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Resumo Fundamento: A pandemia da COVID-19 tem causado um impacto sobre a mortalidade por várias doenças em todo o mundo, especialmente por doenças cardiovasculares (DCVs). O Brasil é um país de dimensões continentais com diferenças significativas na estrutura de saúde entre seus estados. Objetivo: Analisar a mortalidade hospitalar por DCV no sistema público de saúde durante o primeiro ano da pandemia por COVID-19 (2020) no Brasil. Métodos: Este é um estudo ecológico analisando o número absoluto de mortes hospitalares e a taxa de mortalidade hospitalar no Brasil, suas macrorregiões, e unidades federativas. Os dados foram obtidos do Sistema de Informações Hospitalares (SIH) do Ministério da Saúde. O P-escore foi usado para analisar o excesso de mortalidade. O escore compara os eventos observados com os eventos esperados para um dado local e período. O escore-P foi corrigido por um modelo de regressão joinpoint, com um intervalo de confiança de 95% e nível de significância de 5%. Resultados: Houve 93.104 óbitos hospitalares por DCV no Brasil em 2020, o que representa 1495 menos óbitos (escore-P: -1,58) que o esperado. A região centro-oeste apresentou um escore-P positivo, com um aumento de 15,1% no número de mortes. Dez estados apresentaram um maior número de óbitos em 2020. Ainda, observou-se um excesso de 13,3% de mortalidade hospitalar no país como um todo, e um excesso de mortalidade hospitalar em todas as macrorregiões. Conclusões: Houve uma diminuição no número absoluto de óbitos hospitalares, bem como um aumento na taxa de mortalidade por DCV no Brasil em 2020, após o início da pandemia por COVID-19.

As Doenças Crônicas Não Transmissíveis (DCNT) configuram um importante problema de saúde pública devido ao seu caráter progressivo, crônico e multifatorial e que acompanha o impacto promovido pelo aumento da expectativa de vida na era da transição demográfica. O presente artigo trata-se de uma revisão integrativa de literatura, na qual foram consultadas as bases de dados PubMed e BVS em 2020, selecionando-se estudos publicados entre 2000 e 2020. Os principais resultados evidenciaram maior prevalência de DCNTs no sexo feminino, as doenças mais prevalentes foram hipertensão arterial, diabetes, osteoartrite e transtornos mentais, que tiveram expressiva associação com variáveis sociodemográficas e as condições de saúde da população idosa. Dessa forma, tem-se como objetivo analisar a prevalência das DCNT em idosos com 60 anos ou mais residentes no Nordeste brasileiro, através de uma revisão integrativa.

Resumo Fundamentos As doenças isquêmicas do coração (DIC) são a primeira causa de mortes dentre as doenças cardiovasculares (DCV). Objetivo Descrever o perfil sociodemográfico e analisar tendência da taxa de mortalidade por DIC, segundo sexo e por faixa etária, nos estados da região Nordeste do Brasil, 1996-2016. Métodos Estudo ecológico envolvendo a mortalidade por DIC nos estados do Nordeste. Variáveis analisadas: sexo, idade, escolaridade, estado civil, categoria do CID-10 e estado de residências. Foram calculadas taxas brutas e padronizadas. Os dados de óbitos foram coletados do Sistema de Informações sobre Mortalidade; e os dados populacionais, do Instituto Brasileiro de Geografia e Estatística (IBGE). Nas análises temporais, utilizou-se o modelo de regressão por pontos de inflexão, com cálculo do percentual de variação anual (APC, Annual Percent Change) e do percentual de variação médio do período (AAPC, Average Annual Percent Change). Considerou-se intervalo de confiança de 95% e significância de 5%. Resultados Registrou-se 405.916 óbitos por DIC na região Nordeste durante o período estudado. O perfil de óbitos caracteriza-se por homens (n=229.006; 56,42%), idosos (n=301.379; 74,25%), raça/cor parda (n=197.936; 48,76%), fundamental ou

Abstract Objective: To describe the epidemiological profile and to analyze the trend in the incidence rate of exogenous poisoning concerning children and adolescents (0–19 years old) in the city of Arapiraca, Alagoas, Brazil, in the period from 2007 to 2015. Methods: Observational study with data extracted from the Notifiable Diseases Information System. The variables sex, age group, toxic agent, and circumstance were analyzed using descriptive statistics. For temporal analysis, cut-off rates of incidence/10,000 inhabitants were calculated and the inflection point regression model was used for analysis. Results: There were 5,539 cases of exogenous intoxication in individuals aged 0–19 years in the city, of which 53.1% (n=2,944) occurred in girls and 61.5% (n=3,405) in children aged 0–9 years. Medicines consisted in the main agent responsible for intoxications (28.5%; n=1,580), mainly by accidental use (18.2%; n=1,010). There was a significant increase in the events during the study period (Average Annual Percent Change: 12.7; 95%CI 1.1–25.6; p

ABSTRACT Objective To assess the temporal trends of hospitalizations for pulmonary embolism (PE) in Brazil, its regions, and states between 2008 and 2019. Methods An ecological and time series study was conducted. Data were obtained from the Hospital Information System (SIH) of the Brazilian Ministry of Health. The inflection point regression model was applied for temporal trend analyses. Trends were classified as increasing, decreasing, or stationary according to the slope of the regression line. The Annual Percent Charge (APC) and the Average Annual Percent Change (AAPC) were calculated considering a confidence interval of 95% and p-value

The determinant variables of the performance of small and medium companies (SMEs) are associated to aspects of entrepreneurial capacity, regional economy, positioning in the market and type of operational management. These aspects are all influenced by the use of information technology (IT). This paper presents the intervening factors in the management process of these companies and a model that contemplates IT as an integrant part of the enterprise planning. The model, based on the Competence Theory, identifies in the business context of the company the critical factors to its success, the capacities and resources necessary to its sustain and the metrical which should reflect the evolution of the results of the company in relation to its objectives. Associated to these capacities IT resources are identified to be applied to upgrade the existing competences, or to develop new ones, according to the strategic focus and positioning of the company in the market. It is presented also a case study of a manufacturing SME of beverages where the model is being applied. The case shows some metrical results which certify the effectiveness of the model, although the short time of implantation. In spite of still being in the validation phase, with implementations in companies of other sectors, the model has shown favorable aspects mainly due to its cognitive and recurrent approach, which is well appropriate to the management process of SMEs.

Abstract Background Regionalised models of health care delivery have important implications for people with disabilities and chronic illnesses yet the ethical issues surrounding disability and regionalisation have not yet been explored. Although there is ethics-related research into disability and chronic illness, studies of regionalisation experiences, and research directed at improving health systems for these patient populations, to our knowledge these streams of research have not been brought together. Using the Canadian province of Ontario as a case study, we address this gap by examining the ethics of regionalisation and the implications for people with disabilities and chronic illnesses. The critical success factors we provide have broad applicability for guiding and/or evaluating new and existing regionalised health care strategies. Discussion Ontario is in the process of implementing fourteen Local Health Integration Networks (LHINs). The implementation of the LHINs provides a rare opportunity to address systematically the unmet diverse care needs of people with disabilities and chronic illnesses. The core of this paper provides a series of composite case vignettes illustrating integration opportunities relevant to these populations, namely: (i) rehabilitation and services for people with disabilities; (ii) chronic illness and cancer care; (iii) senior's health; (iv) community support services; (v) children's health; (vi) health promotion; and (vii) mental health and addiction services. For each vignette, we interpret the governing principles developed by the LHINs – equitable access based on patient need, preserving patient choice, responsiveness to local population health needs, shared accountability and patient-centred care – and describe how they apply. We then offer critical success factors to guide the LHINs in upholding these principles in response to the needs of people with disabilities and chronic illnesses. Summary This paper aims to bridge an important gap in the literature by examining the ethics of a new regionalisation strategy with a focus on the implications for people with disabilities and chronic illnesses across multiple sites of care. While Ontario is used as a case study to contextualize our discussion, the issues we identify, the ethical principles we apply, and the critical success factors we provide have broader applicability for guiding and evaluating the development of – or revisions to – a regionalised health care strategy.

An estimated 37,000 cisgender and transgender women work as sex workers in Malaysia, a population that has been disproportionately affected by the HIV epidemic . Although Malaysia provides no-cost antiretroviral therapy (ART) to people with HIV, little is known about sex workers' engagement in the HIV care continuum. We analyzed data from 57 HIV-infected cisgender women ( n  = 33) and transgender women ( n  = 24) sex workers from a respondent-driven sampling study on HIV prevalence among sex workers in Kuala Lumpur, Malaysia. We examined the proportion of women who were newly diagnosed with HIV, had a baseline CD-4 count test, were initiated and retained on antiretroviral treatment (ART). Overall, only 26.3% had ever been HIV tested and almost 60% were newly diagnosed. Only a small proportion of cisgender (15.2%) and transgender (12.5%) women were currently taking ART. Interventions to enhance sex workers' engagement in the HIV care continuum are urgently needed. Deployment of evidence-based strategies to improve linkage and retention in HIV care should be adapted to address the unique needs of this important key population.

Nuclear DNA in eukaryotes is wrapped around histone proteins to form nucleosomes on a chromatin fiber. Dynamic folding of the chromatin fiber into loops and variations in the degree of chromatin compaction regulate essential processes such as transcription, recombination, and mitotic chromosome segregation. Our understanding of the physical properties that allow chromatin to be dynamically remodeled even in highly compacted states is limited. Previously, we reported that chromatin has an intrinsic capacity to phase separate and form dynamic liquid-like condensates, which can be regulated by cellular factors [B. A. Gibson et al. , Cell 179 , 470-484.e421 (2019)]. Recent contradictory reports claim that a specific set of solution conditions is required for fluidity in condensates that would otherwise be solid [J. C. Hansen, K. Maeshima, M. J. Hendzel, Epigenetics Chromatin 14 , 50 (2021); H. Strickfaden et al. , Cell 183 , 1772-1784.e1713 (2020)]. We sought to resolve these discrepancies, as our ability to translate with confidence these biophysical observations to cells requires their precise characterization. Moreover, whether chromatin assemblies are dynamic or static affects how processes such as transcription, loop extrusion, and remodeling will engage them inside cells. Here, we show in diverse conditions and without specific buffering components that chromatin fragments form phase separated fluids in vitro. We also explore how sample preparation and imaging affect the experimental observation of chromatin condensate dynamics. Last, we describe how liquid-like in vitro behaviors can translate to the locally dynamic but globally constrained chromatin movement observed in cells.

Dividing eukaryotic cells package extremely long chromosomal DNA molecules into discrete bodies to enable microtubule-mediated transport of one genome copy to each of the newly forming daughter cells 1-3 . Assembly of mitotic chromosomes involves DNA looping by condensin 4-8 and chromatin compaction by global histone deacetylation 9-13 . Although condensin confers mechanical resistance to spindle pulling forces 14-16 , it is not known how histone deacetylation affects material properties and, as a consequence, segregation mechanics of mitotic chromosomes. Here we show how global histone deacetylation at the onset of mitosis induces a chromatin-intrinsic phase transition that endows chromosomes with the physical characteristics necessary for their precise movement during cell division. Deacetylation-mediated compaction of chromatin forms a structure dense in negative charge and allows mitotic chromosomes to resist perforation by microtubules as they are pushed to the metaphase plate. By contrast, hyperacetylated mitotic chromosomes lack a defined surface boundary, are frequently perforated by microtubules and are prone to missegregation. Our study highlights the different contributions of DNA loop formation and chromatin phase separation to genome segregation in dividing cells., (© 2022. The Author(s).)

Context.—: Pathology reports are the main modality in which results are communicated to other physicians. For various reasons, the diagnosis may be qualified on a spectrum of uncertainty., Objective.—: To examine how communication of uncertainty is an unexamined source of possible medical error. No study to our knowledge has examined pathology reports across multiple institutions. This study seeks to identify commonly used phrases of diagnostic uncertainty and their interpreted meanings by surgical pathologists and clinicians., Design.—: Anonymous surveys were completed at 3 major US academic institutions by 18 practicing staff pathologists, 12 pathology residents, 53 staff clinicians, and 50 resident/allied health professional clinicians at 5 standard tumor boards. All participants rated percentage certainty associated with 7 diagnostic terms. Pathologists answered 2 questions related to the ability to clarify a diagnosis using a comment and comfort wording pathology reports. Clinicians answered questions on how often they read a pathology report comment, if they found the comment helpful, and how comfortable they were in reading pathology reports., Results.—: A wide range in percentage certainty was found for each of the 7 diagnostic phrases. Both staff and resident clinicians and residents showed wide variability in interpreting the phrases. Twenty-five of 50 staff clinicians (52%) were very comfortable reading a pathology report, whereas only 4 of 53 resident clinicians (8%) were very comfortable reading a pathology report. Twenty-four of 53 staff clinicians (63%) reported always reading the comment, yet only 20 of 53 (27%) always found the comment helpful. The phrases "diagnostic of" and "consistent with" had the strongest agreement in meaning. The weakest agreement was between "suspicious for" and "compatible with.", Conclusions.—: Efforts to standardize diagnostic terms may improve communication.

The use of amphetamine-type stimulants (ATS) has been associated with increased sexual risk behaviors and HIV transmission, among other adverse health outcomes. However, ATS use among female sex workers (FSWs) in Malaysia has not yet been characterized. We examined the prevalence and correlates associated with ATS use among Malaysian FSW. Between February and December 2016, 492 FSWs, including cisgender ( n = 299) and transgender ( n = 193) women, were recruited using respondent-driven sampling in Greater Kuala Lumpur, Malaysia. A structured questionnaire was used to collect demographic characteristics, sexual behaviors, ATS and other substance use, behavioral health issues, involvement in criminal justice, and experience of physical and sexual trauma. Logistic regression analyses were conducted to determine factors associated with active ATS use, defined as ATS use in the last 30 days. Nearly one-third (32.3%) of participants reported active ATS use. In the multivariable model, ATS use was associated with drug use during sex work (aOR = 17.10; 8.32-35.15), having moderate to severe level of substance use disorder (aOR = 3.38; 1.48-7.70), and engaging in sex work with multiple clients per day (two clients: aOR = 3.39; 1.36-8.46; three clients: aOR = 5.06; 1.81-14.10). A high prevalence of ATS use was documented in our sample. The presence of moderate to severe substance use disorder, the use of drugs during sex work activity, and having multiple sex work clients per day were significantly associated with active ATS use. Given these findings, prevention and harm reduction strategies need to be tailored to address the increasing ATS use and the associated adverse health consequences among FSWs in Malaysia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pedersen, Wickersham, Altice, Kamarulzaman, Khoshnood, Gibson, Khati, Maviglia and Shrestha.)

Data that inform preexposure prophylaxis (PrEP) implementation for women involved in criminal justice (WICJ) systems are scarce. In a survey of PrEP attitudes, acceptability, and barriers across the criminal justice system, incarcerated women ( n  = 48) were more likely than WICJ on probation ( n  = 125) to be eligible for PrEP (29% vs. 15%; p  = .04) and willing to take PrEP if offered (94% vs. 78%; p  = .01). In multivariate models, PrEP eligibility directly correlated with being incarcerated (adjusted odds ratio [aOR] 4.81, 95% confidence interval [CI] 1.76-13.1) and inversely correlated with Hispanic/Latina ethnicity (aOR 0.31; 95% CI 0.10-0.96). Recent partner violence exposure was associated with PrEP eligibility (aOR 3.29; 95% CI 1.54-7.02) and discordant risk perception (aOR 2.36; 95% CI 1.18-4.70). Findings demonstrate high potential for PrEP for all WICJ, though implementation efforts will need to address partner violence.

Context: Caregivers often provide unpaid care for family members and friends with physical disabilities, often to the detriment of their health and well-being. Caregivers often experience pain, and individuals with physical disabilities also are likely to experience pain. Merging yoga and self-management to Develop Skills Study (MY-Skills) is an intervention that merges self-management education with yoga for dyads experiencing chronic pain., Aim: This article presents the yoga protocol for the MY-Skills intervention., Methods: The yoga protocol was revised based on feedback from six caregiving dyads. The protocol focuses on reducing pain interference and supporting the caregiving dyad., Results: The final yoga protocol incorporated the following elements: Centering and mantra, prana vidya and pranayama, asanas, mudra, and guided savasana/dhyana., Conclusion: The MY-Skills yoga protocol was modified by a yoga therapist with feedback from study participants. Revisions focused on the caregiving dyad, with specific attention to reducing pain interference., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 International Journal of Yoga.)

Globally, cisgender women sex workers (CWSWs) and transgender women sex workers (TWSWs) experience increased vulnerabilities to HIV infection. Unfortunately, there is limited data on the drivers of HIV infection in these two understudied populations, particularly in Southeast Asia. To better understand factors associated with HIV infection, we evaluated correlates of newly diagnosed HIV infection in these two populations in Greater Kuala Lumpur, Malaysia. A total of 469 women (CWSW: n = 283; TWSW: n = 186) were included in this study. Most participants who tested HIV+ were unaware of their infection (59.6%; n = 34/57). Separate binary and multivariable logistic regressions were conducted to identify correlates of newly diagnosed HIV in CWSWs and TWSWs. Among CWSWs, Chlamydia trachomatis (aOR = 5.66; p = 0.007) and lifetime use of ecstasy/MDMA (aOR = 5.34; p = 0.03) were associated with newly diagnosed HIV, while condomless vaginal sex with clients was associated with lower likelihood of HIV infection (aOR = 0.98; p = 0.01). Among TWSWs, being single (aOR = 6.76; p = 0.03), using mobile application to solicit clients (aOR = 25.33; p = 0.006), and having C. trachomatis infection (aOR = 88.22, p = 0.02) were associated with newly diagnosed HIV. Expansion of HIV/sexually transmitted infection screening is needed to increase detection of HIV and linkage to care for sex workers. Interventions to reduce HIV infection among CWSWs and TWSWs should be tailored to these populations' unique vulnerabilities.

Genome engineering nucleases must access chromatinized DNA. Here, we investigate how AsCas12a cleaves DNA within human nucleosomes and phase-condensed nucleosome arrays. Using quantitative kinetics approaches, we show that dynamic nucleosome unwrapping regulates target accessibility to Cas12a and determines the extent to which both steps of binding-PAM recognition and R-loop formation-are inhibited by the nucleosome. Relaxing DNA wrapping within the nucleosome by reducing DNA bendability, adding histone modifications, or introducing target-proximal dCas9 enhances DNA cleavage rates over 10-fold. Unexpectedly, Cas12a readily cleaves internucleosomal linker DNA within chromatin-like, phase-separated nucleosome arrays. DNA targeting is reduced only ~5-fold due to neighboring nucleosomes and chromatin compaction. This work explains the observation that on-target cleavage within nucleosomes occurs less often than off-target cleavage within nucleosome-depleted genomic regions in cells. We conclude that nucleosome unwrapping regulates accessibility to CRISPR-Cas nucleases and propose that increasing nucleosome breathing dynamics will improve DNA targeting in eukaryotic cells., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose protein substrates and biological activities are poorly understood. We observed that PARP7 mRNA levels are lower in ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g. growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD + analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes., Competing Interests: LP, SC, TN, MS, DH, JL No competing interests declared, BG holds the patents on the anti-MAR binding reagent (United States Patent No. 9,599,606) and the asPARP technology (United States Patent No. 9,926,340) described herein. UT Southwestern Medical Center has licensed the anti-MAR binding reagent to EMD Millipore, which markets it for research purposes. BIOLOG Life Science Institute, a coholder of United States Patent No. 9,926,340, sells the NAD+ analog 8-Bu(3-yne)T-NAD+. WK is a founder consultant for Ribon (Therapeutics, Inc). Holds the patents on the anti-MAR binding reagent (United States Patent No. 9,599,606) and the asPARP technology (United States Patent No. 9,926,340) described herein. UT Southwestern Medical Center has licensed the anti-MAR binding reagent to EMD Millipore, which markets it for research purposes. BIOLOG Life Science Institute, a coholder of United States Patent No. 9,926,340, sells the NAD+ analog 8-Bu(3-yne)T-NAD+., (© 2021, Palavalli Parsons et al.)

Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status., (©2019 American Association for Cancer Research.)

Eukaryotic chromatin is highly condensed but dynamically accessible to regulation and organized into subdomains. We demonstrate that reconstituted chromatin undergoes histone tail-driven liquid-liquid phase separation (LLPS) in physiologic salt and when microinjected into cell nuclei, producing dense and dynamic droplets. Linker histone H1 and internucleosome linker lengths shared across eukaryotes promote phase separation of chromatin, tune droplet properties, and coordinate to form condensates of consistent density in manners that parallel chromatin behavior in cells. Histone acetylation by p300 antagonizes chromatin phase separation, dissolving droplets in vitro and decreasing droplet formation in nuclei. In the presence of multi-bromodomain proteins, such as BRD4, highly acetylated chromatin forms a new phase-separated state with droplets of distinct physical properties, which can be immiscible with unmodified chromatin droplets, mimicking nuclear chromatin subdomains. Our data suggest a framework, based on intrinsic phase separation of the chromatin polymer, for understanding the organization and regulation of eukaryotic genomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Patients regularly request to take possession of their human tissues after they have become surgical pathology specimens. To date, few formal research studies have examined the prevalence of this practice or the reasoning patients' request that their specimens to be returned to them. This study interviews patients from 2015 to 2017 at one US academic medical center who requested their surgical pathology specimens. Of the 22 eligible patients, 8 patients agreed to be interviewed. Interviews lasted 10 to 30 minutes and included 5 questions. The questions were: (1) What motivated your decision to obtain your surgical pathology specimen, (2) What, if anything, did you do with your specimen, (3) What were positive aspects of your experience, (4) What were negative aspects of your experience, (5) What can the pathology department change to better support patients who request their surgical pathology specimens? Verbatim transcripts were generated and a mixed-methods analysis was performed. The type of specimens included products of conception, placenta and cord, costal cartilage and ribs, loop explant recorder, pacemaker, below knee amputation, and cervix, uterus, Fallopian tubes, and ovaries. The dominant themes included adversity, medical interest, souvenir, cultural beliefs, and curiosity. Subthemes included becoming whole in the afterlife, preservation, my body, restoration, honoring, and regret. In conclusion, pathologists can expand their role as patient advocates and advance patient-centered pathology by supporting patient's individual needs, motivations, and goals, when they request their surgical pathology specimens., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Metformin has recently been shown to have potential to reduce prostate cancer risk. We conducted a randomized, double-blind, placebo-controlled trial to determine the modulating effects of metformin on tissue and systemic biomarkers of drug activity and its distribution into the prostate tissue. Twenty patients with prostate cancer scheduled to undergo prostatectomy were randomly assigned to receive either extended-release metformin or placebo for a median of 34 days before surgery. Prostatectomy and serum samples were analyzed for metformin concentrations, serum biomarkers of drug activity (prostate-specific antigen, insulin, insulin-like growth factor-1, insulin-like growth factor binding protein 3, sex hormone-binding globulin, and testosterone) and tissue biomarkers of proliferation, apoptosis, cell cycle regulation, and mTOR inhibition. For participants in the metformin arm, the prostate tissue and serum metformin concentrations ranged from 0.88 to 51.2 μg/g tissue and from not detectable to 3.6 μg/ml, respectively. There were no differences between the two groups in either the postintervention tissue biomarker expression in the prostatectomy tissue or pre to postintervention changes in serum biomarkers. We conclude that metformin distributes to human prostate tissue, suggesting that metformin could exert its effects directly on tissue targets. However, there was no difference in tissue and systemic drug effect biomarkers between the two treatment arms. Future studies with longer intervention duration and larger sample size should be considered in order to evaluate the potential of metformin for prostate cancer prevention.

Purpose: In Malaysia, an estimated 9.7%-12.4% of transgender women (TW) are HIV positive, with higher estimates among those engaged in sex work. According to the 90-90-90 Joint United Nations Programme on HIV/AIDS strategy, HIV testing is the first crucial step in curbing the HIV epidemic. This study examines correlates of recent HIV testing among TW in Greater Kuala Lumpur, Malaysia., Methods: TW (N = 199) in Greater Kuala Lumpur completed a survey on healthcare access and utilization, including HIV testing history. Bivariate logistic regression and penalized multivariate logistic regression were used to explore correlates of HIV testing in the last 12 months., Results: Overall, 41.7% of TW reported having ever been tested for HIV. Among participants who were HIV negative or not sure of their HIV status (n = 187), only 18.7% (n = 35) had been tested for HIV in the last 12 months. The multivariate analysis indicated that having a primary care provider (PCP), being 26-40 years of age, and having higher mental health functioning were positively associated with recent HIV testing. Active amphetamine use and previous depression diagnosis were also associated with recent HIV testing., Conclusion: HIV testing is the first step in linking individuals to prevention and treatment interventions. Our findings suggest that having a PCP can improve engagement in HIV testing. Moreover, PCPs can serve as a valuable link to HIV treatment and prevention services. Current interventions that target social and behavioral risk factors for HIV, on their own, may be insufficient at engaging all HIV-vulnerable TW.

Nuclear poly(ADP-ribose) polymerases (PARPs), including PARPs 1, 2, and 3 and the Tankyrases, belong to a family of enzymes that can bind to chromatin and covalently modify histone- and chromatin-associated proteins with ADP-ribose derived from nuclear NAD + . The genomic loci where the nuclear PARPs bind and covalently modify chromatin are a fundamental question in PARP biology. Chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) has become an essential tool for determining specific sites of binding and modification genome-wide. Few methods are available, however, for localizing PARP-specific ADP-ribosylation events across the genome. Here we describe a variation of ChIP-seq, called Click-ChIP-seq, for identifying sites of ADP-ribosylation mediated by specific PARP family members. This method uses analog-sensitive PARP (asPARP) technology, including asPARP mutants and the alkyne-containing "clickable" NAD + analog 8-Bu(3-yne)T-NAD + . In this assay, nuclei from cells expressing an asPARP protein of interest are incubated with 8-Bu(3-yne)T-NAD + , which is incorporated into ADP-ribose modifications mediated only by that specific asPARP protein. The nuclei are then subjected to cross-linking with formaldehyde, and the protein-linked analog ADP-ribose is clicked to biotin using copper-catalyzed alkyne-azide "click" chemistry. The chromatin is fragmented, and the fragments containing analog ADP-ribose are enriched using streptavidin-mediated precipitation. Finally, the enriched DNA is analyzed by qPCR or deep-sequencing experiments to determine which genomic loci contain ADP-ribose modifications mediated by the specific PARP protein of interest. Click-ChIP-seq has proven to be a robust and reproducible method for identifying chromatin-associated, PARP-specific ADP-ribosylation events genome-wide.

ADP-ribosylation is an enzyme-catalyzed post-translational modification of proteins in which the ADP-ribose (ADPR) moiety of NAD + is transferred to a specific amino acid in a substrate protein. The biological functions of ADP-ribosylation are numerous and diverse, ranging from normal physiology to pathological conditions. Biochemical and cellular studies of the diverse forms and functions of ADPR require immunological reagents that can be used for detection and enrichment. The lack of a complete set of tools that recognize all forms of ADPR [i.e., mono-, oligo-, and poly(ADP-ribose)] has hampered progress. Herein, we describe the generation and characterization of a set of recombinant antibody-like ADP-ribose binding proteins, in which naturally occurring ADPR binding domains, including macrodomains and WWE domains, have been functionalized by fusion to the Fc region of rabbit immunoglobulin. These reagents, which collectively recognize all forms of ADPR with different specificities, are useful in a broad array of antibody-based assays, such as immunoblotting, immunofluorescent staining of cells, and immunoprecipitation. Observations from these assays suggest that the biology of ADPR is more diverse, rich, and complex than previously thought. The ARBD-Fc fusion proteins described herein will be useful tools for future exploration of the chemistry, biochemistry, and biology of ADP-ribose.

Background: Sex workers face a disproportionate burden of human immunodeficiency virus (HIV) and sexually transmitted infections (STI) worldwide. For cisgender women sex workers (CWSW), global HIV prevalence is over 10%, whereas transgender women sex workers (TWSW) face an HIV burden of 19% to 27%., Methods: We used respondent-driven sampling to recruit 492 sex workers, including CWSW (n = 299) and TWSW (n = 193) in Greater Kuala Lumpur, Malaysia. Participants completed an in-depth survey and were screened for HIV, syphilis, Chlamydia trachomatis, and Neisseria gonorrhoeae. Sample characteristics stratified by gender identity and interview site are presented. Bivariate analyses comparing CWSW and TWSW were conducted using independent samples t tests for continuous variables and χ tests for categorical variables., Results: Pooled HIV prevalence was high (11.7%; 95% confidence interval [CI], 8.8-14.5), and was similar for CWSW (11.1%) and TWSW (12.4%). Rates of syphilis 25.5% (95% CI, 21.6-29.5), C. trachomatis (14.8%; 95% CI, 11.6-18.0) and N. gonorrhoeae (5.8%; 95% CI, 3.7-7.9) were also concerning. Both groups reported lifetime HIV testing (62.4%), but CWSW were less likely to have ever been HIV tested (54.5%) than TWSW (74.6%). Median time since last HIV test was 24 months. Previous screening for STI was low. Inconsistent condom use and drug use during sex work were not uncommon., Conclusions: High HIV and STI prevalence, coupled with infrequent HIV and STI screening, inconsistent condom use, and occupational drug use, underscore the need for expanded HIV and STI prevention, screening, and treatment efforts among CWSW and TWSW in Malaysia.

Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARylation has been studied extensively, few examples of definitive biological roles for site-specific PARylation have been reported. Here we show that C/EBPβ, a key pro-adipogenic transcription factor, is PARylated by PARP-1 on three amino acids in a conserved regulatory domain. PARylation at these sites inhibits C/EBPβ's DNA binding and transcriptional activities and attenuates adipogenesis in various genetic and cell-based models. Interestingly, PARP-1 catalytic activity drops precipitously during the first 48 hr of differentiation, corresponding to a release of C/EBPβ from PARylation-mediated inhibition. This promotes the binding of C/EBPβ at enhancers controlling the expression of adipogenic target genes and continued differentiation. Depletion or chemical inhibition of PARP-1, or mutation of the PARylation sites on C/EBPβ, enhances these early adipogenic events. Collectively, our results provide a clear example of how site-specific PARylation drives biological outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Community Health Care Van (CHCV) is a mobile medical clinic (MMC) that has served vulnerable populations in New Haven, Connecticut since 1993. This study explores utilization patterns to understand if certain populations frequently rely upon non-traditional health care within a representative MMC. Patient characteristics, services used, and visitation frequency were described and compared for 8,415 unique clients making 29,728 visits. Negative binomial regression was used to model the impact of specific indicators on visitation. Clients receiving buprenorphine had the highest visitation rates, with 2.09 visits per person-year. Increased CHCV visitation was positively associated with being foreign-born (additional 3.42 visits on average, p < .001), injection drug use (additional 1.69 visits on average, p < .001) and having hypertension (additional 1.09 visits on average, p < .001). As the Affordable Care Act has increased health insurance coverage, MMCs will continue their role in assisting entry into continuous health care and offering low-threshold acute care for urban vulnerable populations.

The PARP family of ADP-ribosyl transferases contains 17 members in human cells, most of which catalyze the transfer of the ADP-ribose moiety of NAD + onto their target proteins. This posttranslational modification plays important roles in cellular signaling, especially during cellular stresses, such as heat shock, inflammation, unfolded protein responses, and DNA damage. Knowing the specific proteins that are substrates for individual PARPs, as well as the specific amino acid residues in a given target protein that are ADP-ribosylated, is a key step in understanding the biology of individual PARPs. Recently, we developed a robust NAD + analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition ("click chemistry") reactions. When coupled with proteomics and mass spectrometry, the analog-sensitive PARP approach can be used to identify the specific amino acids that are ADP-ribosylated by individual PARP proteins. In this chapter, we describe the key facets of the experimental design and application of the analog-sensitive PARP methodology to identify site-specific modification of PARP target proteins.

Transgender women (TGW) face compounded levels of stigma and discrimination, resulting in multiple health risks and poor health outcomes. TGW identities are erased by forcing them into binary sex categories in society or treating them as men who have sex with men (MSM). In Malaysia, where both civil and religious law criminalise them for their identities, many TGW turn to sex work with inconsistent prevention methods, which increases their health risks. This qualitative study aims to understand how the identities of TGW sex workers shapes their healthcare utilisation patterns and harm reduction behaviours. In-depth, semi-structured interviews were conducted with 21 male-to-female transgender (mak nyah) sex workers in Malaysia. Interviews were transcribed, translated into English, and analysed using thematic coding. Results suggest that TGW identity is shaped at an early age followed by incorporation into the mak nyah community where TGW were assisted in gender transition and introduced to sex work. While healthcare was accessible, it failed to address the multiple healthcare needs of TGW. Pressure for gender-affirming health procedures and fear of HIV and sexually transmitted infection screening led to potentially hazardous health behaviours. These findings have implications for developing holistic, culturally sensitive prevention and healthcare services for TGW.

In order to document perceptions of text comments appearing in surgical pathology reports, questionnaires were distributed to 4 groups of caregivers: university staff pathologists, resident pathologists, faculty clinicians (other than pathologists), and resident clinicians at a teaching hospital. Results of this pilot study showed a wide degree of variability existed within each group of surgical pathology report users, with respect to percent confidence assigned to various phrases, commonly used to express diagnostic uncertainty, appearing often as free-text comments in surgical pathology reports. The unavailability of immunohistochemistry tests, or ambiguous immunohistochemistry test results, was especially problematic. With respect to modes of communication between the surgical pathology laboratory and its service users, clinicians indicated they preferred to use tumor boards/interdisciplinary conferences, face-to-face meetings, and phone calls to clarify their interpretations of a pathologist's diagnoses, as compared with simply reading free-text comments. On the other hand, surgical pathologists rely heavily on their use of the comment portion of a surgical pathology report to clarify, modify, or expand on the diagnoses they render. The majority of clinicians stated that they "always" read the free-text comment portion of a surgical pathology report, whereas some acknowledged they do not always read it. Pathology residents had significantly less confidence in the ability of a free-text comment on a surgical pathology report to clarify a diagnosis (χ 2 = 46.36, P < .0001). Pathology departments should consider standardizing definitions and weighting the words and phrases they use in their free-text comment sections of surgical pathology reports., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Prior research strongly implicates gastric acid and bile acids, two major components of the gastroesophageal refluxate, in the development of Barrett's esophagus and its pathogenesis. Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to protect esophageal cells against oxidative stress induced by cytotoxic bile acids. We conducted a pilot clinical study to evaluate the clinical activity of UDCA in patients with Barrett's esophagus. Twenty-nine patients with Barrett's esophagus received UDCA treatment at a daily dose of 13 to 15 mg/kg/day for 6 months. The clinical activity of UDCA was assessed by evaluating changes in gastric bile acid composition and markers of oxidative DNA damage (8-hydroxydeoxyguanosine), cell proliferation (Ki67), and apoptosis (cleaved caspase-3) in Barrett's esophagus epithelium. The bile acid concentrations in gastric fluid were measured by liquid chromatography/mass spectrometry. At baseline, UDCA (sum of unchanged and glycine/taurine conjugates) accounted for 18.2% of total gastric bile acids. After UDCA intervention, UDCA increased significantly to account for 93.4% of total gastric bile acids (P < 0.0001). The expression of markers of oxidative DNA damage, cell proliferation, and apoptosis was assessed in the Barrett's esophagus biopsies by IHC. The selected tissue biomarkers were unchanged after 6 months of UDCA intervention. We conclude that high-dose UDCA supplementation for 6 months resulted in favorable changes in gastric bile acid composition but did not modulate selected markers of oxidative DNA damage, cell proliferation, and apoptosis in the Barrett's esophagus epithelium. Cancer Prev Res; 9(7); 528-33. ©2016 AACRSee related article by Brian J. Reid, p. 512., (©2016 American Association for Cancer Research.)

Poly[adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of nicotinamide adenine dinucleotide (NAD(+)) onto substrate proteins. Here we report a robust NAD(+) analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1-mediated ADP-ribosylation sites across the genome. We found that PARP-1 ADP-ribosylates and inhibits negative elongation factor (NELF), a protein complex that regulates promoter-proximal pausing by RNA polymerase II (Pol II). Depletion or inhibition of PARP-1 or mutation of the ADP-ribosylation sites on NELF-E promotes Pol II pausing, providing a clear functional link between PARP-1, ADP-ribosylation, and NELF. This analog-sensitive approach should be broadly applicable across the PARP family and has the potential to illuminate the ADP-ribosylated proteome and the molecular mechanisms used by individual PARPs to mediate their responses to cellular signals., (Copyright © 2016, American Association for the Advancement of Science.)

Segmental arterial mediolysis (SAM) is a rare vasculopathy characterized by lysis of the outer media in splanchnic arteries and formation of dissecting pseudoaneurysms that may spontaneously rupture, leading to massive and often fatal intraabdominal hemorrhage. The pathogenesis of SAM is poorly understood. Healed SAM lesions closely resemble fibromuscular dysplasia (FMD), leading some authors to postulate that SAM represents a precursor to FMD despite distinct clinical differences between these two disorders. Herein, we present a 61-year-old woman with fatal SAM who showed histologic features in her aorta suggesting the opposite pathogenetic relationship, with an unclassified "FMD-like" arteriopathy preceding development of SAM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Despite new Hepatitis C virus (HCV) therapeutic advances, challenges remain for HCV testing and linking patients to care. A point-of-care (POC) HCV antibody testing strategy was compared to traditional serological testing to determine patient preferences for type of testing and linkage to treatment in an innovative mobile medical clinic (MMC). From 2012 to 2013, all 1,345 MMC clients in New Haven, CT underwent a routine health assessment, including for HCV. Based on patient preferences, clients could select between standard phlebotomy or POC HCV testing, with results available in approximately 1 week versus 20 min, respectively. Outcomes included: (1) accepting HCV testing; (2) preference for rapid POC HCV testing; and (3) linkage to HCV care. All clients with reactive test results were referred to a HCV specialty clinic. Among the 438 (32.6 %) clients accepting HCV testing, HCV prevalence was 6.2 % (N = 27), and 209 (47.7 %) preferred POC testing. Significant correlates of accepting HCV testing was lower for the "baby boomer" generation (AOR 0.67; 95 % CI 0.46-0.97) and white race (AOR 0.55; 95 % CI 0.36-0.78) and higher for having had a prior STI diagnosis (AOR 5.03; 95 % CI 1.76-14.26), prior injection drug use (AOR 2.21; 95 % CI 1.12-4.46), and being US-born (AOR 1.76; 95 % CI 1.25-2.46). Those diagnosed with HCV and preferring POC testing (N = 16) were significantly more likely than those choosing standard testing (N = 11) to be linked to HCV care within 30 days (93.8 vs. 18.2 %; p < 0.0001). HCV testing is feasible in MMCs. While patients equally preferred POC and standard HCV testing strategies, HCV-infected patients choosing POC testing were significantly more likely to be linked to HCV treatment. Important differences in risk and background were associated with type of HCV testing strategy selected. HCV testing strategies should be balanced based on costs, convenience, and ability to link to HCV treatment.

We mapped mobile medical clinic (MMC) clients for spatial distribution of their self-reported locations and travel behaviors to better understand health-seeking and utilization patterns of medically vulnerable populations in Connecticut. Contrary to distance decay literature, we found that a small but significant proportion of clients was traveling substantial distances to receive repeat care at the MMC. Of 8404 total clients, 90.2% lived within 5 miles of a MMC site, yet mean utilization was highest (5.3 visits per client) among those living 11-20 miles of MMCs, primarily for those with substance use disorders. Of clients making >20 visits, 15.0% traveled >10 miles, suggesting that a significant minority of clients traveled to MMC sites because of their need-specific healthcare services, which are not only free but available at an acceptable and accommodating environment. The findings of this study contribute to the important research on healthcare utilization among vulnerable population by focusing on broader dimensions of accessibility in a setting where both mobile and fixed healthcare services coexist., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Despite recommendations for generation-based HCV and once lifetime HIV screening, thousands of individuals in the U.S. still remain untested and undiagnosed. This cross-sectional study examines the correlates of HCV and HIV monoinfection and HIV/HCV coinfection in an urban Northeast setting., Methods: Utilizing an electronic database from a mobile medical clinic in New Haven, CT from January 2003 to July 2011, 8,311 individuals underwent structured health assessment and screening for HIV and HCV., Results: HIV [N = 601 (8.0%)] and HCV [N = 753 (10.1%)] infection were identified, and 197 (26.1%) of the 753 with HCV were coinfected with HIV. Both monoinfection and coinfection status were independently correlated with crack cocaine use and increasing age. HIV/HCV coinfection was correlated with men having sex with men (MSM) (AOR = 38.53, p<0.0080), shooting gallery use (AOR = 3.06, p<0.0070), and not completing high school (AOR = 2.51, p<0.0370). HCV monoinfection correlated with health insurance (AOR = 2.16, p<0.0020), domestic violence (AOR = 1.99, p<0.0070), and being Hispanic (AOR = 2.63, p<0.0001), while HIV monoinfection correlated with having had syphilis (AOR = 2.66, p<0.0001) and being Black (AOR = 1.73, p = 0.0010)., Conclusions: Though HIV and HCV share common transmission risk behaviors, independent correlates with viral infection status in an urban Northeast setting are distinct and have important implications for surveillance, healthcare delivery, disease prevention, and clinical care.

Objective: To examine in a longitudinal occupational assessment whether changes in serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are associated with changes in non-high-density lipoprotein (HDL) cholesterol., Methods: Baseline and end-of-project PFOA, PFOS, lipid, and hepatic clinical chemistries were measured in 204 workers involved with the demolition of former perfluoroalkyl manufacturing facilities. Analyses were restricted to the 179 workers who did not take lipid-lowering medications. Two thirds had baseline PFOA and PFOS levels similar to the general population., Results: The change in non-HDL cholesterol was not associated with the changes in PFOA or PFOS. An increase in HDL was associated with an increase in PFOA, although the magnitude was small. This increase in HDL resulted in a decrease in the total cholesterol/HDL ratio., Conclusion: Adverse associations were not observed between changes in PFOA, PFOS, non-HDL cholesterol, HDL, and hepatic clinical chemistries.

Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses. PARPs act in a complex response network that is driven by the cellular, molecular and chemical biology of poly(ADP-ribose) (PAR). This PAR-dependent response network is crucial for a broad array of physiological and pathological responses and thus is a good target for chemical therapeutics for several diseases.

Gas phase excitation and emission spectra of three naphthylmethyl radical chromophores are presented. These resonance-stabilized species, 1-naphthylmethyl, 2-naphthylmethyl, and α-acenaphthenyl, each possessing an sp(2) carbon adjacent to a naphthalene moiety, are studied by resonant two-color two-photon ionization, laser induced fluorescence, and dispersed fluorescence spectroscopy. Identification of the radicals is made through a combination of dispersed fluorescence and density functional theory calculations. All three species possess spectra in the 580 nm region. The possible relevance to unidentified spectroscopic features such as the diffuse interstellar bands and emission from the Red Rectangle nebula is discussed.

The D(1)((2)A("))-D(0)((2)A(")) electronic transition of the resonance-stabilized 1-phenylpropargyl radical, produced in a jet-cooled discharge of 3-phenyl-1-propyne, has been investigated in detail by laser-induced fluorescence excitation and dispersed single vibronic level fluorescence (SVLF) spectroscopy.The transition is dominated by the origin band at 21,007 cm(-1), with weaker Franck-Condon activity observed in a(') fundamentals and even overtones and combinations of a(") symmetry. Ab initio and density functional theory calculations of the D(0) and D(1) geometries and frequencies were performed to support and guide the experimental assignments throughout. Analysis of SVLF spectra from 16 D(1) vibronic levels has led to the assignment of 15 fundamental frequencies in the excited state and 19 fundamental frequencies in the ground state; assignments for many more normal modes not probed directly by fluorescence spectroscopy are also suggested. Duschinsky mixing, in which the excited state normal modes are rotated with respect to the ground state modes, is prevalent throughout, in vibrations of both a(') and a(") symmetry.

In light of the Canadian Nurses Association's position that the baccalaureate degree would be the requirement for entry to practice by the year 2000, plus evidence of a rapidly changing health care system, changing client characteristics, and on-going economic constraints, administrators of nursing programs in Edmonton recognized the need for a more process-oriented curriculum to prepare nurses to be more capable of facing future challenges. Not surprisingly, limited funds and differing human and material resources meant they could not complete a major curriculum change individually. Collaboration proved to be the key that increased access to baccalaureate nursing education in Alberta.