title: Effects of a single-dose methylphenidate challenge on resting-state functional connectivity in stimulant-treatment naive children and adults with ADHD

abstract: Prior studies suggest that methylphenidate, the primary pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), alters functional brain connectivity. As the neurotransmitter systems targeted by methylphenidate undergo significant alterations throughout development, the effects of methylphenidate on functional connectivity may also be modulated by age. Therefore, we assessed the effects of a single methylphenidate challenge on brain network connectivity in stimulant-treatment naive children and adults with ADHD. We obtained resting-state functional MRI from 50 boys (10-12 years of age) and 49 men (23-40 years of age) with ADHD (DSM IV, all subtypes), before and after an oral challenge with 0.5 mg/kg methylphenidate; and from 11 boys and 12 men as typically-developing controls. Connectivity strength (CS), eigenvector centrality (EC), and betweenness centrality (BC) were calculated for the striatum, thalamus, dorsal anterior cingulate cortex (dACC), and prefrontal cortex (PFC). In line with our hypotheses, we found that methylphenidate decreased measures of connectivity and centrality in the striatum and thalamus in children with ADHD, but increased the same metrics in adults with ADHD. Surprisingly, we found no major effects of methylphenidate in the dACC and PFC in either children or adults. Interestingly, pre-methylphenidate, participants with ADHD showed aberrant connectivity and centrality compared to controls predominantly in frontal regions. Our findings demonstrate that methylphenidates effects on connectivity of subcortical regions are age-dependent in stimulant-treatment naive ADHD patients, likely due to ongoing maturation of dopamine and noradrenaline systems. These findings highlight the importance for future studies to take a developmental perspective when studying the effects of methylphenidate treatment.

category: psychiatry and clinical psychology


title: Quantifying the risks versus benefits of the Pfizer COVID-19 vaccine in Australia: a Bayesian network analysis

abstract: The Pfizer COVID-19 vaccine is associated with increased myocarditis incidence. Constantly evolving evidence regarding incidence and case fatality of COVID-19 and myocarditis related to infection or vaccination, creates challenge for risk-benefit analysis of vaccination programs. Challenges are complicated further by emerging evidence of waning vaccine effectiveness, and variable effectiveness against variants. Here, we build on previous work on the COVID-19 Risk Calculator (CoRiCal) by integrating Australian and international data to inform a Bayesian network that calculates probabilities of outcomes for the Delta variant under different scenarios of Pfizer COVID-19 vaccine coverage, age groups ([≤]12 years), sex, community transmission intensity and vaccine effectiveness. The model estimates that in a population where 5% were unvaccinated, 5% had one dose, 60% had two doses and 30% had three doses, the probabilities of developing and dying from COVID-19-related myocarditis were 239-5847 and 1430-384,684 times higher (depending on age and sex), respectively, than developing vaccine-associated myocarditis. For one million people with this vaccine coverage, where transmission intensity was equivalent to 10% chance of infection over two months, 68,813 symptomatic COVID-19 cases and 981 deaths would be prevented, with 42 and 16 expected cases of vaccine-associated myocarditis in males and females, respectively. The model may be updated to include emerging best evidence, data pertinent to different countries or vaccines, and other outcomes such as long COVID.

category: public and global health


title: Deploying wearable sensors for pandemic mitigation

abstract: Wearable sensors can continuously and passively detect potential respiratory infections, before or absent symptoms. However, the population-level impact of deploying these devices during pandemics is unclear. We built a compartmental model of Canadas second COVID-19 wave and simulated wearable sensor deployment scenarios, systematically varying detection algorithm accuracy, uptake, and adherence. With current detection algorithms and 4% uptake, we found that deploying wearable sensors could have averted 9% of second wave SARS-CoV-2 infections, though 29% of this reduction is attributed to incorrectly quarantining uninfected device users. Improving detection specificity and offering confirmatory rapid tests each minimized incorrect quarantines and associated costs. With a sufficiently low false positive rate, increasing uptake and adherence became effective strategies for scaling averted infections. We concluded that wearable sensor deployment can meaningfully contribute to pandemic mitigation; in the case of COVID-19, technology improvements or supporting measures are required to reduce social and economic costs to acceptable levels.


title: Evaluating Fomite Risk of Brown Paper Bags Storing Personal Protective Equipment Exposed to SARS-CoV-2: A Quasi-Experimental Study

abstract:
IntroductionLiterature is lacking on the safety of storing contaminated PPE in paper bags for reuse, potentially increasing exposure to frontline healthcare workers (HCW) and patients.

ObjectivesTo evaluate the effectiveness of paper bags as a barrier for fomite transmission of SARS-CoV-2 by storing limited reusable face masks, respirators, and face shields.

MethodsThis quasi-experimental study evaluated the presence of SARS-CoV-2 on the interior and exterior surfaces of paper bags containing PPE that had aerosolized exposures in clinical and simulated settings. Between May and October 2020, 30 unique PPE items were collected from critical and intermediate care COVID-19 units at two urban hospitals. Exposed PPE, worn by either an infected patient or HCW during a SARS-CoV-2 aerosolizing event, were placed into an unused brown paper bag. Samples were tested at 30-minute and 12-hour intervals.

ResultsA total of 177 swabs were processed from 30 PPE samples. We found a (12/177 total) 6.8% positivity rate among all samples across both collection sites. Highest positivity rates were associated with ventilator disconnection (1/6 samples, 16.7% positivity) and exposure to respiratory droplets from coughing (2/24 samples, 8.3% positivity), compared to exposure to high-flow nasal cannula (8/129 samples, 6.2% positivity) or tracheostomy surgery (1/18 samples, 5.6% positivity). Positivity rates differed between hospital units. Total positivity rates were similar between 30-minute (6.7%) and 12-hour (6.9%) sample testing time intervals. Control samples exposed to inactivated SARS-CoV-2 droplets had higher total viral counts than samples exposed to nebulized aerosols.

ConclusionsData suggests paper bags are not a significant fomite risk for SARS-CoV-2 transmission. However, controls demonstrated a risk with droplet exposure. Data can inform guidelines for storing and re-using PPE in situations of limited supplies during future pandemics.

category: occupational and environmental health


title: Decoding molecular programs in melanoma brain metastases

abstract: The systemic dissemination of tumor cells and the spatiotemporal development of organ- metastases are associated with loss of therapeutic control and decreased overall survival (OS). The emergence of solitary or multiple brain metastases is frequently observed in melanoma patients and responsible for disease progression and dismal prognosis. Here, we used whole transcriptome and methylome profiling as well as targeted sequencing (TargetSeq) of intraoperative/snap frozen or archived melanoma brain metastases to unravel molecular subgroups and subclonal heterogeneity. We discovered that E-cadherin (Ecad)/BRAFV600E/K, CD271/NRASQ61L/R/K, and tumor infiltrated lymphocytes (TIL)-status molecularly subdivided tumors into proliferative/pigmented and invasive/stem-like irrespective of the intracranial location. Moreover, we identified 46 differentially methylated regions in promoters of 14 genes, subdividing MBM into BRAFmut and NRASmut subgroups. We observed that therapy-resistant, migratory CD271+/Ecadneg subclones derived from Ecad+tumors in an epithelial-mesenchymal transition (EMT)-like process and fostered intracranial progression. Hence, CD271high MBM present a therapy-resistant, progressive subset of tumors that are refractory to conventional therapeutic strategies. The knockdown of CD271 or SOX4 in in vitro established, MBM-derived cell lines decreased cell migration, proliferation, and number of suspension cells that were shed by cell lines of progressive tumors. In summary, we propose that an Ecad-to-CD271 switch of MBM is a rate-limiting process that potentially determines intracranial progression in melanoma patients. The therapeutic control of this process may prevent intracranial progression, increasing patients overall survival.

category: oncology


title: Long-term outcome of corneal collagen crosslinking with riboflavin and UV-A irradiation for keratoconus

abstract:
PurposeTo evaluate long-term outcomes of corneal collagen crosslinking (CXL) using riboflavin and UV-A irradiation and to determine when to repeat CXL.

MethodsIn this retrospective consecutive interventional case series 131 eyes of 131 patients (95 male, 36 female, mean age 29.7{+/-}11.4 years) between 2006 and 2016 received standard CXL (Dresden protocol, epithelium-off) for progressive keratoconus. Corrected distance visual acuity (CDVA) and corneal tomography (K1, K2, Kmax) were repeatedly recorded 1 year (n=103 eyes) to 10 years (n=44) postoperatively. Only one eye per patient was included. Paired t-test or Wilcoxon matched-pairs signed rank test was used for parametric and nonparametric data, respectively.

Results1 to 3 years preoperatively, median K2 significantly increased by 1.1D (p<0.001). Postoperatively, median K2 increased by 0.1D after 1 year, then decreased over the remaining postoperative period by 0.85D (p=0.021). Median apical corneal thickness decreased by 16{micro}m (p=0.012) after 5 years and then returned to preoperative values. Mean CDVA showed a significant improvement (decrease in logMAR 0.12 after 10 years, p=0.010). Kmax fluctuated without significant change. CXL non-responders, defined by a postoperative increase in Kmax>2D, increased from 16% after 5 to 33% after 10 years. Risk factors for non-response were young age, high astigmatism, thin cornea, and atopic dermatitis. 4 eyes were re-treated 3-4 years after first CXL without complications and keratoconus stabilized thereafter.

ConclusionsCXL can slow or stop keratoconus progression. However, as the number of responders declines after 5 years, patients with risk factors may require re-treatment.

category: ophthalmology


title: Developing and testing an integrated patient mHealth and provider dashboard application system for type 2 diabetes management among Medicaid-enrolled pregnant individuals based on a user-centered approach: Mixed-methods study

abstract:
BackgroundMeaningful integration of mobile health (mHealth) applications that capture and provide feedback on important dimensions is lacking and is required to promote behavioral changes that are linked to better maternal and birth outcomes among pregnant individuals. The design and use of digital health technologies among individuals covered by public health insurance is typically overlooked and has implications for how this group can manage their health with the support of technology. Medicaid-enrolled patients with type 2 diabetes (T2D) during pregnancy struggle to manage their diabetes due to clinical and social needs barriers. There is an opportunity to develop a tailored and integrated technology solution (patient mHealth application and provider dashboard) that provides a 360-degree view of the patient for this group that could improve health outcomes and address health inequities.

ObjectiveOur objective is to describe a formative study that developed an integrated patient based mHealth and provider dashboard application system for management among Medicaid-enrolled pregnant patients with T2D. Our goals were to: 1) develop a set of user specifications for the mHealth and dashboard applications; 2) develop prototypes based on user needs; and 3) collect initial impressions of the prototypes to subsequently develop refined tools that are ready for deployment.

MethodsStudy activities followed a double diamond framework with a participatory design mindset. We first conducted a literature review to articulate the problem. Phase I subsequently involved a qualitative inquiry of the needs faced by patients and their providers and current clinical workflows at our AMC (Discover), and brainstorming activities (Define) to ideate and define the value specifications our mHealth and dashboard applications to our end-users. Phase II involved the design and development of low- and high-fidelity prototypes that incorporated a core set of functions based on our Phase I findings and the theoretical underpinnings of social cognitive theory (Develop). We conducted usability and cognitive tests of our high-fidelity prototypes with potential users to gather feedback about the content, function, and aesthetics of the prototypes (Delivery).

ResultsWe recruited seven patients and seven providers in our study. All participants completed Phase I, and three patients (42%) and four providers (57%) completed Phase II. We identified three themes that exemplified pregnancy experience among Medicaid-enrolled individuals with T2D: managing exhaustion, adherence to a new regimen, and preparing for pregnancy. Patients expressed a core set of expected features for an mHealth application: electronically captured and managed information, access to support systems, use of diabetes technology, and help through problem solving and personalized recommendations. Providers indicated a general set of expectations for a dashboard application, including features such as dynamic and actionable data, unmet social needs, enhanced patient-provider communication. We developed "as-is" and "to-be" swim lanes to depict clinical workflows and critical gaps, and we designed high-fidelity prototypes using this information. Participants provided notable feedback to improve the mHealth application (e.g., from a content perspective, patients asked for more details about the achievement of goals) and dashboard (e.g., from a functional perspective, providers suggested to add a checklist for patient completion of educational resources related to T2D during pregnancy). For both applications, participants reported scores for the NASA Task Load Survey (TLX) that were in the 20th percentile of national TLX scores.

ConclusionsDigital health tools have the ability to transform health care among Medicaid-enrolled patients with T2D during pregnancy, with the goal of managing their blood glucose levels, which is a precursor to experiencing a successful pregnancy and birth. Distilling patient and provider needs and preferences - and then using that information, along with prior studies and theory, to develop applications - holds great potential in tackling complicated health care issues. The methods described in our study can be used as a template for future design considerations specific to the development of digital health interventions, including those focused on understudied populations.

category: health informatics


title: A FLOT1 host regulatory allele is associated with a recently expanded Mtb clade in patients with tuberculosis

abstract: The outcome of infectious diseases may depend on the interaction between human and pathogen genomic variations. We explore this relationship in tuberculosis (TB) by conducting a genome-to-genome (g2g) study of paired genomes from humans and the infectious agent Mycobacterium tuberculosis (Mtb) in 1,556 Peruvian TB patients. We identified a significant association between a human variant in the FLOT1 gene and a unique Mtb Lineage 2 (L2) subclade. The host allele affects FLOT1 expression in multiple tissue and cell types including lung, the primary site of TB disease. Phylogenetic analysis shows that the Mtb subclade has expanded rapidly in Peru since its emergence in the 1950s. Unbiased phenotypic profiling demonstrates that strains from the interacting Mtb subclade display different redox metabolism from other L2 strains. This study presents clear evidence that human and bacterial genetic variation interact together to produce different clinical outcomes.

category: infectious diseases


title: Evaluation of a Rapid and Accessible RT-qPCR Approach for SARS-CoV-2 Variant of Concern Identification

abstract:
The ability to distinguish between SARS-CoV-2 variants of concern (VOCs) is of ongoing interest due to differences in transmissibility, response to vaccination, clinical prognosis, and therapy. Although detailed genetic characterization requires whole-genome sequencing (WGS), targeted nucleic acid amplification tests can serve a complementary role in clinical settings, as they are more rapid and accessible than sequencing in most laboratories.

We designed and analytically validated a two-reaction multiplex reverse transcription quantitative PCR (RT-qPCR) assay targeting spike protein mutations L452R, E484K, and N501Y in Reaction 1, and del69-70, K417N, and T478K in Reaction 2. This assay had 95-100% agreement with WGS in 502 upper respiratory swabs collected between April 26 and August 1, 2021, consisting of 43 Alpha, 2 Beta, 20 Gamma, 378 Delta, and 59 non-VOC infections. Validation in a separate group of 230 WGS-confirmed Omicron variant samples collected in December 2021 and January 2022 demonstrated 100% agreement.

This RT-qPCR-based approach can be implemented in clinical laboratories already performing SARS-CoV-2 nucleic acid amplification tests to assist in local epidemiological surveillance and clinical decision-making.


title: The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic

abstract:
BackgroundThe diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and primarily indicated for screening of at-risk relatives.

ObjectivesEvaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with highest likelihood of having a monogenic disease.

MethodsRetrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset and severe phenotype, whereas low scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated.

ResultsA total of 888 probands fulfilled inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%), and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15-20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing.

ConclusionResearch-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis, and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.

category: cardiovascular medicine


title: Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity

abstract: Hepatic de novo lipogenesis is influenced by the branched-chain -keto acid dehydrogenase (BCKDH) kinase (BCKDK). We aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain -ketoacids (BCKAs) and hepatic BCKDK expression are associated with the presence and severity of non-alcoholic fatty liver disease (NAFLD).Eighty metabolites (3 BCKA, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 bariatric surgery patients with severe obesity (BMI > 35 kg/m2) with scored liver biopsy samples. Metabolite principal component analysis (PCA) factors, BCKA, branched-chain amino acids (BCAA), and the BCKA:BCAA ratio were tested for associations with steatosis grade and presence of non-alcoholic steatohepatitis (NASH). Of all analytes tested, only the valine-derived BCKA, -ketoisovalerate, and the BCKA:BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from two independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowers BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

category: endocrinology


title: Disentangling "Bayesian brain" theories of autism spectrum disorder

abstract:
BackgroundBayesian theories of perception have provided a variety of alternative mechanistic explanations for autistic symptoms, including (1) overprecise sensations, (2) imprecise priors, (3) inflexible priors, and (4) altered hierarchical learning. Here, we designed a set of experiments to systematically test predictions from each of the four hypotheses in individuals with autism spectrum disorder (ASD).

MethodsTwo versions of a two-alternative forced-choice (2AFC) random dot motion task were developed to disentangle the influence of sensory inputs and prior expectations and test implications of the four Bayesian hypotheses. Using a cross-sectional observational study design, behavioural data were obtained from participants with autism spectrum disorder (N=47) and a control group (N=50). Analyses used mixed effects models and a drift diffusion model.

ResultsContrary to the sensory overprecision hypothesis, individuals with ASD did not differ from controls in performance or parameter estimates during the perceptual 2AFC task. When adding cues to the task, individuals with ASD profited less from this prior information than controls, as predicted by the imprecise prior hypothesis. However, individuals with ASD were still able to update their initial priors, contradicting the inflexible prior hypothesis. Finally, in line with the hierarchical learning hypothesis, volatility differentially modulated expectation effects, exerting a significantly smaller effect in the ASD group compared to the control group.

ConclusionOur findings support two mutually compatible alterations of perception in ASD (imprecise priors and, to a lesser degree, altered hierarchical learning). By contrast, they are not compatible with the notions of sensory overprecision and inflexible priors.


title: Dopaminergic medication increases motivation to exert cognitive control by reducing subjective effort costs in Parkinson's patients

abstract: Engaging in demanding mental activities requires the allocation of cognitive control, which can be effortful and aversive. Individuals thus tend to avoid exerting cognitive effort if less demanding behavioral options are available. Recent accounts propose a key role for dopamine in motivating behavior by increasing the sensitivity to rewards associated with effort exertion. Whether dopamine additionally plays a specific role in modulating the sensitivity to the costs of cognitive effort, even in the absence of any incentives, is much less clear. To address this question, we assessed cognitive effort avoidance in patients (n = 38) with Parkinsons disease, a condition characterized by loss of midbrain dopaminergic neurons, both ON and OFF dopaminergic medication and compared them to healthy controls (n = 24). Effort avoidance was assessed using the Demand Selection Task (DST), in which participants could freely choose between performing a high-demand or a low-demand version of a task-switching paradigm. Critically, participants were not offered any incentives to choose the more effortful option, nor for good performance. Healthy controls and patients OFF their dopaminergic medications preferred the low-demand option, in keeping with the tendency to avoid effort on this task previously demonstrated in young adults. In contrast, patients ON dopaminergic medications displayed significantly less effort avoidance than when they were OFF medications. This change in preference could not be explained by differences in task-switching performance or the patients ability to detect the different levels of cognitive demand in the DST. Our findings provide evidence that dopamine replacement in Parkinsons patients increases the willingness to engage in cognitively demanding behavior, even in the absence of any clear benefits. These results suggest that dopamine plays a role in reducing the sensitivity to effort costs that is independent of its role in enhancing the sensitivity to the benefits of effort exertion.

category: neurology


title: A novel pathway phenotype of temporal lobe epilepsy and comorbid psychiatric disorders: results of precision nomothetic medicine

abstract: No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities were developed to date. This observational 11study aimed to develop a precision nomothetic, data driven comorbid TLE model with endophenotype classes and pathways phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion a) PP symptoms belong to the TLE phenome and signal increased severity; and b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.


title: Choroid plexus volume predicts expansion of chronic lesions and brain atrophy

abstract:
Background and ObjectivesThe expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus are linked to chronic inflammation and microglial activation. In the current study, we investigated the association between plexus volume and subsequent lesion expansion in patients with relapsing remitting MS.

MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients with relapsing-remitting MS. Choroid plexus volume and lesion activity were analysed between baseline and 48 months.

ResultsPlexus volume remained stable during follow-up period. There was a strong correlation between baseline plexus volume and subsequent rate of chronic lesion expansion (r=0.77, p<0.001), which was stronger in close proximity to CSF. Furthermore, baseline plexus volume was also associated with change of Mean Diffusivity (MD) inside expanding area (r=0.55, p<0.001). There was, however, no correlation between baseline plexus volume and volume of new lesions. A cut-off of 98 x 10-5 plexus/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. Plexus volume larger than a cut-off was associated with >8-fold increased risk of chronic lesion expansion. Furthermore, baseline plexus volume significantly correlated with change of MD in lesional core during the study period (r=0.67, p<0.001) and with central brain atrophy (r=0.57, p<0.001).

ConclusionOur data demonstrate that baseline plexus volume predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage.


title: Methylation risk scores are associated with a collection of phenotypes within electronic health record systems

abstract: Inference of clinical phenotypes is a fundamental task in precision medicine, and has therefore been heavily investigated in recent years in the context of electronic health records (EHR) using a large arsenal of machine learning techniques, as well as in the context of genetics using polygenic risk scores (PRS). In this work, we considered the epigenetic analog of PRS, methylation risk scores (MRS), a linear combination of methylation states. Since methylation states are influenced by both environmental and genetic factors, we hypothesized that MRS would complement PRS and EHR-based machine-learning methods, improving overall prediction accuracy. To evaluate this hypothesis, we performed the largest assessment of methylation risk scores in clinical datasets to be conducted to date. We measured methylation across a large cohort (n=831) of diverse samples in the UCLA Health biobank, for which both genetic and complete EHR data are available. We constructed MRS for 607 phenotypes spanning diagnoses, clinical lab tests, and medication prescriptions. When added to a baseline set of predictive features, MRS significantly improved the imputation of 139 outcomes, whereas the PRS improved only 22 (median improvement for methylation 10.74%, 141.52%, and 15.46% in medications, labs and diagnosis codes, respectively, whereas genotypes only improved the labs at a median increase of 18.42%). We added significant MRS to state-of-the-art EHR imputation methods that leverage the entire set of medical records, and found that including MRS as a medical feature in the algorithm significantly improves EHR imputation in 37% of lab tests examined (median R2 increase 47.6%). Finally, we replicated several MRS in multiple external studies of methylation (minimum p-value of 2.72 x 10-7) and replicated 22 of 30 tested MRS internally in two separate cohorts of different ethnicity. In summary, our work provides a comprehensive evaluation of MRS in comparison to PRS and EHR imputation on the largest dataset consisting of methylation, genotype, and EHR data. Our publicly available results and weights show promise for methylation risk scores as clinical and scientific tools.

category: genetic and genomic medicine


title: Transcriptional profiles predict treatment outcome in patients with tuberculosis and diabetes at diagnosis and at two weeks after initiation of anti-tuberculosis treatment

abstract:
BackgroundGlobally, the anti-tuberculosis (TB) treatment success rate is approximately 85%, with treatment failure, relapse and death occurring in a significant proportion of pulmonary TB patients. Treatment success is lower among people with diabetes mellitus (DM). Predicting treatment failure early after diagnosis would allow early treatment adaptation and may improve global TB control.

MethodsSamples were collected in a longitudinal cohort study of adult TB patients with or without concomitant DM from South Africa and Indonesia to characterize whole blood transcriptional profiles before and during anti-TB treatment, using unbiased RNA-Seq and targeted gene dcRT-MLPA.

FindingsWe report differences in whole blood transcriptome profiles, which were observed before initiation of treatment and throughout treatment, between patients with a good versus poor anti- TB treatment outcome. An eight-gene and a 22-gene blood transcriptional signature distinguished patients with a good treatment outcome from patients with a poor treatment outcome at diagnosis (AUC=0{middle dot}815) or two weeks (AUC=0{middle dot}834) after initiation of anti-TB treatment, respectively. High accuracy was obtained by cross-validating this signature in an external cohort (AUC=0{middle dot}749).

InterpretationThese findings suggest that transcriptional profiles can be used as a prognostic biomarker for treatment failure and success, even in patients with concomitant DM.

FundingThe research leading to these results, as part of the TANDEM Consortium, received funding from the European Communitys Seventh Framework Programme (FP7/2007-2013 Grant Agreement No. 305279) and the Netherlands Organization for Scientific Research (NWO-TOP Grant Agreement No. 91214038).


title: SARS-CoV-2 Seroprevalence in three Kenyan Health and Demographic Surveillance Sites, December 2020-May 2021

abstract:
BackgroundMost of the studies that have informed the public health response to the COVID-19 pandemic in Kenya have relied on samples that are not representative of the general population. We conducted population-based serosurveys at three Health and Demographic Surveillance Systems (HDSSs) to determine the cumulative incidence of infection with SARS-CoV-2.

MethodsWe selected random age-stratified population-based samples at HDSSs in Kisumu, Nairobi and Kilifi, in Kenya. Blood samples were collected from participants between 01 Dec 2020 and 27 May 2021. No participant had received a COVID-19 vaccine. We tested for IgG antibodies to SARS-CoV-2 spike protein using ELISA. Locally-validated assay sensitivity and specificity were 93% (95% CI 88-96%) and 99% (95% CI 98-99.5%), respectively. We adjusted prevalence estimates using classical methods and Bayesian modelling to account for the sampling scheme and assay performance.

ResultsWe recruited 2,559 individuals from the three HDSS sites, median age (IQR) 27 (10-78) years and 52% were female. Seroprevalence at all three sites rose steadily during the study period. In Kisumu, Nairobi and Kilifi, seroprevalences (95% CI) at the beginning of the study were 36.0% (28.2-44.4%), 32.4% (23.1-42.4%), and 14.5% (9.1-21%), and respectively; at the end they were 42.0% (34.7-50.0%), 50.2% (39.7-61.1%), and 24.7% (17.5-32.6%), respectively. Seroprevalence was substantially lower among children (<16 years) than among adults at all three sites (p[≤]0.001).

ConclusionBy May 2021 in three broadly representative populations of unvaccinated individuals in Kenya, seroprevalence of anti-SARS-CoV-2 IgG was 25-50%. There was wide variation in cumulative incidence by location and age.


title: Bacterial Pneumonia and Respiratory Culture Utilization among Hospitalized Patients with and without COVID-19 in New York City

abstract: COVID-19 is associated with prolonged hospitalization and a high risk of intubation, which raises concern for bacterial co-infection and antimicrobial resistance. Previous research has shown a wide range of bacterial pneumonia rates for COVID-19 patients in a variety of clinical and demographic settings, but none have compared hospitalized COVID-19 patients to patients testing negative for SARS-CoV-2 in similar care settings. We performed a retrospective cohort study on hospitalized patients with COVID-19 testing from 10 March 2020 to 31 December 2020. A total of 19,219 patients were included, of which 3,796 tested positive for SARS-CoV-2. We found a 2.6-fold increase (p < 0.001) in respiratory culture ordering in COVID-19 patients. On a per-patient basis, COVID-19 patients were 1.5-fold more likely than non-COVID patients to have abnormal respiratory cultures (46.8% vs. 30.9%, p < 0.001), which was primarily driven by patients requiring intubation. Among patients with pneumonia, a significantly higher proportion of COVID-19 patients had ventilator-associated pneumonia (VAP) relative to non-COVID patients (85.7% vs 55.1%, p <0.001), but a lower proportion had community-acquired (12.2% vs 22.1%, p < 0.01) or hospital-acquired pneumonia (2.1% vs. 22.8%, p < 0.001). There was also a significantly higher proportion of respiratory cultures positive for MRSA, K. pneumoniae, and antibiotic-resistant organisms in COVID-19 patients. Increased rates of respiratory culture ordering for COVID-19 patients therefore appear to be clinically justified for patients requiring intubation, but further research is needed to understand how SARS-CoV-2 increases the risk of VAP.


title: Cardiovascular Signatures of COVID-19 Predict Mortality and Identify Barrier Stabilizing Therapies

abstract:
STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSEndothelial cell (EC) activation, endotheliitis, vascular permeability, and thrombosis have been observed in patients with severe COVID-19, indicating that the vasculature is affected during the acute stages of SARS-CoV-2 infection. It remains unknown whether circulating vascular markers are sufficient to predict clinical outcomes, are unique to COVID-19, and if vascular permeability can be therapeutically targeted.

MethodsEvaluating the prevalence of circulating inflammatory, cardiac and EC activation markers, and the development of a microRNA atlas in 241 patients with suspected SARS-CoV-2 infection, allowed their prognostic value to be assessed by a Random Forest model machine learning approach. Subsequent ex vivo experiments assessed EC permeability responses to patient plasma and were used to uncover modulated gene regulatory networks from which rational therapeutic design was inferred.

FindingsMultiple inflammatory and EC activation biomarkers were associated with mortality in COVID-19 patients and in severity-matched SARS-CoV-2-negative patients, while dysregulation of specific microRNAs at presentation was specific for poor COVID-19-related outcomes and revealed disease-relevant pathways. Integrating the datasets using a machine learning approach further enhanced clinical risk prediction for in-hospital mortality. Exposure of ECs to COVID-19 patient plasma resulted in severity-specific gene expression responses and EC barrier dysfunction which was ameliorated using angiopoietin-1 mimetic or recombinant Slit2-N.

InterpretationIntegration of multi-omics data identified microRNA and vascular biomarkers prognostic of in-hospital mortality in COVID-19 patients and revealed that vascular stabilizing therapies should be explored as a treatment for endothelial dysfunction in COVID-19, and other severe diseases where endothelial dysfunction has a central role in pathogenesis.

RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWhile diagnostic testing has allowed for the rapid identification of COVID-19 cases, the lack of post-diagnosis risk assessment metrics, especially among the highest-risk subgroups, thereby undermined the cascade and allocation of care. To date, the integration of clinical data with broad omics technologies has opened up new avenues for efficiently delineating complex patient phenotypes and their associations with clinical outcomes, with circulating profiles of plasma microRNAs (miRNA), in particular, having been shown to be tightly associated with disease, and capable of providing not only detailed prognostic information but also mechanistic insight.

Added value of this studyMarkers of endothelial dysfunction at presentation, while indicative of poor outcomes in COVID-19-positive patients, likely reflect systemic vascular dysfunction in critically ill patients and are not specific to SARS-CoV-2 infection. More so, the generation of a plasma microRNA atlas uncovers COVID-19-specific prognostic markers and multiple disease-specific pathways of interest, including endothelial barrier dysfunction. Furthermore, synthesis of electronic health record data with clinically relevant multi-omic datasets using a machine learning approach provides substantially better metrics by which mortality can be estimated in patients with severe COVID-19. Finally, targeted stabilization of the endothelial barrier with Q-Peptide and Slit2-N are novel therapeutic avenues that should be explored in COVID-19 patients.

Implications of all the available evidenceTogether, our work provides biological insight into the role of the endothelium in SARS-CoV-2 infection, the importance of miRNA as disease- and pathway-specific biomarkers, and the exciting possibility that endothelial barrier stabilizing treatments might hold promise in COVID-19.

category: intensive care and critical care medicine


title: Monitoring SARS-CoV-2 in wastewater during New York City's second wave of COVID-19: Sewershed-level trends and relationships to publicly available clinical testing data

abstract: New York Citys ongoing wastewater monitoring program tracked trends in sewershed-level SARS-CoV-2 loads starting in the fall of 2020, just before the start of the Citys second wave of the COVID-19 outbreak. During a five-month study period, from November 8, 2020 to April 11, 2021, viral loads in influent wastewater from each of New York Citys 14 wastewater treatment plants were measured and compared to new laboratory-confirmed COVID-19 cases for the populations in each corresponding sewershed, estimated from publicly available clinical testing data. We found significant positive correlations between viral loads in wastewater and new COVID-19 cases. The strength of the correlations varied depending on the sewershed, with Spearmans rank correlation coefficients ranging between 0.38 and 0.81 (mean = 0.55). Based on a linear regression analysis of a combined data set for New York City, we found that a 1 log10 change in the SARS-CoV-2 viral load in wastewater corresponded to a 0.6 log10 change in the number of new laboratory-confirmed COVID-19 cases/day in a sewershed. An estimated minimum detectable case rate between 2 - 8 cases/day/100,000 people was associated with the method limit of detection in wastewater. This work offers a preliminary assessment of the relationship between wastewater monitoring data and clinical testing data in New York City. While routine monitoring and method optimization continue, information on the development of New York Citys ongoing wastewater monitoring program may provide insights for similar wastewater-based epidemiology efforts in the future.

category: epidemiology


title: Post-acute sequelae of COVID-19 and adverse psychiatric outcomes: an etiology and risk systematic review protocol

abstract:
IntroductionThe post-acute sequelae of COVID-19 (PASC) is a syndrome characterized by persistent COVID-19 symptoms or the onset of new symptoms following recovery from the initial or acute phase of the illness. Such symptoms often occur four or more weeks after being diagnosed with COVID-19. Although a lot of work has gone into understanding the long-term mental health effects of PASC, many questions related to the etiology and risk of this condition remain. Thus, this protocol is for a systematic review assessing the association between PASC and adverse psychiatric outcomes and whether people with PASC are at greater risk of developing an adverse psychiatric outcome than those without PASC.

Methods and analysisVarious medical databases (e.g., PubMed and EMBASE) will be searched for eligible articles using predefined search criteria. Gray literature will also be explored. Epidemiological observational studies and secondary analyses of randomized controlled trials that report a quantitative relationship between PASC and at least one adverse psychiatric outcome will be included. The Population, Exposure of interest, Comparator, and Outcome (PECO) framework will be used as a standardized framework for the inclusion criteria. The Joanna Briggs Institute (JBI) critical appraisal tools will be used to assess methodological quality and critically appraise the risk of bias in included studies. A random-effects meta-analysis will be conducted if possible. A formal narrative synthesis will be performed if a meta-analysis is impossible due to substantial heterogeneity across studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to rate the cumulative certainty of the evidence for all outcomes.

Ethics and DisseminationEthical approval is not required for this study. The study results will be published in a peer-reviewed journal.

Prospero registration numberCRD42022308737

Strengths and limitations of this study{blacksquare} This study documents and addresses etiology, risk factors, and long-term symptoms of COVID-19 among people with post-acute sequelae of COVID-19 (PASC).
{blacksquare}It focuses on a key priority area for new evidence syntheses on the clinical management of COVID-19 and pandemic-related conditions.
{blacksquare}It will include evidence on non-hospitalized and hospitalized patients with a history of PASC.
{blacksquare}Substantial heterogeneity across studies may limit the ability to perform a meta-analysis.
{blacksquare}Findings will inform disease prevention, decision-making, healthcare policy, and clinical research.


title: Community vaccination can shorten the COVID-19 isolation period: an individual-based modeling approach

abstract:
BackgroundIsolation of infected individuals and quarantine of their contacts are usually employed to mitigate the transmission of SARS-CoV-2. While 14-day isolation of infected individuals could effectively reduce the risk of subsequence transmission, it also significantly impacts the patients financial, psychological, and emotional well-being. It is, therefore, vital to investigate how the isolation duration could be shortened when effective vaccines are available and in what circumstances we can live with COVID-19 without isolation and quarantine.

MethodsAn individual-based modeling approach was employed to estimate the likelihood of secondary infections and the likelihood of an outbreak following the isolation of an index case for a range of isolation periods. Our individual-based model integrates the viral loads and infectiousness profiles of vaccinated and unvaccinated infected individuals. The effects of waning vaccine-induced immunity against Delta and Omicron variant transmission were also investigated.

ResultsIn the baseline scenario in which all individuals are unvaccinated, and no nonpharmaceutical interventions are employed, there is a chance of about 3% that an unvaccinated index case will make at least one secondary infection after being isolated for 14 days, and a sustained chain of transmission can occur with a chance of less than 1%. We found that at the outbreak risk equivalent to that of 14-day isolation in the baseline scenario, the isolation duration can be shortened to 7.33 days (95% CI 6.68-7.98) if 75% of people in the community are fully vaccinated during the last three months. In the best-case scenario in which all individuals in the community are fully vaccinated, isolation of infected individuals may no longer be necessary. However, to keep the outbreak risk low, a booster vaccination may be necessary three months after full vaccination. Finally, our simulations showed that the reduced vaccine effectiveness against transmission of the Omicron variant does not much affect the risk of an outbreak if the vaccine effectiveness against infection is maintained at a high level via booster vaccination.

ConclusionsThe isolation duration of a vaccine breakthrough infector could be safely shortened if a majority of people in the community are immune to SARS-CoV-2 infection. A booster vaccination may be necessary three months after full vaccination to keep the outbreak risk low.


title: Both general- and central- obesity are causally associated with polycystic ovarian syndrome: Findings of a Mendelian randomization study

abstract:
IntroductionObesity is observed in a majority of women with polycystic ovarian syndrome (PCOS). Using body mass index (BMI) as a proxy, previous Mendelian randomization studies revealed general obesity potentially causes PCOS. Central obesity frequently demonstrates a stronger association with PCOS, although evidence on its causality is sparse.

ObjectivesTo investigate causal effects of both central- and general- obesity on the development of PCOS via two-sample Mendelian randomization (2SMR).

MethodsSummary GWAS data of female-only, large-sample cohorts of European ancestry were retrieved for anthropometric markers of central obesity (waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR)) and general obesity (BMI and its constituent variables - weight and height), from the IEU Open GWAS Project. As the outcome data, we acquired summary data from a large-sample GWAS (96391 samples; 219 cases and 96172 controls) from the FinnGen cohort. Four 2SMR methods were applied: inverse variance weighted (IVW); MR Egger (MRE); weighted median (WME); weighted mode (WMO). Single SNP-, leave-one-out-, heterogeneity-, horizontal pleiotropy- and outlier- analyses were conducted. Genetic architectures underlying causal associations were explored.

ResultsAll SNPs selected as instrumental variables demonstrated no weak instrument bias (F > 10). Three anthropometric exposures, namely, BMI (OR: 5.55 - 7.24, WC (OR: 6.79 - 24.56), and HC (OR: 6.78 - 24.56), significantly causally associated with PCOS as per IVW, WME, and WMO models. Single SNP- and leave-one-out- sensitivity analysis results were indicative of robust causal estimates. No significant heterogeneity, horizontal pleiotropy, and outliers were observed. We observed a considerable degree of overlap (7 SNPs; 17 genes) across significant causal findings as well as a number of SNPs and genes that were not shared between causal associations.

ConclusionsThis study revealed that both and general- and central obesity potentially cause PCOS. Findings underscore the importance of addressing obesity and adiposity for the prevention and management of PCOS.


title: Heterogeneity of Irritability: Psychometrics of The Irritability and Dysregulation of Emotion Scale (TIDES-13).

abstract:
ObjectiveWe designed The Irritability and Dysregulation of Emotion Scale (TIDES-13) to test whether irritability consisted of several sub-dimensions that would correlate differentially with internalizing/externalizing psychopathology, age, and gender.

MethodParent-report (n = 3935, mean age = 8.9) and youth self-report (n = 579, mean age = 15.1) versions of TIDES-13 were administered to a population-based sample. Exploratory and confirmatory factor analyses were conducted on separate sub-samples. We fit multivariable regression models between TIDES-13 sub-dimensions and age, gender, anxiety, depression, ODD and ADHD trait levels.

ResultsA higher order model with a global irritability dimension and Proneness to Anger, Internalized Negative Emotional Reactivity, Externalized Negative Emotional Reactivity and Reactive Aggression sub-dimensions showed good to excellent fit in both parent-report and self-report. The global irritability dimension had a strong influence on all item variance ({omega}Hierarchical; parent report = .0.94, {omega}Hierarchical; self report = .90). Proneness to Anger, Externalized Negative Emotional Reactivity and Reactive Aggression decreased with age in males, whereas Internal Negative Emotional Reactivity increased with age in females. Internalized Negative Emotional Reactivity was associated with internalizing traits, over and above global irritability. ODD and ADHD were predicted primarily by the global irritability.

ConclusionAlthough irritability can be estimated as an essentially unidimensional construct, differential associations of Internalized Negative Emotional Reactivity with gender and age, and internalizing psychopathology warrant examination in clinical populations. These results support TIDES-13 as a reliable and valid multidimensional measure of irritability and thus may be useful for research and clinical purposes.


title: Robust Determinants of Neurocognitive Development in Children: Evidence from the Pune Maternal Nutrition Study (PMNS)

abstract: Neurocognitive development is a dynamic process over the life course and is influenced by intrauterine factors as well as later life environment. Using data from the Pune Maternal Nutrition Study (PMNS) from 1994 to 2008, we investigate the association of in-utero, birth, and childhood conditions with offspring neurocognitive development in 686 participants of the cohort, at age 12 years. The life course exposure variables in the analysis include maternal pre-pregnancy size and nutrition during pregnancy, offspring birth measurements, nutrition and physical growth at age 12 years along with parental education and socio-economic status. We used the novel Bayesian Model Averaging (BMA) approach; which has been shown to have better predictive performance over traditional tests of associations. Our study employs 8 standard neurocognitive tests that measure intelligence, working memory, visuo-conceptual and verbal learning, and decision-making/attention at 12 years of age. We control for nutritional-metabolic information based on blood measurements from the pregnant mothers and the children at 12 years of age. Our findings highlight the critical role of parental education and socioeconomic background in determining child neurocognitive performance. Maternal characteristics (pre-pregnancy BMI, fasting insulin during pregnancy) and child height at 12 years were also robust predictors on the BMA. A range of early factors - such as maternal folate and ferritin concentrations during pregnancy, and childs head circumference at birth - remained important determinants of some dimensions of childs neurocognitive development, but their associations were not robust once we account for model uncertainty. Our results suggest that intrauterine influences on long term neurocognitive outcomes may be potentially reversible by post birth remediation. In addition to the current nutritional interventions, public health policy should also consider social interventions in children born into families with low socio-economic status to improve human capital.


title: Improving breast cancer diagnostics with artificial intelligence for MRI

abstract:
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has a very high sensitivity in detecting breast cancer, but it often leads to unnecessary biopsies and patient workup. In this paper, we used an artificial intelligence (AI) system to improve the overall accuracy of breast cancer diagnosis and personalize management of patients undergoing DCE-MRI. On the internal test set (N=3,936 exams), our system achieved an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% CI: 0.92-0.93). In a retrospective reader study, there was no statistically significant difference between 5 board-certified breast radiologists and the AI system (mean {Delta}AUROC +0.04 in favor of the AI system). Radiologists performance improved when their predictions were averaged with AIs predictions (mean {Delta}AUPRC [area under the precision-recall curve] +0.07). Those hybrid predictions also increase interreader agreement (Fleiss kappa {Delta} +0.21 (0.16-0.26)). We demonstrated the generalizability of the AI system using multiple data sets from Poland and the US. In subgroup analysis, we observed consistent results across different cancer subtypes and patient demographics. Using the decision curve analysis, we showed that the AI system can reduce unnecessary biopsies in the range of clinically relevant risk thresholds. This would lead to avoiding benign biopsies in up to 20% of all BI-RADS category 4 patients. Finally, we performed an error analysis, investigating situations where AI predictions were mostly incorrect. This exploratory work creates a foundation for deployment and prospective analysis of AI-based models for breast MRI.

One Sentence SummaryWe developed and evaluated an AI system for predicting breast cancer in MRI that matches the performance of board-certified radiologists and has the potential to prevent unnecessary biopsies.

category: radiology and imaging


title: A Match Made in Cyberspace: Applicant Perspectives on Virtual Residency Interviews

abstract:
PurposeThe COVID-19 pandemic precipitated an entirely virtual 2020-2021 residency application cycle. As many specialties plan to continue virtual interviews, it is essential to evaluate what aspects worked well and what can be improved.

MethodsFrom April to June 2021, authors surveyed participants of the 2020-2021 Match about their experiences with the virtual application cycle. Survey items asked about benefits and drawbacks of virtual interviews, the utility of social media, and thoughts regarding preference signaling mechanisms and application/interview limits.

ResultsParticipants (n=158) represented 24 states and applied to 31 specialties. The majority (73.1%) were satisfied with their experience during the 2020-2021 Match. Applicants found Twitter (78.4%) and Instagram (69.1%) to be the most helpful social media platforms. Almost all applicants (98.1%) believed that the virtual setting increased financial access to interviews. The majority (68.6%) indicated that residency programs should continue to provide virtual interviews. However, most applicants (73.9%) felt that the virtual setting allowed more students to "hoard" interviews. Many (66.1%) also felt their medical school did not provide adequate electronic equipment for conducting virtual interviews. While many applicants (56.9%) did not support a cap on the number of applications one can submit, most supported a limit on the number of interviews one can attend (62.7%) as well as a mechanism to signal genuine interest in a program (59.7%).

ConclusionsOur study highlights that, across geography and specialty, many applicants would like virtual interviews to continue and offers insight into how medical schools and residency programs can best support applicants in the virtual environment. The virtual setting also provides an opportunity to evaluate mechanisms to address the congestion from the increasingly high number of applications residency programs receive, with most applicants supporting interview caps and preference signaling.

category: medical education


title: The changes in white matter pathways that occur in acute sports-related mild Traumatic Brain Injury

abstract: Sports-related concussion, a form of mild traumatic brain injury (mTBI), is characterised by transient disturbances of brain function. There is increasing evidence that functional brain changes are driven by subtle abnormalities in white matter microstructure, and diffusion MRI has been instrumental in demonstrating these white matter abnormalities in vivo. However, the reported location and direction of the observed white matter changes in mTBI are quite variable, which is likely attributable to the inherent limitations of the white matter models used. In this cross-sectional study, we apply an advanced and robust technique known as fixel-based analysis to investigate fibre tract-specific abnormalities in professional Australian Football League players with a recent mTBI. We used the fixel-based analysis framework to identify common abnormalities found in specific fibre tracts in participants with an acute mTBI (< 2 weeks after injury; n = 15). We then assessed whether similar changes exist in subacute mTBI (> 2 weeks and < 3 months after injury; n = 15). The control group was 30 neurologically healthy control participants. We assessed microstructural differences in fibre density and fibre bundle morphology and performed whole-brain fixel-based analysis to compare groups. Subsequent tract-of-interest analyses were performed within five selected white matter tracts, to investigate the relationship between the observed tract-specific abnormalities and days since injury, as well as the relationship between these tract-specific changes with cognitive abnormalities. Our whole-brain analyses revealed significant increases in fibre density and bundle cross-section in acute mTBI when compared to controls. Acute mTBI showed even more extensive differences when compared to subacute mTBI than to controls. The fibre structures affected in acute mTBI included the corpus callosum, left prefrontal and left parahippocampal white matter. The fibre density and cross-sectional increases were independent of time since injury in acute mTBI, and were not associated with cognitive deficits. Overall, this study demonstrates that acute mTBI is characterised by specific white matter abnormalities, which are compatible with tract-specific cytotoxic oedema. These oedematous changes were absent in our subacute mTBI participants, although subtle abnormalities may persist in the subacute stage.


title: Marker genes of incident type 1 diabetes in peripheral blood mononuclear cells of children: A machine learning strategy for large-p, small-n scenarios

abstract:
Background and objectiveType 1 diabetes (TID) is a complex, polygenic disorder, the etiology of which is not fully elucidated. Machine learning (ML) genomics could provide novel insights on disease dynamics while high-dimensionality remains a challenge. This study aimed to identify marker genes of incident T1D in peripheral blood mononuclear cells (PBMC) of children via a ML strategy attuned to high-dimensionality.

MethodsUsing samples from 105 children (81 with incident T1D and 24 healthy controls), we analyzed microarray transcriptomics via a workflow consisting of three sequential steps: application of dimension reduction strategies on the processed transcriptome; ML on the reduced gene expression matrix; and downstream network analyses to demarcate seed nodes (statistically significant genes) and hub genes. Sixteen dimension-reduction algorithms belonging to three groups (3 tailored; 3 regularizations; 10 classic) were applied. Four ML algorithms (multivariate adaptive regression splines, adaptive boosting, random forests, XGB-DART) were trained on the reduced feature set and internally-validated using repeated, 10-fold cross-validation. Marker genes were determined via variable importance metrics. Seed nodes were identified by the  OmicsNet platform while nodes having above average betweenness, closeness, and degree in the network were demarcated as hub genes.

ResultsThe processed gene expression matrix comprised 13515 genes which was reduced to contain 1003 genes collectively selected by dimension reduction algorithms. All four ML algorithms on this reduced feature set attained perfect and uniform predictive performance on internal validation. On removal of redundancies, variable importance metrics identified 30 marker genes of incident T1D in this cohort, while Early Growth Response 2 (EGR2) was uniformly selected by all four ML algorithms as the most important marker gene. Network analyses classified all 30 marker genes as seed nodes. Additionally, we identified 14 hub genes, 7 of which were found to be marker genes of incident T1D elucidated by ML.

ConclusionsWe identified marker genes of incident T1D in PBMC of children via a ML analytic strategy attuned to the high dimensional structure of microarrays, with downstream analyses providing high biological plausibility. The demonstrated ML strategy would be useful in analyzing other high-dimensional biomedical data for biomarker discovery.


title: A recombinant BCG-based vaccine against the human respiratory syncytial virus induces a balanced cellular immune response against viral and mycobacterial antigens

abstract:
BACKGROUNDThe human respiratory syncytial virus (hRSV) is a respiratory pathogen responsible for most cases of acute lower respiratory tract infections in infants worldwide. Although this virus represents a significant social and economic burden, there are no safe and effective available vaccines. rBCG-N-hRSV is a vaccine candidate consisting of a recombinant attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) expressing the nucleoprotein of hRSV (N-hRSV).

METHODSrBCG-N-hRSV was applied intradermally in three different doses (5x103, 5x104, or 1x105 CFU) to healthy adults enrolled in a randomized, double-blind, dose-escalating phase 1 clinical trial (NCT03213405). Blood samples were taken before and at various time points after immunization. Cellular and humoral immune parameters were assessed by analyzing circulating immune cells and sera, respectively.

RESULTSPerforin- and Granzyme B-producing PBMCs recognizing viral or mycobacterial antigens were found to increase after immunization with rBCG-N-hRSV. These cells also upregulated IFN-{gamma} and IL-10 secretion in response to N-hRSV and upregulated IFN-{gamma}, IL-6, and TNF- secretion in response to mycobacterial proteins. While naive T cell populations contracted over time, no specific memory T cell subset expanded significantly. Although binding to C1q by anti-N-hRSV or anti-mycobacterial antibodies decreased slightly after immunization, no apparent changes were found in the concentration of IgG subclasses against N-hRSV or mycobacterial antigens.

CONCLUSIONSThe immune response elicited by immunization with rBCG-N-hRSV consists mainly of antigen-specific T cells. The data reported here provide novel information about the characteristics of the immune response elicited after immunization with rBCG-N-hRSV, supporting the safety and immunogenicity of this vaccine.


title: COPD and social distancing in the UK

abstract:
BackgroundThose with Chronic Obstructive Pulmonary Disease (COPD) were at a higher risk of experiencing severe illness in the event of contracting COVID-19. Did they therefore act more cautiously?

AimThe aim was to determine whether the condition of COPD incurred significant change in social distancing behavior compared to the general public.

Design and SettingData was used from the Imperial  COVID-19 Behavioural Tracker, which details results of regular public surveying on attitudes surrounding COVID-19 guidance.

MethodsResponses by U.K. participants to twenty questions reflecting willingness to adhere to social distancing guidance were compared in those reporting COPD and non-COPD status.

ResultsThose with COPD stated a significantly greater willingness to wear face masks during early stages of pandemic. There was greater reluctance to go out and go shopping. There was no apparent or significant difference in willingness to use public transport, suggesting that this was an unavoidable necessity for all. The relationship between level of adherence and COVID-19 case numbers was weak both for those of both COPD and non-COPD status.

DiscussionThese results suggest that those with COPD were more cautious and followed guidance more willingly. Advice provided by GPs and healthcare professionals is likely to be beneficial in guiding patient behaviour.


title: The interaction effect between hemoglobin and hypoxemia on COVID-19 mortality in a sample from Bogota, Colombia: An exploratory study.

abstract:
PurposeWe aimed to assess the effect of hemoglobin (Hb) concentration and oxygenation index on COVID-19 patients mortality risk.

Patients and methodsWe retrospectively reviewed sociodemographic and clinical characteristics, laboratory findings, and clinical outcomes from patients admitted to a tertiary care hospital in Bogota, Colombia. We assessed exploratory associations between oxygenation index and Hb concentration at admission and clinical outcomes. We used a generalized additive model (GAM) to evaluate the nonlinear relations observed and the classification and regression trees (CART) algorithm to assess the interaction effects found.

ResultsFrom March to July 2020, 643 patients were admitted, of which 52% were male. The median age was 60 years old, and the most frequent comorbidity was hypertension (35.76%). The median value of SpO2/FiO2 was 419, and the median Hb concentration was 14.8 g/dL. The mortality was 19.1% (123 patients). Age, sex, and history of hypertension were independently associated with mortality. We described a nonlinear relationship between SpO2/FiO2, Hb concentration and neutrophil-to-lymphocyte ratio with mortality and an interaction effect between SpO2/FiO2 and Hb concentration. Patients with a similar oxygenation index had different mortality likelihoods based upon their Hb at admission. CART showed that patients with SpO2/FiO2 < 324, who were older than 62 years, and had an Hb of [≥] 16 g/dl had the highest mortality risk (96%). Additionally, patients with SpO2/FiO2 > 324 but Hb of < 12 and neutrophil-to-lymphocyte ratio of > 4 had a higher mortality likelihood (57%). In contrast, patients with SpO2/FiO2 > 324 and Hb of > 12 g/dl had the lowest mortality risk (10%).

ConclusionWe found that a decreased SpO2/FiO2 increased mortality risk. Extreme values of Hb, either low or high, showed an increase in likelihood of mortality. However, Hb concentration modified the SpO2/FiO2 effect on mortality; the likelihood of death in patients with low SpO2/FiO2 increased as Hb increased.


title: Post marketing surveillance for Microwave Treatment of Plantar and Common Warts in Adults.

abstract:
A handheld microwave device (Swift(R), Emblation Limited) has been licenced and available for clinical use since 2016 in the fields of podiatry and dermatology and has been extensively used in treating cutaneous warts. As part of post marketing surveillance by the manufacturer, an online 79-item survey was distributed to podiatry clinics in the United Kingdom with a Swift(R) device. A total of 126 clinics responded (59.6%). 6998 adults (<65 years) underwent wart treatment with microwave (81.9% plantar warts; 18.1% common, non-plantar warts). The median efficacy rate was reported as 79.2% (65.9 - 87.5%) and 82.3% (71.4 - 100%) respectively. In older adults (over 65 years) efficacy rates were similar for both sites: plantar (73.2%, 50-90%, n=1232) and non-plantar (80.0%, 42.1-100%, n=276). A median of three treatments was required to bring about resolution. Sub-group analysis of the data revealed good clearance rates in patients with diabetes (79.6%), but less in immunocompromised individuals (61.3%) and those with autoimmune disease (58.6%). Overall, mean user satisfaction was rated as "very satisfied" on a 10-point scale (n=93 practices). A small number of adverse events were reported including blistering, superficial ulceration and poor healing were reported (n=7). Despite the limitations of a post-marketing questionnaire survey, these data provide good evidence of the safety and efficacy for Swift(R) microwave treatment of cutaneous warts.

What is already known about this topic?O_LIMicrowave treatment has shown to be effective in the treatment of cutaneous warts.
C_LI

What does the study add?O_LIThis survey of clinics using SWIFT microwave treatments reports on the effectiveness and safety of the device in the treatment of 8506 adult patients with common and plantar warts.
C_LIO_LIResponding user clinics reporting efficacy with good clearance rates and low levels of adverse events demonstrating microwave is a safe and effective treatment for plantar and common warts.
C_LI

category: dermatology


title: Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer

abstract:
Genome-wide association studies (GWAS) have identified numerous genetic loci associated with breast and prostate cancer risk, suggesting that germline genetic dysregulation influences tumorigenesis. However, the biological function underlying many genetic associations is not well-understood. Previous efforts to annotate loci focused on protein-coding genes (pcGenes) largely ignore non-coding RNAs (ncRNAs) which account for most transcriptional output in human cells and can regulate transcription of both pcGenes and other ncRNAs. Though the biological roles of most ncRNAs are not well-defined, many ncRNAs are involved in cancer development. Here, we explore one regulatory hypothesis: ncRNAs as trans-acting mediators of gene expression regulation in non-cancerous and tumor breast and prostate tissue. Using germline genetics as a causal anchor, we categorize distal (>1 Megabase) expression quantitative trait loci (eQTLs) of pcGenes significantly mediated by local-eQTLs of ncRNAs (within 1 Megabase). We find over 300 mediating ncRNAs and show the linked pcGenes are enriched for immunoregulatory and cellular organization pathways. By integrating eQTL and cancer GWAS results through colocalization and genetically-regulated expression analyses, we detect overlapping signals in nine known breast cancer loci and one known prostate cancer locus, and multiple novel genetic associations. Our results suggest a strong transcriptional impact of ncRNAs in breast and prostate tissue with implications for cancer etiology. More broadly, our framework can be systematically applied to functional genomic features to characterize genetic variants distally regulating transcription through trans-mechanisms.

SIGNIFICANCEThis study identifies non-coding RNAs that potentially regulate gene expression in trans-pathways and overlap with genetic signals for breast and prostate cancer susceptibility, with implications for interpretation of cancer genome-wide association studies.


title: Signatures of immune senescence predict outcomes and define checkpoint blockade-unresponsive microenvironments in acute myeloid leukemia

abstract: The function of senescent-like T cells, transcriptomic features of immune effector senescence (IES) and their influence on therapeutic response were investigated in independent AML clinical cohorts comprising 1,864 patients treated with chemotherapy and/or immune checkpoint blockade (ICB). We show that senescent-like bone marrow CD8+ T cells are impaired in killing autologous AML blasts, and that their proportion negatively correlates with overall survival (OS). We define new IES signatures using two gene expression platforms and report that IES scores correlate with adverse-risk molecular lesions, stemness, and poor outcomes as a potentially more powerful predictor of OS than 2017-ELN risk or LSC17 stemness score. IES expression signatures also identify an ICB- unresponsive tumor microenvironment and predict significantly worse OS in AML as well as in solid tumors. The newly described IES scores provide improved AML risk stratification and could facilitate the delivery of personalized immunotherapies to patients who are most likely to benefit.

category: hematology


title: Using routine programmatic data to estimate the population-level impacts of HIV self-testing: The example of the ATLAS program in Cote d'Ivoire

abstract:
BackgroundHIV self-testing (HIVST) is recommended by the World Health Organization as an additional HIV testing approach. Since 2019, it has been implemented in Cote dIvoire through the ATLAS project, including primary and secondary distribution channels. While the discreet and flexible nature of HIVST makes it appealing for users, it also makes the monitoring and estimation of the population-level programmatic impact of HIVST programs challenging. We used routinely collected data to estimate the effects of ATLAS HIVST distribution on access to testing, conventional testing (self-testing excluded), diagnoses, and antiretroviral treatment (ART) initiations in Cote dIvoire.

MethodsWe used the ATLAS projects programmatic data between the third quarter (Q) of 2019 (Q3 2019) and Q1 2021, in addition to routine HIV testing services program data obtained from the Presidents Emergency Plan for AIDS Relief dashboard. We performed ecological time series regression using linear mixed models.

FindingsThe results are presented for 1000 HIVST kits distributed through ATLAS. They show a negative but nonsignificant effect of the number of ATLAS HIVST on conventional testing uptake (-190 conventional tests [95% CI: -427 to 37, p=0{middle dot}10]). We estimated that for 1000 additional HIVST distributed through ATLAS, +590 [95% CI: 357 to 821, p<0{middle dot}001] additional individuals have accessed HIV testing, assuming an 80% HIVST utilization rate (UR) and +390 [95% CI: 161 to 625, p<0{middle dot}001] assuming a 60% UR. The statistical relationship between the number of HIVST and HIV diagnoses was significant and positive (+8 diagnosis [95% CI: 0 to 15, p=0{middle dot}044]). No effect was observed on ART initiation (-2 ART initiations [95% CI: -8 to 5, p=0{middle dot}66]).

InterpretationsSocial network-based HIVST distribution had a positive impact on access to HIV testing and diagnoses in Cote dIvoire. This approach offers a promising way for countries to assess the impact of HIVST programs.

FundingUnitaid 2018-23-ATLAS

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed between November 9 and 12, 2021, for studies assessing the impact of HIVST on HIV testing,  conventional testing, HIV diagnoses and ART initiation. We searched published data using the terms "HIV self-testing" and "HIV testing"; "HIV self-testing" and "traditional HIV testing" or "conventional testing"; "HIV self-testing" and "diagnosis" or "positive results"; and "HIV self-testing" and "ART initiation" or "Antiretroviral treatment". Articles with abstracts were reviewed. No time or language restriction was applied. Most studies were individual-based randomized controlled trials involving data collection and some form of HIVST tracking; no studies were conducted at the population level, none were conducted in western Africa and most focused on subgroups of the population or key populations. While most studies found a positive effect of HIVST on HIV testing, evidence was mixed regarding the effect on conventional testing, diagnoses, and ART initiation.

Added value of this studyHIVST can empower individuals by allowing them to choose when, where and whether to test and with whom to share their results and can reach hidden populations who are not accessing existing services. Inherent to HIVST is that there is no automatic tracking of test results and linkages at the individual level. Without systematic and direct feedback to program implementers regarding the use and results of HIVST, it is difficult to estimate the impact of HIVST distribution at the population level. Such estimates are crucial for national AIDS programs. This paper proposed a way to overcome this challenge and used routinely collected programmatic data to indirectly estimate and assess the impacts of HIVST distribution in Cote dIvoire.

Implications of all the available evidenceOur results showed that HIVST increased the overall HIV testing uptake and diagnoses in Cote dIvoire without significantly reducing conventional HIV testing uptake. We demonstrated that routinely collected programmatic data could be used to estimate the effects of HIVST kit distribution outside a trial environment. The methodology used in this paper could be replicated and implemented in different settings and enable more countries to routinely evaluate HIVST programming at the population level.

category: hiv aids


title: Symptoms and severity in vaccinated and unvaccinated patients hospitalised with SARS-CoV-2 delta (B.1.617.2) variant infection

abstract:
BackgroundThe diffusion of the SARS-CoV-2 delta (B.1.617.2) variant and the waning of immune response after primary Covid-19 vaccination favoured the breakthrough SARS-CoV-2 infections in vaccinated subjects. To assess the impact of vaccination, we determined the severity of infection in hospitalised patients according to vaccine status.

MethodsWe retrospectively analysed data from patients hospitalised in 10 centres with a SARS-CoV-2 infection (delta variant) from July to November 2021: i) all patients who had completed their primary vaccination at least 14 days before hospital admission; and ii) the same number of completely unvaccinated patients. We assessed the impact of vaccination and other risk factors through logistic regression.

FindingsWe included 955 patients (474 vaccinated and 481 unvaccinated). Vaccinated patients were significantly older, more frequently males, and with more comorbidities. They were less often admitted for Covid-19 (59{middle dot}3% vs. 75{middle dot}1%, p<0{middle dot}001), showed fewer lung lesions, and required oxygen less frequently (57{middle dot}5% vs. 73{middle dot}0%, p<0{middle dot}001), at a lower flow (3{middle dot}0 vs. 6{middle dot}0 L/min, p<0{middle dot}001), and for a shorter duration (3 vs. 6 days, p<0{middle dot}001). They less frequently required intensive care unit admission (16{middle dot}2 % vs. 36{middle dot}0 %, p<0{middle dot}001). Mortality at day 28 was not different between the two groups (16{middle dot}7% vs. 12.2%, p=0{middle dot}075), but multivariate logistic regression showed that vaccination significantly decreased the risk of negative outcomes, including mortality, even when considering older patients, and those with comorbidities.

ConclusionsAmong patients hospitalised with a delta variant SARS-CoV-2 infection, vaccination was associated with less severe forms, even in the presence of comorbidities.


title: Model-based estimates of deaths averted and cost per life saved by scaling-up mRNA COVID-19 vaccination in low and lower-middle income countries in the COVID-19 Omicron variant era

abstract:
BackgroundWhile almost 60% of the world has received at least one dose of COVID-19 vaccine, the global distribution of vaccination has not been equitable. Only 4% of the population of low-income countries has received a full primary vaccine series, compared to over 70% of the population of high-income nations.

MethodsWe used economic and epidemiologic models, parameterized with public data on global vaccination and COVID-19 deaths, to estimate the potential benefits of scaling up vaccination programs in low and lower-middle income countries (LIC/LMIC) in 2022 in the context of global spread of the Omicron variant of SARS-CoV2. Outcomes were expressed as number of avertable deaths through vaccination, costs of scale-up, and cost per death averted. We conducted sensitivity analyses over a wide range of parameter estimates to account for uncertainty around key inputs.

FindingsGlobal scale up of vaccination to provide two doses of mRNA vaccine to everyone in LIC/LMIC would cost $35.5 billion and avert 1.3 million deaths from COVID-19, at a cost of $26,900 per death averted. Scaling up vaccination to provide three doses of mRNA vaccine to everyone in LIC/LMIC would cost $61.2 billion and avert 1.5 million deaths from COVID-19 at a cost of $40,800 per death averted. Lower estimated infection fatality ratios, higher cost-per-dose, and lower vaccine effectiveness or uptake lead to higher cost-per-death averted estimates in the analysis.

InterpretationScaling up COVID-19 global vaccination would avert millions of COVID-19 deaths and represents a reasonable investment in the context of the value of a statistical life (VSL). Given the magnitude of expected mortality facing LIC/LMIC without vaccination, this effort should be an urgent priority.


title: Safety and immunogenicity of inactivated whole virion vaccine CoviVac against COVID-19: a multicenter, randomized, double-blind, placebo-controlled phase I/II clinical trial

abstract:
We present the results of a randomized, double-blind, placebo-controlled, multi-center clinical trial of the tolerability, safety, and immunogenicity of the inactivated whole virion concentrated purified coronavirus vaccine CoviVac in adult volunteers aged 18-60.

Safety of the vaccine was assessed in 398 volunteers who received two doses of the vaccine (n=298) or placebo (n=100). The studied vaccine has shown good tolerability and safety. No deaths, serious adverse events (AE), or other significant AE related to vaccination have been detected. The most common AE in vaccinated participants was pain at the injection site (p<0.05).

Immunogenicity assessment was performed in 167 volunteers (122 vaccinated and 45 in Placebo Group) separately for the participants who were anti-SARS-CoV-2 nAB negative (69/122 in Vaccine Group and 28/45 in Placebo Group) or positive (53/122 in Vaccine Group and 17/45 in Placebo Group) at screening.

At Day 42 after the first immunization the seroconversion rate in participants who were seronegative at screening was 86.9% with average the geometric mean neutralizing antibody (nAB) titer of 1:20. Statistically significant (p<0.05) increase of IFN-{gamma} production by peptide-stimulated T-cells was observed at Days 14 and 21 after the first immunization.

In participants who were seropositive at screening but had nAB titers below 1:256 the rate of 4-fold increase in nAB levels was 85.2%, while in the participants with nAB titers >1:256 the rate of 4-fold increase in nAB levels was below 45%. For the participants who were seropositive at screening the second immunization did not lead to a significant increase in nAB titers.

In conclusion, inactivated vaccine CoviVac has shown good tolerability and safety, with 86.9% seroconversion rates in participants, who were seronegative at screening. In participants who were seropositive at screening and had nAB titers below 1:256, a single immunization lead to a 4-fold increase in nAB levels in 85.2% cases.


title: Physical behaviours and their association with type 2 diabetes risk in urban South African middle-aged adults: An isotemporal substitution approach

abstract:
IntroductionTo examine the associations between physical behaviours and type 2 diabetes mellitus (T2DM) risk in middle-aged South African men and women.

Research design and methodsThis cross-sectional study included middle-aged men (n=403; age: median [IQR], 53.0 [47.8-58.8] years) and women (n=324; 53.4 [49.1-58.1] years) from Soweto, South Africa. Total movement volume (average movement in milli-g) and time (minutes/day) spent in different physical behaviours, including awake sitting/lying, standing, light intensity physical activity (LPA) and moderate-to-vigorous intensity physical activity (MVPA), were determined by combining the signals from two triaxial accelerometers worn simultaneously on the hip and thigh. All participants completed an oral glucose tolerance test, from which indicators of diabetes risk were derived. Associations between physical behaviours and T2DM risk were adjusted for sociodemographic factors and body composition.

ResultsTotal movement volume was inversely associated with measures of fasting and 2-h glucose and directly associated with insulin sensitivity, basal insulin clearance, beta-cell function, but these associations were not independent of fat mass, except for basal insulin clearance in women. In men, replacing 30 minutes of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 1.2-1.4 mmol/L lower fasting glucose and 12.3-13.4 mgl2/mUmin higher insulin sensitivity. In women, substituting sitting/lying with the same amount of standing time or LPA was associated with 0.5-0.8 mmol/L lower fasting glucose. Substituting 30 minutes sitting/lying with the same amount of standing time was also associated with 3.2 mgl2/mUmin higher insulin sensitivity, and substituting 30 minutes of sitting/lying, standing or LPA with the same amount of MVPA time was associated with 0.25-0.29 ng/mIU higher basal insulin clearance in women.

ConclusionMVPA is important in reducing T2DM risk in men and women but LPA appears to be important in women only. Recommendations for PA may differ by sex.


title: Increasing viral transmission paradoxically reduces progression rates to severe COVID-19 during endemic transition

abstract: Natural infection with SARS-CoV-2 or vaccination induces virus-specific immunity protecting hosts from infection and severe disease. While the infection-preventing immunity gradually declines, the severity-reducing immunity is relatively well preserved. Here, based on the different longevity of these distinct immunities, we develop a mathematical model to estimate courses of endemic transition of COVID-19. Our analysis demonstrates that high viral transmission unexpectedly reduces the rates of progression to severe COVID-19 during the course of endemic transition despite increased numbers of infection cases. Our study also shows that high viral transmission amongst populations with high vaccination coverages paradoxically accelerates the endemic transition of COVID-19 with reduced numbers of severe cases. These results provide critical insights for driving public health policies in the era of  living with COVID-19.

category: public and global health


title: Food Insecurity Among Older Adults with a History of Incarceration

abstract:
ObjectivesTo examine the association between history of incarceration (HOI) and food insecurity (FI) among older adults.

MethodsThis is a secondary analysis utilizing data from 12,702 respondents aged 51+ who participated in the 2012 and 2014 waves of The Health and Retirement Study. Multiple logistic regression was used to estimate the association between HOI and FI, adjusting for demographic variables using odds ratios (OR) and 95% confidence intervals (CI).

ResultsIn our sample, 12.8% of participants reported FI. Having a HOI increased odds of FI (OR 1.83; 95% CI 1.52-2.21), especially among Blacks (OR 1.78; 95% CI 1.29-2.46) and Whites (OR 2.27; 95% CI 1.74-2.97), but not Hispanics (OR 1.11; 95% CI 0.69-1.77) or other racial/ethnic groups (OR 1.79; 95% CI 0.71-4.52).

DiscussionFI is an important issue among older adults with a HOI. Stronger linkages between formerly incarcerated older adults and existing food assistance programs are needed.


title: Trajectories of Neurological Recovery 12 Months after Hospitalization for COVID-19: A Prospective Longitudinal Study

abstract:
Background/ObjectivesLittle is known about trajectories of recovery 12-months after hospitalization for severe COVID.

MethodsWe conducted a prospective, longitudinal cohort study of patients with and without neurological complications during index hospitalization for COVID-19 from March 10, 2020-May 20, 2020. Phone follow-up batteries were performed at 6- and 12-months post-COVID symptom onset. The primary 12-month outcome was the modified Rankin Scale (mRS) comparing patients with or without neurological complications using multivariable ordinal analysis. Secondary outcomes included: activities of daily living (Barthel Index), telephone Montreal Cognitive Assessment (t-MoCA) and Neuro-QoL batteries for anxiety, depression, fatigue and sleep. Changes in outcome scores from 6 to 12-months were compared using non-parametric paired-samples sign test.

ResultsTwelve-month follow-up was completed in N=242 patients (median age 65, 64% male, 34% intubated during hospitalization) and N=174 completed both 6- and 12-month follow-up. At 12-months 197/227 (87%) had [≥]1 abnormal metric: mRS>0 (75%), Barthel<100 (64%), t-MoCA[≤]18 (50%), high anxiety (7%), depression (4%), fatigue (9%) and poor sleep (10%). 12-month mRS scores did not differ significantly among those with (N=113) or without (N=129) neurological complications during hospitalization after adjusting for age, sex, race, pre-COVID mRS and intubation status (adjusted OR 1.4, 95% CI0.8-2.5), though those with neurological complications had higher fatigue scores (T-score 47 vs 44, P=0.037). Significant improvements in outcome trajectories from 6- to 12-months were observed in t-MoCA scores (56% improved, median difference 1 point, P=0.002), and Neuro-QoL anxiety scores (45% improved, P=0.003). Non-significant improvements occurred in fatigue, sleep and depression scores in 48%, 48% and 38% of patients, respectively. Barthel and mRS scores remained unchanged between 6 and 12-months in >50% of patients.

DiscussionAt 12-months post-hospitalization for severe COVID, 87% of patients had ongoing abnormalities in functional, cognitive or Neuro-QoL metrics and abnormal cognition persisted in 50% of patients without a prior history of dementia/cognitive abnormality. Only fatigue severity differed significantly between patients with or without neurological complications during index hospitalization. However, significant improvements in cognitive (t-MoCA) and anxiety (Neuro-QoL) scores occurred in 56% and 45% of patients, respectively, between 6- to 12-months. These results may not be generalizable to those with mild/moderate COVID.


title: Factors associated with contraceptive failure in Uganda: Analysis of the 2016 Uganda Demographic and Health Survey

abstract:
IntroductionSustained motivation is essential for effective use of contraceptive methods by women in low- and middle-income countries as many women are likely to abandon use of contraceptives especially when they continually experience episodes of failure. We aimed to determine contraceptive failure rates and associated factors among Ugandan women using data from the 2016 Uganda Demographic Health Survey (UDHS).

MethodsWe analyzed data collected by the UDHS conducted in Uganda 2016. All eligible women aged 15 to 49 years at the time of the survey were enrolled. Discontinuation of contraceptive use due to failure within a 5-year period preceding the survey was the dependent variable.

ResultsA total of 18,505 women were included in this study, 70.8% (n=5153) lived in rural areas while 56.9% (n=5153) owned a mobile phone. The mean age of the women was 29.6years (SD 7.6). The overall prevalence of contraceptive failure was 5.6%, and was higher (7.8%) among women aged 25-29 years or had completed secondary education (7.1%). The odds of contraceptive failure was 38% lower in women who had an informed choice on contraceptives compared to those who didnt [Adjusted Odd ratio, 0.62; 95% confidence interval, 0.50 - 0.77; p< 0.001].

ConclusionThe burden of contraceptive failure among women of reproductive age in Uganda is substantial and significantly varied by socio-demographic characteristics.

category: obstetrics and gynecology


title: Where is Omicron? Comparison of SARS-CoV-2 RT-PCR and Antigen Test Sensitivity at Commonly Sampled Anatomic Sites Over the Course of Disease

abstract:
BackgroundUpper respiratory samples for SARS-CoV-2 detection include the gold standard nasopharyngeal (NP) swab, and mid-turbinate (MT) nasal swabs, oropharyngeal (OP) swabs, and saliva. Following the emergence of the omicron (B.1.1.529) variant, limited preliminary data suggest that OP swabs or saliva samples may be more sensitive than nasal swabs, highlighting the need to understand differences in viral load across different sites.

MethodsMT, OP, and saliva samples were collected from symptomatic individuals presenting for evaluation in Atlanta, GA, in January 2022. Longitudinal samples were collected from a family cohort following COVID-19 exposure to describe detection of viral targets over the course of infection.

ResultsSARS-CoV-2 RNA and nucleocapsid antigen measurements demonstrated a nares-predominant phenotype in a familial cohort. A consistent dominant location for SARS-CoV-2 was not found among 54 individuals. Positive percent agreement for virus detection in MT, OP and saliva specimens were 66.7 [54.1-79.2], 82.2 [71.1-93.4], and 72.5 [60.3-84.8] by RT-PCR, respectively, and 46.2 [32.6-59.7], 51.2 [36.2-66.1], and 72.0 [59.6-84.4] by ultrasensitive antigen assay. The composite of positive MT or OP assay was not significantly different than either alone for both RT-PCR and antigen assay (PPA 86.7 [76.7-96.6] and 59.5 [44.7-74.4], respectively).

ConclusionsOur data suggest that SARS-CoV-2 nucleocapsid and RNA exhibited similar kinetics and diagnostic yield in three upper respiratory sample types across the duration of symptomatic disease. Collection of OP or combined nasal and OP samples does not appear to increase sensitivity versus validated nasal sampling for rapid detection of viral antigen.


title: Half the truth is often a great lie: testing for tick-borne diseases and implications for surveillance

abstract:
ImportanceTick-borne diseases (TBD) including Spotted Fever Group Rickettsiosis (SFGR), ehrlichiosis, and increasingly Lyme disease represent a substantial public health concern throughout much of the Southeastern United States. Yet, there is uncertainty about the epidemiology of these diseases due to pitfalls in existing diagnostic test methodologies.

ObjectiveTo examine patterns of diagnostic testing and incidence of TBD in a large, academic healthcare system.

DesignCross-sectional study of diagnostic test results from UNC Health for the period January 1st, 2017 to November 30th, 2020.

SettingLarge, academic healthcare system in central North Carolina including inpatient and outpatient facilities.

ParticipantsAll Individuals seeking routine care at UNC Health facilities who had testing for SFGR, ehrlichiosis or Lyme disease performed during the study period

MeasurementsRates of test positivity, testing completeness, and incidence of TBD

ResultsAmong the 20,528 diagnostic tests performed, we identified 47 laboratory-confirmed, incident cases of SFGR, 27 of ehrlichiosis, and 76 of Lyme, representing incidence rates of 4.7%, 7.1%, and 0.7% respectively. However, 79.3% of SFGR tests and 74.3% Ehrlichia tests lacked a paired convalescent sample. The total number of tests for Lyme disease was more than SFGR and ehrlichiosis combined, despite the relatively low incidence of disease in region. Most striking, testing for ehrlichiosis was performed in only half of patients in whom SFGR was ordered, suggesting that this disease remains underrecognized. Overall, we estimate that there were 187 incident cases of SFGR and 309 of ehrlichiosis that were not identified due to incomplete testing; a number that would drastically increase - and in the case of ehrlichiosis, nearly double - the total number of cases reported.

Conclusions and RelevanceA majority of patients suspected of having TBD did not have testing performed in accordance with established guidelines, substantially limiting our understanding of TBD epidemiology. Furthermore, there appears to be a large discrepancy between the local burden of disease and the testing that is performed. These findings underscore the need to pursue more robust, active surveillance strategies to estimate the burden of TBDs and distribution of causative pathogens.