Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries BackgroundThrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries.

MethodsElectronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner.

FindingsA total of 25,432,658 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 30.9 (28.6 to 33.3) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event.

InterpretationAlthough rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

FundingThis study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3).
Human lipoproteins comprise at least 12 different classes that are lognormally distributed. Lipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors.
iBKH: The integrative Biomedical Knowledge Hub The rapidly increasing biomedical knowledge, derived from biological experiments or gained from clinical practice, has become the important treasure in the biomedical research. The emerging knowledge graphs (KGs) provide an efficient and effective way to organize and retrieval the huge and increasing volume of biomedical knowledge. A biomedical KG (BKG) typically stores and represents knowledge by constructing a semantic network describing entities and the relationships between them. Previous efforts have been conducted to construct and curate BKGs by comprehensively integrating various biomedical data resources. Though the resulting BKGs have made a significant progress in this filed in advancing biological and medical research, there remain a big gap to a perfect one that is comprehensive and fine-grained enough. To this end, in the present study, we collected and integrated data from diverse well-curated biomedical knowledge bases and BKGs to curate a more comprehensive one, named the integrative Biomedical Knowledge Hub (iBKH). To enhance the usage in accelerating biomedical research, we deployed iBKH using the famous graph database, Neo4j. This is a continuing effort and we are adding in more and more contents in iBKH to support the various complex needs in biomedical data analysis. Please contact us if you have better ideas and suggestions. Simple risk scores to predict hospitalization or death in outpatients with COVID-19 including the Omicron variant ImportanceOutpatient physicians need guidance to support their clinical decisions regarding management of patients with COVID-19, in particular whether to hospitalize a patient and if managed as an outpatient, how closely to follow them.

ObjectiveTo develop and prospectively validate a clinical prediction rule to predict the likelihood of hospitalization for outpatients with COVID-19 that does not require laboratory testing or imaging.

DesignDerivation and temporal validation of a clinical prediction rule, and prospective validation of two externally derived clinical prediction rules.

SettingPrimary and Express care clinics in a Pennsylvania health system.

ParticipantsPatients 12 years and older presenting to outpatient clinics who had a positive polymerase chain reaction test for COVID-19.

Main outcomes and measuresClassification accuracy (percentage in each risk group hospitalized) and area under the receiver operating characteristic curve (AUC).

ResultsOverall, 7.4% of outpatients in the early derivation cohort (5843 patients presenting before 3/1/21) and 5.5% in the late validation cohort (3806 patients presenting 3/1/21 or later) were ultimately hospitalized. We developed and temporally validated three risk scores that all included age, dyspnea, and the presence of comorbidities, adding respiratory rate for the second score and oxygen saturation for the third. All had very good overall accuracy (AUC 0.77 to 0.78) and classified over half of patients in the validation cohort as very low risk with a 1.7% or lower likelihood of hospitalization. Two externally derived risk scores identified more low risk patients, but with a higher overall risk of hospitalization (2.8%).

Conclusions and relevanceSimple risk scores applicable to outpatient and telehealth settings can identify patients with very low (1.6% to 1.7%), low (5.2% to 5.9%), moderate (14.7% to 15.6%), and high risk (32.0% to 34.2%) of hospitalization. The Lehigh Outpatient COVID Hospitalization (LOCH) risk score is available online as a free app: https://ebell-projects.shinyapps.io/LehighRiskScore/. Stability of the stroke code during the COVID-19 pandemic in the region of Madrid: a retrospective cohort study Acute Stroke (AS) is the most common time-dependent disease attended in the Emergency Medicine Service (EMS) of Madrid (SUMMA 112). Community of Madrid has been one of the most affected regions in Spain by the coronavirus disease 2019 (COVID19) pandemic. A significant reduction in AS hospital admissions has been reported during the COVID-19 pandemic compared to the same period one year before. As international clinical practice guidelines support those patients with suspected acute stroke should be accessed via EMS, it is important to know whether the pandemic has jeopardized urgent pre-hospital stroke care, the first medical contact for most patients. We aimed to examine the impact of the COVID-19 in stroke codes (SC) in our EMS among three periods of time: the COVID-19 period, the same period the year before, and the 2019-2020 seasonal influenza period. Methods: We compared the SC frequency among the periods with high cumulative infection rate (above the median of the series) of the first wave of COVID-19, seasonal influenza, and also with the same period of the year before. Results: 1,130 SC were attended during the three periods. No significant reduction in SC was found during the COVID-19 pandemic. The reduction of hospital admissions might be attributable to patients attending the hospital by their means. The maximum SC workload seen during seasonal influenza has not been reached during the pandemic. We detected a non-significant deviation from the SC protocol, with a slight increase in hospitals transfers to hospitals without stroke units. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. Lipid peroxidation induced ApoE receptor-ligand disruption as a unifying hypothesis underlying sporadic Alzheimer's disease in humans Structured AbstractO_ST_ABSBackgroundC_ST_ABSSporadic Alzheimers disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the central core of neuritic plaques, the hallmark plaques and tangles, and the selective vulnerability of entorhinal-hippocampal structures.

ObjectiveWe hypothesized that (1) high expression of ApoER2 (receptor for ApoE and Reelin) could help explain the selective anatomical vulnerability; and (2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting ApoE delivery and Reelin-ApoER2 signaling cascades.

MethodsWe conducted in vitro biochemical experiments, single-marker immunohistochemistry (IHC), and multiplex fluorescence-IHC (MP-IHC) in postmortem specimens from 26 individuals who died cognitively normal, with Mild Cognitive Impairment or with sAD.

ResultsIn biochemical experiments, Lys- and His-enriched peptides within the binding domains of ApoE and ApoER2 and their corresponding recombinant proteins, were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC and MP-IHC, we observed that: (1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal  perforant path projections that underlie memory; (2) ApoE and lipid aldehyde-modified ApoE, Reelin, ApoER2 and several downstream components of Reelin-ApoER2 signaling cascades accumulated in the immediate vicinity of neuritic plaques in perforant path terminal zones in sAD cases; and (3) several ApoE/Reelin-ApoER2 pathway markers--including the ApoER2 ligand binding domain, Disabled homolog-1 (Dab1), and Thr19-phosphorylated PSD95 (marker of synaptic disassembly)--were higher in sAD cases than controls and positively correlated with histological progression and cognitive deficits.

ConclusionResults provide proof-of-concept that ApoE and ApoER2 are vulnerable to lipid aldehyde induced adduction and crosslinking and demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in AD. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE particles and ApoE receptors in sAD in humans. 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. Monitoring socioeconomic inequalities across HIV knowledge, attitudes, behaviours and prevention in 18 sub-Saharan African countries ObjectivesSocioeconomic inequalities in HIV prevention services coverage constitute important barriers to global prevention targets, especially in sub-Saharan Africa (SSA). We aimed at monitoring these inequalities from population-based survey data in 18 SSA countries between 2010 and 2018.

MethodsWe defined eight HIV indicators aimed at capturing uptake of HIV prevention services among adult participants. Country-specific wealth-related inequalities were measured using the Relative and Slope Index of Inequalities (RII and SII, respectively) and then pooled using random-effects meta-analyses. We compared inequalities between African regions using the Wilcoxon rank-sum test.

ResultsThe sample consisted of 358,591 participants (66% women). Despite variability between countries and indicators, the meta-analysis revealed significant levels of relative and absolute inequalities in 6 out of 8 indicators: HIV-related knowledge, positive attitudes toward people living with HIV (PLHIV), condom use at last sexual intercourse, participation to prevention of mother-to-child transmission programs, medical male circumcision and recent HIV testing. The largest inequalities were reported in condom use, with condom use reported 5 times more among the richest versus the poorest (RII=5.02, 95% Confidence interval, CI: 2.79-9.05) and in positive attitudes toward PLHIV, with a 32-percentage point difference between the richest and poorest (SII=0.32, 95% CI: 0.26-0.39). Conversely, no significant inequalities were observed in multi-partnership and HIV seropositivity among youth. Overall, inequalities tended to be larger in West and Central vs. East and Southern African countries.

ConclusionsDespite efforts to scale-up HIV-prevention programs, socioeconomic inequalities remain substantial over the continuum of HIV primary and secondary prevention in several SSA countries. Comparison Of respiratory protection during exercising tasks between different wearing methods of replaceable particulate respirators and powered air-purifying respirators BackgroundThis study evaluated the differences in respiratory protection between replaceable particulate respirators (RPRs) and powered air-purifying respirators (PAPRs), with different wearing methods, during exercising tasks.

MethodsTen participants wore either RPR or PAPR according to the recommended method, with a knit cover placed between the facepiece cushion and the face, or with the headband on a helmet. We measured the number of particles inside and outside the respiratory protective equipment (RPE) during exercising tasks for each wearing variation. The exercise state was set to exercise with an ergometer set at 80W load. While exercising tasks, the participants performed five actions adopted from JIS T8150 in 2018 (1. Normal breathing, 2. Deep breathing, 3. Turning head side to side, 4. Moving head up and down, 5. Talking). Each action was performed for 1 min. For measurements of exercise state, after 10 minutes of exercise tasks, we measured while the exercise was continued. The fit factor was calculated by dividing the concentration within the RPE by the concentration outside of it. Data were analyzed after they were log-transformed with a linear mixed model, with fit factor as the dependent variable.

ResultsWe compared the results with experimental data of resting state reported in our previous studies. Fit factor of RPRs in the exercise state was significantly lower (p<0.001) than that in the resting state, indicating inadequate respiratory protection. In contrast, the fit factor of PAPRs during exercising tasks was significantly lower (p<0.001) than that at rest; however, respiratory protection was maintained. PAPR did not show a significant decrease (p=1.000) in fit factor owing to the wearing variations during exercising tasks.

ConclusionsPAPRs were found to be superior to RPRs in terms of respiratory protection. PAPRs are better than RPRs for workers who have to wear RPE inappropriately due to health problems. Poor neutralization and rapid decay of antibodies to SARS-CoV-2 variants in vaccinated dialysis patients Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma samples from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naive hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy. Hairpin structure facilitates multiplex high-fidelity DNA amplification in real-time PCR Clinically and biologically, it is essential to detect rare DNA-sequence variants for early cancer diagnosis or drug-resistance mutations identification. Some of the common quantitative PCR (qPCR)-based variant detection methods are restricted in the limit of detection (LoD) because the DNA polymerases used have a high polymerase misincorporation rate, thus the detection sensitivity is sometimes unsatisfactory. With the proofreading activity, high-fidelity (HiFi) DNA polymerases have a 50- to 250-fold higher fidelity. However, there are currently no proper probe-based designs as the fluorescence indicator allowing multiplexed HiFi qPCR reactions, thus restricting the application of HiFi DNA polymerases like the variant detection. We presented the Occlusion System, composed of a 5-overhanged primer with fluorophore modification and a probe with a short-stem hairpin and a 3 quencher modification. We demonstrated that the Occlusion System allowed multiplexing HiFi qPCR reaction, and it was compatible with the current variant-enrichment method to improve the LoD up to 10-fold. Thus, the Occlusion System satisfactorily functioned as efficient fluorescence indicator in HiFi qPCR reactions and allowed application of HiFi DNA polymerases in variant detection methods to improve detection sensitivity. Safety and efficacy of Pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID Study): A prospective, randomised, single-blind, controlled trial BackgroundPulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia.

MethodsIn this randomised, single-blind, controlled trial, we enrolled hospitalized, non-intubated patients (18 to 75 years with oxygen saturation (Spo2) in free-air breathing [&le;]90%) with COVID-19 pneumonia at a referral hospital. Participants were randomly assigned (1:1) to receive PPT (six sessions PPT with breathing exercises and airway clearance techniques) or basic care. The primary outcomes were venous blood O2 (pO2) and CO2 (pCO2) pressures, Spo2, and three-minute walking test (3MWT) that were assessed before and end of sixth session. Secondary outcomes included level of dyspnea, venous blood PH, one-month mortality, three-month mortality and short form-36 (SF-36) after one and three months. The assessor was blinded to the assignment. This trial is registered with ClinicalTrials.gov (NCT04357340).

FindingsIn April-May 2020, 40 participants were randomly assigned to PPT or basic care groups. While at the end of intervention, pO2 (adjusted mean difference to baseline measure (AMD) 6.43 mmHg [95%CI 2.8, 10.07], P<0.01), Spo2 (AMD 4.43% [95%CI 2.04, 6.83], P=0.0011), and 3MTW (AMD 91.44 m [95%CI 68.88, 113.99], P<0.01) were higher in PPT group and basic care group, pCO2 was not improved (AMD -2.1 mmHg [95%CI-6.36, 2.21], P=0.33). Mortality rate was 20% (OR adjusted to baseline Spo2 .19 [95%CI .03, 1.30], P=.09) and 25% (OR adjusted to baseline Spo2 .16 [95%CI .26, 1.05], P=.056) lower in the PPT group at three-month at one-month and three-month, respectively. There were no significant differences in most SF-36 domains scores after one and three months. No serious adverse event was observed during PPT sessions.

ConclusionEarly PPT can be considered a safe and effective therapeutic choice for patients with severe COVID-19. Grey and white matter micro-structure is associated with polygenic risk for schizophrenia BackgroundRecent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition.

MethodsWe used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons.

ResultsPolygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures and 14 white matter tracts. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia.

ConclusionsRisk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical and white matter micro-structure may be linked to the genetic mechanisms of schizophrenia. Generalized Prediction of Hemodynamic Shock in Intensive Care Units Early prediction of hemodynamic shock in the ICU can save lives. Several studies have leveraged a combination of vitals, lab investigations, and clinical data to construct early warning systems for shock. However, these have a limited potential of generalization to diverse settings due to reliance on non-real-time data. Monitoring data from vitals can provide an early real-time prediction of Hemodynamic shock which can precede the clinical diagnosis to guide early therapy decisions. Generalization across age and geographical context is an unaddressed challenge. In this retrospective observational study, we built real-time shock prediction models generalized across age groups (adult and pediatric), ICU-types, and geographies. We trained, validated, and tested a shock prediction model on the publicly available eICU dataset on 208 ICUs across the United States. Data from 156 hospitals passed the eligibility criteria for cohort building. These were split hospital-wise in a five-fold training-validation-test set. External validation of the model was done on a pediatric ICU in New Delhi and MIMIC-III database with more than 0.23 million and one million patient-hours vitals data, respectively. Our models identified 92% of all the shock events more than 8 hours in advance with AUROC of 86 %(SD= 1.4) and AUPRC of 93% (SD =1.2) on the eICU testing set. An AUROC of 87 % (SD =1.8), AUPRC 92 % (SD=1.6) were obtained in external validation on the MIMIC-III cohort. The New Delhi Pediatric SafeICU data achieved an AUROC of 87 % (SD =4) AUPRC 91% (SD=3), despite being completely different geography and age group. In this first, we demonstrate a generalizable model for predicting shock, and algorithms are publicly available as a pre-configured Docker environment at https://github.com/tavlab-iiitd/ShoQPred. Chemosensory dysfunctions induced by COVID-19 can persist up to 7 months: A study of over 700 healthcare workers Several studies have revealed either self-reported chemosensory alterations in large groups or objective quantified chemosensory impairments in smaller populations of patients diagnosed with COVID-19. However, due to the great variability in published results regarding COVID-19-induced chemosensory impairments and their follow-up, prognosis for chemosensory functions in patients with such complaints remains unclear. Our objective is to describe the various chemosensory alterations associated with COVID-19 and their prevalence and evolution after infection. A cross-sectional study of 704 healthcare workers with a RT-PCR confirmed SARS-CoV-2 infection between 28/2/2020 and 14/6/2020 was conducted 3 to 7 months after onset of symptoms. Data were collected with an online questionnaire. Outcomes included differences in reported chemosensory self-assessment of olfactory, gustatory, and trigeminal functions across time points and Chemosensory Perception Test scores from an easy-to-use at-home self-administered chemosensory test. Among the 704 participants, 593 (84.2%) were women, the mean (SD) age was 42 (12) years, and the questionnaire was answered on average 4.8 (0.8) months after COVID-19. During COVID-19, a decrease in olfactory, gustatory, and trigeminal sensitivities were reported by 81.3%, 81.5% and 48.0% respectively. Three to seven months later, reduced sensitivity was still reported by 52.0%, 41.9% and 23.3% respectively. Chemosensory Perception Test scores indicate that 19.5% of participants had objective olfactory impairment. These data suggest a significant proportion of COVID-19 cases have persistent chemosensory impairments at 3 to 7 months after their infection but the majority of those who had completely lost their olfactory, gustatory, and trigeminal sensitivity have improved. PENet: Continuous-Valued Pulmonary Edema Severity Prediction On Chest X-ray Using Siamese Convolutional Networks For physicians to take rapid clinical decisions for patients with congestive heart failure, the assessment of pulmonary edema severity in chest radiographs is vital. While deep learning has been promising in detecting the presence or absence, or even discrete grades of severity, of such edema, prediction of the continuous-valued severity yet remains a challenge. Here, we propose PENet, a deep learning framework to assess the continuous spectrum of pulmonary edema severity from chest X-rays. We present different modes of implementing this network, and demonstrate that our best model outperforms that of earlier work (mean area under the curve of 0.91 over 0.87, for nine comparisons), while saving training data and computation. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Epicardial adipose tissue thickness is associated with increased COVID-19 severity and mortality BACKGROUNDIncreased adiposity and visceral obesity have been linked to adverse COVID-19 outcomes. The amount of epicardial adipose tissue (EAT) may have relevant implications given its proximity to the heart and lungs. Here, we explored the role of EAT in increasing the risk for COVID-19 adverse outcomes.

METHODSWe included 748 patients with COVID-19 attending a reference center in Mexico City. EAT thickness, sub-thoracic and extra-pericardial fat were measured using thoracic CT scans. We explored the association of each thoracic adipose tissue compartment with COVID-19 mortality and severe COVID-19 (defined as mortality and need for invasive mechanical ventilation), according to the presence or absence of obesity. Mediation analyses evaluated the role of EAT in facilitating the effect of age, body mass index and cardiac troponin levels with COVID-19 outcomes.

RESULTSEAT thickness was associated with increased risk of COVID-19 mortality (HR 1.18, 95%CI 1.01-1.39) independent of age, gender, comorbid conditions and BMI. Increased EAT was associated with lower SpO2 and PaFi index and higher levels of cardiac troponins, D-dimer, fibrinogen, C-reactive protein, and 4C severity score, independent of obesity. EAT mediated 13.1% (95%CI 3.67-28.0%) and 5.1% (95%CI 0.19-14.0%) of the effect of age and 19.4% (95%CI 4.67-63.0%) and 12.8% (95%CI 0.03-46.0%) of the effect of BMI on requirement for intubation and mortality, respectively. EAT also mediated the effect of increased cardiac troponins on myocardial infarction during COVID-19.

CONCLUSIONEAT is an independent risk factor for severe COVID-19 and mortality independent of obesity. EAT partly mediates the effect of age and BMI and increased cardiac troponins on adverse COVID-19 outcomes. 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. 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. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

O_TBL View this table:
org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

O_TBL View this table:
org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

O_TBL View this table:
org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

O_TBL View this table:
org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services. Indomethacin use for Mild & Moderate hospitalised Covid-19 patients: An open label randomised clinical trial IntroductionIndomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been presented as a broad-spectrum antiviral agent. This randomised clinical trial in a hospital setting evaluated the efficacy and safety of this drug in RT-PCR-positive coronavirus disease 2019 (COVID-19) patients.

Materials & MethodsA total of 210 RT-PCR-positive COVID-19 patients, who provided consent were allotted, to control or case arm, based on block randomisation. The control arm received standard of care comprising paracetamol, ivermectin, and other adjuvant therapies. The patients in the case arm received indomethacin instead of paracetamol, with other medications retained. The primary endpoint was the development of hypoxia/desaturation with SpO2 [&le;] 93, while time to become afebrile and time for cough and myalgia resolution were the secondary endpoints.

ResultsThe results of 210 patients were available, with 103 and 107 patients in the indomethacin and paracetamol arms, respectively. We monitored patient profiles along with everyday clinical parameters. Blood chemistry at the time of admission and discharge was assessed.

As no one in either of the arms required high-flow oxygen, desaturation with SpO2 level of 93 and below was an important goal. In the indomethacin group, none of the 103 patients developed desaturation. On the other hand, 20 of the 107 patients in the paracetamol arm developed desaturation. Patients who received indomethacin also experienced more rapid symptomatic relief than those in the paracetamol arm, with most symptoms disappearing in half the time. 56 patients out of 107 in the paracetamol arm had fever on the seventh day, while no patient in the indomethacin group had fever. Neither arm reported any adverse event. The fourteenth-day follow-up revealed that the paracetamol arm patients had faced several discomforts, including myalgia, joint pain, and tiredness; indomethacin arm patients mostly complained only of tiredness.

ConclusionIndomethacin is a safe and effective drug for treating patients with mild and moderate covid-19.