Bio-Rad, IMMY SQ and Dynamiker assays. The IMMY CrAg SQ grading (+1 to +5) showed 67% of CrAg positive results had a grading [≥]3, indicative of higher CrAg concentration (infection severity). False-negative results across all assays were <2%, with sensitivity >95% for all. False-positive results were highest for the Dynamiker LFA (14%) with a specificity of 77% (p=0.001). IMMY SQ and Bio-Rad assays specificities exceeded 90% (p=0.6 and 0.12). Internal quality control showed 100% accuracy for all assays.

ConclusionPerformance verification of newer CrAg LFA assays under typical laboratory conditions varied, with best results by IMMY SQ and Bio-Rad. The high burden of HIV and cryptococcal disease in South Africa requires high specificity and - sensitivity (>90%) to prevent unnecessary treatment/hospitalization. The added value of positivity grading for patient management needs confirmation.


title: Adiposity and the risk of dementia: mediating effects from inflammation and lipid levels

abstract:
ObjectiveWhile midlife adiposity is a risk factor for dementia, adiposity in late-life appears to be associated with lower risk. What drives the associations is poorly understood, especially the inverse association in late-life.

MethodsUsing results from genome-wide association studies, we identified inflammation and lipid metabolism as biological pathways involved in both adiposity and dementia. To test if these factors mediate the effect of midlife and/or late-life adiposity on dementia, we then used cohort data from the Swedish Twin Registry, with measures of adiposity and potential mediators taken in midlife (age 40-64, n=5999) or late-life (age 65-90, n=7257). Associations between body-mass index (BMI), waist-hip ratio (WHR), C-reactive protein (CRP), lipid levels, and dementia were tested in survival and mediation analyses.

ResultsOne standard deviation (SD) higher WHR in midlife was associated with 25% (95% CI 2-52%) higher dementia risk, with slight attenuation when adjusting for BMI. No evidence of mediation through CRP or lipid levels was present. After age 65, one SD higher BMI, but not WHR, was associated with 8% (95% CI 1-14%) lower dementia risk. The association was partly mediated by higher CRP and suppressed by lower high-density lipoprotein.

InterpretationThe negative effects of midlife adiposity on dementia risk were driven directly by factors associated with body fat distribution, and not mediated by inflammation or lipid levels. There was an inverse association between late-life adiposity and dementia risk, especially where the bodys inflammatory response and lipid homeostasis is intact.


title: The relationship between BMI and COVID-19: exploring misclassification and selection bias in a two-sample Mendelian randomisation study

abstract:
ObjectiveTo use the example of the effect of body mass index (BMI) on COVID-19 susceptibility and severity to illustrate methods to explore potential selection and misclassification bias in Mendelian randomisation (MR) of COVID-19 determinants.

DesignTwo-sample MR analysis.

SettingSummary statistics from the Genetic Investigation of ANthropometric Traits (GIANT) and COVID-19 Host Genetics Initiative (HGI) consortia.

Participants681,275 participants in GIANT and more than 2.5 million people from the COVID-19 HGI consortia.

ExposureGenetically instrumented BMI.

Main outcome measuresSeven case/control definitions for SARS-CoV-2 infection and COVID-19 severity: very severe respiratory confirmed COVID-19 vs not hospitalised COVID-19 (A1) and vs population (those who were never tested, tested negative or had unknown testing status (A2)); hospitalised COVID-19 vs not hospitalised COVID-19 (B1) and vs population (B2); COVID-19 vs lab/self-reported negative (C1) and vs population (C2); and predicted COVID-19 from self-reported symptoms vs predicted or self-reported non-COVID-19 (D1).

ResultsWith the exception of A1 comparison, genetically higher BMI was associated with higher odds of COVID-19 in all comparison groups, with odds ratios (OR) ranging from 1.11 (95%CI: 0.94, 1.32) for D1 to 1.57 (95%CI: 1.57 (1.39, 1.78) for A2. As a method to assess selection bias, we found no strong evidence of an effect of COVID-19 on BMI in a  no-relevance analysis, in which COVID-19 was considered the exposure, although measured after BMI. We found evidence of genetic correlation between COVID-19 outcomes and potential predictors of selection determined a priori (smoking, education, and income), which could either indicate selection bias or a causal pathway to infection. Results from multivariable MR adjusting for these predictors of selection yielded similar results to the main analysis, suggesting the latter.

ConclusionsWe have proposed a set of analyses for exploring potential selection and misclassification bias in MR studies of risk factors for SARS-CoV-2 infection and COVID-19 and demonstrated this with an illustrative example. Although selection by socioeconomic position and arelated traits is present, MR results are not substantially affected by selection/misclassification bias in our example. We recommend the methods we demonstrate, and provide detailed analytic code for their use, are used in MR studies assessing risk factors for COVID-19, and other MR studies where such biases are likely in the available data.

SummaryO_ST_ABSWhat is already known on this topicC_ST_ABS- Mendelian randomisation (MR) studies have been conducted to investigate the potential causal relationship between body mass index (BMI) and COVID-19 susceptibility and severity.
- There are several sources of selection (e.g. when only subgroups with specific characteristics are tested or respond to study questionnaires) and misclassification (e.g. those not tested are assumed not to have COVID-19) that could bias MR studies of risk factors for COVID-19.
- Previous MR studies have not explored how selection and misclassification bias in the underlying genome-wide association studies could bias MR results.

What this study adds- Using the most recent release of the COVID-19 Host Genetics Initiative data (with data up to June 2021), we demonstrate a potential causal effect of BMI on susceptibility to detected SARS-CoV-2 infection and on severe COVID-19 disease, and that these results are unlikely to be substantially biased due to selection and misclassification.
- This conclusion is based on no evidence of an effect of COVID-19 on BMI (a  no-relevance control study, as BMI was measured before the COVID-19 pandemic) and finding genetic correlation between predictors of selection (e.g. socioeconomic position) and COVID-19 for which multivariable MR supported a role in causing susceptibility to infection.
- We recommend studies use the set of analyses demonstrated here in future MR studies of COVID-19 risk factors, or other examples where selection bias is likely.


title: Covid-19 Exposure Assessment Tool (CEAT): Easy-to-use tool to quantify exposure based on airflow, group behavior, and infection prevalence in the community

abstract: The COVID-19 Exposure Assessment Tool (CEAT) allows users to compare respiratory relative risk to SARS-CoV-2 for various scenarios, providing understanding of how combinations of protective measures affect exposure, dose, and risk. CEAT incorporates mechanistic, stochastic and epidemiological factors including the: 1) emission rate of virus, 2) viral aerosol degradation and removal, 3) duration of activity/exposure, 4) inhalation rates, 5) ventilation rates (indoors/outdoors), 6) volume of indoor space, 7) filtration, 8) mask use and effectiveness, 9) distance between people, 10) group size, 11) current infection rates by variant, 12) prevalence of infection and immunity in the community, 13) vaccination rates of the community, and 14) implementation of COVID-19 testing procedures. Demonstration of CEAT, from published studies of COVID-19 transmission events, shows the model accurately predicts transmission. We also show how health and safety professionals at NASA Ames Research Center used CEAT to manage potential risks posed by SARS-CoV-2 exposures. Given its accuracy and flexibility, the wide use of CEAT will have a long lasting beneficial impact in managing both the current COVID-19 pandemic as well as a variety of other scenarios.


title: Integrative analyses identify potential key genes and calcium-signaling pathway in familial AVNRT using whole-exome sequencing

abstract:
BackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.

ObjectiveTo investigate the genetic contribution of familial AVNRT using a WES approach.

MethodsBlood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using whole-exome sequencing. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.

ResultsAmong 95 reference genes, seven pathogenic genes have been identified both in sporadic and familial AVNRT, including CASQ2, AGXT, ANK2, SYNE2, ZFHX3, GJD3, and SCN4A. Among the 37 reference genes from sporadic AVNRT, five pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, RYR2, COL4A3, NOS1, and ATP2C2. Considering the unique internal pathogenic gene within pedigrees, three genes, TRDN, CASQ2, and WNK1, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including CASQ2, RYR2, TRDN, NOS1, ANK2, and ATP2C2.

ConclusionThese results revealed the underlying mechanism for familial AVNRT.

category: pathology


title: Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity

abstract:
BackgroundThe 3q29 deletion (3q29Del) is a copy number variant (CNV) with the highest known effect size for psychosis-risk (>40-fold increased risk). Systematic research on this CNV offers promising avenues for identifying mechanisms underlying psychosis and related disorders. Relative to other high-impact CNVs like 22q11.2Del, far less is known about the phenotypic presentation and pathophysiology of 3q29Del. Emerging findings indicate that posterior fossa abnormalities are common among 3q29Del carriers; however, their clinical relevance is unknown.

MethodsHere, we report the first in-depth evaluation of psychotic symptoms in study participants with 3q29Del (N=23), using the Structured Interview for Psychosis-Risk Syndromes (SIPS), and compare to SIPS data from 22q11.2Del participants (N=31) and healthy controls (N=279). We also investigate the relationship between psychotic symptoms, cerebellar morphology, and cystic/cyst-like malformations of the posterior fossa in 3q29Del by structural brain imaging.

ResultsCumulatively, 48% of the 3q29Del sample exhibited a psychotic disorder (N=4) or attenuated positive symptoms (N=7), with three individuals with attenuated symptoms meeting the frequency and timing criteria for clinical high risk for psychosis. Males with 3q29Del scored higher in negative symptoms than females. 3q29Del participants had more severe ratings than controls on all domains and exhibited less severe negative symptoms than 22q11.2Del participants. An inverse relationship was identified between positive symptom severity and cerebellar cortex volume in 3q29Del, while cystic/cyst-like malformations yielded no clinical link with psychosis.

ConclusionsOverall, our findings establish the unique and shared profiles of psychotic symptoms across two CNVs and highlight cerebellar involvement in elevated psychosis-risk in 3q29Del.