Covid-19 Associated Hepatitis in children (CAHC) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon. Objective: While pediatric population has largely remained free of severe COVID-19, in some cases SARS-CoV-2 infection has been associated with complications like Multiple Inflammatory Syndrome in children (MIS-C). We mention another unique presentation subsequent to asymptomatic infection of SARS-CoV-2, a unique form of hepatitis designated by us as COVID-19 Associated Hepatitis in Children (CAH-C). The contrasting clinical presentations, temporal association and viral parameters of CAH-C cases, to the MIS-C cases are presented here. Methods: As a retrospective and follow-up observational study we reviewed all children testing positive for SARS-CoV-2 during study period. Children presenting with sudden onset of hepatitis, elevated transaminases, non-obstructive jaundice, lacking marked inflammatory responses and without evidence of (a) other known causes of acute hepatitis or previous underlying liver disease (b) multi-system involvement were classified as CAH-C, are described here. Results: Among 475 children who tested positive, 47 patients presented with hepatitis, 37 patients who had features of CAH-C, having symptoms of hepatitis only, with un-elevated inflammatory markers and uneventful recovery following supportive treatment. Whereas remaining 10 MIS-C hepatitis had protracted illness, multiple system involvement, required admission to critical care, and had mortality of 30%. Conclusion: With the emergence of newer variants of concern (VOC) including the Delta variant which predominated the second wave of infections in India and has now spread to more than 142 countries with changing presentations, CAH-C might be one of them. Cases of such new entities need to be identified early and differentiated from other emerging syndromes in children during the ongoing pandemic for preventing adversities by timely intervention.
Uncovering the gastrointestinal passage, intestinal epithelial cellular uptake and Ago2 loading of milk miRNAs in neonates using xenobiotic tracers BackgroundExclusive breastfeeding is the best source of nutrition for most infants, but it is not always possible. Enteral nutrition influences intestinal gene regulation and the susceptibility for inflammatory bowel disorders, such as necrotizing enterocolitis (NEC). In modern neonatology it is observed that lactase activity increases during intestinal maturation, but formula-fed infants exhibit lower activity levels than milk-fed infants.

ObjectiveWe interrogate the transmissibility of milk miRNAs, since human breast milk has a high miRNA content in comparison to other body fluids. Our data contribute to the controversial discussion whether milk miRNAs could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals.

DesignFollowing their cross-species profiling via miRNA deep-sequencing we utilized dietary xenobiotic taxon-specific milk miRNA as tracers in human and porcine neonates, followed by functional studies in primary human fetal intestinal epithelial cells (HIEC-6) using Ad5-mediated miRNA-gene transfer.

ResultsWe show that mammals have in common many milk miRNAs yet exhibit taxon-specific miRNA fingerprints. We traced intact bovine-specific miRNAs from formula-nutrition in human preterm stool and 9 days after the onset of enteral feeding in intestinal cells of preterm piglets. Few hours after introducing enteral feeding in preterm piglets with supplemented reporter miRNAs (cel-miR-39-5p/-3p), we observed enrichment of the xenobiotic cel-miR in blood serum and in Ago2-immunocomplexes from intestinal biopsies. In contrast, we did not observe xenobiotic miRNAs in neonatal porcine cerebrospinal fluid.

ConclusionsTaken together, our data point to a transmissibility of milk miRNA signals, which could be relevant at least for intestinal maturation. Ad5-based miRNA-gene transfer into HIEC-6 revealed putative milk miRNA targets on the protein and transcriptome levels. Results suggest that milk miRNAs could influence gene expression in intestinal epithelia of neonates under special conditions.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/21262525v4_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@8e0435org.highwire.dtl.DTLVardef@1b6747corg.highwire.dtl.DTLVardef@1998821org.highwire.dtl.DTLVardef@b84a04_HPS_FORMAT_FIGEXP  M_FIG C_FIG It is already known that exclusive breastfeeding is the best source of nutrition for neonates.Human breast milk has a high miRNA content in comparison to other body fluids. It is controversially discussed whether they could influence gene regulation in term and preterm neonates and thus might vertically transmit developmental relevant signals. Here, we contribute important new findings: Mammals have in common a significant number of milk miRNAs yet exhibit taxon-specific fingerprints. These differences allowed us to exploit xenobiotic miRNAs as tracers in human preterm neonates, who routinely received formula-supplemented nutrition in addition to breast milk. Tracer miRNAs survived the gastrointestinal (GI) transit in human preterm neonates. In a preterm piglet model the reporter miRNA did not only survive GI transit, but accumulated in the bloodstream few hours post-feeding. Moreover, we show that, cel-mir-39-5p and cel-miR-39-3p became loaded to Ago2 in intestinal tissue samples, which is prerequisite for milk microRNAs biological relevance. Adenovirus type 5-based miRNA-gene transfer into HIEC-6 allowed us to examine predicted bovine milk miRNA targets on the protein and transcriptome levels.
Hepatic resection versus transarterial chemoembolization for the intermediate stage hepatocellular carcinoma：A cohort study BackgroundThe selection criterion for hepatic resection(HR) in intermediate-stage(IM) hepatocellular carcinoma(HCC) is still controversial. We used real-world data to evaluate the overall survival (OS) treated with HR or TACE.

MethodsIn all, 942 patients with IM-HCC were categorized in HR and TACE groups. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score- matched (PSM) analyses. The smooth curve was performed through the generalized additive model. The interaction test was performed to evaluate the HR impact on OS concerning risk factors. Also, we used multiple imputation to deal with the missing data.

ResultsTotally, 23.0% (n=225) of patients received HR. At a median overall survival of 23.7 months, HR was associated with the improved OS on multivariate analysis (hazard ratio, 0.45; 95%CI: 0.35, 0.58; after PSM: 0.56; 95%CI: 0.41, 0.77). Landmark analyses limited to long-term survivors of [&ge;] 6 months, [&ge;] 1, and [&ge;] 2 years demonstrated better OS with HR in all subsets (all P<0.05). After PSM analysis, however, HR increased 20% risk of death (HR, 1.20; 95%CI: 0.67, 2.15) in the subgroup of LDH [&le;]192 U/L (P for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and the HR with respect to 1-, 3-, and 5-year observed survival rate (all P<0.05).

ConclusionHepatic resection was superior to TACE for intermediate-stage HCC in the range of LDH level > 192 U/L. Moreover, TACE might be suitable for patients with LDH level [&le;] 192 U/L.

SynopsisO_LIHepatectomy was superior to TACE for BCLC-B HCC.
C_LIO_LIHepatectomy increased 20% risk of death for LDH < 192 U/L after matching.
C_LIO_LIA significant interaction was robust between LDH and with respect to hepatectomy the 1-, 3-, and 5-year observed survival rate.
C_LI Symptoms of depression and anxiety among Vietnamese immigrants in Japan during the COVID-19 pandemic: a cross-sectional web-based study ObjectiveWe aimed to examine the mental health status and related factors among Vietnamese immigrants in Japan during the coronavirus disease 2019 (COVID-19) pandemic.

DesignOnline cross-sectional survey administered from September 21 to October 21, 2021

SettingOnline survey of Vietnamese immigrants in Japan

ParticipantsThe inclusion criteria for participation were 1) Vietnamese citizenship or Japanese citizenship in those of Vietnamese descent, current residence in Japan, and 2) age [&ge;]18 years.

Main OutcomesPatient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scores were considered the main outcome measures. Multivariable logistic regression was used to identify factors related to symptoms of depression and anxiety, and the chosen variables were entered simultaneously in the survey.

ResultsAmong 621 participants (age: 26.0{+/-}4.8 years; male: 347 [55.9%]) who completed the questionnaire, 73.7% reported a decrease in income when compared with the period before the COVID-19 pandemic, and 60.4% reported being recently affected by poor socioeconomic status. Moderate-to-severe symptoms of depression (PHQ-9 score [&ge;]10 points) and mild-to-severe symptoms of anxiety (GAD-7 [&ge;]5 points) were observed in 203 (32.7%) and 285 (45.9%) individuals, respectively. Factors related to depressive symptoms were age (odds ratio [OR]=0.94, p=0.043), medical or psychiatric co-morbidity (OR=2.46, p<0.001), and low socioeconomic status (OR=2.47, p<0.001). Factors related to anxiety symptoms were being single (OR=1.72, p=0.044), medical or psychiatric co-morbidity (OR=2.52, p<0.001), low socioeconomic status (OR=2.72, p<0.001), and absence of a partner with whom to discuss ones health (OR=1.66, p=0.013).

ConclusionsThe current findings demonstrate that, when compared with Japanese citizens, Vietnamese immigrants experienced a decrease in income, worsening working conditions, and poor mental health status during the COVID-19 pandemic. These findings highlight the potential contribution of low socioeconomic status and social isolation to poor mental health status.

Strengths and limitations of this studyO_LIVietnamese immigrants, who are the second largest immigrant group in Japan, were studied. No previous assessment of their mental health during the COVID-19 pandemic has been carried out.
C_LIO_LIThis study provided a non-contact approach to prevent infection using online surveys. Therefore, we received a wide range of responses from areas with low COVID-19 infection rate area to high COVID-19 infection rate area in Japan.
C_LIO_LIThe survey may not be a complete representation of all Vietnamese immigrants living in Japan, as some elderly Vietnamese immigrants may not have been able to participate due to the online format.
C_LI The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. 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. 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. A rapid pharmacogenomic assay to detect NAT2 polymorphisms and guide isoniazid dosing for tuberculosis treatment RationaleStandardized weight-based dose of anti-tubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug levels achieved. Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase-2 (NAT2) gene explain the majority of interindividual pharmacokinetic variability of isoniazid (INH). However, an obstacle to implementing pharmacogenomic-guided dosing is the lack of a point-of-care assay.

ObjectivesTo develop and test a NAT2 classification algorithm, validate its performance in predicting isoniazid clearance, and develop a prototype pharmacogenomic assay.

MethodsWe trained random forest models to predict NAT2 acetylation genotype from unphased SNP data using a global collection of 8,561 phased genomes. We enrolled 48 pulmonary TB patients, performed sparse pharmacokinetic sampling, and tested the acetylator prediction algorithm accuracy against estimated INH clearance. We then developed a cartridge-based multiplex qPCR assay on the GeneXpert platform and assessed its analytical sensitivity on whole blood samples from healthy individuals.

Measurements and Main ResultsWith a 5-SNP model trained on two-thirds of the data (n=5,738), out-of-sample acetylation genotype prediction accuracy on the remaining third (n=2,823) was 100%. Among the 48 TB patients, predicted acetylator types were: 27 (56.2%) slow, 16 (33.3%) intermediate and 5 (10.4%) rapid. INH clearance rates were lowest in predicted slow acetylators (median 19.3 L/hr), moderate in intermediate acetylators (median 41.0 L/hr) and highest in fast acetylators (median 46.7 L/hr). The cartridge-based assay accurately detected all allele patterns directly from 25ul of whole blood.

ConclusionsAn automated pharmacogenomic assay on a platform widely used globally for tuberculosis diagnosis could enable personalized dosing of isoniazid.

SummaryThis manuscript describes the development and validation of point-of-care multiplex pharmacogenomic assay to guide personalized dosing of isoniazid for treatment or prevention of tuberculosis. 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. Development and validation of a multimodal neuroimaging biomarker for electroconvulsive therapy outcome in depression: a multicenter machine learning analysis BackgroundElectroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, mono-center studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers.

ObjectiveTo develop and validate neuroimaging biomarkers for ECT outcome in a multi-center setting.

MethodsMultimodal data (i.e., clinical, sMRI and resting-state fMRI) was collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluated which data modalities or combinations thereof could provide the best predictions for treatment response ([&ge;]50% symptom reduction) or remission (HAM-D score [&le;]7) using a support vector machine classifier.

ResultsRemission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82-0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers, and remained acceptable when validated using leave-one-site-out cross-validation (0.70-0.73 AUC).

ConclusionsThese results show that multimodal neuroimaging data is able to provide good prediction of remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. This suggests that these biomarkers are robust, indicating that future development of a clinical decision support tool applying these biomarkers may be feasible. The Association of Opening K-12 Schools with the Spread of COVID-19 in the United States: County-Level Panel Data Analysis AO_SCPLOWBSTRACTC_SCPLOWThis paper empirically examines how the opening of K-12 schools and colleges is associated with the spread of COVID-19 using county-level panel data in the United States. Using data on foot traffic and K-12 school opening plans, we analyze how an increase in visits to schools and opening schools with different teaching methods (in-person, hybrid, and remote) is related to the 2-weeks forward growth rate of confirmed COVID-19 cases. Our debiased panel data regression analysis with a set of county dummies, interactions of state and week dummies, and other controls shows that an increase in visits to both K-12 schools and colleges is associated with a subsequent increase in case growth rates. The estimates indicate that fully opening K-12 schools with in-person learning is associated with a 5 (SE = 2) percentage points increase in the growth rate of cases. We also find that the positive association of K-12 school visits or in-person school openings with case growth is stronger for counties that do not require staff to wear masks at schools. These results have a causal interpretation in a structural model with unobserved county and time confounders. Sensitivity analysis shows that the baseline results are robust to timing assumptions and alternative specifications. Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy.

Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients.

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation.

Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN.

Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs.

The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin.

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. 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. Survey of Contaminated Percutaneous Injuries in Anesthesia Practitioners BackgroundAnesthesia practitioners are at inherent risk for percutaneous injuries by blood-contaminated needles and sharp objects. These exposures may result in transmission of HIV and hepatitis viruses. Data about this occupational hazard from contaminated needles and sharp devices is limited and decades old. We conducted a web-based survey to assess the occurrence, reporting, characteristics, and outcome of contaminated percutaneous injuries (CPI) in anesthesia residents, fellows, and attendings.

MethodsAfter institutional research board approval, an email was sent to 217 anesthesia practitioners requesting their participation in an online survey about contaminated percutaneous injuries. Responses were collected from February through March 2020. Results are reported as absolute numbers and proportions with 95% confidence interval (CI).

ResultsThe overall survey response rate was 51% (110/217). 59% (65/110) (95% CI, 50-68) of participants reported having one or more contaminated percutaneous injury during their years of anesthesia practice (42% (21/50) of residents, 50% (4/8) of fellows, 77% (40/52) of anesthesia attendings). Prevalence of injuries related to attendings years of anesthesia practice was 69% (95% CI, 44-94) for 5-10 years, 62.5% (95% CI, 29-96) for 10-15 years, and 79% (95% CI, 63- 95) for greater than 15 years of practice.

35% (95% CI, 26-44) of participants reported having one or more CPI within the last 5 years (40% of residents, 50% of fellows, 29% of attendings). Occurrence of CPI within the last 5 years based on attending anesthesiologist years of practice was 57% for less than 5 years, 37.5% for 10-15 years, and 20% for 15-20 years of practice. 75% (95% CI, 65-85) reported the incident at the time of injury. 59% (95% CI, 48-70) of injuries were due to hollow bore needles. 50% (95% CI, 39-61) of total injuries were high risk. 26% of injured anesthesia practitioners received post-exposure prophylaxis and there were zero seroconversions.

ConclusionMost anesthesiologists will sustain a contaminated percutaneous injury during their careers. Incidence of these injuries decreases with years of practice. Occurrence of these injuries is high among anesthesia residents, with the majority reporting their injuries. Half of the injuries are high risk with a quarter requiring postexposure prophylaxis. More education and interventions are needed to reduce percutaneous injuries and improve reporting. Cognitive impairment and functional change in COVID-19 patients undergoing inpatient rehabilitation Cognitive impairment is increasingly recognized as a sequela of COVID-19. It is unknown how cognition changes and relates to functional gain during inpatient rehabilitation. We administered the Montreal Cognitive Assessment (MoCA) at admission to 77 patients undergoing inpatient rehabilitation for COVID-19 in a large U.S. academic medical center. 45 patients were administered the MoCA at discharge. Functional gain was assessed by change in the Quality Indicator for Self-Care (QI-SC). In the full sample, 80.5% of patients exhibited cognitive impairment on admission, which was associated with prior delirium. Among 45 patients with retest data, there were significant improvements in MoCA and QI-SC. QI-SC score gain was higher in patients who made clinically meaningful changes on the MoCA, an association that persisted after accounting for age and delirium history. Cognitive impairment is frequent among COVID-19 patients, but improves over time and is associated with functional gain during inpatient rehabilitation. Clinical Characteristics and Outcomes of Critically ill Mechanically Ventilated COVID-19 Patients Receiving interleukin-6 Receptor Antagonists and Corticosteroid Therapy: A Multicenter International Observational Study ObjectivesThe interest in interleukin-6 receptor antagonists (IL-6RA) and steroids have increased recently due to their potential role as immunomodulatory effect in critically ill coronavirus disease (COVID-19). The magnitude of this therapy in subgroups of patients with invasive mechanical ventilation (MV) remains to be fully clarified. We compared the clinical characteristics and outcomes of patients requiring iMV, and receiving IL-6RA and steroids with different steroids regimens.

DesignInternational, multicenter, observational study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Marginal structural modeling was used to adjust time-dependent confounders; observations were weighted using inverse probability of treatment weight. A sensitivity analysis was conducted for target trial design.

Setting168 hospitals, 16 countries.

PatientsCovid-19 ICU patients ([&ge;]18 years) requiring MV between March 01,2020, and January 10,2021.

InterventionNone.

Measurements and Main ResultsOf 860 patients met eligibility criteria, 589 received steroids, 170 IL-6RA, and 101 combinations; groups were balanced after adjustment. Median daily steroid dose was 7.5 mg dexamethasone or equivalent (IQR:6-14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. The median C-reactive protein level was >75 mg/L in majority of our cohort. The use of IL-6R antagonists alone or in combination was not associated with a significant difference in ventilator-free days (VFD) compared to steroids alone with different steroids regimens (adjusted incidence rate ratio [95% CI]): IL-6R antagonists (1.12 [0.88,1.4]), combination (0.83 [0.6,1.14]). Patients treated with low or high-dose steroids had non-significant differences in VFD compared to IL-6RA ({beta}=0.62, 95% CI -1.54,2.78 for low-dose steroid; {beta}=-1.19, 95% CI -3.85,1.47 for high-dose steroid). There was no difference in 28-day mortality and hospital mortality with IL-6RA alone or in combination compared to steroids alone (28-day mortality adjusted odds ratio [95% CI]): IL-6RA (0.68[0.44,1.07]), combination (1.07[0.67,1.70]). Sensitivity analysis findings were consistent with primary analysis. Liver dysfunction was higher in IL-6RA (p=0.04) while rate of bacteremia did not differ among groups.

ConclusionsIn adult ICU COVID-19 patients on iMV, we found no difference in outcomes between those who received IL-6RA, steroids, or combination therapy and those who received IL-6RA or low-or high-dose steroids. Further randomized trials are needed to enhance our understanding for IL-6RA safety with different steroids regimen and the magnitude of benefit in those subgroups of patients. 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. CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [&ge;]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response. Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. 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. Treatment interruption is a risk factor for sickness presenteeism: a large-scale cross-sectional study during the COVID-19 pandemic ObjectivesThis study examined the relationship between interruption to routine medical care during the coronavirus disease 2019 pandemic and sickness presenteeism among workers in Japan.

MethodsA cross-sectional study using data obtained from an internet monitor questionnaire was conducted. Interruption to medical care was defined based on the response "I have not been able to go to the hospital or receive treatment as scheduled." The fraction of sickness presenteeism days in the past 30 days was employed as the primary outcome. A fractional logit model was used for analysis to treat bounded data.

ResultsOf the 27,036 participants, 17,526 (65%) were workers who did not require routine medical care, 8,451 (31%) were using medical care as scheduled, and 1,059 (4%) experienced interrupted medical care. The adjusted odds ratio (aOR) of sickness presenteeism was significantly higher among workers who experienced interrupted medical care (3.44; 95% confidence interval [CI]: 3.04-3.89) than those who did not require routine medical care. In terms of symptoms, the highest aOR was observed among workers with mental health symptoms (aOR: 5.59, 95%CI: 5.04-6.20).

ConclusionsThis study suggests the importance of continuing necessary treatment during a pandemic to prevent presenteeism. 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. 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