Characterization of basal ganglia volume changes in the context of HIV and polysubstance use

HIV and psychoactive substances can impact the integrity of the basal ganglia (BG), a neural substrate of cognition, motor control, and reward-seeking behaviors. This study assessed BG gray matter (GM) volume as a function of polysubstance (stimulant and opioid) use and HIV status. We hypothesized that comorbid polysubstance use and HIV seropositivity would alter BG GM volume differently than would polysubstance use or HIV status alone. We collected structural MRI scans, substance use history, and HIV diagnoses. Participants who had HIV (HIV +), a history of polysubstance dependence (POLY +), both, or neither completed assessments for cognition, motor function, and risk-taking behaviors (N = 93). All three clinical groups showed a left-lateralized pattern of GM reduction in the BG relative to controls. However, in the HIV + /POLY + group, stimulant use was associated with increased GM volume within the globus pallidus and putamen. This surpassed the effects from opioid use, as indicated by decreased GM volume throughout the BG in the HIV-/POLY + group. Motor learning was impaired in all three clinical groups, and in the HIV + /POLY + group, motor learning was associated with increased caudate and putamen GM volume. We also observed associations between BG GM volume and risk-taking behaviors in the HIV + /POLY- and HIV-/POLY + groups. The effects of substance use on the BG differed as a function of substance type used, HIV seropositivity, and BG subregion. Although BG volume decreased in association with HIV and opioid use, stimulants can, inversely, lead to BG volume increases within the context of HIV

Emergency Medicine Clinician Experiences Addressing Uncertainty in First-Trimester Bleeding.

The purpose of this work is to understand Emergency Department (ED) clinicians\u27 experiences in communicating uncertainty about first-trimester bleeding (FTB) and their need for training on this topic. This cross-sectional study surveyed a national sample of attending physicians and advanced practice providers (APPs). The survey included quantitative and qualitative questions about communicating with patients presenting with FTB. These questions assessed clinicians\u27 frequency encountering challenges, comfort, training, prior experience, and interest in training on the topic. Of 402 respondents, 54% reported that they encountered challenges at least sometimes when discussing FTB with patients where the pregnancy outcome is uncertain. While the majority (84%) were at least somewhat prepared for these conversations from their training, which commonly addressed the diagnostic approach to this scenario, 39% strongly or moderately agreed that they could benefit from training on the topic. Because the majority of ED clinicians identified at least sometimes encountering challenges communicating with pregnant patients about FTB, our study indicates a need exists for more training in this skill

A Prioritized Patient-Centered Research Agenda to Reduce Disparities in Telehealth Uptake: Results from a National Consensus Conference

Introduction: We hosted a national consensus conference with a diverse group of stakeholders to develop a patient-centered research agenda focused on reducing disparities in telehealth use. Methods: Attendees were purposively invited to participate in a 2-day virtual conference. The group developed a prioritized research agenda focused on reducing disparities in telehealth uptake, with discussion informed by findings from a scoping review. All work was conducted in partnership with a Steering Committee of national experts in telehealth and patient-centered care (n = 5) and a community-based Telehealth Advisory Board with experience with telehealth use and barriers (n = 8). Results: Sixty individuals participated in the conference and discussion resulted in a final list of 20 questions. Fifty-two attendees voted on the final prioritization of these questions. Results were aggregated for all voters (n = 52) and patient-only voters (n = 8). The top question identified by both groups focused on patient and family perspectives on important barriers to telehealth use. The entire group voting identified telehealth’s impact on patient outcomes as the next most important questions, while the patient-only group identified trust-related considerations and cultural factors impacting telehealth use as next priorities. Conclusions: This project involved extensive patient and stakeholder engagement. While voting varied between patients only and the entire group of conference attendees, top identified priorities included patient and family perspectives on important barriers to telehealth, trust and cultural barriers and facilitators to telehealth, and assessment of telehealth’s impact on patient outcomes. This research agenda can inform design of future research focused on addressing disparities in telehealth use

Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

© The Author 2014. Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylomeis sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is alsowarranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure

Inducible Costimulator Expression Regulates the Magnitude of Th2-Mediated Airway Inflammation by Regulating the Number of Th2 Cells

Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS+/+ and ICOS+/- mice in a Th2 model of airway inflammation, we found that T cells from the ICOS+/- mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS+/- mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS+/- is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation

A Prioritized Patient-Centered Research Agenda to Reduce Disparities in Telehealth Uptake: Results from a National Consensus Conference

Introduction: We hosted a national consensus conference with a diverse group of stakeholders to develop a patient-centered research agenda focused on reducing disparities in telehealth use. Methods: Attendees were purposively invited to participate in a 2-day virtual conference. The group developed a prioritized research agenda focused on reducing disparities in telehealth uptake, with discussion informed by findings from a scoping review. All work was conducted in partnership with a Steering Committee of national experts in telehealth and patient-centered care (n?=?5) and a community-based Telehealth Advisory Board with experience with telehealth use and barriers (n?=?8). Results: Sixty individuals participated in the conference and discussion resulted in a final list of 20 questions. Fifty-two attendees voted on the final prioritization of these questions. Results were aggregated for all voters (n?=?52) and patient-only voters (n?=?8). The top question identified by both groups focused on patient and family perspectives on important barriers to telehealth use. The entire group voting identified telehealth's impact on patient outcomes as the next most important questions, while the patient-only group identified trust-related considerations and cultural factors impacting telehealth use as next priorities. Conclusions: This project involved extensive patient and stakeholder engagement. While voting varied between patients only and the entire group of conference attendees, top identified priorities included patient and family perspectives on important barriers to telehealth, trust and cultural barriers and facilitators to telehealth, and assessment of telehealth's impact on patient outcomes. This research agenda can inform design of future research focused on addressing disparities in telehealth use

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study—Observational Study

BackgroundCardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia.ObjectivesThe clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study.MethodsOf 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model.ResultsUC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11).ConclusionsLong-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome

Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study—Observational Study

BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study – Observational Study (FATS-OS). METHODS: Of 175 CAD subjects with mean LDL-C of 191 mg/dl and mean age of 50 years, who completed the randomized and placebo-controlled FATS, 100 choose receiving lipid management by their physicians (UC) and 75 elected to receive an intensive lipid therapy (IT) with lovastatin (40mg/day), niacin (2.5g/day) and colestipol (20g/day) from 1989 to 2004, followed by double therapy with simvastatin (40–80mg/day) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40–80 mg/day plus niacin during 2007–2012. Death from CVD, non-CVD and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more sever CAD. Mean LDL-C levels were 167 mg/dl from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119 mg/dl, 97, and 83 in the 3 time periods. Compared to UC, IT significantly reduced total mortality (11.1 vs. 26.3 per 1,000 PY, HR=0.45, 95% CI: 0.26–0.77, p=0.003) and CVD mortality (10.6 vs. 27.7 per 1,000 PY, HR=0.34, 95% CI: 0.15–0.80, p=0.009). The non-CVD mortality was also reduced, but was not of statistical significance (6.8 vs. 12.7 per 1,000 PY, HR=0.55, 95% CI: 0.27–1.14, p=0.11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in FATS-OS. These results support the importance of lifetime risk management to improve long-term outcome

Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1

BACKGROUND: The normal progression of the cell cycle requires sequential expression of cyclins. Rapid induction of cyclin D1 and its associated binding with cyclin-dependent kinases, in the presence or absence of mitogenic signals, often is considered a rate-limiting step during cell cycle progression through the G(1) phase. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, human umbilical cord blood stem cells (hUCBSC) in co-cultures with glioblastoma cells (U251 and 5310) not only induced G(0)-G(1) phase arrest, but also reduced the number of cells at S and G(2)-M phases of cell cycle. Cell cycle regulatory proteins showed decreased expression levels upon treatment with hUCBSC as revealed by Western and FACS analyses. Inhibition of cyclin D1 activity by hUCBSC treatment is sufficient to abolish the expression levels of Cdk 4, Cdk 6, cyclin B1, β-Catenin levels. Our immuno precipitation experiments present evidence that, treatment of glioma cells with hUCBSC leads to the arrest of cell-cycle progression through inactivation of both cyclin D1/Cdk 4 and cyclin D1/Cdk 6 complexes. It is observed that hUCBSC, when co-cultured with glioma cells, caused an increased G(0)-G(1) phase despite the reduction of G(0)-G(1) regulatory proteins cyclin D1 and Cdk 4. We found that this reduction of G(0)-G(1) regulatory proteins, cyclin D1 and Cdk 4 may be in part compensated by the expression of cyclin E1, when co-cultured with hUCBSC. Co-localization experiments under in vivo conditions in nude mice brain xenografts with cyclin D1 and CD81 antibodies demonstrated, decreased expression of cyclin D1 in the presence of hUCBSC. CONCLUSIONS/SIGNIFICANCE: This paper elucidates a model to regulate glioma cell cycle progression in which hUCBSC acts to control cyclin D1 induction and in concert its partner kinases, Cdk 4 and Cdk 6 by mediating cell cycle arrest at G(0)-G(1) phase