The Association Between Phosphodiesterase-5 Inhibitors and Colorectal Cancer in a National Cohort of Patients

INTRODUCTION: To examine the association between phosphodiesterase-5 (PDE-5) inhibitor use and incidence of colorectal cancer among patients with erectile dysfunction treated in the Veterans Affairs (VA) Healthcare System. METHODS: A retrospective cohort study using the Veterans Affairs Informatics and Computing Infrastructure was conducted, with data spanning January 2001-December 2016. Patients were followed up from index until (i) the first diagnosis of colorectal cancer, (ii) death, or (iii) the end of study period. Statistical analyses evaluated demographics and baseline characteristics between cohorts (PDE-5 exposed or not) and the effect of additional dosages of each specific PDE-5 inhibitor using adjusted multivariate Cox proportional hazards models. RESULTS: A total of 221,538 patients met the study inclusion criteria, 192,691 patients in the PDE-5 cohort and 29,227 patients in the never use PDE-5 cohort. The multivariate Cox proportional hazards model results revealed that the those who had any exposure to a PDE-5 inhibitor have an 18% lower hazard of colorectal cancer (adjusted hazard ratio [HR] = 0.816, 95% confidence interval [CI] = 0.754-0.882). For each additional 100-mg dosage of sildenafil and 10-mg dosage of tadalafil, the hazard of colorectal cancer is reduced by 2.4% (adjusted HR = 0.976, 95% CI = 0.973-0.979) and 1.7% (adjusted HR = 0.983, 95% CI = 0.972-0.996), respectively. DISCUSSION: PDE-5 inhibitor usage in patients with erectile dysfunction is associated with a lower hazard of colorectal cancer compared with patients not exposed to PDE-5 inhibitors

Odds of Acute Kidney Injury in Patients Receiving Dipeptidyl Peptidase 4 Inhibitors: A National Cohort Study Within the Department of Veterans Affairs

Preclinical and clinical data of dipeptidyl peptidase 4 (DPP‐4) inhibitors have demonstrated discordant data regarding acute kidney injury (AKI). Therefore, we aimed to evaluate the association between DPP‐4 use and AKI. This cohort study utilized data from the Department of Veterans Affairs evaluating patients diagnosed with type 2 (T2) diabetes with a DPP‐4 inhibitor and compared with nondiabetic and diabetic patients. The primary end point is the development of AKI, and statistical analyses were performed to examine the association. DPP‐4 use is associated with a lower odds of AKI compared with diabetics (adjusted odds ratio (OR) = 0.39; 95% confidence interval (CI) = 0.32–0.48) and nondiabetics (OR = 0.64; 95% CI = 0.52–0.79). DPP‐4 use in patients with T2 diabetes mellitus is associated with lower odds of AKI within 120 days compared with nondiabetic and diabetic controls when adjusting for study covariates

Geologic Map of the Ganiki Planitia Quadrangle (V–14), Venus

Our current research focuses on addressing four specific questions. Has the dominant style of volcanic expression within the quadrangle varied in a systematic fashion over time? Does the tectonic deformation within the quadrangle record significant regional patterns that vary spatially or temporally, and if so what are the scales, orientations and sources of the stress fields driving this deformation? If mantle upwelling and downwelling have played a significant role in the formation of Atla Regio and Atalanta Planitia as has been proposed, does the geology of Ganiki Planitia record evidence of northwest-directed lateral mantle flow connecting the two sites? Finally, can integration of the tectonic and volcanic histories preserved within the quadrangle help constrain competing resurfacing models for Venus

Age-Related Effects on the Potency of Human Adipose-Derived Stem Cells: Creation and Evaluation of Superlots and Implications for Musculoskeletal Tissue Engineering Applications

Human adipose-derived stem cells (hASC) are now a prevalent source of adult stem cells for studies in tissue engineering and regenerative medicine. However, researchers utilizing hASC in their investigations often encounter high levels of donor-to-donor variability in hASC differentiation potential. Because of this, conducting studies with this primary cell type can require extensive resources to generate statistically significant data. We present a method to generate pooled donor cell populations, termed “superlots,” containing cell populations derived from four to five age-clustered donors. The goal of generating these superlots was to 1) increase experimental throughput, 2) to utilize assay resources more efficiently, and 3) to begin to establish global hASC differentiation behaviors that may be associated with donor age. With our superlot approach, we have validated that pooled donor cell populations exhibit proliferative activity representing the combined behavior of each individual donor cell line. Further, the superlots also exhibit differentiation levels roughly approximating the average combined differentiation levels of each individual donor cell line. We established that high donor-to-donor variability exists between the pre-, peri-, and postmenopausal age groupings and that proliferation and differentiation characteristics can vary widely, independent of age. Interestingly, we did observe that cell lines derived from postmenopausal donors demonstrated a relatively high proclivity for osteogenic differentiation and a relatively lowered proclivity for adipogenic differentiation as compared with cells derived from pre- and perimenopausal donors. In general, superlots effectively represented the average differentiation behavior of each of their contributing cell populations and could provide a powerful tool for increasing experimental throughput to more efficiently utilize resources when studying hASC differentiation

Repurposing Anti-Inflammasome NRTIs for Improving Insulin Sensitivity and Reducing Type 2 Diabetes Development

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P \u3c 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes

Quantitative Evidence for the Effects of Multiple Drivers on Continental-Scale Amphibian Declines

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a “smoking gun” was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed

Quantitative Evidence for the Effects of Multiple Drivers on Continental-Scale Amphibian Declines

Since amphibian declines were first proposed as a global phenomenon over a quarter century ago, the conservation community has made little progress in halting or reversing these trends. The early search for a “smoking gun” was replaced with the expectation that declines are caused by multiple drivers. While field observations and experiments have identified factors leading to increased local extinction risk, evidence for effects of these drivers is lacking at large spatial scales. Here, we use observations of 389 time-series of 83 species and complexes from 61 study areas across North America to test the effects of 4 of the major hypothesized drivers of declines. While we find that local amphibian populations are being lost from metapopulations at an average rate of 3.79% per year, these declines are not related to any particular threat at the continental scale; likewise the effect of each stressor is variable at regional scales. This result - that exposure to threats varies spatially, and populations vary in their response - provides little generality in the development of conservation strategies. Greater emphasis on local solutions to this globally shared phenomenon is needed

Genome-Wide Analysis of Light- and Temperature-Entrained Circadian Transcripts in Caenorhabditis elegans

Transcriptional profiling experiments identify light- and temperature-entrained circadian transcripts in C. elegans

Corporate Structure and Performance Feedback: Aspirations and Adaptation in M-Form Firms

In this study, we examine how business units of multidivisional (M-form) firms adapt their activities in response to poor performance at the corporate and business unit levels. By linking performance feedback theory with theories of attention and M-form organizations, we show that corporate structure influences the relationship between performance below aspirations and business unit adaptation. Because corporate structure vertically differentiates performance goals and problemistic search, solutions to performance problems vary across corporate and business unit levels, with divergent implications for business unit adaptation. We examine business unit adaptation empirically through new product introductions in the global mobile device industry, finding that poor performance at the business unit level leads to greater new product introductions. In contrast, corporate-level responses to performance problems have a negative cross-level effect on new product introductions. We also find that these negative effects are attenuated for strategically significant business units, which have more input into corporate responses. By linking structural and behavioral drivers of action, this paper contributes to the knowledge and understanding of adaptive behavior in multidivisional firms