title: Automated identification of unstandardized medication data: A scalable and flexible data standardization pipeline using RxNorm on GEMINI multicenter hospital data

abstract:
ObjectivePatient data repositories often assemble medication data from multiple sources, necessitating standardization prior to analysis. We implemented and evaluated a medication standardization procedure for use with a wide range of pharmacy data inputs across all drug categories, which supports research queries at multiple levels of granularity.

MethodsThe GEMINI-RxNorm system automates the use of multiple RxNorm tools in tandem with other datasets to identify drug concepts from pharmacy orders. GEMINI-RxNorm was used to process 2,090,155 pharmacy orders from 245,258 hospitalizations between 2010 and 2017 at 7 hospitals in Ontario, Canada. The GEMINI-RxNorm system matches drug-identifying information from pharmacy data (including free-text fields) to RxNorm concept identifiers. A user interface allows researchers to search for drug terms and returns the relevant original pharmacy data through the matched RxNorm concepts. Users can then manually validate the predicted matches and discard false positives. We designed the system to maximize recall (sensitivity) and enable excellent precision (positive predictive value) with minimal manual validation. We compared the performance of this system to manual coding (by a physician and pharmacist) of 13 medication classes.

ResultsManual coding was performed for 1,948,817 pharmacy orders and GEMINI-RxNorm successfully returned 1,941,389 (99.6%) orders. Recall was greater than 98.5% in all 13 drug classes, and the F-Measure and precision remained above 90.0% in all drug classes, facilitating efficient manual review to achieve 100.0% precision. GEMINI-RxNorm saved time substantially compared to manual standardization, reducing the time taken to review a pharmacy order row from an estimated 30 seconds to 5 seconds and reducing the number of rows needed to be reviewed by up to 99.99%.

Discussion and ConclusionGEMINI-RxNorm presents a novel combination of RxNorm tools and other datasets to enable accurate, efficient, flexible, and scalable standardization of pharmacy data. By facilitating efficient minimal manual validation, the GEMINI-RxNorm system can allow researchers to achieve near-perfect accuracy in medication data standardization.


title: Complementary non-sputum diagnostic testing using oral swabs and urine LAM testing for TB in people with HIV

abstract: Testing for mycobacterial lipoarabinomannan (LAM) in urine is a practical but insensitive alternative to sputum testing to diagnose tuberculosis (TB) in people with HIV (PWH). We evaluated urine LAM testing conducted in parallel with tests for Mycobacterium tuberculosis DNA in oral swabs. In a cohort of 131 South Africans (92% with HIV), combined urine LAM and oral swab testing was significantly more sensitive than either sample tested alone (57% vs. 35% and 39%, respectively), and 97% specific, compared to reference sputum testing (TB culture and Xpert Ultra). Complementary non-sputum sample testing increased sensitivity of TB diagnosis, without sacrificing specificity.

category: infectious diseases


title: Spatial Correlation of Left Atrial Low Voltage Substrate in Sinus Rhythm versus Atrial Fibrillation: Identifying the Pathological Substrate Irrespective of the Rhythm

abstract:
BackgroundLow voltage substrate (LVS) identified during electroanatomical mapping is a potential target for atrial fibrillation (AF) ablation. However, it is not clear how the location and extent of LVS correlate between mapping in sinus rhythm (SR) and AF.

Objectives(1) Identify voltage dissimilarities between mapping in SR and AF. (2) Identification of regional voltage thresholds that improve cross-rhythm sub-strate detection. (3) Comparison of LVS between SR and native vs. induced AF.

MethodsForty-one ablation-naive persistent AF patients underwent high-density voltage mapping in SR and AF. Each patients voltage information was mapped to a joint geometry for analysis. Global and regional voltage thresholds in AF were identified which best match LVS<0.5mV and <1.0mV in SR. Additionally, the correlation between SR-LVS with induced vs. native AF LVS was assessed.

ResultsSubstantial voltage differences (median: 0.52, IQR: 0.33-0.69, max: 1.19mV) with predominance of the posterior/inferior LA wall exist between the rhythms. An AF threshold of 0.34mV for the entire atrium provides an accuracy, sensitivity and specificity of 69%, 67% and 69% to identify SR-LVS<0.5mV, respectively. Lower thresholds for the posterior wall (0.27 mV) and inferior wall (0.3mV) result in higher spatial concordance to SR-LVS (4% and 7% increase). Concordance with SR-LVS was higher for induced AF compared to native AF (AUC: 0.80 vs. 0.73). AF-LVS<0.5mV corresponds to SR-LVS<0.97mV using high-definition mapping (AUC: 0.73).

ConclusionThe proposed voltage thresholds during AF maximise the consistency of LVS identification as determined during SR. Regional thresholds can further improve concordance.

category: cardiovascular medicine


title: Quantitative bias analysis in practice: Review of software for regression with unmeasured confounding

abstract: Failure to appropriately account for unmeasured confounding in analyses may lead to bias and erroneous conclusions. Quantitative bias analysis (QBA) for unmeasured confounding is used to quantify the potential direction and impact of the bias. The adoption of QBA by applied researchers has been slow, partly due to the focus of methods for binary outcomes and exposure, and partly due to the lack of accessible software. We provide a review of the latest developments in QBA software during 2010 to 2020. We describe in detail 5 QBA methods and their software implementations that can be applied when the analysis of interest is a linear regression. We illustrate application of these software programs to real data and provide R and Stata software code along with a practice example. In our review, all software implementations were of deterministic QBA methods and mostly implemented as R packages. Graphical presentations of the results and benchmarking are useful aids of interpretation. However, sole reliance on summary measures at tipping points should be discouraged as it can encourage analysts to place too much emphasis on statistical significance. The diversity of QBA methods presents challenges in the widespread uptake of QBA. Guidelines are needed on the appropriate choice of QBA method, along with provision of software implementations in platforms other than R.

category: epidemiology


title: Closing the health inequity gap during the pandemic: COVID-19 mortality among racial and ethnic groups in Connecticut, March 2020 to December 2021

abstract: COVID-19 has disproportionally burdened racial and ethnic minority groups within the United States. Leveraging statewide data, we examined the evolution of racial and ethnic disparities in COVID-19 related deaths among Connecticut residents residing in non-congregate settings over three periods of the COVID-19 pandemic. Despite observing large disparities in the age-adjusted mortality rates between Hispanics, non-Hispanic Blacks, and non-Hispanic Whites during the initial pandemic period (March to August 2020), we observed meaningful reductions in the disparities during the subsequent periods (August 2020 to July 2021; July to mid December 2021). Further, during the third period, we failed to find a significant difference in age-adjusted mortality between non-Hispanic Blacks and non-Hispanic Whites. These findings provide evidence that attenuation of racial and ethnic disparities in COVID-19 related outcomes are achievable.


title: COVID-19 Surveillance in the Biobank at the Colorado Center for Personalized Medicine

abstract:
BackgroundCharacterizing the experience and impact of the COVID-19 pandemic among various populations remains challenging due to the limitations inherent in common data sources such as the electronic health record (EHR) or convenience sample surveys.

ObjectiveTo describe testing behaviors, symptoms, impact, vaccination status and case ascertainment during the COVID-19 pandemic using integrated data sources.

MethodsIn summer 2020 and 2021, we surveyed participants enrolled in the Biobank at the Colorado Center for Personalized Medicine (CCPM, N = 180,599) about their experience with COVID-19. Prevalence of testing, symptoms, and the impacts of COVID-19 on employment, family life, and physical and mental health were calculated overall and by demographic categories. Using the Electronic Health Record (EHR), we compared COVID-19 case ascertainment and characteristics in the EHR versus the survey.

ResultsOf the 25,063 survey respondents (13.9%), 42.5% had been tested for COVID-19 and of those, 12.8% tested positive. Nearly half of those tested had symptoms and/or had been exposed to someone who was infected. Young adults (18-29 years) and Hispanics were more likely to have positive tests compared to older adults and persons of other racial/ethnic groups. Mental health (54.6%) and family life (48.8%) were most negatively affected by the pandemic and more so among younger groups and women; negative impacts on employment were more commonly reported among Black respondents. After integration with EHR data up to the time of the survey completion, 4.0% of survey respondents (n=1,006) had discordant COVID-19 case status between the EHR and the survey. Using all longitudinal EHR and survey data, we identified 11,472 COVID-positive cases among Biobank participants (6.4%). In comparison to COVID-19 cases identified through the survey, EHR-identified cases were younger and more likely to be Hispanic.

ConclusionsIntegrated data assets such as the Biobank at the CCPM are key resources for population health monitoring in response to public health emergencies, such as the COVID-19 pandemic.


title: Evaluating Chinese Handwriting Performance of Primary School Students Using the Smart Handwriting Analysis and Recognition Platform (SHARP)

abstract:
BackgroundHandwriting is one of the fundamental skills for school-aged children, and it is an intricate and interacting process. An innovative computerized handwriting assessment system, the Smart Handwriting Analysis and Recognition Platform (SHARP) was used to provide a comprehensive and quantitative analysis of Chinese handwriting performance and identify children with handwriting difficulties objectively, accurately, and efficiently.

Aims/ObjectivesThe purpose of this study is to provide quantitative data on childrens Chinese handwriting process and products using SHARP; to investigate the handwriting difficulties in children with neurodevelopmental problems, and to explore the associations between handwriting and sensorimotor performance, including fine motor skills, visual perceptual skills, visual-motor integration, and oculomotor proficiency.

Material and MethodsTypically developing students and students with neurodevelopmental problems were recruited through teachers and therapists from six primary schools in Hong Kong. SHARP and tests of sensorimotor skills were performed.

ResultsThe quantitative analysis using the SHARP system showed a progressive developmental change in handwriting performance among the typically developing children at their primary education. There were also significant differences between the typically developing students group and those with neurodevelopmental problems, both in handwriting speed and writing errors. Significant associations between the handwriting process parameters and fine motor skills were identified, while handwriting product parameters were closely correlated with visual-perceptual skills of these typical developing students.

Conclusions and SignificanceSHARP appears to provide a comprehensive, quantitative and objective evaluation of students handwriting performances, thus assisting both teachers and parents in comparing students performance objectively, thus identifying students with handwriting difficulties as early as P1 level. It was observed that handwriting performance has strong relationships with young childrens visual perceptual skills and fine motor skills. The findings could help to facilitate early intervention for those students with handwriting problems.

category: pediatrics


title: Effects of bilateral sequential theta-burst stimulation on functional connectivity in treatment-resistant depression: first results

abstract:
BackgroundPrevious studies suggest that transcranial magnetic stimulation exerts antidepressant effects by altering functional connectivity (FC). However, knowledge about this mechanism is still limited. Here, we aimed to investigate the effect of bilateral sequential theta-burst stimulation (TBS) on FC in treatment-resistant depression (TRD) in a sham-controlled longitudinal study.

MethodsTRD patients (n = 20) underwent a three-week treatment of intermittent TBS of the left and continuous TBS of the right dorsolateral prefrontal cortex (DLPFC). Upon this trials premature termination, 15 patients had received active TBS and five patients sham stimulation. Resting-state functional magnetic resonance imaging was performed at baseline and after treatment. FC (left and right DLPFC) was estimated for each participant, followed by group statistics (T-tests). Furthermore, depression scores were analyzed (linear mixed models analysis) and tested for correlation with FC.

ResultsBoth groups exhibited reductions of depression scores, however, there was no significant main effect of group, or group and time. Anticorrelations between DLPFC and the subgenual cingulate cortex (sgACC) were observed for baseline FC, corresponding to changes in depression severity. Treatment did not significantly change DLPFC-sgACC connectivity, but significantly reduced FC between the left stimulation target and bilateral anterior insula.

ConclusionsOur data is compatible with previous reports on the relevance of anticorrelation between DLPFC and sgACC for treatment success. Furthermore, FC changes between left DLPFC and bilateral anterior insula highlight the effect of TBS on the salience network.

LimitationsDue to the limited sample size, results should be interpreted with caution and are of exploratory nature.

category: psychiatry and clinical psychology


title: Antipsychotic Effects on Longitudinal Cognitive Functioning in First-Episode Psychosis: A randomised, triple-blind, placebo-controlled study

abstract:
ObjectiveCognitive impairment occurs in antipsychotic-naive first-episode psychosis (FEP), but antipsychotics confound interpretation of the longitudinal course of cognition. The primary aim was to disentangle the effects of illness from antipsychotics on cognition over the first 6-months of FEP treatment.

MethodsRandomised, triple-blind placebo-controlled trial (Staged Treatment and Acceptability Guidelines in Early Psychosis; STAGES), where cognition was a secondary outcome. Antipsychotic-naive FEP patients were allocated to receive risperidone/paliperidone (N=38) or placebo (N=40) in addition to intensive psychosocial therapy for 6-months. A healthy control group (N=42) was also recruited. A cognitive battery assessing attention, working memory, processing speed, verbal fluency, cognitive control and verbal paired-associate learning and memory was administered at baseline and 6-months. Twelve- and 24-month follow-up was also conducted.

ResultsOver the 6-month trial period, cognitive performance remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. The exception was for verbal paired-associate learning and memory, where a significant group-by-time interaction was observed. The placebo and healthy control groups improved, and the medication group deteriorated on immediate paired-associate recall (p=0.039) and delayed cued recall (p=0.005); effect sizes were medium-to-large. Findings were similar when only trial completers were included in the analysis.

ConclusionsRisperidone/paliperidone may cause progression of memory impairment in the early months of FEP. Replication is needed in confirmatory trials. The findings support the need for careful consideration of the risks and benefits of various antipsychotics and the importance of accounting for their cognitive effects in longitudinal research.

Trial registrationAustralian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/ ACTRN12607000608460).


title: The burden of vaccine hesitancy for routine immunization in Yaounde-Cameroon: restrictive sampling technique

abstract: Immunization is the most cost-effective health intervention in the world yet, vaccination uptake is still low with less than 50% of children aged 12-23 months fully vaccinated Cameroon. The objective of this study was to estimate the burden of vaccine hesitancy associated with routine EPI vaccines in Yaounde-Cameroon. A two-stage cross-sectional cluster survey was conducted in Yaounde in May-June 2022, targeting parents/guardians of children 0-59 months. Clusters were selected with probability proportionate to size (PPS) and households selection done using a restricted sampling method. Data collection was done using an interviewer-administered questionnaire. Data were cleaned using MS-Excel 2019, and analyzed with R version 4.1.0 (2021-05-18). A total of 529 participants were enrolled out of 708 visited, giving a non-response rate of 25%. In total, vaccine hesitancy was reported in 137(25.90[22.35-29.80] %), and vaccine hesitancy prevalence did not vary significantly across different households wealth levels (p-value= 0.3786). However, in wealthy households refusal of vaccines (14%) was less than in poorer households (20%). Lack of trust, confidence, and perceived complacency are the leading causes of vaccine hesitancy related to routine immunization in Yaounde-Cameroon. We, therefore, recommend that the burden of vaccine hesitancy should be assessed at national scale and identify sources of misinformation that are at the origin of vaccine hesitancy. Having a clear notion of the effect of social media(Facebook, Instagram, WhatsApp, etc,), radio, TV, and other information sources might guide interventions to combat vaccine hesitancy.

category: public and global health


title: Community engaged tick surveillance and tickMAP as a public health tool to track the emergence of ticks and tick-borne diseases in New York

abstract: A community engaged passive surveillance program was utilized to acquire ticks and associated information throughout New York state. Ticks were speciated and screened for several tick-borne pathogens. Of these ticks, only I. scapularis was commonly infected with pathogens of human relevance, including B. burgdorferi, B. miyamotoi, A. phagocytophilum, B. microti, and Powassan virus. In addition, the geographic and temporal distribution of tick species and pathogens was determined. This enabled the construction of a powerful visual analytical mapping tool, tickMAP to track the emergence of ticks and tick-borne pathogens in real-time. The public can use this tool to identify hot-spots of disease emergence, clinicians for supportive evidence during differential diagnosis, and researchers to better understand factors influencing the emergence of ticks and tick-borne diseases in New York. Overall, we have created a community-engaged tick surveillance program and an interactive visual analytical tickMAP that other regions could emulate to provide real-time tracking and an early warning for the emergence of tick-borne diseases.


title: Radiographic Imaging of Power Injectable Medical Access Ports as a Supplemental Identification Tool

abstract:
PurposeOur aims were to describe characteristic radiographic features of two power injectable medical access ports (MAPs) on various imaging modalities for rapid and precise identification; and to demonstrate the value of this approach in identifying other types of MAPs via "pictorial atlas".

MethodsWe analyzed two commonly seen MAPs at our clinical center, Smart Port(R) CT-Injectable Port and PowerPort(R) M.R.I.(R) Implantable Port. Photographs of these two MAPs were retrospectively compared with identity-verified MAPs seen on chest X-ray (CXR), computed tomography (CT) and dual energy subtraction radiography (DESR) images from routine patient encounters at our clinical center. Visualized radiographic features were used for MAP differentiation and identification.

ResultsBased on selected patient case examples for these two MAPs, physical characteristics seen on imaging were used for MAP identification. These properties included port body and chamber shape; location and number of suture holes; and radiopaque and radiolucent features. Each imaging modality provided a unique set of radiographic features and highlighted specific components of each MAP for rapid and precise identification. CXR offered better visualization of unique MAP features compared to CT.

ConclusionsRadiographic imaging can serve as a tool for medical staff to quickly identify MAPs. Hospital-specific "pictorial atlases" can be developed to display MAPs along with their associated distinctive radiographic and physical features for rapid and precise identification. This may be useful for large referral centers that see a wide array of MAPs by mitigating complications associated with MAP misidentification and usage, thus improving patient care.

category: radiology and imaging


title: Insights on Telemedicine Use by Physiatrists Before, During, and Beyond the COVID-19 Pandemic

abstract:
PurposeTo determine if physiatrists increased their use of telemedicine during the first 11 months of the COVID-19 pandemic and if changes are expected to persist post-pandemic. And to identify key tasks which require video for telemedicine.

Materials and MethodsA survey containing questions about the telemedicine tools used before, during, and after (planned) the COVID-19 pandemic was distributed to physiatrists. Analysis was conducted to evaluate the change in usage of telemedicine due to the pandemic and predict whether the pandemic will lead to a durable change in usage. Tasks which physiatrists have/believe they can complete with different modes of interaction were explored.

ResultsResponses from 56 physiatrists showed a 105% increase in video-based telemedicine use during the pandemic. The use of phone and video communications for care delivery significantly increased. 79% of respondents planned to use video-based telemedicine post-pandemic, a significant increase from pre-pandemic use. Motor assessments, cognitive assessments, stretching, strength building, and orthotics assessment and prescription were identified as key tasks that require video for telemedicine.

ConclusionThis study confirms increased use of telemedicine by physiatrists during the pandemic and suggests this shift will be durable. Key tasks where video is necessary for telemedicine were identified.

category: rehabilitation medicine and physical therapy


title: Prevalence and Outcome of Cardio-Embolic Stroke Patients Admitted at Referral Neurology Hospital in Bangladesh

abstract:
BackgroundStroke is the second leading cause of mortality worldwide; where the majority of stroke is ischemic. Among ischemic stroke, cardio-embolic has both higher severity and mortality.

ObjectiveTo find out clinical outcomes and determine predictors of mortality related to cardio-embolic stroke.

MethodologyThis prospective cohort study was conducted among patients of acute ischemic stroke of cardiac origin admitted at the National Institute of Neurosciences and Hospital, Bangladesh from 1st October 2020 to 30 September, 2021. Patients were kept under follow-up to 90 days from discharge.

ResultsA total of 689 ischemic stroke patients were screened, 156 had confirmed Cardio-embolic stroke. So, the frequency of cardio-embolic stroke was 22.64%. Male to female ratio was 1.3:1, mean age of 63 years. Hypertension 119 (76.3%), atrial fibrillation 107 (68.6%), and IHD 40 (25.6%) were most common comorbidities. Interestingly, we found only 23 (14.7%) patients with chronic rheumatic heart diseases. NIH Stroke scale score (median, IQR) during admission was 13 [7-19]. Overall mortality was 47 (29.9%), among them 30 (19.2%) died within 48 hours of hospital admission while 17 (10.9%) within 90 days of hospital discharge. Modified Rankin score at 90 days was 2 [min 0, max 5] those who survived. Cumulative incidence of recurrent stroke was 9 (7.1%) and incidence of anticoagulant induced hemorrhage were 5 (3.2%) among them. Risk factors associated with mortality (odds ratio, [95% CI], p value) were acute myocardial infarction (1.6 [1.14 - 2.52], 0.04), raised Troponin (1.89 [1.16-2.99], 0.01), reduced ejection fraction (3.38 [2.17-5.27], <0.001), hypotension (3.12 [2.07 - 4.68], < 0.001), chronic kidney disease (1.82 [1.06 - 3.10], 0.04), raised Creatinine (2.41 [1.52 - 3.84], 0.01), raised blood sugar (1.82 [1.14 - 2.89], 0.02), severe stroke (9.45 [3.57 - 25.03], <0.001), large infarct (53.67 [7.59 - 379.47], < 0.001), hemorrhagic transformation (4.43 [2.89 - 6.84], < 0.001) and aspiration pneumonia (1.9 [1.28-2.39], 0.01).

ConclusionOverall frequency, severity, functional disability, and mortality in cardio-embolic stroke are higher. Acute myocardial infarction, severe stroke, presence of hyperglycemia, hypotension, renal impairment, low ejection fraction, large infarct, hemorrhagic transformations, and aspiration pneumonia are both clinically and statistically significantly associated with mortality in cardio-embolic stroke.

category: neurology


title: Toxic heavy metals in the breast milk of diabetic and non-diabetic postpartum mothers in Yenagoa, Nigeria

abstract:
BackgroundBreast milk is considered to be the best substance for neonatal nutrition. It is not well known whether diabetes increases the expression of toxic heavy metals in the breast milk of postpartum mothers. This study compared the concentration of toxic heavy metals in breast milk between diabetic and non-diabetic postpartum mothers in Yenagoa.

Material and methodsA cross-sectional design was utilized on a purposive sample of 144 consenting postpartum mothers (72 diabetic and 72 non-diabetic mothers) from one tertiary, one secondary, and one primary medical centre. Breast milk samples were collected at 5-6 weeks postpartum between 1st November 2020 and 30th April 2021. A spectrophotometer was used to analyze the breast milk samples. A pro forma was used for data extraction and data were analyzed at a 5% significance level.

ResultThe Diabetes group had levels of Arsenic (63.9%), Lead (95.8%), Mercury (68.1%), and Cadmium (84.7%) above the WHO permissible limits. The mean concentrations were 0.6 ng/ml (Arsenic), 13.2ng/ml (Lead), 2.9ng/ml (Mercury), and 3.3ng/ml (Cadmium). The non-diabetic mothers also had high levels of Arsenic (62.5%), Lead (95.8%), Mercury (72.2%), and Cadmium (86.1%); and the mean concentrations were 0.6ng/ml (Arsenic), 12.2 ng/ml (Lead), 3.0ng/ml (Mercury), and 3.2ng/ml (Cadmium). There was no significant difference in the concentration of toxic heavy metals in breast milk between the diabetic and non-diabetic postpartum mothers (p = > 0.585).

ConclusionsDiabetes did not seem to increase the concentration of toxic heavy metals expressed in breast milk. More rigorous studies are needed to confirm these findings.

category: nursing


title: Spatial Point Process Model Predicts Survival in Clear Cell Renal Cell Carcinoma

abstract: Among renal cell carcinomas (RCCs), clear cell RCCs (ccRCCs) is a highly aggressive class characterized by highly invasive clinical course and poor survival. The presence of a sarcomatoid component implicates an even poorer prognosis. Spatial measures can establish features that could be routinely used in clinical practice to stratify important RCC outcomes. Therefore, we tested the effectiveness of spatial features as predictors of survival differentiation in 58 Grade 2 ccRCCs. We developed a machine learning model using the acquired spatial features to predict survival in Grade 2 ccRCCs which we termed "SurvCal". The receiver operating characteristic accuracy from the derived model was 0.812. Subsequent feature analysis identified the spatial model fitting intensity parameter Gamma and the pair correlation function as critical features in distinguishing the classes. In the light of the increasing digitization of pathology routines, our results demonstrate the importance of spatial point pattern features as determinants of ccRCC survival outcomes and phenotypes.

category: oncology


title: Genetic constraint at single amino acid resolution improves missense variant prioritisation and gene discovery

abstract: The clinical impact of most germline missense variants in humans remains unknown. Genetic constraint identifies genomic regions under negative selection, where variations likely have functional impacts, but the spatial resolution of existing constraint metrics is limited. Here we present the Homologous Missense Constraint (HMC) score, which measures genetic constraint at quasi single amino-acid resolution by aggregating signals across protein homologues. We identify one million possible missense variants under strong negative selection. HMC precisely distinguishes pathogenic variants from benign variants for both early-onset and adult-onset disorders. It outperforms existing constraint metrics and pathogenicity meta-predictors in prioritising de novo mutations from probands with developmental disorders (DD), and is orthogonal to these, adding power when used in combination. We demonstrate utility for gene discovery by identifying seven genes newly-significant associated with DD that could act through an altered-function mechanism. Overall, HMC is a novel and strong predictor to improve missense variant interpretation.

category: genetic and genomic medicine


title: Genetic influences on neurodevelopmental disorders and their overlap with co-occurring conditions in childhood and adolescence: A meta-analysis.

abstract: A systematic understanding of the aetiology of neurodevelopmental disorders (NDDs), their co-occurrence, and co-occurrence with other conditions during childhood and adolescence remains incomplete. This meta-analysis bridges gaps in our knowledge. First, we meta-analysed the literature on the relative contribution of genetic and environmental factors to NDDs. Second, we considered the literature on the overlap between different NDD categories. Lastly, we synthesized the literature on the co-occurrence between NDDs and disruptive, impulse control and conduct disorders (DICCs). We performed multilevel, random-effects meta-analyses on 296 independent studies, including over 4 million children and adolescents. We found all NDDs to be substantially heritable (family-based heritability (h2) = 0.66; SNP h2 = 0.19). Meta-analytic genetic correlations between NDDs, and between NDDs and DICCs were moderate to strong. However, given the paucity of available studies covering the co-occurrence of NDDs and DICCs, these could only be estimated for a few disorders. While our work provides direct evidence to inform and potentially guide clinical and educational diagnostic procedures and practice, it also highlights the imbalance in the research effort that has characterized developmental genetics research.


title: Detailed Clinical and Functional Studies of New MTOR Variants in Smith-Kingsmore Syndrome Reveal Deficits of Circadian and Sleep Homeostasis

abstract: Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore Syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures. A few dozen individuals are reported in the literature. Here, we report a cohort of 28 individuals with SKS that represent 9 new MTOR pathogenic variants, including p.R1480_C1483del or {Delta}(R1480-C1483). We conducted a detailed natural history study on these patients and found prevalent pathophysiological deficits among SKS individuals, in addition to the common neurodevelopmental symptoms. The new symptoms include sleep-wake disturbance, hyperphagia, and hyperactivity, which are indicative of homeostatic imbalance. To better characterize SKS variants, we developed MTOR mutant cellular models and performed biochemical and cellular circadian rhythm assays to study the variants. We showed that these SKS alleles display a range of MTOR activities under nutrient-deficient basal conditions and respond to MTOR inhibitors differently. For example, {Delta}(R1480-C1483) is more active than the classic SKS variant C1483F and less responsive to MTOR inhibition by rapamycin. Further, we showed that optimal MTOR activity, important for metabolic and protein homeostasis, is required for normal circadian function. These data can help guide treatment strategies. As SKS is caused by gain of function mutations in MTOR, we used rapamycin to treat several patients. While higher doses caused delayed sleep-wake phase disorder, lower doses improved not only sleep but also aggression and repetitive behaviors. Thus, our study expands both the clinical and molecular spectrum of SKS and offers treatment options guided by molecular and sleep/wake data to improve both cognitive and non-cognitive homeostatic functions.


title: An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19 - Final results from the DisCoVeRy trial

abstract:
ObjectivesWe evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-{beta}-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring.

MethodsWe conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely.

ResultsThe intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-{beta}-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-{beta}-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.

ConclusionIn adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-{beta}-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.


title: Optimal intervention strategies for minimizing total incidence during an epidemic

abstract: This article considers the minimization of the total number of infected individuals over the course of an epidemic in which the rate of infectious contacts can be reduced by time-dependent nonpharmaceutical interventions. The societal and economic costs of interventions are taken into account using a linear budget constraint which imposes a trade-off between short-term heavy interventions and long-term light interventions. We search for an optimal intervention strategy in an infinite-dimensional space of controls containing multiple consecutive lockdowns, gradually imposed and lifted restrictions, and various heuristic controls based for example on tracking the effective reproduction number. Mathematical analysis shows that among all such strategies, the global optimum is achieved by a single constant-level lockdown of maximum possible magnitude. Numerical simulations highlight the need of careful timing of such interventions, and illustrate their benefits and disadvantages compared to strategies designed for minimizing peak prevalence. Rather counterintuitively, adding restrictions prior to the start of a well-planned intervention strategy may even increase the total incidence.


title: Genomic monitoring unveils a high prevalence of SARS-CoV 2 Omicron Variant in vaccine breakthrough cases in Bahia, Brazil

abstract: Genome sequencing proved to be an excellent tool to monitor the molecular epidemiology of the disease caused by SARS-CoV-2, i.e., coronavirus disease (COVID-19). Some reports of infected, vaccinated individuals have aroused great interest because they are primarily being infected with circulating variants of concern (VOCs). To investigate the cases of infected, vaccinated individuals in Salvador, Bahia, Brazil, we performed genomic monitoring to estimate the magnitude of the different VOCs in these cases. Nasopharyngeal swabs from infected (symptomatic and asymptomatic), fully vaccinated individuals (n=29) who were of varying age and had RT-qPCR Ct values of [≤]30 were subjected to viral sequencing using Nanopore technology. Our analysis revealed that the Omicron variant was found in 99% of cases and that only one case was due to the Delta variant. Infected, fully vaccinated patients have a favorable clinical prognosis; however, within the community, they become viral carriers with the aggravating factor of viral dissemination of VOCs not neutralized by the vaccines.


title: The validity and reliability of parents recall for routine Immunization in Cameroon: an evaluative study

abstract:
ObjectiveThe objective of this study was to determine the validity of parents recall for immunization using the vaccination card as the reference in Yaounde-Cameroon.

SettingsThis study was a communitybased study in all the 6 health districts in Yaounde, Cameroon

ParticipantsThe study targeting parents of children aged 0-59months who had their childrens vaccination cards. The immunization history of each child was taken based on both parents recall and vaccination card. Using the vaccination card as a reference, the sensitivity, specificity, positive predictive value and negative predictive value of parents recall were calculated. The degree of agreement and the kappa statistics between the two methods were calculated using R version 4.1.0 (2021-05-18).

ResultsA total of 529 households were visited and 87 elligible parents enrolled. Approximately 55.2% of the children were girls and 53% of them were aged 12-59 months. In total, 94.25% of the participants enrolled were one of the biological parents of the children, with mothers making the majority 86.20% of participants. When combined for all vaccines, the sensitivity, specificity, positive predictive value, and negative predictive value of parents recall were 63%, 60%, 90%, and 23% respectively. The degree of agreement between the two sources was highest for BCG(94%) and lowest with Polio2(32%). Parents recall(94%) was most likely to correctly predict BCG vaccination status of a child than using the scars on the forarm(74%).

ConclusionOur conclusion is that validity and reliability of parents recall vary a lot across different vaccines and parents recall is not very reliable for immunization status assessment in children. Parents recall is preferred for verifying BCG immunization to scars on the forarm. In general, we recommend that parents recall for routine immunization should be used only as a last resort or for BCG, and measles and Yellow Fever vaccines.


title: The use of hippocampal grading as a biomarker for early MCI

abstract:
INTRODUCTIONChanges in the hippocampus are associated with both increased age and cognitive decline due to mild cognitive impairment (MCI) and Alzheimers disease (AD). Most studies have examined the association between hippocampal changes and episodic memory, with many reporting a relationship between hippocampal measurements and global cognition. However, these studies often find associations only in the later stages of cognitive decline. The goal of this study was to examine if hippocampal grading is associated with global cognition in cognitively normal controls (NC), early MCI (eMCI), late (lMCI), and AD, and whether such associations differ across diagnostic cohorts.

METHODSData from 1620 Alzheimers Disease Neuroimaging Initiative older adults were examined in this study (495 NC, 262 eMCI, 545 lMCI, and 318 AD). Participants were included if they completed baseline MRI scans and the Alzheimers disease Assessment Scale (ADAS-13) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) cognitive tests. Linear regressions examined the influence of hippocampal grading on cognitive scores.

RESULTSLower global cognition (i.e., increased ADAS-13 scores) was associated with hippocampal grading scores in all cohorts, including normal controls. Lower global cognition (i.e., increased CDR-SB scores) was associated with hippocampal grading scores in lMCI and AD, but not in eMCI or NC groups.

DISCUSSIONThese findings suggest that hippocampal grading is associated with changes in global cognition in NC, eMCI, lMCI, and AD depending on the cognitive test. Thus, hippocampal grading may be a useful measure that is sensitive to progressive changes early in the disease course.


title: SARS-CoV-2 antibody persistence after five and twelve months: A cohort study from South-Eastern Norway

abstract:
ObjectivesTo assess total antibody levels against Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS CoV-2) spike protein up to 12 months after Coronavirus Disease (COVID-19) infection in non-vaccinated individuals and the possible predictors of antibody persistence.

MethodsThis is a prospective multi-centre longitudinal cohort study.

ParticipantsThe study included SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) positive and negative participants in South-Eastern Norway from February to December 2020. Possible predictors of SARS-CoV-2 total antibody persistence was assessed. The SARS-CoV-2 total antibody levels against spike protein were measured three to five months after PCR in 391 PCR-positive and 703 PCR-negative participants; 212 PCR-positive participants were included in follow-up measurements at 10 to 12 months. The participants completed a questionnaire including information about symptoms, comorbidities, allergies, body mass index (BMI), and hospitalisation.

Primary outcomeThe SARS-CoV-2 total antibody levels against spike protein three to five and 10 to 12 months after PCR positive tests.

ResultsSARS-CoV-2 total antibodies against spike protein were present in 366 (94%) non-vaccinated PCR-positive participants after three to five months, compared with nine (1%) PCR-negative participants. After 10 to 12 months, antibodies were present in 204 (96%) non-vaccinated PCR-positive participants. Of the PCR-positive participants, 369 (94%) were not hospitalised. The mean age of the PCR-positive participants was 48 years (SD 15, range 20-85) and 50% of them were male. BMI [≥] 25 kg/m2 was positively associated with decreased antibody levels (OR 2.34, 95% CI 1.06 to 5.42). Participants with higher age and self-reported initial fever with chills or sweating were less likely to have decreased antibody levels (age: OR 0.97, 95% CI 0.94 to 0.99; fever: OR 0.33, 95% CI 0.13 to 0.75).

ConclusionOur results indicate that the level of SARS-CoV-2 total antibodies against spike protein persists for the vast majority of non-vaccinated PCR-positive persons at least 10 to 12 months after mild COVID-19.


title: BIRC6 modifies risk of invasive bacterial infection in Kenyan children

abstract: Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.


title: Wastewater surveillance using ddPCR reveals highly accurate tracking of omicron variant due to altered N1 probe binding efficiency

abstract: Wastewater surveillance for SARS-CoV-2 is being used worldwide to understand COVID-19 infection trends in a community. We found the emergence and rapid timeline for dominance of the Omicron variant was accurately reflected in wastewater when measured with droplet digital (dd)PCR. We were able to distinguish Omicron from the circulating Delta variant because Omicron has a mutation in the N1 probe binding region that diminished the fluorescent signal within individual droplets. The ddPCR platform may be advantageous for wastewater surveillance since analysis of the data can segregate fluorescent signals from different individual templates. In contrast, platforms such as qPCR that rely solely on the intensity of fluorescence for quantification would not distinguish a subset of variants with mutations affecting the reaction and could underestimate SARS-CoV-2 concentrations. The proportion of Omicron in wastewater was tightly correlated to clinical cases in five cities and provided a higher resolution timeline of appearance and dominance (>75%) than sequenced clinical samples, which were limited in less populated areas. Taken together, this work demonstrates wastewater is a reliable metric for tracking SARS-CoV-2 at a population level.


title: Athletes' access to, attitudes towards, and experiences of help-seeking for mental health: A scoping review protocol

abstract:
IntroductionAthletes are not immune to mental health issues but are less likely to seek help than nonathletes and experience barriers including lack of access to services, lack of knowledge as to how to access services and negative past experiences for help-seeking. Formal and semi-formal sources of support (e.g. support provided in healthcare, sporting context, and higher education systems) are key places for athletes to seek help for mental health, and there is a need to synthesise the evidence on athletes access, attitudes to, and experiences of, these services. This protocol outlines a scoping review that will be used to map the evidence, identify gaps in the literature, and summarise findings on athletes access, attitudes to and experiences of help-seeking for their mental health.

Methods and analysisThe methodological frameworks of Arksey and OMalley (2005), Levac et al. (2010), and the Joanna Briggs Institute (2020 & 2021) were used to inform this scoping review protocol alongside the PRISMA-P checklist and published scoping review protocols within sport and health. This protocol outlines the background evidence, need for this scoping review, and the steps that will be taken.

DisseminationThe evidence will be mapped numerically and thematically to describe studies and highlight key concepts, themes, and gaps in the literature. The published scoping review will be disseminated to relevant stakeholders and policymakers including those in healthcare, the sporting context, and the higher education system. The resulting outputs will be in the form of both peer-reviewed and non-peer reviewed publications (e.g. multimedia in the form of a blog post and at conferences).

Strengths and limitationsO_LIStrength: The protocol outlines a novel scoping review that will contribute to a gap in the literature, and impact further research directions.
C_LIO_LIStrength: Informed by best practice methodological frameworks to ensure rigour.
C_LIO_LILimitation: Lack of quality assessment of papers.
C_LIO_LILimitation: The review will only focus on formal and semi-formal sources of help-seeking (e.g. healthcare, the sporting context and higher education) and will not include research on informal or self-help sources.
C_LI

category: sports medicine


title: Whole Exome Sequencing of Nigerian Prostate Tumors from the Prostate Cancer Transatlantic Consortium (CaPTC) Reveals DNA Repair Genes Associated with African Ancestry

abstract: In this study, we used whole-exome sequencing of a cohort of 45 advanced-stage, treatment-naive Nigerian (NG) primary prostate cancer (PCa) tumors and 11 unmatched non-tumor tissues to compare genomic alterations with African American (AA) and European American (EA) TCGA PCa. NG samples were collected from 6 sites in central and southwest Nigeria. After whole-exome sequencing, samples were processed using GATK best practices. BRCA1 (100%), BARD1 (45%), BRCA2 (27%), and PMS2(18%) had germline alterations in at least two NG non-tumor samples. Across 111 germline variants, the AA cohort reflected a pattern [BRCA1 (68%), BARD1 (34%), BRCA2 (28%), and PMS2 (16%)] similar to NG samples. Of the most frequently mutated genes, BRCA1 showed a statistically (p [≤] 0.05) higher germline mutation frequency in men of African ancestry (MAA) and increasing variant frequency with increased African ancestry. Disaggregating gene level mutation frequencies by variants revealed both ancestry-linked and NG-specific germline variant patterns. Driven by rs799917 (T>C), BRCA1 showed an increasing mutation frequency as African admixture increased. BRCA2_rs11571831 was present only in MAAs, and BRCA2_rs766173 was elevated in NG men. 133 somatic variants were present in 26 PCa-associated genes within the NG tumor cohort. BRCA2 (27%), APC (20%), ATM (20%), BRCA1 (13%), DNAJC6 (13%), EGFR (13%), MAD1L1 (13%), MLH1 (11%), and PMS2 (11%) showed mutation frequencies > 10%. Compared to TCGA cohorts, NG tumors showed statistically significant elevated frequencies of BRCA2, APC, and BRCA1. The NG cohort variant pattern shared similarities (cosign similarities [≥] 0.734) with COSMIC signatures 5 and 6, and mutated genes showed significant (q < 0.001) GO and functional enrichment in mismatch repair and non-homologous repair deficiency pathways. Here, we showed that alterations in DNA damage response (DDR) genes were higher in NG PCa samples and that a portion of those alterations correlate with African ancestry. Moreover, we identified variants of unknown significance that may contribute to population-specific routes of tumorigenesis and treatment. These results present the most comprehensive characterization of the NG PCa exome to date and highlight the need to increase diversity of study populations.


title: Four doses of the inactivated SARS-CoV-2 vaccine redistribute humoral immune responses away from the Receptor Binding Domain

abstract: A recent MMWR reported that the effectiveness of a 3rd dose of SARS-CoV-2 mRNA vaccine waned quickly in the Omicron-predominant period. Similarly, a substantial decline of immune responses induced by a 3rd dose of inactivated vaccines was also observed in our study. In response to the fast waning immune response and the great threat of Omicron variant of concern (VOC) to frontline healthcare workers (HCWs), 38 HCWs who were in our previous cohort investigating responses to the first three doses of inactivated vaccines participated in the current study and volunteered to receive a 4th homologous booster. Here, we demonstrated that the 4th dose is safe and capable of recalling waned immune responses 6 months after the 3rd dose. However, a greater suppression on the induction of overall Neutralizing antibodies (NAbs) and NAbs targeting the receptor-binding domain (RBD) was found in participants with stronger immune responses after the 3rd dose. As a result, a stepwise elevation of RBD-NAbs from the 1st to the 3rd vaccination achieved a "turning point". The peak RBD-NAbs level induced by the 4th dose was inferior to the peak of the 3rd dose. Accompanied with reduced induction of RBD-NAbs, the immune system shifted responses to the nucleocapsid protein (NP) and the N-terminal domain (NTD) of the spike protein. Although NTD directed antibodies are capable of neutralization, they only compensated the loss of RBD-NAbs to ancestral SARS-CoV-2 virus but not to the Omicron variant due to a substantial conformational change of Omicron NTD. This longitudinal clinical study monitored the immune response of the same cohort for every doses, shaping a relationship between the trajectory of immune focus and the dynamics of the neutralizing potency against the evolving virus. Our data reveal that immune responses could not be endlessly elevated, while suppression of heightened immune responses focusing on one subunit together with a shift of immune responses to other subunits would occur after repeated vaccination. Thus, an updated vaccine with more diverse epitopes capable of inducing NAbs against VOCs would be a future direction for boosters.


title: Systematic review and meta-analysis to estimate the burden of fatal and non-fatal overdose among people who inject drugs

abstract:
BackgroundPeople who inject drugs (PWID) have high overdose risk. To assess the burden of drug overdose among PWID in light of opioid epidemic-associated increases in injection drug use (IDU), we estimated rates of non-fatal and fatal overdose among PWID living in Organization for Economic Cooperation and Development (OECD) countries using data from 2010 or later.

MethodsPubMed, Psych Info, and Embase databases were systematically searched to identify peer-reviewed studies reporting prevalence or rates of recent (past 12 months) fatal or non-fatal overdose events among PWID in OECD countries. Data were extracted and meta-analyzed using random effects models to produce pooled non-fatal and fatal overdose rates.

Results57 of 13,307 identified reports were included in the review, with 33/57 studies contributing unique data and included in the meta-analysis. Other (24/57) studies presented overlapping data to those included in meta-analysis. The rates of non-fatal and fatal overdose among PWID in OECD countries were 24.74 per 100 person years (PY) (95% CI: 19.86 - 30.83; n=28; I2=98.5%) and 0.61 per 100 PY (95% CI: 0.32 - 1.16; n=8; I2=93.4%), respectively. The rate of non-fatal overdose was 27.79 in North American countries, 25.71 in Canada, 28.59 in the U.S., and 21.44 in Australia.

ConclusionThese findings suggest there is a fatal overdose for every 40 non-fatal overdose events among PWID in OECD countries. The magnitude of overdose burden estimated here underscores the need for expansion of overdose prevention and treatment programs and serves as a baseline estimate for monitoring success of such programs.

category: addiction medicine


title: Demographic profiles of contact lens wearers and their association with lens wear characteristics in Trinidad and Tobago: A retrospective study

abstract:
PurposeContact lenses (CL) remain a popular mode of refractive error correction globally and in the Caribbean, mostly among young people. However, no data on the characteristics of the CL population wearers in the Caribbean is available. This study reported on the characteristics of CL wearers and the associated factors in Trinidad and Tobago (T&T).

MethodsClinical records of 243 CL wearers attending the University of the West Indies (UWI) optometry clinic between 2017 and 2018 were reviewed. Data on their demographic profiles, CL wearing characteristics including lens type, material, purpose of wear, replacement schedule and care systems were extracted and analyzed. The associations between the demographic characteristics and CL wearing characteristics were also determined.

ResultsAbout half of the respondents wear CL wearers and used them for various purposes such as fashion (more among those aged 18 to 30 years, 61.0%), therapeutic (more among those <18 years, 43.8%, P = 0.001) and refractive error correction purposes (more in those >40 years, P =0.001). Females were more likely to use CLs for fashion compared with males (67.0% versus 40.7%). Age (P<0.0005) and gender (P=0.030) were associated with the lens materials. Those aged 18-30 years were more likely use hydrogels compared with the younger ones (64.1% versus 25.0%). Rigid gas permeable (RGP) CL use was more common in males than females (21.8% versus 10.9%, P = 0.031). Daily disposables were predominantly used by younger respondents (18-30 year-olds, 31.3%, P < 0.001) and more in females than males (66.7% vs 49.4%, P = 0.040).

ConclusionsContact lens use appears be more common among younger females for fashion and older males for refractive correction. Age, gender and employment status were the main determinants of lens wear among respondents attending the university clinic in T&T.

category: ophthalmology


title: Understanding how the design and implementation of Online Consultations influence primary care outcomes: Systematic review of evidence with recommendations for designers, providers, and researchers

abstract:
BackgroundOnline consultations (OCs) allow patients to contact their care provider online, and have been promoted as a way to address increasing workload and decreasing workforce capacity in primary care. Globally, OCs have been rolled out rapidly due to policy initiatives and the COVID-19 pandemic, though there is a lack of evidence regarding how their design and implementation influence care outcomes.

ObjectiveInformed by existing theories, synthesise quantitative and qualitative research on: 1) outcomes of OCs in primary care; 2) how these are influenced by OC system design and implementation.

MethodsWe searched Ovid Medline, Embase, Web of Science, Scopus, NTIS, HMIC, and ZETOC from 2010 to November 2021. We included quantitative and qualitative studies of real-world OC use in primary care, written in English, and published 2010 onwards. Quantitative data were transformed into qualitative themes. For objective 1 we used thematic synthesis informed by the Institute of Medicines domains of healthcare quality. For objective 2 we used Framework Analysis informed by the NASSS framework and Realistic Evaluation. Critical appraisal was conducted using the Mixed Methods Appraisal Tool and strength of evidence judged using GRADE-CERQual.

ResultsWe synthesised 62 studies (quantitative n=32, qualitative n=12, mixed methods n=18) in nine countries covering 30 unique OC systems, 13 of which used Artificial Intelligence (AI). Twenty-six were published in 2020 onwards, and 11 were post-COVID-19. There was no quantitative evidence for negative impacts of OCs on patient safety, and qualitative studies suggested perceptions of OC safety varied. Some participants believed OCs improved safety, particularly when patients could describe their queries using unstructured free-text. Staff workload decreased when sufficient resources were allocated to implement OCs, and patients used them for simple problems or could describe their queries using free-text. Staff workload increased when OCs were not integrated with other software or organisational workflows, and patients used them for complex queries. OC systems that required patients to describe their queries using multiple choice questionnaires (MCQs) increased workload for both them and staff. Health costs were reduced when patients used OCs for simple queries, and increased when used for complex ones. Patients using OCs were more likely to be female, younger, native speakers, with higher socioeconomic status than those not using OCs. However, OCs increased primary care access for patients with mental health conditions, verbal communication difficulties, and barriers to attending in-person appointments. Access also increased by providing a timely response to patients queries. Patient satisfaction increased when using OCs due to better primary care access, though could decrease when using MCQ formats.

ConclusionsThis is the first theoretically-informed synthesis of research on OCs in primary care, and includes studies conducted during COVID-19. It contributes new knowledge that in addition to producing positive outcomes such as increased access and patient satisfaction, they can also have negative outcomes such as increased workload and costs. These negative outcomes can be mitigated by appropriate OC system design (e.g. free-text format), incorporating advanced technologies (e.g. AI), and integration into technical and organisational workflows (e.g. timely responses).

Study protocolPROSPERO (CRD42020191802).

category: primary care research


title: Gut microbiome alterations in fecal samples of treatment-naïve de novo Parkinson's disease patients

abstract:
Gut microbiota alterations in Parkinsons disease (PD) have been found in several studies and are suggested to contribute to the pathogenesis of PD. However, previous results could not be adequately adjusted for a potential confounding effect of PD medication and disease duration, as almost all PD participants were already using dopaminergic medication and were included several years after diagnosis. Here, the gut microbiome composition of treatment-naive de novo PD subjects was assessed compared to healthy controls (HC) in two large independent case-control cohorts (n=136 and 56 PD, n=85 and 87 HC), using 16S-sequencing of fecal samples. Relevant variables such as technical batches, diet and constipation were assessed for their potential effects.

Overall gut microbiome composition differed between PD and HC in both cohorts, suggesting gut microbiome alterations are already present in de novo PD subjects at the time of diagnosis, without the possible confounding effect of dopaminergic medication. Although no differentially abundant taxon could be replicated in both cohorts, multiple short chain fatty acids (SCFA) producing taxa were decreased in PD in both cohorts. In particular, several taxa belonging to the family Lachnospiraceae were decreased in abundance. Fewer taxonomic differences were found compared to previous studies, indicating smaller effect sizes in de novo PD.

Trial registrationDUPARC: NCT04180865

NMDAT: NCT02650843


title: Performance of plasma amyloid, tau, and astrocyte biomarkers to identify cerebral AD pathophysiology

abstract:
IntroductionPlasma amyloid-{beta} (A{beta}), phosphorylated tau (p-tau), and glial fibrillar acid protein (GFAP) can identify Alzheimers disease (AD) pathophysiology with high accuracy. However, comparing their performance in the same individuals remains under-explored.

MethodsWe compared the predictive performance of plasma A{beta}42/40, p-tau(at threonine 181 and 231), neurofilament light (NfL), and GFAP to identify A{beta}- and tau-PET positivity in 138 cognitive unimpaired (CU) and 87 cognitive impaired (CI) individuals.

ResultsIn CU, plasma p-tau231 had the best performance to identify both A{beta}- and tau-PET positivity. In CI, plasma GFAP showed the best predictive accuracy to identify both A{beta} and tau-PET positivity.

DiscussionOur results support plasma p-tau231 as a marker of early AD pathology and, that GFAP best identifies both PET A{beta} and tau abnormalities in the brain of CI individuals. These findings highlight that the performance of blood-based protein biomarkers to identify the presence of AD pathophysiology is disease-stage dependent.


title: Alteration of plasma von Willebrand factor in the treatment of retinal vein occlusion with cystoid macular edema

abstract: Retinal vein occlusion (RVO) is a major retinal disease accompanied by venous thrombosis. Although several studies have proposed an association between venous thrombosis and von Willebrand factor (VWF), the association between RVO and VWF remains unclear. We aimed to investigate the association between RVO and VWF and the alteration of VWF levels under the anti-vascular endothelial growth factor (VEGF) treatment. We enrolled 55 patients with RVO involved cystoid macular edema. They received intravitreal injection of anti-VEGF drugs, either ranibizumab or aflibercept. We examined the clinical data, measured plasma VWF: antigen (VWF: Ag) and plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13: AC) and analyzed them to identify variabilities during the treatment. At the baseline there was no significant difference between the RVO group and age-matched controls in both VWF: Ag and ADAMTS13: AC levels but ADAMTS13:AC was significantly lower in central RVO (CRVO) than in branch RVO (BRVO) (P = 0.015). In BRVO, the negative correlation was found between VWF: Ag and central choroidal thickness (CCT) (r = -0.51, P < 0.001). In BRVO after the anti-VEGF treatment, VWF: Ag decreased significantly from 134% at the baseline to 109% at 1 day after (P = 0.002) and to 107% at 1 month after (P = 0.030). In contrast, ADAMTS13: AC showed no significant difference during this period. In BRVO at 1 month after treatment, we found a negative correlation between VWF: Ag and CCT (r = -0.47, P = 0.001). Our findings suggest an association between VWF and CCT in patients with BRVO, thus the measurement of VWF may be useful for evaluating the disease activity and prognosis.


title: COVID-19 vaccine incentive scheduling using an optimally controlled reinforcement learning model

abstract: We model Covid-19 vaccine uptake as a reinforcement learning dynamic between two populations: the vaccine adopters, and the vaccine hesitant. Using data available from the Center for Disease Control (CDC), we calculate a payoff matrix governing the dynamic interaction between these two groups and show they are playing a Hawk-Dove evolutionary game with an internal evolutionarily stable Nash equilibrium (the asymptotic percentage of vaccinated in the population). We then ask whether vaccine adoption can be improved by implementing dynamic incentive schedules that reward/punish the vaccine hesitant, and if so, what schedules are optimal and how effective are they likely to be? When is the optimal time to start an incentive program, and how large should the incentives be? By using a tailored replicator dynamic reinforcement learning model together with optimal control theory, we show that well designed and timed incentive programs can improve vaccine uptake by shifting the Nash equilibrium upward in large populations, but only so much, and incentive sizes above a certain threshold show diminishing returns.

category: health informatics


title: Estrogen receptor negative breast cancer incidence rates are similar in Ghanaian and Non-Hispanic Black women in the USA

abstract: Age-standardized incidence rates of estrogen receptor negative (ERN) breast cancers in the US are higher among Non-Hispanic Black (NHB) compared to Non-Hispanic White (NHW) women. We aimed to determine if incidence rates were similar between NHB and Ghanaians, given that a high proportion of NHB share West African genetic ancestry. We compared US rates (per 100,000 women) to those in Ghana, using data from US SEER, the Ghanaian census, and the Ghana Breast Health Study (GBHS), a population-based case-control study conducted between 2013-2015 in Accra and Kumasi. ERN age-standardized rates were similar among Ghanaian (40.7) and US NHB women (43.1), and both were higher compared to US NHW (24.0). Estrogen receptor-positive (ERP) rates were lower in Ghanaian (43.7) than US NHB (84.4), and highest in US NHW (128.5). Our data support higher ERN rates among women in Ghana similar to US NHB suggesting shared putative risk factors that require investigation.


title: Persisting pulmonary dysfunction in pediatric post-acute Covid-19

abstract: The frequency and extent of persistent sequelae in children and adolescents after infection with SARS-CoV-2 still needs to be comprehensively determined. In this cross-sectional clinical trial, we used non-invasive, label-free morphologic and free-breathing phase-resolved functional low-field magnetic resonance imaging (LF-MRI) to identify pulmonary changes in children and adolescents from 5 to <18 years after previously PCR-confirmed SARS-CoV-2 infection. While morphological pathologies were less frequent in children, functional LF-MRI visualized widespread ventilation, perfusion and combined ventilation/perfusion defects compared to healthy controls. The loss of functional lung parenchyma was more pronounced in long Covid than recovered patients. While pulmonary dysfunction was persistent even month after primary infection, LF-MRI demonstrated high capability to visualize and detect these changes in children and adolescents. (Clinicaltrials.org ID NCT04990531)


title: Effects of bilateral sequential theta-burst stimulation on 5-HT1A receptors on dorsolateral prefrontal cortex in treatment resistant depression

abstract: Theta-burst stimulation (TBS) represents a brain stimulation technique effective for treatment-resistant depression (TRD) as underlined by meta-analyses. While the methodology undergoes constant refinement, bilateral stimulation of the dorsolateral prefrontal cortex (DLPFC) appears promising to restore left DLPFC hypoactivity and right hyperactivity found in depression. The post-synaptic inhibitory serotonin-1A (5-HT1A) receptor, also occurring in the DLPFC, might be involved in this mechanism of action. To test this hypothesis, we performed PET-imaging using the tracer [carbonyl-11C]WAY-100635 including arterial blood sampling before and after a three-week treatment with TBS in 11 TRD patients compared to sham stimulation (n=8 and n=3, respectively). Treatment groups were randomly assigned, and TBS protocol consisted in excitatory intermittent TBS to the left and inhibitory continuous TBS to the right DLPFC. A linear mixed model including group, hemisphere time and Hamilton Rating Scale for Depression (HAMD) score revealed a 3-way interaction effect of group time and HAMD on 5-HT1A receptor specific binding VS. While post-hoc comparisons showed no significant changes of 5-HT1A VS in either group, higher 5-HT1A VS after treatment correlated with greater difference in HAMD (r=-0.62), indicative of potential effects of TBS on the 5-HT1A receptor. Due to the small sample size, all results, however, must be regarded with caution.


title: Characterizing Affective Variability in Bipolar Disorder and Borderline Personality Disorder, and the Effects of Lithium, Using a Generative Model of Affect

abstract: The affective variability of Bipolar Disorder (BD) is thought to qualitatively differ from that of Borderline Personality Disorder (BPD), with changes in affect persisting for longer in BD. However, quantitative studies have not been able to confirm this distinction. It has therefore not been possible to accurately quantify how treatments like lithium influence affective variability in BD. We assessed the affective variability associated with BD and BPD as well as the effect of lithium using a novel computational model that defines two subtypes of variability: affective changes that persist (volatility) and changes that do not (noise). We hypothesized that affective volatility would be raised in the BD group, noise would be raised in the BPD group and that lithium would impact affective volatility. Daily affect ratings were prospectively collected for up to 3 years from patients with BD, BPD and non-clinical controls. In a separate experimental-medicine study, patients with BD were randomized to receive lithium or placebo, with affect ratings collected from week -2 to +4. We found a diagnostically specific pattern of affective variability. Affective volatility was raised in patients with BD whereas affective noise was raised in patients with BPD. Rather than suppressing affective variability, lithium increased the volatility of positive affect in both studies. These results provide a quantitative measure of the affective variability associated with BD and BPD. They suggest a novel mechanism of action for lithium, whereby periods of persistently low or high affect are avoided by increasing the volatility of affective responses.


title: Quantifying the effect of isolation and negative certification on COVID-19 transmission

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSIsolation of close contact people and negative test certification are used to manage the spread of new coronavirus infections worldwide. These effectively prevent the spread of infection in advance, but they can lead to a decline in socio-economic activity. Thus, the present study quantified the extent to which isolation and negative test certification respectively reduce the risk of infection.

MethodsA discrete-time SEIR model was used as the infectious disease model, and equations for calculating the conditional probability of non-infection status given negative test results on two different days were derived.

ResultsThe respective non-infection probabilities with two negative PCR test results, and with one negative PCR test result and one antigen test result, were quantified. By substituting initial parameters of the SEIR model into these probabilities, the present study revealed the following: (1) isolating close contact individuals can reduce by 80% the risk of infection during the first five days, but five more days are needed to reduce the risk 10% more, and seven more days to reduce the risk 20% more; and (2) if an individual with a negative PCR test result has a negative antigen test result the next day, then his or her infection probability is between 0.6% and 0.7%.

ConclusionsFive-day isolation has a proportionally greater effect on risk reduction, compared to longer isolation; and thus, if an isolation period of longer than five days is contemplated, both the risk reduction and the negative effects from such increased isolation should be considered. Regarding negative test certification, our results provide those in managerial positions, who must decide whether to accept the risk and hold mass-gathering events, with quantitative information that may be useful in their decision-making.


title: Nipah virus from bats - another potential pandemic? Risk mapping the impact of anthropogenic and climate change on the transmission of Nipah virus infection to humans.

abstract: Henipavirus infection (NiV), a fatal disease transmitted by bats has caused human death and disease in India and Bangladesh. With an average case fatality rate of more than 70%, NiV has the potential to cause widespread outbreaks that can have a devastating impact on human health. Spillover of NiV from bats to humans is influenced by several factors mainly human behaviour and human interaction with bats. Climatic conditions and habitat destruction influence the shedding of the virus and the transmission of the disease to humans. Limited research has been conducted on the factors driving these spillover events. As the world has recently witnessed the devastating impact of the COVID-19 global pandemic, a forewarning of spillover events will enable the adoption of adequate measures to prevent and control future outbreaks. Our study maps the likely changing distribution of NiV reservoir Pteropus medius bat species using future climate and land-use change predictions. We use existing data to predict which districts within India and Bangladesh have increased risk of spillover of NiV in the future. We use Species Distribution Modelling to predict the likely change in the distribution of P. medius under different future scenarios and the concurrent increase in the risk of NiV spillover events. We focus on the influence of anthropogenic changes in different socioeconomic scenarios to predict future spillover events. We consider climate and social goals set by the International Panel on Climate Change (IPPC) to create accurate predictions of regions at risk of NiV spillovers. We find that the risk of NiV spillover events in India and Bangladesh will likely increase. More districts are predicted to be at risk of NiV spillovers under the high population growth and persistent environmental degradation scenario than under moderate population growth and medium challenges to achieve climate goals. This highlights the significance of population growth and climate change when considering disease outbreaks and public health. Our findings will enable the authorities in the predicted spillover regions to take public health measures to prevent and control NiV outbreaks.


title: Higher knee hypertension in patients with hemiplegia correlates lower lateral and medial meniscus volume in the paretic leg

abstract: Stroke is a disease with high morbidity and disability rate. After stroke, slower walking velocity, shorter step length, higher cadence, larger step width, and longer stance phase duration can be apparently observed. Additionally, these abnormal gait parameters eventually lead to knee hyperextension, known as genu recurvatum. Walking with such knee hyperextension usually induces knee pain and joint lesions, leading to cumulative damage and degenerative changes and further decreasing the standing phases stability. However, do higher angles of knee hyperextension have any correlation between the gait parameters, the kinematics, the kinetic parameters, the meniscus volume, and the water content of meniscus in paretic and non-paretic legs? This study attempted to answer these questions. The results revealed that 1) longer time since hemiplegia led to larger angles of knee hyperextension, 2) larger angles of knee hyperextension led to more tears in medial/lateral meniscus, and 3) larger angles of knee hyperextension decreased water content of the lateral meniscus in the non-paretic leg but increased water content of the medial meniscus. This was the first study to demonstrate these three above-mentioned observations through magnetic resonance imaging and motion capture system. These results suggested that 1) the knee hyperextension needed to be diagnosed and treated as early as possible; 2) the time since hemiplegia could be an indicator of sign of knee hyperextension; and 3) it might be not effective to identify the knee hyperextension by using spatial-temporal gait parameters.


title: Interactive network-based clustering and investigation of multimorbidity association matrices with associationSubgraphs

abstract:
SummaryMaking sense of association networks is vitally important to many areas of high-dimensional analysis. Unfortunately, as the data-space dimensions grow, the number of association pairs increases in O(n2); this means traditional visualizations such as heatmaps quickly become too complicated to parse effectively. Here we present associationSubgraphs: a new interactive visualization method to quickly and intuitively explore high-dimensional association datasets using network science-derived statistics and visualization. As a use case example, we apply associationSubgraphs to a phenome-wide multimorbidity association matrix generated from an electronic health record (EHR) and provided an online, interactive demonstration for exploring multimorbidity subgraphs.

AvailabilityAn R package implementing both algorithm and visualization components of associationSubgraphs is available at https://github.com/tbilab/associationsubgraphs. Online documentation is available at https://prod.tbilab.org/associationsubgraphs_info/. A demo using a multimorbidity association matrix is available at https://prod.tbilab.org/associationsubgraphs-example/.


title: Examining disparities relating to service reach and patient engagement with COVID-19 remote home monitoring services in England: a mixed methods rapid evaluation

abstract:
BackgroundThe adoption of remote methods of care has been accelerated by the COVID-19 pandemic, but concerns exist relating to the potential impact on health disparities. This evaluation explores the implementation of COVID-19 remote home monitoring services across England, focussing on patients experiences and engagement with the service.

MethodsThe study was a rapid, multi-site, mixed methods evaluation. Data were collected between January and June 2021. We conducted qualitative interviews with staff service leads, and patients and carers receiving the service. We conducted quantitative surveys with staff delivering the service, and patients and carers receiving the service across 28 sites in England, UK. Qualitative data were analysed using thematic analysis and quantitative data were analysed using univariate and multivariate methods.

FindingsMany sites designed their service to be inclusive to the needs of their local population. Strategies included widening eligibility criteria, prioritising vulnerable groups, and creating referral pathways. Many sites also adapted their services according to patient needs, including providing information in different languages or more accessible formats, offering translation services, offering non-digital options, or providing face-to-face assessments. Despite these adaptions, disparities were reported across patient groups (e.g. age, health status, ethnicity, level of education) in their experience of and engagement with the service.

InterpretationServices must determine how best to design and implement remote monitoring services to be of value to all populations. National guidance should play a role in supporting services to best serve the needs of their populations, and patients and staff must play an active role in service design.

FundingThis is independent research funded by the National Institute for Health Research, Health Services & Delivery Research programme (RSET Project no. 16/138/17; BRACE Project no. 16/138/31) and NHSEI. NJF is an NIHR Senior Investigator. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence shows COVID-19 has a disproportionate impact on certain population groups, such as ethnic minority groups, older adults and those with comorbidities. The rapid adoption and spread of remote home monitoring services in England must be accompanied by evaluations at a local level to monitor the impact on health disparities in local populations.

Added value of this studyThis rapid mixed methods evaluation of COVID-19 home monitoring services adopted across 28 sites in England aimed to increase understanding of how services have been designed and delivered to address local population needs to increase accessibility to the service and facilitate engagement with the service. We add to the literature by identifying a range of local service adaptations which aim to increase reach and facilitate patient engagement, and consider their potential impact on health disparities. We found strategies included prioritising vulnerable groups, creating referral pathways, offering translation services, offering non-digital options, or providing face-to-face assessments. Despite efforts to adapt services to meet local needs, disparities across patient groups in their experience of, and engagement with, the service (related to age, health status, ethnicity, and level of education) were reported.

Implications of the available evidenceAt both a national and local level, and particularly given the increasing use of remote home monitoring schemes, lessening health disparities must be a primary focus in the design and delivery of remote monitoring models for COVID-19 and other conditions. Future research should focus on how best to design and evaluate remote monitoring services, for a range of conditions, especially for patients residing in areas where significant health disparities persist, as well as addressing the effectiveness of any strategies on specific population groups.

category: health systems and quality improvement


title: Strengthening health systems capacity for pre-exposure Prophylaxis for adolescent girls and young women and adolescent boys and young men in South Africa (SHeS'Cap - PrEP): Protocol for a mixed methods study in KwaZulu-Natal, South Africa

abstract:
IntroductionPre-exposure prophylaxis (PrEP) is an effective prevention intervention that can be used to control HIV incidence especially among people who are at increased risk for HIV such as adolescent girls and young women (AGYW) and adolescent boys and young men (ABYM). In South Africa, various approaches of delivering PrEP have been adopted at different service delivery points (facility-based only, school-based only, community-based only and hybrid school-facility and community-facility models) to overcome challenges associated with individual, structural, and health systems related barriers that may hinder access to and uptake of PrEP among these populations. However, little is known about how to optimize PrEP implementation and operational strategies to achieve high sustained uptake of good quality services for AGYW and ABYM. This study aims to identify effective and feasible PrEP models of care for improving PrEP uptake, continuation, and adherence among AGYW and ABYM.

Methods and analysisA sequential explanatory mixed-methods study will be conducted in 22 service delivery points (SDPs) in uMgungundlovu district, KwaZulu-Natal, South Africa. We will recruit 600 HIV negative, sexually active, high risk, AGYW (aged 15-24 years) and ABYM (aged 15-35 years). Enrolled participants will be followed up at 1-, 4- and 7-months to determine continuation and adherence to PrEP. We will conduct two focus group discussions (with 8 participants in each group) across four groups (i. Initiated PrEP within 1 month, ii. Did not initiate PrEP within 1 month, iii. Continued PrEP at 4/7 months and iv. Did not continue PrEP at 4/7 months) and 48 in-depth interviews from each of the four groups (12 per group). Twelve key informant interviews with stakeholders working in HIV programs will also be conducted. Associations between demographic characteristics stratified by PrEP initiation and by various service-delivery models will be assessed using Chi-square/Fishers exact tests or t-test/Mann Whitney test. A general inductive approach will be used to analyze the qualitative data.

Ethics and disseminationThe protocol was approved by the South African Medical Research Council Health Research Ethics Committee (EC051-11/2020). This project was reviewed by the U.S. Centers for Disease Control and Prevention (Atlanta, GA), Centers for Global Health Associate Director for Science in accordance with CDC human research protection procedures and was determined to be research, but CDC investigators did not interact with human subjects or have access to identifiable data or specimens for research purposes. Provincial and district level approval has been granted. Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer-reviewed journal articles and research capacity building through research degrees.

category: hiv aids


title: Influenza vaccination reveals and partly reverses sex dimorphic immune imprints associated with prior mild COVID-19

abstract: Viral infections can have profound and durable functional impacts on the immune system. There is an urgent need to characterize the long-term immune effects of SARS-CoV-2 infection given the persistence of symptoms in some individuals and the continued threat of novel variants including the recent rapid acceleration in infections. As the majority of COVID-19 patients experienced mild disease, here we use systems immunology approaches to comparatively assess the post-infection immune status (mean: 151 [5th - 95th percentile: 58 - 235] days after diagnosis) and subsequent innate and adaptive responses to seasonal influenza vaccination (as an "immune challenge") in 33 previously healthy individuals after recovery from mild, non-hospitalized COVID-19, as compared to 40 age- and sex-matched healthy controls with no history of COVID-19. Sex-specific, temporally stable shifts in signatures of metabolism, T-cell activation, and innate immune/inflammatory processes suggest that mild COVID-19 can establish new post-infection immunological set-points. COVID-19-recovered males had an increase in CD71hi B-cells (including influenza-specific subsets) before vaccination and more robust innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy males. Intriguingly, by day 1 post-vaccination in COVID-19-recovered subjects, the expression of numerous innate defense/immune receptor genes (e.g., Toll-like receptors) in monocytes increased and moved away from their post-COVID-19 repressed state toward the pre-vaccination baseline of healthy controls, and these changes tended to persist to day 28 in females, hinting that the acute inflammatory responses induced by vaccination could partly reset the immune states established by prior mild COVID-19. Our study reveals sex-dimorphic immune imprints and in vivo functional impacts of mild COVID-19 in humans, suggesting that prior COVID-19 could change future responses to vaccination and in turn, vaccines could help reset the immune system after COVID-19, both in an antigen-agnostic manner.

category: infectious diseases


title: Accuracy of tongue swab testing using Xpert MTB-RIF Ultra for tuberculosis diagnosis

abstract: Tongue dorsum swabs have shown promise as alternatives to sputum for detecting Mycobacterium tuberculosis (MTB) in patients with pulmonary tuberculosis (TB). Some of the most encouraging results have come from studies that used manual quantitative PCR (qPCR) to analyze swabs. Studies using the automated Cepheid Xpert(R) MTB/RIF Ultra qPCR test (Xpert Ultra) have yielded less encouraging results with tongue swabs, possibly because Xpert Ultra is optimized for testing sputum, not tongue swab samples. Using two new sample processing methods that demonstrated good sensitivity in preliminary experiments, we assessed diagnostic accuracy and semi-quantitative signals of 183 tongue swab samples using Xpert Ultra in a clinical setting. Relative to a sputum Xpert Ultra reference standard, the sensitivity of tongue swab Xpert Ultra was 68.5% (95% CI 54.4-80.5) and specificity was 100.0% (95% CI 97.2-100.0). When compared to a microbiological reference standard (MRS) incorporating both sputum Xpert Ultra and sputum culture, sensitivity was 64.9 (95% CI 51.1-77.1) and specificity remained the same. Higher sensitivity was observed (77.8% CI 64.4-88.0) when "trace" Xpert results were included among positive swabs. Semi-quantitative Xpert Ultra results were generally lower with swabs than with sputum. None of the eight sputum Xpert Ultra "trace" or "very low" results were detected using tongue swabs. Tongue swabs should be considered when sputum cannot be collected for Xpert Ultra testing, or in certain mass-screening settings. Further optimization of tongue swab analysis is needed to achieve parity with sputum-based molecular testing for TB.


title: The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria

abstract: Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. The sequestration of parasitized erythrocytes in the microvasculature of vital organs is a central pathophysiological feature. The plasma concentration of the parasite protein P. falciparum Histidine-Rich Protein 2 (PfHRP2) has diagnostic and prognostic value in severe malaria. In the current study we investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of plasma PfHRP2 to circulating parasites) as quantitative traits in the conduct of case-only genetic association studies of severe malaria. We demonstrate the utility of this approach using data from over 2,000 Kenyan children with severe malaria, genotyped for 14 major candidate genes that were found to be associated with protection against severe malaria in previous studies. We show that PfHRP2 is a more informative quantitative trait than peripheral parasite density, and that polymorphisms in four major red cell genes (the {beta}S sickle mutation in HBB, the blood group mutation O in ABO, the -thalassaemia mutation in HBA, and the Dantu blood group mutation in GYP) are associated with substantially lower concentrations of plasma PfHRP2 at admission. Further, the effect sizes we observed were considerably larger than those relating to peripheral parasite density. An unexpected outlier was the rs1541255 A>G polymorphism in ATP2B4 for which we saw higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for how this might be explained in the context of this specific protective allele.


title: Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-a-chip technology

abstract: The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between translating assays from microarray analysis (expensive lab-based discovery method) to ISFET arrays (cheap point-of-care diagnostics) providing benefits on tackling infectious disease outbreak and diagnostic testing in hard-to-reach areas of the world.