Neighborhood Characteristics and Elevated Blood Pressure in Older Adults

IMPORTANCE: The local environment remains an understudied contributor to elevated blood pressure among older adults. Untargeted approaches can identify neighborhood conditions interrelated with racial segregation that drive hypertension disparities. OBJECTIVE: To evaluate independent associations of sociodemographic, economic, and housing neighborhood factors with elevated blood pressure. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, the sample included Health and Retirement Study participants who had between 1 and 3 sets of biennial sphygmomanometer readings from 2006 to 2014 or 2008 to 2016. Statistical analyses were conducted from February 5 to November 30, 2021. EXPOSURES: Fifty-one standardized American Community Survey census tract variables (2005-2009). MAIN OUTCOMES AND MEASURES: Elevated sphygmomanometer readings over the study period (6-year period prevalence): a value of at least 140 mm Hg for systolic blood pressure and/or at least 90 mm Hg for diastolic blood pressure. Participants were divided 50:50 into training and test data sets. Generalized estimating equations were used to summarize multivariable associations between each neighborhood variable and the period prevalence of elevated blood pressure, adjusting for individual-level covariates. Any neighborhood factor associated (Simes-adjusted for multiple comparisons P ≤ .05) with elevated blood pressure in the training data set was rerun in the test data set to gauge model performance. Lastly, in the full cohort, race- and ethnicity-stratified associations were evaluated for each identified neighborhood factor on the likelihood of elevated blood pressure. RESULTS: Of 12 946 participants, 4565 (35%) had elevated sphygmomanometer readings (median [IQR] age, 68 [63-73] years; 2283 [50%] male; 228 [5%] Hispanic or Latino, 502 [11%] non-Hispanic Black, and 3761 [82%] non-Hispanic White). Between 2006 and 2016, a lower likelihood of elevated blood pressure was observed (relative risk for highest vs lowest tertile, 0.91; 95% CI, 0.86-0.96) among participants residing in a neighborhood with recent (post-1999) in-migration of homeowners. This association was precise among participants with non-Hispanic White and other race and ethnicity (relative risk, 0.91; 95% CI, 0.85-0.97) but not non-Hispanic Black participants (relative risk, 0.97; 95% CI, 0.85-1.11; P = .48 for interaction) or Hispanic or Latino participants (relative risk, 0.84; 95% CI, 0.65-1.09; P = .78 for interaction). CONCLUSIONS AND RELEVANCE: In this cohort study of older adults, recent relocation of homeowners to a neighborhood was robustly associated with reduced likelihood of elevated blood pressure among White participants but not their racially and ethnically marginalized counterparts. Our findings indicate that gentrification may influence later-life blood pressure control

PD-1T TILs as a predictive biomarker for clinical benefit to PD-1 blockade in patients with advanced NSCLC

PURPOSE Durable clinical benefit to PD-1 blockade in NSCLC is currently limited to a small fraction of patients, underlining the need for predictive biomarkers. We recently identified a tumor-reactive tumor-infiltrating T lymphocyte (TIL) pool, termed PD-1T TILs, with predictive potential in NSCLC. Here, we examined PD-1T TILs as biomarker in NSCLC. EXPERIMENTAL DESIGN PD-1T TILs were digitally quantified in120 baseline samples from advanced NSCLC patients treated with PD-1 blockade. Primary outcome was Disease Control (DC) at 6 months. Secondary outcomes were DC at 12 months and survival. Exploratory analyses addressed the impact of lesion-specific responses, tissue sample properties and combination with other biomarkers on the predictive value of PD-1T TILs. RESULTS PD-1T TILs as a biomarker reached 77% sensitivity and 67% specificity at 6 months, and 93% and 65% at 12 months, respectively. Particularly, a patient group without clinical benefit was reliably identified, indicated by a high negative predictive value (NPV) (88% at 6 months, 98% at 12 months). High PD-1T TILs related to significantly longer progression-free (HR 0.39, 95% CI: 0.24-0.63, p<0.0001) and overall survival (HR 0.46, 95% CI: 0.28-0.76, p<0.01). Predictive performance was increased when lesion-specific responses and samples obtained immediately before treatment were assessed. Notably, the predictive performance of PD-1TTILs was superior to PD-L1 and TLS in the same cohort. CONCLUSIONS This study established PD-1T TILs as predictive biomarker for clinical benefit to PD-1 blockade in advanced NSCLC patients. Most importantly, the high NPV demonstrates an accurate identification of a patient group without benefit

Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer

Optimum risk stratification in early-stage endometrial cancer (EC) combines clinicopathological factors and the molecular EC classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid ECs from the PORTEC-1&amp;-2 trials. The relationship between immune cell density and clinicopathological/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular EC classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate and low densities, with highly significant variation in the proportion of molecular EC subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of EC recurrence; multivariable analysis confirmed this was independent of pathological factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular EC classification in early-stage EC

A dusty, normal galaxy in the epoch of reionization

Candidates for the modest galaxies that formed most of the stars in the early universe, at redshifts $z > 7$, have been found in large numbers with extremely deep restframe-UV imaging. But it has proved difficult for existing spectrographs to characterise them in the UV. The detailed properties of these galaxies could be measured from dust and cool gas emission at far-infrared wavelengths if the galaxies have become sufficiently enriched in dust and metals. So far, however, the most distant UV-selected galaxy detected in dust emission is only at $z = 3.25$, and recent results have cast doubt on whether dust and molecules can be found in typical galaxies at this early epoch. Here we report thermal dust emission from an archetypal early universe star-forming galaxy, A1689-zD1. We detect its stellar continuum in spectroscopy and determine its redshift to be $z = 7.5\pm0.2$ from a spectroscopic detection of the Ly{\alpha} break. A1689-zD1 is representative of the star-forming population during reionisation, with a total star-formation rate of about 12M$_\odot$ yr$^{-1}$. The galaxy is highly evolved: it has a large stellar mass, and is heavily enriched in dust, with a dust-to-gas ratio close to that of the Milky Way. Dusty, evolved galaxies are thus present among the fainter star-forming population at $z > 7$, in spite of the very short time since they first appeared.Comment: Nature in press. 14 pages, 10 figures, including methods sectio

Genome-wide Association Study of Smoking Initiation and Current Smoking

For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network showing cellular location and direct interaction of their proteins. Several interesting groups of proteins stood out, including glutamate receptors (e.g., GRIN2B, GRIN2A, GRIK2, GRM8), proteins involved in tyrosine kinase receptor signaling (e.g., NTRK2, GRB14), transporters (e.g., SLC1A2, SLC9A9) and cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms