In addition to its well-established role in gamma-secretase cleavage, presenilin (PS) also plays a role in regulating the stability of cytosolic beta-catenin, a protein involved in Wnt signaling. Several familial Alzheimer's disease-associated PS1 mutations have been shown to increase the stability of the signaling pool of beta-catenin, correlating with enhanced cell proliferation. Accordingly, we hypothesized that in the setting of PS1 mutations, abnormal activation of Wnt/beta-catenin signaling leads to increased cell division. We tested this hypothesis by examining whether there is evidence of increased neurogenesis in the hippocampus of adult transgenic mice that overexpress the PS1 A246E mutation. In PS1/PS2-deficient fibroblasts, expression of PS1 A246E Familial AD mutation failed to restore the rapid turnover of beta-catenin compared with wild-type PS1. We then examined whether the same mutation enhanced neurogenesis in vivo in adult hippocampus of PS1-deficient mice when restored by wild-type human PS1 (PS1(-/-)WT) or A246E PS1 mutation (PS1(-/-)AE). The PS1 A246E mutation stimulated the proliferation of progenitor cells in the dentate gyrus of adult mice, as assessed by 5-bromo-2-deoxyuridine incorporation, but did not influence their survival or differentiation. These observations suggest that the PS1 A246E mutation influences cell growth putatively via abnormal beta-catenin signaling in vivo.

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In the United States (U.S.), the HIV infection rate is disproportionately high among incarcerated individuals. HIV-infected individuals typically receive antiretroviral therapy (ART) to suppress HIV and reduce the threat of transmission. Although HIV-infected individuals are generally ART-adherent while incarcerated, the public health benefits experienced during incarceration are often lost as HIV-infected individuals struggle to maintain optimal adherence post-incarceration. While the importance of maintaining adherence in the post-incarceration period has been acknowledged, research on barriers to ART adherence during this period is limited. To better understand post-release barriers to ART adherence, we conducted in-depth interviews with 20 HIV-infected formerly incarcerated individuals in New York City; we also followed up with 18 (90%) participants after three months to explore whether their adherence challenges changed over time. Viral load testing results from their most recent physician visit were also recorded at each interview. Interviews were transcribed using transcription software and reviewed for accuracy by a researcher. Thematic coding based on discussion guide prompts were then used to identify commonly mentioned barriers to adherence. The results identified four overarching themes that affected study participants' efforts to adhere to their ART regimen: medication burden, forgetfulness, mental health and emotional difficulties, and perceived conflict between substance use and medication adherence. These barriers were the most commonly cited and largely persisted at three-month follow-up. The results suggest that interventions addressing these challenges are essential for promoting ART adherence among HIV-infected formerly incarcerated individuals. Effective interventions may include mobile-based text messaging reminders and those that facilitate patient-provider communication. Additionally, interventions or programs that integrate substance use and mental health treatment into HIV-related care, along with other types of behavioral health support, may also be beneficial for this population. Such interventions should be a routine part of discharge planning and support for incarcerated individuals returning to the community.

Background Due to the advent and success of antiretroviral therapy (ART), the number of people living and aging with HIV has grown substantially. Although PLHIV are experiencing longer life expectancies, this achievement may be undermined by increasing and disproportionate chronic disease burden among PLHIV. Methods This study is a retrospective analysis of adult (≥18 years) inpatient hospital discharges from a large hospital system in the New York City, New York metropolitan area, between January 1st, 2006 and December 31st, 2016. We aimed to investigate 1) changes in the prevalence of Charlson-defined comorbidities among PLHIV hospitalized between 2006 and 2016, and 2) changes in the unadjusted prevalence ratio (PR) of comorbidities in HIV-positive versus HIV-negative admissions over time. Results Of 898,139 hospital admissions from 2006-2016, 19,039 (2.1%) were HIV-positive. Across all admissions during the study period, the greatest comorbidity disparities between HIV-positive and HIV-negative admissions were mild liver disease (PR=4.9, 95% CI: [4.8,5.1]), moderate or severe liver disease (PR=2.2 [2.0,2.4]), and chronic pulmonary disease (PR=1.8 [1.8,1.8]). Conclusions The prevalence and relative burden of comorbidities among hospitalized PLHIV is changing over time. Careful monitoring and intensive discharge planning may be effective strategies for addressing the evolving health needs of PLHIV.

Background. Loneliness and social isolation are emerging public health challenges for aging populations. Methods. We followed N=11,305 US Health and Retirement Study (HRS) participants aged 50-95 from 2006-2014 to measure persistence of exposure to loneliness and social isolation. We tested associations of longitudinal loneliness and social-isolation phenotypes with disability, morbidity, mortality, and biological aging through 2018. Results. During follow-up, 18% of older adults met criteria for loneliness and, for 6%, symptoms persisted across two or more follow-up assessments. For social isolation, these fractions were 21% and 8%. HRS participants who experienced loneliness and social isolation were at increased risk for disease, disability, and mortality. Older adults experiencing persistent loneliness were at a 59% increased hazard of mortality compared to those who were never lonely. For social isolation, the increase was 28%. Effect-sizes were somewhat larger for counts of prevalent activity limitations and somewhat smaller for counts of prevalent chronic diseases. Covariate adjustment for socioeconomic and psychological risks attenuated but did not fully explain associations. Older adults who experienced loneliness and social isolation also exhibited physiological indications of advanced biological aging (Cohen's-d for persistent loneliness and social isolation=0.26 and 0.21, respectively). For loneliness, but not social isolation, persistence of symptoms was associated with increased risk. Conclusion. Deficits in social connectedness prevalent in a national sample of older adults in the US were associated with morbidity, disability, and mortality and with more advanced biological aging. Bolstering social connection to interrupt experiences of loneliness may promote healthy aging.