Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

Sedentary behavior and risk of cardiovascular disease and all-cause mortality in United States adults with hypertension.

BACKGROUND: Growing evidence has implicated sedentary behavior is associated with cardiovascular and all-cause mortality, independent of moderate to vigorous physical activity (MVPA). Contrary to national physical activity guidelines, reductions in sedentary behavior are not promoted as a lifestyle modification in hypertensive adults. This may be in part because of a paucity of evidence demonstrating that sedentary behavior confers morbidity and mortality risk in hypertensive adults. PURPOSE: To examine the association between device-measured sedentary behavior and risk of cardiovascular and all-cause mortality and in hypertensive adults. METHODS: Data for this analysis come from the 2003 to 2006 National Health and Nutrition Examination Survey, a nationally representative survey of US adults. Sedentary behavior and MVPA were assessed with an ActiGraph 7164 accelerometer. Hypertension was classified as blood pressure at least 140/≥90 mmHg or antihypertensive medication use. RESULTS: Median follow-up was 14.5 years. After adjusting for covariates and MVPA, greater time spent in sedentary behavior was associated with an increased risk of cardiovascular mortality [quartile 1: REF, quartile 2: hazard ratio = 1.41 [95% confidence interval (95% CI) 0.83-2.38], quartile 3: hazard ratio = 1.25 (95% CI 0.81-1.94), quartile 4: hazard ratio = 2.14 (95% CI 1.41-3.24); P trend <0.001]. Greater sedentary behavior was also associated with an increased risk of all-cause mortality [quartile 1: REF: quartile 2: hazard ratio = 1.13 (95% CI 0.83-1.52), quartile 3: hazard ratio = 1.33 (95% CI 1.00-1.78), quartile 4: hazard ratio = 2.06 (95% CI 1.60, 2.64); P trend <0.001]. CONCLUSION: Greater sedentary behavior is associated with increased risk of cardiovascular mortality and all-cause mortality among US adults with hypertension. These findings suggest reductions in sedentary behavior should be considered to reduce mortality risk in hypertensive adults.

Impact of Native Language, English Proficiency, and Language Concordance on Interpersonal Care During Evaluation of Acute Coronary Syndrome.

BACKGROUND: High-quality interpersonal interactions between clinicians and patients can improve communication and reduce health disparities among patients with novice English proficiency (NEP). Yet, little is known about the impact of native language, NEP, and native language concordance on patient on perceptions of interpersonal care in the emergency department (ED). OBJECTIVE: To determine the associations of native language, NEP, and native language concordance with patient perceptions of interpersonal care among patients undergoing evaluation for suspected acute coronary syndrome (ACS) in the ED. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 1000 patients undergoing evaluation for suspected ACS at an urban ED from 2013 to 2016. MAIN MEASURES: English- and Spanish-speaking patients were surveyed to identify native language, English proficiency (classified as advanced, intermediate, or novice), and perceived language of the treating ED clinician. Patient perceptions of interpersonal care were assessed using the Interpersonal Processes of Care (IPC) survey, a validated 18-item tool for assessing social-psychological domains of patient-clinician interactions. IPC scores ≤ 4 were categorized as sub-optimal (range, 1-5). The associations between native language, English proficiency, and native language concordance with sub-optimal communication were assessed using hierarchical logistic regression adjusted for all three language variables, sociodemographic characteristics, and depression. KEY RESULTS: Nine hundred thirty-three patients (48.0% native non-English-speaking, 55.7% Hispanic) completed the IPC; 522 (57.4%) perceived native language concordance. In unadjusted analyses, non-English native language (OR 1.38, 95% CI 1.04-1.82) and NEP (OR 1.45, 95% CI 1.06-1.98) were associated with sub-optimal communication, whereas language concordance was protective (OR 0.61, 95% CI 0.46-0.81). In fully adjusted analyses, only language concordance remained significantly associated with sub-optimal communication (AOR 0.62, 95% CI 0.42-0.93). CONCLUSIONS: This study suggests that perceived native language concordance acts as a protective factor for patient-clinician interpersonal care in the acute setting, regardless of native language or English proficiency.

Molecular examination of the endogenous opioid system in rhesus macaque monkeys with self-injurious behavior.

Self-injurious behavior (SIB) can lead to serious injury and occurs in approximately 1%-4% of the adult population, with higher incidences in adolescent and institutionalized populations, as well as in children with developmental disorders such as Autism. SIB also spontaneously occurs in a low percentage of captive monkeys. Rhesus macaque (Macaca mulatta) monkeys are evolutionarily and physiologically similar to humans, share 93% genetic sequence similarity to humans, and have long been used as testing subjects for vaccine and clinical trials. Previous studies hypothesized that altered endogenous opioid expression occurs in the brains of individuals and animals that self-injure. We examined the regional mRNA expression of opioid signaling genes in sixteen rhesus macaques that exhibited SIB and eight sex- and age- matched controls. The brain regions examined are linked to reward reinforcement and stress adaptation including the hypothalamus, orbital frontal cortex, nucleus accumbens, hippocampus, caudate, and the amygdala. We found decreased µ-opioid receptor (OPRM1) in the amygdala of monkeys with SIB, and reduced prodynorphin (PDYN) in the hypothalamus. Our data suggest dysfunction in the regulation of opioid peptide precursors and calls for further investigation of the endogenous opioid system in SIB.

Anestesia total intravenosa libre de opioides guiada por qCON y qNOX en paciente obesa / Total Intravenous anesthesia in patients with intestinal occlusive syndrome

Introducción: En los últimos años la anestesia libre de opioides ha constituido una alternativa más a las técnicas tradicionales de anestesia general. Con la exclusión de este grupo de fármacos se evitan los múltiples efectos adversos y complicaciones asociados al mismo. A pesar de que la anestesia libre de opioides tiene sus indicaciones y que ha demostrado sus beneficios en cierto grupo de pacientes, existen aún controversias en relación con su utilidad en el paciente obeso. Características como la obesidad hacen que los modelos multimodales empleados para programar la anestesia libre de opioides sean cada vez más complejos. Objetivos: Describir un caso clínico realizado con la técnica de anestesia libre de opioides que constituye la primera experiencia en Ecuador. Presentación del caso: Se presenta el caso de una paciente obesa intervenida de colecistectomía laparoscópica mediante infusión de propofol, ketamina, lidocaína, sulfato de magnesio, y dexmedetomidina. La titulación de estos fármacos se realizó mediante cálculo de concentraciones plasmáticas a través de modelos farmacocinéticos y guiada por monitorización de profundidad anestésica y analgésica, con lo cual se logró optimizar el consumo de fármacos, disminuir las complicaciones y una evolución clínica favorable. Hasta donde se conoce a nivel local y de país (Ecuador) es la primera experiencia que se reporta con esta técnica. Conclusiones: La anestesia libre de opioides puede resultar una elección en el paciente obeso ya que asegura una adecuada recuperación sin efectos adversos asociados(AU)

Introduction: In recent years, opioid-free anesthesia has become another alternative in front of traditional general anesthesia techniques. The exclusion of this group of drugs avoids the numerous adverse effects and complications associated with its usage. Although opioid-free anesthesia has its indications and has showed its benefits in a certain group of patients, there is still controversy regarding its usefulness in the obese patient. Characteristics such as obesity make the multimodal models used to program opioid-free anesthesia increasingly complex. Objectives: To describe a clinical case involving the opioid-free anesthesia technique, which is the first experience in Ecuador. Case presentation: The case is presented of a female obese patient who underwent laparoscopic cholecystectomy by infusion of propofol, ketamine, lidocaine, magnesium sulfate and dexmedetomidine. Titration of these drugs was carried out by calculating plasma concentrations through pharmacokinetic models and guided by monitoring of anesthetic and analgesic depth, thus optimizing drug consumption, reducing complications and achieving a favorable clinical evolution. As far as known locally and in the country (Ecuador), this is the first reported experience with this technique. Conclusions: Opioid-free anesthesia may be a choice in the obese patient, since it ensures adequate recovery without associated adverse effects(AU)

COVID-19 Vaccine Uptake and Factors Associated With Being Unvaccinated Among Lesbian, Gay, Bisexual, Transgender, Queer, and Other Sexual Identities (LGBTQ+) New Yorkers.

Routine data on vaccine uptake are not disaggregated by lesbian, gay, bisexual, transgender, queer, and other sexual identities (LGBTQ+) populations, despite higher risk of infection and severe disease. We found comparable vaccination uptake patterns among 1032 LGBTQ+ New Yorkers and the general population. We identified critical socioeconomic factors that were associated with vaccine hesitancy in this economically vulnerable population.

Is Sedentary Behavior a Novel Risk Factor for Cardiovascular Disease?

PURPOSE OF REVIEW: Review the most recent evidence on the role of sedentary behavior in the prevention of cardiovascular disease (CVD). RECENT FINDINGS: Prospective cohort studies continue to suggest a relationship between sedentary behavior and CVD, but the dose-response association, and the implications of sedentary pattern (vs. total volume) and context on CVD risk require further investigation. Most recent evidence suggests that physical activity influences the association between sedentary time and CVD risk, and that replacing sedentary time with other movement behaviors yields cardiometabolic benefits. Short-term intervention studies have further demonstrated that interrupting prolonged sitting with bouts of physical activity can elicit acute improvements on cardiometabolic biomarkers and vascular function relative to prolonged, uninterrupted sitting, albeit limited evidence exists on the long-term effects. More conclusive evidence regarding the implications of sedentary time on CVD risk is warranted before the optimal sedentary behavior reduction prescription for the prevention of CVD can be elucidated.

Association of Hispanic ethnicity and linguistic acculturation with cardiovascular medication adherence in patients with suspected acute coronary syndrome.

Despite a higher prevalence of cardiovascular disease (CVD) risk factors, Hispanic-Americans have lower rates of CVD-related and all-cause mortality, as well as higher life expectancy than non-Hispanic whites - a phenomenon known as the Hispanic health paradox. However, this survival benefit attenuates with increased acculturation to Western lifestyles, potentially due to adoption of unhealthy behaviors. Accordingly, we assessed whether Hispanic ethnicity and linguistic acculturation, as measured by English proficiency, were associated with nonadherence to cardiovascular medications. We enrolled patients presenting to an academic medical center emergency department with suspected acute coronary syndrome between May 2014 and November 2017. Ethnicity, native language, and English proficiency were self-reported. Cardiovascular medication adherence was assessed using an electronic pill bottle that recorded the date and time of each bottle opening. Generalized linear models with a logit link were used to examine the association of Hispanic ethnicity and English proficiency with daily cardiovascular medication adherence, adjusting for demographics, comorbidities, and dosing frequency of the electronically-monitored medication. Among 332 included patients, mean age was 61.68 ± 12.05 years, 43.07% were women, and 62.95% were Hispanic, of whom 80.38% were native Spanish-speakers. Overall, Hispanics had higher odds of medication adherence than non-Hispanics (adjusted OR 1.31, 95% CI 1.16-1.49, p < 0.001). However, among native Spanish-speaking Hispanics, greater English proficiency was associated with lower odds of medication adherence (adjusted OR 0.80 per 1-point increase in English proficiency, 95% CI 0.75-0.86, p < 0.001). Although Hispanics had better medication adherence than non-Hispanics overall, increased linguistic acculturation among native Spanish-speakers was associated with worse adherence behaviors.

Intervening on fear after acute cardiac events: Rationale and design of the INFORM randomized clinical trial.

OBJECTIVE: Many acute coronary syndrome (ACS) patients are nonadherent to cardiovascular medications despite their known benefits for lowering risk of recurrent cardiovascular events. Research suggests that greater cardiac-related fear of recurrence (FoR) may be associated with higher nonadherence to cardiovascular medications and avoidance of physical activity. We aim to test the effect of an intervention that targets FoR as a potentially modifiable mechanism underlying nonadherence to recommended health behaviors among patients with suspected ACS. METHOD: The INFORM trial ("INvestigating Fear Of Recurrence as a modifiable Mechanism of behavior change to improve medication adherence in acute coronary syndrome patients") is a double-blind, parallel-group randomized clinical trial. It compares an 8-session, at-home, electronic tablet-delivered, cognitive bias modification training (CBMT) intervention with a sham control. Patients who experience high perceived threat at the time of presentation to the emergency department (ED) with a suspected ACS are enrolled and randomized within 6 weeks of their ED visit. The primary outcome, FoR, is measured by the adapted Concerns about Recurrent ACS Scale. The trial also tests the intervention's effect on a potential mechanism of health behavior change that is inversely correlated with fear: an expansive future time perspective. Additional outcomes include electronically measured adherence to a cardiovascular medication and self-reported physical activity. CONCLUSIONS: This study takes a mechanistic approach to addressing the dangerous problem of poor health behaviors after ACS. The trial will test whether targeting FoR or future time perspective by CBMT is a promising approach to improving nonadherence after ACS. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Short Sleep Duration After Hospital Evaluation for Acute Coronary Syndrome Is Associated With Increased Risk of 6-Month Readmission.

OBJECTIVE: Hospital readmission after acute coronary syndrome (ACS) is associated with worsened patient outcomes and financial burden. Short sleep duration is a risk factor for cardiovascular events and may therefore represent a behavioral factor that increases risk of adverse posthospitalization outcomes. This study examined whether short sleep duration in the month after hospital evaluation for ACS is associated with 6-month all-cause emergency department (ED) and hospital readmission. METHODS: The current analyses entail a secondary analysis of a larger prospective observational cohort study. Sleep duration during the month after hospital evaluation for ACS was assessed subjectively and dichotomized as short (<6 hours) or not short (≥6 hours). A Cox proportional hazards model was used to assess the association between short sleep duration during the month after ACS hospital evaluation and 6-month all-cause ED/hospital readmission. RESULTS: A total of 576 participants with complete data were included in analyses. Approximately 34% of participants reported short sleep duration during the month after ACS evaluation. Short sleep duration was significantly associated with 6-month all-cause ED/hospital readmission (hazard ratio = 2.03; 95% confidence interval = 1.12-3.66) in the model adjusted for age, sex, race/ethnicity, clinical severity, cardiac and renal markers, depression, acute stress, and including a sleep duration by ACS status interaction. CONCLUSIONS: Short sleep duration after ACS hospital evaluation is prevalent and is associated with increased risk of all-cause readmission within 6 months of discharge. Current findings suggest that short sleep duration is an important modifiable behavioral factor to consider after hospital evaluation for ACS.

Task-switching inefficiencies in currently ill, but not remitted anorexia nervosa.

OBJECTIVE: Models of anorexia nervosa (AN) posit that set-shifting deficits may contribute to behavioral inflexibility and extreme dietary restriction. Findings from neurocognitive studies of set-shifting in AN have been somewhat mixed, perhaps due to the use of tasks that cannot distinguish shifting from other processes (i.e., learning). To more precisely characterize cognitive flexibility and selectively assess this process independent of rule learning and feedback sensitivity, we examined task-switching ability in AN. METHOD: Women ill with AN, subthreshold AN or atypical AN (IAN; n = 40), women remitted from AN (RAN; n = 24), and age-matched healthy control women (n = 42) completed a computerized cued color-shape task-switching paradigm. Groups were compared on mix costs (reflecting global cognitive control) and switch costs (reflecting transient cognitive control). RESULTS: Although mix costs were equivalent across groups, switch costs were more pronounced in the IAN group, as indicated by a group-by-trial type interaction for reaction times on stay and switch trials. DISCUSSION: Findings indicate that IAN, but not RAN, have difficulty flexibly switching between cognitive task sets, and suggest that prior findings of set-shifting deficits in AN may reflect difficulty with cognitive flexibility independent of learning deficits. As such, task-switching may represent a promising adjunctive treatment target.

Endogenous Specialized Proresolving Mediator Profiles in a Novel Experimental Model of Lymphatic Obstruction and Intestinal Inflammation in African Green Monkeys.

Changes in the intestinal lymphatic vascular system, such as lymphatic obstruction, are characteristic features of inflammatory bowel diseases. The lymphatic vasculature forms a conduit to enable resolution of inflammation; this process is driven by specialized endogenous proresolving mediators (SPMs). To evaluate contributions of lymphatic obstruction to intestinal inflammation and to study profiles of SPMs, we generated a novel animal model of lymphatic obstruction using African green monkeys. Follow-up studies were performed at 7, 21, and 61 days. Inflammation was determined by histology. Luminex assays were performed to evaluate chemokine and cytokine levels. In addition, lipid mediator metabololipidomic profiling was performed to identify SPMs. After 7 days, lymphatic obstruction resulted in a localized inflammatory state, paralleled by an increase in inflammatory chemokines and cytokines, which were found to be up-regulated after 7 days but returned to baseline after 21 and 61 days. At the same time, a distinct pattern of SPMs was profiled, with an increase for D-series resolvins, protectins, maresins, and lipoxins at 61 days. These results indicate that intestinal lymphatic obstruction can lead to an acute inflammatory state, accompanied by an increase in proinflammatory mediators, followed by a phase of resolution, paralleled by an increase and decrease of respective SPMs.

Identifying targets for cardiovascular medication adherence interventions through latent class analysis.

OBJECTIVE: Reasons for nonadherence to cardiovascular medications vary widely between individuals. Yet, adherence interventions are often uniformly applied, limiting their effectiveness. This study employed latent class analysis (LCA) to identify multidimensional profiles of reasons for nonadherence to cardiovascular medications. METHOD: Participants (N = 137; MAge = 58.8, SDAge = 11.8) were drawn from an observational study of the impact of cardiac-induced posttraumatic stress disorder (PTSD) on cardiac medication adherence in patients presenting to the emergency department with a suspected acute coronary syndrome. Demographics and depressive symptoms were assessed at baseline. Extent of nonadherence to cardiovascular medications, reasons for nonadherence, and PTSD symptoms were assessed 1 month after discharge. RESULTS: LCA identified 3 classes of reasons for medication nonadherence: capacity (related to routine or forgetting; approximately 45% of the sample), capacity + motivation (related to routine/forgetting plus informational or psychological barriers; approximately 14% of the sample), and no clear reasons (low probability of endorsing any items; approximately 41% of the sample). Participants reporting greater nonadherence were more likely to be in the capacity + motivation or no clear reasons classes compared with the capacity class. Participants endorsing higher PTSD severity were more likely to be in the capacity + motivation or capacity classes compared with the no clear reasons class. CONCLUSIONS: Three distinct classes of reasons for nonadherence were identified, suggesting opportunities for tailored interventions: capacity, capacity + motivation, and no clear reasons. These preliminary findings, if replicated, could aid identification of patients at risk for greater extent of medication nonadherence and inform tailored interventions to improve adherence. (PsycINFO Database Record (c) 2018 APA, all rights reserved).