Multi-ancestry omic Mendelian randomization revealing putative drug targets of COVID-19 severity Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1,608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritised additional drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions.

MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity only in European ancestry and one protein target, SERPINA1, only showed effect in African ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P=9.96x10-4; OR in Europeans=1.021, P=0.745). One protein, ICAM1, showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P=5.94x10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P=0.045). The phenome-wide MR of the prioritised targets on 622 complex traits identified 726 potential causal effects on other diseases, providing information on potential beneficial and adverse effects. Our study prioritised six proteins as potential drug targets for COVID-19 severity. Several of them were targets of existing drug under trials of COVID-19 or related to the immune system. Most of these targets showed different effects in European and African ancestries, which highlights the value of multi-ancestry MR in informing the generalizability of COVID-19 drug targets across ancestries. This study provides a first step towards clinical investigation on COVID-19 and other types of coronaviruses.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched key terms in PUBMED published before Feb 1st 2022, with the terms: ("COVID-19, "coronavirus") AND ("omics" or "protein" or "transcript") AND ("Genome-wide association study" or "Mendelian randomization"). We found multiple studies identified targeted genes or proteins associated with COVID-19. However, there is little human genetics evidence support the ancestry-consistent or ancestry-specific genes/proteins associated with COVID-19.

Added value of this studyTo our knowledge, this is the first comprehensive genetic study that identified protein targets that showed effect on COVID-19 severity in European and African ancestries. Our study identified one protein, SERPINA1, that showed effects on COVID-19 in African ancestry (OR=0.369, P=9.96x10-4), but not in European ancestry (OR=1.021, P=0.745). In addition, our study identified four additional protein targets, FCRL3, ICAM5, ENTPD5 and OAS1, that showed effect on COVID-19 severity in Europeans. One protein ICAM1 showed suggestive effect in both ancestries. Some of these proteins are related to the immune system and/or are targets of existing drug under trials of COVID-19.

Implications of all available evidenceOur study prioritised six drug targets for COVID-19 severity, five of them showed different effects in European and African ancestries. This suggested that drug targets may have different responses on COVID-19 severity in different ancestries. Our study also highlights the value of intercellular adhesion molecule (ICAM) family in relation with COVID-19 severity in both ancestries.
ENDORSE: a prognostic model for endocrine therapy response in advanced estrogen-receptor positive breast cancers Endocrine therapy remains the primary treatment for advanced and metastatic estrogen receptor-positive (ER+) breast cancers. Patients who progress on endocrine therapy may benefit from add-on treatment targeting the PI3K/MTOR signaling pathways or by switching to chemotherapy. However, these options are only available after progression on first-line treatment with endocrine therapy. In the absence of reliable prognostic tests for advanced ER+ breast cancers, it is currently not possible to stratify patients into pertinent treatment arms at the baseline. To address this, we have developed a low-dimensional endocrine response signature (ENDORSE) model for advanced ER+ breast cancers. The ENDORSE model was developed using the baseline tumor transcriptomes and long-term survival outcomes of >800 invasive ER+ breast cancers and predicts the risk of death on endocrine therapy. ENDORSE was validated in multiple clinical trial datasets for endocrine therapy response in metastatic ER+ breast cancers and demonstrated superior predictive performance over clinical factors and published gene signatures. Our results show that ENDORSE is a reproducible and accurate prognostic model for endocrine therapy response in advanced and metastatic ER+ breast cancers.
An observational study of the association between COVID-19 vaccination rates and entry into the "Million Dollar Vax" competition ObjectivesAre financial incentives from entry in a vaccine lottery associated with a higher probability of vaccination for COVID-19?

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

SettingOctober and November 2021, Australia.

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

InterventionsParticipation in the Million Dollar Vaccination Lottery

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

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

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

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

Ethics statementThis study was approved by the University of Melbourne Faculty of Business and Economics & Melbourne Business School Human Ethics Advisory Group (Ref: 2056754.1). Mitigating Covid-19 aerosol infection risk in school buildings: the role of natural ventilation, classroom volume, occupancy and face masks Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Characterization of small fiber neuropathy in hypermobile Ehlers Danlos Syndrome Ehlers Danlos syndromes (EDS) are heritable connective tissue disorders. The hypermobile form (hEDS) is the most frequent, yet the only one without an identified genetic mutation. Patients suffering from symptomatic joint hypermobility, yet not fulfilling the hEDS criteria, enter the Hypermobility Spectrum Disorder (HSD) category. In addition to musculoskeletal pain affecting joints, hEDS/HSD patients often describe painful sensations, hypoesthesia, and autonomic symptoms suggesting a neuropathic component. Small fiber neuropathy (SFN) refers to the dysfunction or damage of A-{delta} and C-fibers, which relay thermal and nociceptive information as well as mediating autonomic function. SFN has been suggested by prior studies in hEDS but these early findings (case series N[&le;]20) with sole reliance on intraepidermal nerve fiber density (IENFD) called for a larger sample combined with functional testing.

In this retrospective chart extraction from 79 hEDS/HSD patients referred to a pain center due to neuropathic pain or dysautonomia, both functional (Quantitative Sensory Testing (QST), N=79) and structural (IENFD, N=69) evaluations of small nerve fibers were analyzed in combination with clinical data and standardized questionnaires.

All the patients reported moderate to severe pain interfering with daily life. A decreased thermal detection (QST) was shown in 55/79 patients (70%) and a decreased IENFD in 54/69 patients (78%). Hence a small fiber neuropathy (both abnormal IENFD and QST) was definite in 40/69 patients (58%), possible in 23/69 patients (33%) and excluded in only 6/69 patients (9%).

These results add strong evidence for a peripheral neuropathic contribution to pain symptoms in hEDS/HSD, in addition to the known nociceptive and central sensitization components. Such neuropathic contribution could raise the hypothesis of a neurological cause of hEDS, the only EDS syndrome still without a known genetic cause. Hence, our data is leading the way to a better stratification of this very heterogeneous population, which could improve symptommanagement and expand pathophysiological research. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients in India: Perspective of an Independent Radiology Practice BackgroundThe COVID-19 patients often undergo a high-resolution CT scan to determine extent of their lung involvement. The aim of this study was to determine lung involvement in confirmed/suspected COVID-19 patients (encountered at an independent radiology practice) and its correlation to vaccination status amidst the second COVID-19 wave in India.

MethodsWe retrospectively queried our data since April 2021 to identify adult patients (>17 years) who had confirmed (positive RT-PCR or antigen test) or suspected COVID-19 (classic symptoms but negative RT-PCR) and received a high-resolution CT scan to determine the extent of their lung involvement using the CT severity (CT-SS) score. Patients were classified in 3 groups based on their vaccination status to determine its correlation with the CT-SS score: fully vaccinated, partially vaccinated, and unvaccinated. Basic descriptive statistics, univariate tests and multivariate linear regression analysis were used.

ResultsWe identified 229 patients (median age 45 years, 60% male) of which 205 (89%) had confirmed COVID-19 (positive RT-PCR) and 24 had suspected disease (negative RT-PCT but classic symptoms). Of the 229 patients 29 (13%) had complete vaccination, 38 (17%) had partial vaccination and 162 (70%) had no vaccination. The CT score of the completely vaccinated patients was significantly lower compared to partially or unvaccinated patients (median 0 v. 3.5 v. 10, respectively p<.01). A multivariate linear regression model showed that partial or fully vaccinated patients had lower CT severity score compared to unvaccinated patients (adjusted R squared = 0.47).

ConclusionWe present here the real-world findings from an independent radiology practice (a unique and common practice model), in India amid the second COVID-19 wave showing significantly lower CT severity score in fully or partially vaccinated patients compared to unvaccinated patients. Complete vaccination in patients could be critical in preventing severe lung disease. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury. The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

DesignParticipants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individuals real-ear or prescribed gain. The second segment was presented with a {+/-}0-12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was "better", "worse" or "no different" from the first.

Study SampleTwenty-nine adults, all with hearing-aid experience.

ResultsThe minimum gain adjustments needed to elicit "better" or "worse" judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable.

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation. Deep Covid -Covid Diagnosis Using Deep Neural Networks and Transfer Learning Coronavirus is a global emergency as of May 2021. If not acted upon by drugs at the right time, coronavirus may result in the death of individuals. Hence early diagnosis is very important along the progress of the disease. This paper focuses on coronavirus detection using x-ray images, for automating the diagnosis pipeline using convolutional neural networks and transfer learning. This could be deployed in places where radiologists are not easily available in order to detect the disease at very early stages. In this study we propose our deep learning architecture for the classification task, which is trained with modified images, through multiple steps of preprocessing. Our classification method uses convolutional neural networks and transfer learning architecture for classifying the images. Our findings yield an accuracy value of 91.03%, precision of 89.76 %, recall value of 96.67% and F1 score of 93.09%. How social engagement against Covid-19 in a Brazilian Slum helped mitigate rising statistics ObjectivesFor many underdeveloped countries, strategies implemented by social communities allied to scientific knowledge may be a rote to attenuate the rapid spread of Covid-19 cases and allow services to the population. This work presents a joint effort collaboration between scientists and underserved community groups from a Brazilian slum/Santa Marta in Rio de Janeiro City in the fight against Covid-19. Measurements of contamination in the air near the ground, georeferencing of data of infected people, were regressed with sanitization activities aiming at reducing the Covid-19 incidence.

MethodsWe monitored aerosol containing SARS-Cov-2 virus in outdoor ambient air using various virus collection mediums (solid, liquid, and gelatinous substrates) at different aerodynamic sizes. We implemented a local statistics survey for the Covid-19 database correlated with varying sanitization levels between April 2020 and June 2021 developed in the Santa Marta slum.

FindingsWe detected the SARS-CoV-2 virus in the air near the ground in diameters ranging from 0.25 to 0.5 {micro}m, demonstrating that there is a circulation of the virus in the slum atmosphere. We demonstrate that Covid-19 cases for the Santa Marta slum were significatively lowered with improved sanitization levels (r = -0.74).

ConclusionsDespite previous publications that discarded the use of sanitization as a relevant tool in the fight against Covid-19, our results suggest that profits can be achieved in mitigating Covid-19 in underserved community sites. Furthermore, a permanent sanitization activity may induce positive social behavior for the sake of combating Covid-19. COMPARISON OF sPLA2-IIA PERFORMANCE WITH HIGH-SENSITIVE CRP, NEUTROPHIL PERCENTAGE, PCT AND LACTATE TO IDENTIFY BACTERIAL INFECTION: A PROSPECTIVE STUDY Early bacterial infection (BI) identification in resource-limiting Emergency Departments (ED) is challenging especially in low- and middle-income counties (LMIC). Misdiagnosis predisposes to antibiotic overuse and propagates antimicrobial resistance. This study evaluates new emerging biomarkers, secretory phospholipase A2 group IIA (sPLA2-IIA), and compares with other biomarkers on their performance characteristic of BI detection in Malaysia, an LMIC. A prospective cohort study was conducted involving 151 consecutive patients admitted to the ED. A single measurement was taken upon patient arrival in ED and was analysed for serum levels of sPLA2-IIA, high-sensitive C-reactive protein (CRP), procalcitonin (PCT), neutrophil percentage (N%), and lactate. All biomarkers performance was compared for the outcomes using area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. The performance of sPLA2-IIA (AUROC 0.93 [95% CI: 0.89-0.97]; Sn 80% [95% CI: 72-87] Sp 94% [95% CI: 81-89]) was the highest among all. It was comparable with high-sensitive CRP (AUROC 0.93 [95% CI: 0.88-0.97]; Sn 75% [95% CI: 66-83]; Sp 91 [95% CI: 77-98]) but had a higher Sn and Sp. The sPLA2-IIA was also found superior to N%, PCT, and lactate. This finding suggested sPLA2-IIA was recommended biomarkers for BI detection in LMIC. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Analysis of MRI-derived spleen iron in the UK Biobank identifies genetic variation linked to iron homeostasis and erythrocyte morphology Aging, and the pathogenesis of many common diseases, involves iron homeostasis. A key role in iron homeostasis is played by the spleen, which is the largest filter of the blood and performs iron reuptake from old or damaged erythrocytes. Despite this important role, spleen iron content has not been measured previously in a large, population-based cohort. In this study, we quantify spleen iron in 41,764 participants of the UK Biobank using magnetic resonance imaging (MRI). We find that epidemiologic and environmental factors such as increased age, higher red meat consumption and lower alcohol intake correlate with higher spleen iron. Through genome-wide association study, we identify genetic associations between spleen iron and common variation at seven loci, including in two hereditary spherocytosis (HS) genes, ANK1 and SPTA1. HS-causing mutations in these genes are associated with lower reticulocyte volume and increased reticulocyte percentage, while our common alleles are associated with increased expression of ANK1 and SPTA1 in blood and with larger reticulocyte volume and reduced reticulocyte percentage. As genetic modifiers, these common alleles may explain mild spherocytosis phenotypes observed in some HS allele carriers. Further, we identify an association between spleen iron and MS4A7, which colocalizes with a quantitative trait locus for MS4A7 alternative splicing in whole blood, and with monocyte count and fraction. Through quantification of spleen iron in a large human cohort, we extend our understanding of epidemiological and genetic factors associated with iron recycling and erythrocyte morphology. Decoding hand and wrist movement intention from chronic stroke survivors with hemiparesis using a user-friendly, wearable EMG-based neural interface Prosthetics and orthotics have been recognized for decades as a potential means to restore hand function and independence to individuals living with impairment due to stroke. However, 75% of stroke survivors, caregivers, and health care professionals (HCP) believe current practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper limb technologies is to infer movement intent non-invasively from surface electromyography (EMG) activity. While this approach has garnered significant attention in the literature, existing technologies are often limited to research settings and struggle to meet stated user needs. To address these limitations, we have developed the NeuroLife(R) EMG System, which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements, including multiple types of grasps from participants with varying levels of chronic impairment from stroke, with an overall accuracy of 77.1{+/-}5.6%. Importantly, we demonstrate the ability to decode a subset of 3 fundamental movements in individuals with severe hand impairment at 85.4{+/-}6.4% accuracy, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeves design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Taken together, the NeuroLife EMG System represents a platform technology to record and decode high-definition EMG for the eventual real-time control of assistive devices in a form factor designed to meet user needs. Right Anterior Temporal Degeneration, Emotions, and Loss of Nonverbal Semantics: The Emotional Semantic Variant Frontotemporal Dementia It has been proposed that focal anterior temporal lobe (ATL) degeneration is a specific, unitary FTLD-TDP-related disease that initially preferentially affects the left or right hemisphere. Patients with early left ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, prompting appropriate neurological care. There is less consensus regarding the symptoms in right ATL (rATL) predominant cases, who most often present with behavioral and emotional changes leading to a misdiagnosis of a psychiatric disorder, and later of behavioral variant frontotemporal dementia (bvFTD). Uncertainties regarding early symptoms and lack of an overarching framework continues to hinder proper diagnosis and care of patients with rATL disease. Here, we present symptom chronology, cognitive and socioemotional profiles of a large, well-characterized, longitudinally followed cohort of patients with rATL-predominant degeneration and propose new criteria and nosology for the syndrome.

We identified individuals with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n=478). Based on neuroimaging criteria, we identified three groups: patients with rATL-predominant atrophy with relative sparing of the frontal lobes (n=46), patients with frontal-predominant atrophy with relative sparing of the rATL (n=79), and patients with lATL-predominant atrophy with relative sparing of the frontal lobes (n=75). Seventy-eight patients had undergone autopsy. We analyzed patients clinical, neuropsychological, genetic, anatomical, and pathological profiles.

In the rATL-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%), and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in emotional theory of mind, identifying famous people from names and face, and facial affect naming (despite preserved face perception) than the lATL- and frontal-predominant groups. The clinical features were highly sensitive (81%) and specific (84%) in differentiating rATL from bvFTD in the first three years of the disease. FTLD-TDP (84%) was the most common pathology.

Our results suggest that rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive loss of semantic memory for concepts of social-emotional relevance. Although this syndrome exists along a clinical, anatomical, and pathological continuum with svPPA, patients present with progressive behavioral changes. To facilitate early identification and care in clinical and research settings, we propose specific diagnostic criteria and the term "emotional semantic variant frontotemporal dementia" to distinguish this syndrome from other forms of frontotemporal dementia. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI Arrhythmic Outcomes in Catecholaminergic Polymorphic Ventricular Tachycardia IntroductionCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify pre-dictive factors for arrhythmic outcomes in CPVT patients from Hong Kong.

MethodsThis was a territory-wide retrospective cohort study of consecutive patients diagnosed with CPVT at public hospitals or clinics in Hong Kong. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).

ResultsA total of 16 (mean presentation age=11{+/-}4 years old) patients were included. All patients presented at or before 19 years of age. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and VT/VF, whereas one patient had PVCs without VT/VF. Genetic tests were performed in 14 patients (87.5%). Eight (57.1%) tested positive for the RyR2 gene. Seven variants have been described else-where (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A). c.14861C>G is a novel RyR2 variant that has not been reported outside this cohort. All patients were treated with beta-blockers, three patients received amiodarone and two received verapamil. Sympathectomy (n=8), ablation (n=1) and implantable-cardioverter defibrillator implantation (n=3) were performed. Over a median follow-up of 127 (IQR: 97-143) months, six patients suffered from incident VT/VF. No significant predictors were identified on Cox regression. Nevertheless, a random survival forest model identified initial VT/VF/sudden cardiac death, palpitations, QTc, initially symptomatic and heart rate as important variables for estimating the probability of developing incident VT/VF.

ConclusionAll CPVT patients who are from Hong Kong presented at or before 19 years of age. Clinical and electrocardiographic findings can be used to predict arrhythmic outcomes. A nonparametric machine learning survival analysis achieved high accuracy for predicting the probability of incident VT/VF. Effectiveness of the Covid-19 vaccines in preventing infection in dental practitioners: results of a cross-sectional questionnaire based survey India started its vaccination program at the beginning of 2021, the main beneficiaries being health workers and frontline workers including police, paramilitary forces, sanitation workers, and disaster management volunteers in the first phase. By the time, the second wave of Covid-19 impacted India, approximately 14 million healthcare and frontline workers, including dentists had been vaccinated.

AimTo study the effectiveness of vaccination on a subset of high-risk healthcare workers i.e. dentists in preventing Covid-19 during the second wave of the pandemic.

Study designA questionnaire based pan-India online survey was carried out to record the Covid-related experiences of dentists prior to and after vaccination.

ResultThe sample size for this survey was 4493 respondents from across India. During the second wave, 9.18% (n=364) respondents became positive in spite of the vaccine, while 14.69%(n=78) became positive in the unvaccinated group. A chi-square test of independence was performed to examine the relation between vaccination and the Covid positivity rate in all age groups. The relation between these variables was highly significant, [X2 (1, N = 4493) = 15.9809, p=.000064].

ConclusionOur pan-India online survey inferred that vaccination has a definitive role to play in reducing the positivity rate amongst dentists during the second wave of the pandemic across all age groups.