Miracle-dz/UniFAR-FTUs huggingface dataset:
Deubiquitinating Enzyme USP21 Inhibits HIV-1 Replication by Downregulating Tat Expression

Ubiquitination plays an essential role in viral infection. Deubiquitinating enzymes (DUBs) reverse ubiquitination by cleaving ubiquitins from target proteins, thereby affecting viral infection. ABSTRACT Ubiquitination plays an important role in human immunodeficiency virus 1 (HIV-1) infection. HIV proteins such as Vif and Vpx mediate the degradation of the host proteins APOBEC3 and SAMHD1, respectively, through the proteasome pathway. However, whether deubiquitylating enzymes play an essential role in HIV-1 infection is largely unknown. Here, we demonstrate that the deubiquitinase USP21 potently inhibits HIV-1 production by indirectly downregulating the expression of HIV-1 transactivator of transcription (Tat), which is essential for transcriptional elongation in HIV-1. USP21 deubiquitylates Tat via its deubiquitinase activity, but a stronger ability to reduce Tat expression than a dominant-negative ubiquitin mutant (Ub-KO) showed that other mechanisms may contribute to USP21-mediated inhibition of Tat. Further investigation showed that USP21 downregulates cyclin T1 mRNA levels by increasing methylation of histone K9 in the promoter of cyclin T1, a subunit of the positive transcription elongation factor b (P-TEFb) that interacts with Tat and transactivation response element (TAR) and is required for transcription stimulation and Tat stability. Moreover, USP21 had no effect on the function of other HIV-1 accessory proteins, including Vif, Vpr, Vpx, and Vpu, indicating that USP21 was specific to Tat. These findings improve our understanding of USP21-mediated functional suppression of HIV-1 production. IMPORTANCE Ubiquitination plays an essential role in viral infection. Deubiquitinating enzymes (DUBs) reverse ubiquitination by cleaving ubiquitins from target proteins, thereby affecting viral infection. The role of the members of the USP family, which comprises the largest subfamily of DUBs, is largely unknown in HIV-1 infection. Here, we screened a series of USP members and found that USP21 inhibits HIV-1 production by specifically targeting Tat but not the other HIV-1 accessory proteins. Further investigations revealed that USP21 reduces Tat expression in two ways. First, USP21 deubiquitinates polyubiquitinated Tat, causing Tat instability, and second, USP21 reduces the mRNA levels of cyclin T1 (CycT1), an important component of P-TEFb, that leads to Tat downregulation. Thus, in this study, we report a novel role of the deubiquitinase, USP21, in HIV-1 infection. USP21 represents a potentially useful target for the development of novel anti-HIV drugs.
Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of chronic myeloid leukemia: A case–control study in a South Indian population

Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non‐synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate.
Continuum beliefs and mental illness stigma: a systematic review and meta-analysis of correlation and intervention studies

Abstract Background Promulgating a continuum model of mental health and mental illness has been proposed as a way to reduce stigma by decreasing notions of differentness. This systematic review and meta-analysis examines whether continuum beliefs are associated with lower stigma, and whether continuum interventions reduce stigma. Methods Following a pre-defined protocol (PROSPERO: CRD42019123606), we searched three electronic databases (PubMed, Web of Science, and PsycINFO) yielding 6726 studies. After screening, we included 33 studies covering continuum beliefs, mental illness, and stigma. Of these, 13 studies were included in meta-analysis. Results Continuum beliefs are consistently associated with lower stigma. Interventions were effective at manipulating continuum beliefs but differ in their effects on stigmatising attitudes. Conclusions We discuss whether and to what extent attitudes towards people with mental illness can be improved by providing information on a mental health-mental illness continuum. It appeared to be relevant whether interventions promoted a feeling of ‘us’ and a process of identification with the person with mental illness. We discuss implications for the design of future interventions.
Bcl‐2‐negative IGH‐BCL2 translocation‐negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl‐2‐positive IGH‐BCL2 translocation‐positive follicular lymphoma

Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl‐2 expression and IGH‐BCL2 translocation. The clinicopathological features exhibited by Bcl‐2‐negative IGH‐BCL2 translocation‐negative FL of the thyroid (Bcl‐2–/IGH‐BCL2– tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl‐2–/IGH‐BCL2– tFL to investigate their epigenetic and genetic aberrations.
More than hurt feelings: The wear and tear of day-to-day discrimination in adults with chronic pain.

OBJECTIVE To examine the extent to which self-reported experiences of discrimination are associated with pain interference among men and women with chronic non-cancer pain. METHODS Data are from the Study of Midlife in the United States (MIDUS) Refresher Cohort. The analytic sample consisted of 207 adults with chronic pain (54.2 ± 12.8 years; 53.6% female) who completed the Major Experiences of Discrimination and Everyday Discrimination scales. Regression analyses examined cross-sectional relations between discrimination and pain interference. RESULTS On average, the level of pain interference was moderate in the sample (M = 3.46, SD = 2.66; observed range 0 - 10). Approximately a third of respondents reported at least one major discriminatory event in their lifetime, while 22% reported 3 or more discriminatory lifetime events. Everyday discrimination scores averaged 14.19 ± 5.46 (observed range 0 - 33). Adjusting for sociodemographics, physical health, cognitive and psychological factors, social isolation, and loneliness, everyday discrimination was associated with increased pain interference (B = .099; 95% confidence interval [CI], .02 to .17). CONCLUSION These findings add weight to the importance of day-to-day experiences of interpersonal discrimination by documenting independent associations with functional interference in adults with chronic pain.
Associations of Common Depression Treatment Metrics With Patient-centered Outcomes

Supplemental Digital Content is available in the text. Background: Various metrics predicated on Patient Health Questionnaire-9 (PHQ-9) scores denote depression “response” or “remission” over time, but few have been empirically validated. We compare the associations of depression response and remission metrics with concomitant clinical improvement in patient-centered outcomes (PCOs). Subjects: Secondary analysis of PHQ-9 and PCO data from the treatment arm (n=906) of the Improving Mood—Promoting Access to Collaborative Treatment (IMPACT) trial. Research Design: We conducted univariate correlations between 9 depression treatment metrics and 4 PCOs. For each PCO, we specified a multivariate linear fixed-effects regression model with penalized LASSO (least absolute shrinkage and selection operator) variable selection that included parameters for each incremental absolute PHQ-9 decrease between 0 and 16 points. Model predictive properties were assessed using a split sample analysis. Results: There was a notable variation in depression improvement rates across metrics. Each metric was significantly associated with PCOs in univariate analyses. In the multivariate models, the cumulative likelihood of PCO improvement was most improved by absolute PHQ-9 score decreases of 7–9 and 14–16 points. The multivariate models showed greater area under the curve (0.671–0.804) in out-of-sample predictions of PCO changes than the univariate models (0.529–0.649). Conclusions: Choice of depression response metric impacts observed response and remission rates, though PCOs tend to improve with depression improvement regardless of metric choice. Absolute incremental PHQ-9 score decreases are broadly associated with an increased likelihood of favorable PCO scores. Our findings support a novel PHQ-9 metric defined by an absolute score change of 8 points or greater.
A conditional approach for the receiver operating characteristic curve construction to evaluate diagnostic test performance in a family-matched case–control design

Receiver operating characteristic curves are widely used in medical research to illustrate biomarker performance in binary classification, particularly with respect to disease or health status. Study designs that include related subjects, such as siblings, usually have common environmental or genetic factors giving rise to correlated biomarker data. The design could be used to improve detection of biomarkers informative of increased risk, allowing initiation of treatment to stop or slow disease progression. Available methods for receiver operating characteristic construction do not take advantage of correlation inherent in this design to improve biomarker performance. This paper will briefly review some developed methods for receiver operating characteristic curve estimation in settings with correlated data from case–control designs and will discuss the limitations of current methods for analyzing correlated familial paired data. An alternative approach using conditional receiver operating characteristic curves will be demonstrated. The proposed approach will use information about correlation among biomarker values, producing conditional receiver operating characteristic curves that evaluate the ability of a biomarker to discriminate between affected and unaffected subjects in a familial paired design.
Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

Objective We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)–causing mutations at risk of disease progression. Methods Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. Results In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Conclusions Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. Trial Registration Information ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. Classification of Evidence This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
Financial Toxicity of Cancer Care: An Analysis of Financial Burden in Three Distinct Health Care Systems

PURPOSE: The financial toxicity of cancer care is a source of significant distress for patients with cancer. The purpose of this study is to understand factors associated with financial toxicity in three distinct care systems. METHODS: We conducted a cross-sectional survey of patients in three care systems, Stanford Cancer Institute (SCI), VA Palo Alto Health Care System (VAPAHCS), and Santa Clara Valley Medical Center (SCVMC), from October 2017 to May 2019. We assessed demographic factors, employment status, and out-of-pocket costs (OOPCs) and administered the validated COmprehensive Score for financial Toxicity tool. We calculated descriptive statistics and conducted linear regression models to analyze factors associated with financial toxicity. RESULTS: Four hundred forty-four of 578 patients (77%) completed the entire COmprehensive Score for financial Toxicity tool and were included in the analysis. Most respondents at SCI were White, with annual household income (AHI) > $50,000 USD and Medicare insurance. At the VAPAHCS, most were White, with AHI ≤ $50,000 USD and insured by the Veterans Administration. At SCVMC, most were Asian and/or Pacific Islander, with AHI ≤ $25,000 USD and Medicaid insurance. Low AHI (P < .0001), high OOPCs (P = .003), and employment changes as a result of cancer diagnosis (P < .0001) were associated with financial toxicity in the pooled analysis. There was variation in factors associated with financial toxicity by site, with employment changes significant at SCI, OOPCs at SCVMC, and no significant factors at the VAPAHCS. CONCLUSION: Low AHI, high OOPCs, and employment changes contribute to financial toxicity; however, there are variations based on site of care. Future studies should tailor financial toxicity interventions within care delivery systems.
Multi-Staged Data-Integrated Multi-Omics Analysis for Symptom Science Research

The incorporation of omics approaches into symptom science research can provide researchers with information about the molecular mechanisms that underlie symptoms. Most of the omics analyses in symptom science have used a single omics approach. Therefore, these analyses are limited by the information contained within a specific omics domain (e.g., genomics and inherited variations, transcriptomics and gene function). A multi-staged data-integrated multi-omics (MS-DIMO) analysis integrates multiple types of omics data in a single study. With this integration, a MS-DIMO analysis can provide a more comprehensive picture of the complex biological mechanisms that underlie symptoms. The results of a MS-DIMO analysis can be used to refine mechanistic hypotheses and/or discover therapeutic targets for specific symptoms. The purposes of this paper are to: (1) describe a MS-DIMO analysis using “Symptom X” as an example; (2) discuss a number of challenges associated with specific omics analyses and how a MS-DIMO analysis can address them; (3) describe the various orders of omics data that can be used in a MS-DIMO analysis; (4) describe omics analysis tools; and (5) review case exemplars of MS-DIMO analyses in symptom science. This paper provides information on how a MS-DIMO analysis can strengthen symptom science research through the prioritization of functional genes and biological processes associated with a specific symptom.
Do mothers who delivered at health facilities return to health facilities for postnatal care follow-up? A multilevel analysis of the 2016 Ethiopian Demographic and Health Survey

Introduction Returning to health facility for postnatal care (PNC) use after giving birth at health facility could reflect the health seeking behavior of mothers. However, such studies are rare though they are critically important to develop vigorous strategies to improve PNC service utilization. Therefore, this study aimed to determine the magnitude and factors associated with returning to health facilities for PNC among mothers who delivered in Ethiopian health facilities after they were discharged. Methods This cross-sectional study used 2016 Ethiopian Demographic and Health Survey data. A total of 2405mothers who gave birth in a health facility were included in this study. Multilevel mixed-effect logistic regression model was fitted to estimate both independent (fixed) effects of the explanatory variables and community-level (random) effects on return for PNC utilization. Variable with p-value of ≤ 0.25 from unadjusted multilevel logistic regression were selected to develop three models and p-value of ≤0.05 was used to declare significance of the explanatory variables on the outcome variable in the final (adjusted) model. Analysis was done using IBM SPSS statistics version 21. Result In this analysis, from the total 2405 participants, 14.3% ((95%CI: 12.1–16.8), (n = 344)) of them returned to health facilities for PNC use after they gave birth at a health facility. From the multilevel logistic regression analysis, being employed (AOR = 1.51, 95%CI: 1.04–2.19), receiving eight and above antenatal care visits (AOR = 2.90, 95%CI: 1.05–8.00), caesarean section delivery (AOR = 2.53, 95%CI: 1.40–4.58) and rural residence (AOR = 0.56, 95%CI: 0.36–0.88) were found significantly associated with return to health facilities for PNC use among women who gave birth at health facility. Conclusion Facility-based PNC utilization among mothers who delivered at health facilities is low in Ethiopia. Both individual and community level variables were determined women to return to health facilities for PNC use. Thus, adopting context-specific strategies/policies could improve PNC utilization and should be paid a due focus.
Reducing failures in daily medical practice: Healthcare failure mode and effect analysis combined with computer simulation

Abstract This study proposes a risk analysis approach for complex healthcare processes that combines qualitative and quantitative methods to improve patient safety. We combine Healthcare Failure Mode and Effect Analysis with Computer Simulation (HFMEA-CS), to overcome widely recognised HFMEA drawbacks regarding the reproducibility and validity of the outcomes due to human interpretation, and show the application of this methodology in a complex healthcare setting. HFMEA-CS is applied to analyse drug adherence performance in the surgical admission to discharge process of pheochromocytoma patients. The multidisciplinary team identified and scored the failure modes, and the simulation model supported in prioritisation of failure modes, uncovered dependencies between failure modes, and predicted the impact of measures on system behaviour. The results show that drug adherence, defined as the percentage of required drugs received at the right time, can be significantly improved with 12%, to reach a drug adherence of 99%. We conclude that HFMEA-CS is both a viable and effective risk analysis approach, combining strengths of expert opinion and quantitative analysis, for analysing human-system interactions in socio-technical systems. Practitioner summary: We propose combining Healthcare Failure Mode and Effects Analysis with Computer Simulation (HFMEA-CS) for prospective risk analysis of complex and potentially harmful processes, to prevent critical incidents from occurring. HFMEA-CS combines expert opinions with quantitative analyses, such that the results are more reliable, reproducible, and fitting for complex healthcare settings.
Shifting toward a healthier dietary pattern through nudging and pricing strategies: A secondary analysis of a randomized virtual supermarket experiment

ABSTRACT Background Nudging and salient pricing are promising strategies to promote healthy food purchases, but it is possible their effects differ across food groups. Objective To investigate in which food groups nudging and/or pricing strategies most effectively changed product purchases and resulted in within–food groups substitutions or spillover effects. Methods In total, 318 participants successfully completed a web-based virtual supermarket experiment in the Netherlands. We conducted a secondary analysis of a mixed randomized experiment consisting of 5 conditions (within subject) and 3 arms (between subject) to investigate the single and combined effects of nudging (e.g., making healthy products salient), taxes (25% price increase), and/or subsidies (25% price decrease) across food groups (fruit and vegetables, grains, dairy, protein products, fats, beverages, snacks, and other foods). Generalized linear mixed models were used to estimate the incidence rate ratios and 95% CIs for changes in the number of products purchased. Results Compared with the control condition, the combination of subsidies on healthy products and taxes on unhealthy products in the nudging and price salience condition was overall the most effective, as the number of healthy purchases from fruit and vegetables increased by 9% [incidence rate ratio (IRR) = 1.09; 95% CI: 1.02, 1.18], grains by 16% (IRR = 1.16; 95% CI: 1.05, 1.28), and dairy by 58% (IRR = 1.58; 95% CI: 1.31, 1.89), whereas the protein and beverage purchases did not significantly change. Regarding unhealthy purchases, grains decreased by 39% (IRR = 0.72; 95% CI: 0.63, 0.82) and dairy by 30% (IRR = 0.77; 95% CI: 0.68, 0.87), whereas beverage and snack purchases did not significantly change. The groups of grains and dairy showed within–food group substitution patterns toward healthier products. Beneficial spillover effects to minimally targeted food groups were seen for unhealthy proteins (IRR = 0.81; 95% CI: 0.73, 0.91). Conclusions Nudging and salient pricing strategies have a differential effect on purchases of a variety of food groups. The largest effects were found for dairy and grains, which may therefore be the most promising food groups to target in order to achieve healthier purchases. The randomized trial on which the current secondary analyses were based is registered in the Dutch trial registry (NTR7293; www.trialregister.nl).