Redox Dysregulation of Vascular Smooth Muscle Sirtuin-1 in Thoracic Aortic Aneurysm in Marfan Syndrome.

BACKGROUND: Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases). METHODS: In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1mgR/mgR), an established model of Marfan syndrome prone to aortic dissection/rupture. RESULTS: Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1mgR/mgR mice, before induction of severe oxidative stress markers. Fbn1mgR/mgR aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFß (transforming growth factor beta), which was increased in Fbn1mgR/mgR aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell-specific deletion of SirT1 in Fbn1mgR/mgR mice (SMKO-Fbn1mgR/mgR) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1mgR/mgR mice, compared with 25% of Fbn1mgR/mgR mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells. CONCLUSIONS: Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA and TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed.

Where are the data to assess the safety of paternal drug exposure? A systematic review of secondary databases: A contribution from IMI concePTION.

BACKGROUND: Most studies assessing the safety of parental drug exposures during pregnancy and around the time of conception describe the effects of maternal exposure. Recent publications have raised awareness of the need for additional research regarding the safety of paternal drug exposures on pregnancy outcomes. OBJECTIVES: To identify and describe studies that use secondary databases in paternal drug safety studies and to describe the secondary databases that were used. METHODS: A systematic review of studies assessing paternal medication exposure and pregnancy and infant outcomes using secondary databases was performed. In addition, the secondary databases used for these studies was described. Literature search was conducted using Embase, Web of Science, and PubMed, over the period January 1, 2012 to April 30, 2023. For each eligible study, paternal drug exposure, outcome, and data source characteristics were extracted in a data extraction form. RESULTS: After reviewing the literature, 17 studies met inclusion criteria. The medications assessed for paternal safety were anti-rheumatic drugs (n = 10), anti-depressants (n = 3), anticonvulsants (n = 2), and anti-diabetes medications (n = 2). Pregnancy safety outcomes included congenital malformations, birth weight, and developmental disorders. The studies used five different databases across Europe and North America. The included studies used databases from Denmark (n = 12), Norway (n = 2), Sweden (n = 1), Canada (n = 1), and the United States (n = 1). The European studies utilized national patient registers that linked fathers to births and prescription histories. The North American databases used included insurance claims and electronic health records. CONCLUSIONS: Our review shows that few studies have been completed on paternal medication exposures and pregnancy outcomes, despite the availability of secondary databases that contain data necessary to link fathers to infants. More research on the potential adverse impacts of paternal medication exposures is needed.

Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity.

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

[Comparison of two types of classification in functional dyspepsia; postprandial distress or epigastric pain vs a multidimensional cluster analysis using unsupervised learning]. / Comparación de dos tipos de clasificación en dispepsia funcional; distrés postprandial o dolor epig ástrico vs un an álisis multidimensional por conglomerados utilizando aprendizaje no supervisado.

Artificial intelligence methods using unsupervised learning tools can support problem solving by establishing unidentified grouping or classification patterns that allow typing subgroups for more individualized management. There are few studies that allow us to know the influence of digestive and extra-digestive symptoms in the classification of functional dyspepsia. This research carried out a cluster unsupervised learning analysis based on these symptoms to discriminate subtypes of dyspepsia and compare with one of the currently most accepted classifications. An exploratory cluster analysis was carried out in adults with functional dyspepsia according to digestive, extra-digestive and emotional symptoms. Grouping patterns were formed in such a way that within each group there was homogeneity in terms of the values adopted by each variable. The cluster analysis method was two-stage and the results of the classification pattern were compared with one of the most accepted classifications of functional dyspepsia. Of 184 cases, 157 met the inclusion criteria. The cluster analysis excluded 34 unclassifiable cases. Patients with type 1 dyspepsia (cluster one) presented improvement after treatment in 100% of cases, only a minority presented depressive symptoms. Patients with type 2 dyspepsia (cluster two) presented a higher probability of failure to treatment with proton pump inhibitor, suffered more frequently from sleep disorders, anxiety, depression, fibromyalgia, physical limitations or chronic pain of a non-digestive nature. This classification of dyspepsia by cluster analysis establishes a more holistic vision of dyspepsia in which extradigestive characteristics, affective symptoms, presence or absence of sleep disorders and chronic pain allow discriminating behavior and response to first-line management.

Demographic and Clinical Characteristics of Mpox in Persons Who Had Previously Received 1 Dose of JYNNEOS Vaccine and in Unvaccinated Persons - 29 U.S. Jurisdictions, May 22-September 3, 2022.

As of November 14, 2022, monkeypox (mpox) cases had been reported from more than 110 countries, including 29,133 cases in the United States.* Among U.S. cases to date, 95% have occurred among males (1). After the first confirmed U.S. mpox case on May 17, 2022, limited supplies of JYNNEOS vaccine (Modified Vaccinia Ankara vaccine, Bavarian Nordic) were made available to jurisdictions for persons exposed to mpox. JYNNEOS vaccine was approved by the Food and Drug Administration (FDA) in 2019 as a 2-dose series (0.5 mL per dose, administered subcutaneously) to prevent smallpox and mpox disease.† On August 9, 2022, FDA issued an emergency use authorization to allow administration of JYNNEOS vaccine by intradermal injection (0.1 mL per dose) (2). A previous report on U.S. mpox cases during July 31-September 3, 2022, suggested that 1 dose of vaccine offers some protection against mpox (3). This report describes demographic and clinical characteristics of cases occurring ≥14 days after receipt of 1 dose of JYNNEOS vaccine and compares them with characteristics of cases among unvaccinated persons with mpox and with the vaccine-eligible vaccinated population in participating jurisdictions. During May 22-September 3, 2022, among 14,504 mpox cases reported from 29 participating U.S. jurisdictions,§ 6,605 (45.5%) had available vaccination information and were included in the analysis. Among included cases, 276 (4.2%) were among persons who had received 1 dose of vaccine ≥14 days before illness onset. Mpox cases that occurred in these vaccinated persons were associated with lower percentage of hospitalization (2.1% versus 7.5%), fever, headache, malaise, myalgia, and chills, compared with cases in unvaccinated persons. Although 1 dose of JYNNEOS vaccine offers some protection from disease, mpox infection can occur after receipt of 1 dose, and the duration of protection conferred by 1 dose is unknown. Providers and public health officials should therefore encourage persons at risk for acquiring mpox to complete the 2-dose vaccination series and provide guidance and education regarding nonvaccine-related prevention strategies (4).

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

A brief guide to the science and art of writing manuscripts in biomedicine.

Publishing articles in international scientific journals is the primary method for the communication of validated research findings and ideas. Journal articles are commonly used as a major input for evaluations of researchers and institutions. Few articles have been published previously about the different aspects needed for writing high-quality articles. In this manuscript, we provide an updated and brief guide for the multiple dimensions needed for writing manuscripts in the health and biological sciences, from current, international and interdisciplinary perspectives and from our expertise as authors, peer reviewers and editors. We provide key suggestions for writing major sections of the manuscript (e.g. title, abstract, introduction, methods, results and discussion), for submitting the manuscript and bring an overview of the peer review process and  of the post-publication impact of the articles.

Predatory journals: Do not judge journals by their Editorial Board Members.

Objective: Given that often the quality of journals is based on its editors, the objective of this study was to describe quantitatively the profiles of members of editorial boards (MEBs) of presumed predatory journals. Methods: The following information was retrieved from 1015 editors taken from journals listed in Beall's list: country, university, position, and degree. The Scopus website was used to identify the number of citations, documents, and h-index. Results: Presumed open access predatory journals are including all types of profiles as their MEBs, which include fake and unqualified editors, but mostly very high-qualified scientists who are professors, medical doctors and/or had a PhD. MEBs were located in 74 different countries, most had an affiliation in the United States of America (USA) (44.4%). The median of publications per editor was 43, number of citations 664 and h-index 14. Conclusions: The results dispute the common belief that it is possible to identify predatory journals by checking their editorial boards. Scientists should not rely on the editors to determine if a journal is predatory. If an author has doubt, the editors should be contacted.

Personality traits and health-related quality of life: the mediator role of coping strategies and psychological distress.

BACKGROUND: The study of health-related quality of life (HRQOL) is an important topic in mental health around the globe. However, there is the need for more evidence about the cumulative influence of psychological variables on HRQOL. The main aim of the study was to evaluate how specific personality traits might explain scores in HRQOL and to explore how this relationship might be mediated by coping styles and psychological distress. METHODS: Young Colombian subjects (N = 274) were included (mean age: 21.3; SD = 3.8). The Short-Form Health Survey was used to measure HRQOL. For assessment of psychological variables, the Hospital Anxiety and Depression Scale, the Zung Self-Rating Anxiety Scale, The Coping Inventory for Stressful Situations and the short version of Big Five Inventory were used. RESULTS: The personality trait that was the best predictor of HRQOL was openness to experience, forming an explanatory model for HRQOL, along with emotional coping style and depressive and anxious symptoms. Emotional coping style and psychological distress were significant mediators of the relationship between openness and HRQOL. CONCLUSIONS: Our findings provide additional data about the cumulative influence of specific psychological variables on HRQOL, in a mostly young female Latin American sample.

Population-Based Study of Tobacco Use Among People Living With HIV in Puerto Rico.

BACKGROUND: Despite substantial advances in the era of highly active antiretroviral therapy, HIV-positive persons are at high risk of tobacco-related disease and mortality. This study describes the prevalence and sociodemographic factors associated with current tobacco use among HIV-positive men and women 18 years and older receiving HIV care in Puerto Rico. METHODS: Data from the 2009 Medical Monitoring Project (MMP) was used. A three-stage sampling design was conducted to obtain annual cross-sectional probability samples of HIV-infected adults in care. Factors associated with current tobacco use were identified using logistic regression models. All analyses were performed using STATA version 11.0. RESULTS: The estimated prevalence of current cigarette use among the population was 29.0% (95%CI: 23.5%-35.2%), daily smoking was reported in 76.7% of them. Multivariate logistic regression models, showed that male drug users (injected and noninjected) were up to nine times more likely to be current smokers (OR = 9.9; 95%CI = 3.1, 31.5) as compared to nonusers. CONCLUSION: Findings highlight the need for smoking cessation strategies in this population, particularly among male HIV+ drug users.

Rural and urban injection drug use in Puerto Rico: Network implications for human immunodeficiency virus and hepatitis C virus infection.

Understanding the short- and long-term transmission dynamics of blood-borne illnesses in network contexts represents an important public health priority for people who inject drugs and the general population that surrounds them. The purpose of this article is to compare the risk networks of urban and rural people who inject drugs in Puerto Rico. In the current study, network characteristics are drawn from the sampling "trees" used to recruit participants to the study. We found that injection frequency is the only factor significantly related to clustering behavior among both urban and rural people who inject drugs.

APOE gene and neuropsychiatric disorders and endophenotypes: A comprehensive review.

The Apolipoprotein E (APOE) gene is one of the main candidates in neuropsychiatric genetics, with hundreds of studies carried out in order to explore the possible role of polymorphisms in the APOE gene in a large number of neurological diseases, psychiatric disorders, and related endophenotypes. In the current article, we provide a comprehensive review of the structural and functional aspects of the APOE gene and its relationship with brain disorders. Evidence from genome-wide association studies and meta-analyses shows that the APOE gene has been significantly associated with several neurodegenerative disorders. Cellular and animal models show growing evidence of the key role of APOE in mechanisms of brain plasticity and behavior. Future analyses of the APOE gene might find a possible role in other neurological diseases and psychiatric disorders and related endophenotypes. © 2016 Wiley Periodicals, Inc.

Cardiovascular safety of vildagliptin in patients with type 2 diabetes: A European multi-database, non-interventional post-authorization safety study.

The aim of this non-interventional, multi-database, analytical cohort study was to assess the cardiovascular (CV) safety of vildagliptin vs other non-insulin antidiabetic drugs (NIADs) using real-world data from 5 European electronic healthcare databases. Patients with type 2 diabetes aged ≥18 years on NIAD treatment were enrolled. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the outcomes of interest (myocardial infarction [MI], acute coronary syndrome [ACS], stroke, congestive heart failure [CHF], individually and as a composite) were estimated using negative binomial regression. Approximately 2.8% of the enrolled patients (n = 738 054) used vildagliptin at any time during the study, with an average follow-up time of 1.4 years, resulting in a cumulative current vildagliptin exposure of 28 330 person-years. The adjusted IRRs (vildagliptin [±other NIADs] vs other NIADs) were in the range of 0.61 to 0.97 (MI), 0.55 to 1.60 (ACS), 0.02 to 0.77 (stroke), 0.49 to 1.03 (CHF), and 0.22 to 1.02 (composite CV outcomes). The IRRs and their 95% CIs were close to 1, demonstrating no increased risk of adverse CV events, including the risk of CHF, with vildagliptin vs other NIADs in real-world conditions.

The structural and health policy environment for delivering integrated HIV and substance use disorder treatments in Puerto Rico.

BACKGROUND: HIV prevalence in Puerto Rico is nearly twice that of the mainland United States, a level that was substantially fueled by injection drug use. Puerto Rico has a longstanding history of health provision by the public sector that directly affects how HIV and substance use disorder (SUD) treatment services are provided and funded. As part of pre-implementation research for a randomized trial of a community-level intervention to enhance HIV care access for substance users in San Juan, Puerto Rico, we sought to understand the structural and health policy environment for providing HIV and SUD treatments. METHODS: We conducted semi-structured qualitative interviews (n = 8) with government and program administrators in English and Spanish. Data were analyzed to identify dominant and recurrent themes. RESULTS: Participants discussed how lack of integration among medical and mental health service providers, lack of public transportation, and turnover in appointed government officials were barriers to integrated HIV and SUD treatment. Federal funding for support services for HIV patients was a facilitator. The Affordable Care Act has limited impact in Puerto Rico because provisions related to health insurance reform do not apply to U.S. territories. DISCUSSION AND CONCLUSIONS: Implications for intervention design include the need to provide care coordination for services from multiple providers, who are often physically separated and working in different reimbursement systems, and the potential for mobile and patient transportation services to bridge these gaps. Continuous interaction with political leaders is needed to maintain current facilitators. These findings are relevant as the current economic crisis in Puerto Rico affects funding, and may be relevant for other settings with substance use-driven epidemics.

Original title: HIV infection and unawareness among men who have sex with men in Puerto Rico: data from The National HIV behavioral surveillance system 2011-2014.

BACKGROUND: Unawareness of HIV infection is a public health challenge that needs to be addressed, particularly in the case of men who have sex with men (MSM), since recent data are reporting increasing rates of HIV in this population in Puerto Rico. OBJECTIVES: We examined differences in the prevalence of HIV infection and unawareness among MSM in 2011 and 2014 using data from the National HIV Behavioral Surveillance System, 2011 and 2014. METHODS: Bivariate analyses was used to compare demographical and behavioral characteristics in both cycles (2011 and 2014). Prevalence ratio (PR) was assessed with Poisson regression models to determine changes in HIV prevalence and unawareness across cycles, using the 2011 NHBS-MSM cycle as reference group. RESULTS: A stable rate in HIV prevalence was observed in 2011 and 2014. There was a higher prevalence in 2014 than in 2011 in multiple behavioral characteristics such as age at sexual initiation, the number of sexual partners in the 12 months prior to being interviewed, HIV testing in the year prior to being interview, and the disclosure of sexual orientation to a healthcare provider. A significant decrease in HIV unawareness was reported (76.67%, 2011; 46.51%, 2014). Age-adjusted regression models showed a marginal reduction of 55% in HIV unawareness for men who disclosed their sexual orientation to their healthcare providers. CONCLUSION: Behavioral surveillance systems in groups such as MSM in on the island will aid to monitor prospectively the effectiveness of HIV testing outreach and engagement, as well as capacity capacity-building strategies targeted towards health care providers, aimed to increase HIV testing and awareness among this group.

Mortality Disparities among HIV+ Men and Women in Puerto Rico: Data from the HIV/AIDS Surveillance System 2003-2014.

OBJECTIVE: Describe the trend of the indirect standardized death rate of HIV for different modes of HIV transmission from 2003 to 2014 in Puerto Rico. Estimate the magnitude of the association between mode of HIV transmission and mortality at different time periods in Puerto Rico. METHODS: ISDRs by sex and mode of transmission were computed using data from the PR National HIV/AIDS Surveillance System (2003-2014). Poisson models were used to assess the annual percent change of the ISDRs and RRs by sex. RESULTS: Injection drug users (IDUs) showed the highest decrease in ISDR (-10.56, for men; -9.32 for women). Compared to men who have sex with men (MSM), IDU men also had the highest RR, representing an increase of 93% (2009-2011) (RRIDU vs MSM: 1.93, 95% CI: 1.66-2.23). Compared to women who were IDUs, heterosexual (HET) women had less risk of dying (48% for the period of 2006 to 2008). CONCLUSION: Mortality has been decreasing in each mode of transmission for both sexes. In addition, though IDUs present the highest decrease of ISDR, it is still the group whose members have the highest risk of dying, both men and women. To better describe health disparities as related to HIV/AIDS mortality, future analyses should be performed using specific causes of death and the evaluation of other relevant clinical and sociodemographic factors. Such data might increase our understanding of mortality in people with HIV/AIDS on the island, as well as help in future efforts to develop intervention strategies for the aforementioned risk groups.

Factors Associated With Recent Human Immunodeficiency Virus Testing Among Men Who Have Sex With Men in Puerto Rico, National Human Immunodeficiency Virus Behavioral Surveillance System, 2011.

BACKGROUND: Annual human immunodeficiency virus (HIV) testing is considered a key strategy for HIV prevention for men who have sex with men (MSM). In Puerto Rico, HIV research has primarily focused on injection drug use, yet male-to-male sexual transmission has been increasing in recent years. METHODS: Cross-sectional data from the National HIV Behavioral Surveillance system collected in 2011 in San Juan, Puerto Rico, were analyzed to identify factors associated with HIV testing in the past 12 months (recent testing). RESULTS: Overall, 50% of participants were tested recently. In the multivariate analysis, testing recently was associated with having multiple partners in the past 12 months (adjusted prevalence ratio [aPR] [≥4 vs 1 partner] = 1.5; 95% confidence interval [95% CI], 1.2-2.0), visiting a health care provider in the past 12 months (aPR, 1.4; 95% CI, 1.04-1.8), and disclosing male-male attraction/sex to a health care provider (aPR< 1.4; 95% CI, 1.1-1.7). CONCLUSIONS: Human immunodeficiency virus testing was suboptimal among MSM in San Juan. Strategies to increase HIV testing among MSM may include promoting HIV testing for all sexually active MSM including those with fewer partners, increasing utilization of the healthcare system, and improving patient-provider communication.

[Assessment of adherence to antihypertensive therapy]. / Prevalencia y determinantes de adherencia a terapia antihipertensiva en pacientes de la Región Metropolitana.

BACKGROUND: Lack of adherence with medications is the main cause of antihypertensive treatment failure. AIM: To assess adherence to antihypertensive drugs and its determinants. MATERIAL AND METHODS: The Morinsky-Green questionnaire to determine treatment adherence was applied to 310 hypertensive patients from primary care centers, aged 60 ± 10 years (65% females) in treatment for 4 ± 1 months. Socio-demographic features, use of medications and quality of life using EQ5D questionnaire were also assessed. RESULTS: Twenty percent of patients were diabetic and 19% were smokers. Fifty four percent were adherent to therapy. A higher age and being unemployed were associated with a higher compliance. The main reasons to justify the lack of adherence were forgetting to take the pills in 67% and adverse effects in 10%. Only diastolic pressure was lower in adherent patients, compared with their non-adherent counterparts (78 ± 12 and 81 ± 17 mmHg, respectively p < 0.01). CONCLUSIONS: Only half of hypertensive patients comply with their antihypertensive therapy.