Search

Background: The decreased mortality of people with HIV (PWH) has revealed non-HIV-associated comorbidities such as neurocognitive disorders (e.g., dementia). There is an urgency to discover therapeutics to prevent or delay neurocognitive decline among PWH., Methods: The artificial intelligence platform Automatic Graph-mining And Transformer based Hypothesis Generation Approach (AGATHA) was utilized to seek potential drugs to be repurposed for the management of non-HIV-associated dementia. AGATHA revealed angiotensin-converting enzyme inhibitors that cross the blood-brain barrier (BBB ACEi) as a target for decreasing dementia. Subsequently, we conducted a retrospective study evaluating incident dementia using the Veterans Affairs Informatics and Computing Infrastructure (VINCI) evaluating ACE inhibitors. Cox proportional hazards models were fit and hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) are presented., Findings: A total 9419 PWH exposed to an BBB ACE inhibitor (ACEi) and 8831 PWH unexposed demonstrated that PWH exposed to BBB ACEi had a 21.4% (univariate) and 15.2% (multivariate) lower hazard of dementia. The propensity score matched analysis demonstrated a 14.3% lower hazard of incident dementia compared to BBB ACEi unexposed (HR 0.857, 95% CI 0.747-0.984)., Interpretation: An artificial intelligence-based literature mining system (AGATHA) was utilized to uncover a medication with potential to be repurposed. AGATHA demonstrated that BBB ACEi as a target for decreasing dementia among PWH. Additionally, we conducted a retrospective study demonstrating a decrease in incident dementia among PWH exposed to BBB ACEi. Future research is needed to explore further and understand the relationship of dementia among PWH exposed to ACEi., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Chronic inflammation is a key factor in type 2 diabetes mellitus (T2DM) development. The cholinergic anti-inflammatory pathway (CAP) reduces inflammation by activating α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, suppressing proinflammatory cytokines. Acetylcholinesterase inhibitors (AChEis), primarily used for Alzheimer's disease (AD), may exert anti-inflammatory effects through the CAP. One AChEi, galantamine, also directly agonizes α7nAChRs, potentially enhancing its anti-inflammatory properties., Objective: This study aimed to investigate the association between AChEi use, particularly galantamine, and T2DM risk in AD patients., Methods: We conducted a retrospective analysis of Veterans Health Administration (VA) data, examining early- and late-onset AD patients receiving galantamine or other AD medications. Propensity score matching was used to balance groups and minimize confounding. Cox proportional hazard models assessed T2DM risk for galantamine, other AChEis and memantine., Results: A total of 40 065 AD patients were included in the study. Among early-onset AD patients, galantamine use significantly reduced T2DM risk (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.66-0.98). Memantine also showed a protective effect (HR = 0.82, 95% CI: 0.69-1) in this group. Neither galantamine nor memantine influenced T2DM risk in late-onset AD. Other AD medications showed no association with T2DM risk., Conclusion: Galantamine use was associated with a lower risk of T2DM in early-onset AD patients, potentially due to enhanced anti-inflammatory effects through both AChE inhibition and direct α7nAChR agonism. Memantine also demonstrated a protective effect. These findings suggest potential new applications for existing AD medications in T2DM prevention, particularly in early-onset AD patients. Further research, including randomized controlled trials with diverse populations, is needed to confirm these results and the underlying mechanisms., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Comorbidities such as schizophrenia and medication such as antipsychotics may influence the risk of dementia among people living with HIV (PLWH). The objective of this paper is to assess the associations among HIV patients with schizophrenia, off-label antipsychotics, and dementia risk., Setting: US Department of Veterans Affairs healthcare facilities from 2000 to September 2023., Methods: Retrospective cohort study of PLWH treated by the U.S. Department of Veterans Affairs with prior history of schizophrenia, off-label antipsychotic use and neither schizophrenia nor antipsychotic use. Propensity score matched non-HIV controls were included for the respective HIV groups. The hazard of dementia is estimated using Cox proportional hazards models., Results: PLWH and schizophrenia, were found to have a 2.49 higher hazard of dementia compared to HIV patients with no history of schizophrenia or antipsychotic medication use (HR=2.49, 95%CI=(1.85-3.35)). PLWH and off-label antipsychotic use were found to have a 1.77-fold higher hazard of dementia compared to HIV patients with no history of schizophrenia or antipsychotic medication use (HR=1.77, 95% CI=(1.37-2.28)). Propensity score matched analysis reveals that, among schizophrenia patientis, those with HIV had a 1.65-fold higher hazard of dementia (HR=1.65, 95%CI=(1.12-2.44)). Among patients with no schizophrenia or antipsychotic medication, those with HIV had a 1.47 fold higher hazard of dementia (HR=1.47, 95%CI=(1.33-1.63))., Conclusions: This study demonstrates that among PLWH, history of schizophrenia or off-label antipsychotic medication use are associated with substantial increases in dementia incidence. Furthermore, propensity-matched control analysis reveals that HIV infection itself is independently and significantly associated with elevated dementia risk., Competing Interests: The authors report no conflicts of interest related to this work., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Neurodegenerative pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, Multiple sclerosis, HIV-associated neurocognitive disorder, and others significantly affect individuals, their families, caregivers, and healthcare systems. While there are no cures yet, researchers worldwide are actively working on the development of novel treatments that have the potential to slow disease progression, alleviate symptoms, and ultimately improve the overall health of patients. Huge volumes of new scientific information necessitate new analytical approaches for meaningful hypothesis generation. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases, such as PubMed. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. Here we focus on drugs that can be repurposed for dementia treatment as an outcome of neurodegenerative diseases. Therefore, we determined dementia-associated genes statistically highly ranked in other disease classes. Additionally, we report a mechanism for detecting genes common to multiple health conditions. These sets of genes were classified based on their presence in biological pathways, aiding in selecting candidates and biological processes that are exploitable with drug repurposing.

Background: By inhibiting xanthine oxidase, subsequent inflammatory cytokine release and the resulting breakdown of the blood-retina barrier, allopurinol may limit the inflammation-driving diabetic macular edema (DME)., Methods: We examined the relationship between allopurinol and DME among type 2 diabetic United States veterans using a retrospective cohort study.  We used propensity score matching and Cox hazard models to estimate the risk of DME., Results: Propensity score-matched Cox models revealed allopurinol was associated with a 24.6% reduction in the risk of DME (HR = 0.754; 95% CI = (0.684-0.831))., Conclusion: Allopurinol could reduce the risk of DME, one of the major causes of visual disturbance among diabetic patients. Further research into the effects of allopurinol on DME is warranted.

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Sutton has received research grants from Boehringer-Ingelheim, Gilead Sciences, Alexion Pharmaceuticals, and United Therapeutics, all for projects unrelated to study. J.A. is a co-founder of DiceRx, iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and, unrelated to this work, he has been a board member for Theragen and consultant for Abbvie/Allergan, Boehringer-Ingelheim, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences. The other authors declare no competing interests.

Importance: Age-related macular degeneration (AMD) is a serious and common ophthalmologic disorder that is hypothesized to result, in part, from inflammatory reactions in the macula. Alzheimer disease (AD) treatment, acetylcholinesterase inhibitors (AChEIs), have anti-inflammatory effects and it remains unclear if they modify the risk of AMD., Objective: To investigate the association between AChEI medications and the incidence of AMD., Design, Setting, and Participants: This propensity score-matched retrospective cohort study took place at health care facilities within the US Department of Veterans Affairs (VA) health care system from January 2000 through September 2023. Participants included patients diagnosed with AD between ages 55 and 80 years with no preexisting diagnosis of AMD in the VA database., Exposure: AChEIs prescription dispensed as pharmacologic treatments for AD., Main Outcomes and Measure: The first diagnosis of AMD., Results: A total of 21 823 veterans with AD (mean [SD] age, 72.3 [6.1] years; 21 313 male participants [97.7%] and 510 female participants [2.3%]) were included. Propensity score-matched Cox model reveals each additional year of AChEI treatment was associated with a 6% lower hazard of AMD (hazard ratio, 0.94; 95% CI, (0.89-0.99)., Conclusions and Relevance: This observational study reports a small reduction in the risk of AMD among veterans with AD receiving AChEIs. Randomized clinical trials would be needed to determine if there is a cause-and-effect relationship and further research is required to validate these findings across diverse populations.

The Europa Imaging System (EIS) consists of a Narrow-Angle Camera (NAC) and a Wide-Angle Camera (WAC) that are designed to work together to address high-priority science objectives regarding Europa's geology, composition, and the nature of its ice shell. EIS accommodates variable geometry and illumination during rapid, low-altitude flybys with both framing and pushbroom imaging capability using rapid-readout, 8-megapixel (4k × 2k) detectors. Color observations are acquired using pushbroom imaging with up to six broadband filters. The data processing units (DPUs) perform digital time delay integration (TDI) to enhance signal-to-noise ratios and use readout strategies to measure and correct spacecraft jitter. The NAC has a 2.3° × 1.2° field of view (FOV) with a 10-μrad instantaneous FOV (IFOV), thus achieving 0.5-m pixel scale over a swath that is 2 km wide and several km long from a range of 50 km. The NAC is mounted on a 2-axis gimbal, ±30° cross- and along-track, that enables independent targeting and near-global (≥90%) mapping of Europa at ≤100-m pixel scale (to date, only ∼15% of Europa has been imaged at ≤900 m/pixel), as well as stereo imaging from as close as 50-km altitude to generate digital terrain models (DTMs) with ≤4-m ground sample distance (GSD) and ≤0.5-m vertical precision. The NAC will also perform observations at long range to search for potential erupting plumes, achieving 10-km pixel scale at a distance of one million kilometers. The WAC has a 48° × 24° FOV with a 218-μrad IFOV, achieving 11-m pixel scale at the center of a 44-km-wide swath from a range of 50 km, and generating DTMs with 32-m GSD and ≤4-m vertical precision. The WAC is designed to acquire three-line pushbroom stereo and color swaths along flyby ground-tracks., Competing Interests: Competing InterestsThe authors have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2024.)

Objective: This study aimed to investigate the associations between total serum bilirubin levels and the incidence of venous thromboembolism (VTE) among patients with influenza infection., Methods: A retrospective cohort study was conducted among outpatients with laboratory-confirmed influenza using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Propensity score weighting was applied to balance study groups across baseline covariates. Cox proportional hazards models assessed VTE risk by total bilirubin levels, adjusting for important covariates including age, sex, race, comorbidity index, BMI, and smoking status., Results: A total of 487 patients with total bilirubin levels <0.3 mg/dL, 8608 patients with levels between 0.3-1 mg/dL, and 1148 patients with levels >1 mg/dL were included. Patients with bilirubin <0.3 mg/dL exhibited a 6-fold higher risk of VTE compared to those with levels 0.3-1 mg/dL within 30 days of infection (HR = 6.2, 95% CI = 1.46-26.42). Elevated risks were noted through 90 days post infection (HR = 4.71, 95% CI = (1.42-15.67))., Conclusions: Serum bilirubin levels, particularly below 0.3 mg/dL, were significantly associated with an increased risk of VTE among individuals with influenza. These findings suggest that lower bilirubin levels may contribute to heightened inflammatory responses and subsequent thromboembolic events in patients with influenza. The underlying mechanisms and potential therapeutic implications for VTE prevention among patients with acute respiratory infection warrants further consideration., Competing Interests: Data AvailabilityAnalyses of the Veterans Health Administration Database were performed using data within the US Department of Veterans Affairs secure research environment, the VA Informatics and Computing Infrastructure (VINCI). The completeness, utility, accuracy, validity, and access methods are described on the VA website, https://www.virec.research.va.gov. Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score-weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14-0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30-0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The aim of this study was to investigate whether the use of nucleoside reverse transcriptase inhibitors (NRTIs) impacts the incidence of prediabetes or type 2 diabetes mellitus (T2DM) or the progression from prediabetes to T2DM in people living with HIV (PLWH). We conducted a retrospective cohort study using the U.S. Veterans Health Administration database among adult patients with an HIV diagnosis from the year 2000 until 2021 to determine the incidence of prediabetes and further progression to T2DM among NRTI exposed and unexposed patients. A multistate model was used to evaluate progression from normoglycemia to prediabetes and then to T2DM, and covariate adjustment with the Cox proportional hazards model was used to estimate the hazard ratios. Among 32,240 veterans diagnosed with HIV, prediabetes and T2DM were observed among 20.2% and 20.7% of patients, respectively. Among those diagnosed with prediabetes, 31.8% progressed to T2DM. Patients exposed to NRTIs at any time (86.6%), had a reduced risk of prediabetes [HR 0.50 (0.47-0.53 95% CI)] and among prediabetics, a lower risk of progression to T2DM [HR 0.73 (0.63-0.85 95% CI)] when compared to patients who never used NRTIs. In summary, NRTIs may reduce the risk of developing prediabetes and the progression from prediabetes to T2DM in PLWH., Competing Interests: J.A. has received support from the UVA Strategic Investment Fund and National Institutes of Health (NIH) grants (R01EY028027, R01EY029799, R01EY031039, R01AG082108). S.S.S., J.M., T.H.C. are supported by NIH grant R01DA054992 and the South Carolina Center for Rural and Primary Healthcare for projects unrelated to this study. J.A. is a co-founder of DiceRx, iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and, unrelated to this work, he has been a consultant for Allergan, Boehringer- Ingelheim, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work. J.W.H. has received consulting fees from Celgene Corporation unrelated to this work. S.S.S has received research grants from Boehringer Ingelheim, Coherus BioSciences, Alexion Pharmaceuticals, and EMD Serono, all for projects unrelated to study. J.A., S.N., and F.P. are named as inventors on patent applications filed by the University of Virginia or the University of Kentucky.

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we evaluated the overall survival (OS) in patients with cancer receiving checkpoint inhibitors combined with fluoxetine. A cohort study was conducted among patients diagnosed with lung, throat (pharynx or larynx), skin, or kidney/urinary cancer treated with checkpoint inhibitor therapy. Utilizing the Veterans Affairs Informatics and Computing Infrastructure, patients were retrospectively evaluated during the period from October 2015 to June 2021. The primary outcome was overall survival (OS). Patients were followed until death or the end of the study period. There were 2316 patients evaluated, including 34 patients who were exposed to checkpoint inhibitors and fluoxetine. Propensity score weighted Cox proportional hazards demonstrated a better OS in fluoxetine-exposed patients than unexposed (HR: 0.59, 95% CI 0.371-0.936). This cohort study among cancer patients treated with checkpoint inhibitor therapy showed a significant improvement in the OS when fluoxetine was used. Because of this study's potential for selection bias, randomized trials are needed to assess the efficacy of the association of fluoxetine or another anti-NLRP3 drug to checkpoint inhibitor therapy.

Objective: The goal of this paper was to analyze patient outcomes related to gout treatment including, serum uric acid (sUA) measures and treatment adherence across patients in metropolitan, micropolitan or rural counties., Methods: We conducted a drug-disease cohort study among patients with gout initiating urate lowering therapy. The proportion of patients with sUA < 6 mg/dL at 1 year of follow-up is compared over the cohort groups using a chi-square test and adjusted logistic regression. Adherence to urate lowering therapy was calculated using the proportion of days covered (PDC). A T -test was used to compare the average PDC and an adjusted logistic regression model was used to estimate the odds of a PDC greater than 80%., Results: A total of 9922 patients were included in the study. Most patients were in a metropolitan (77.4%) area, followed by micropolitan (11.8%) and finally, (10.8%) in a rural area. We found no statistically significant difference among the proportion of patients achieving target sUA of <6 mg/dL, 37.17% among metropolitan patients, 38.9% among micropolitan patients, and 37.7% for those in a rural area, P -value = .502. The proportion of patients achieving 80% treatment adherence was 49.92% in the metropolitan, 51.78% in the micropolitan, and 55.05% in the rural areas, P -value = .005. Adjusted regression models showed no statistically significant difference in proportions achieving target sUA levels or 80% adherence., Conclusions: Urban patients treated for gout did not have better gout outcomes compared to rural patients. Future research should consider provider-based interventions to improve outcomes.

Background: Clostridioides difficile ( C. difficile ) infection (CDI) is strongly associated with inflammation and has the potential to cause recurrent infections. Pre-clinical data suggest that melatonin has beneficial effects in the gastrointestinal tract due to its anti-inflammatory and antibacterial properties. This analysis examines the association between melatonin and the risk of recurrent CDI. Methods: A retrospective cohort study was conducted among patients with an inpatient diagnosis of CDI along with a positive C. difficile polymerase chain reaction (PCR) or enzyme immunoassay (EIA) test result. Patients were followed until the first study end point (death) or the first instance of recurrent infection. Propensity-score weighting was utilized accounting for confounding factors and weighted Cox models were estimated. Results: A total of 24,782 patients met the inclusion criteria, consisting of 3457 patients exposed to melatonin and 21,325 patients with no melatonin exposure. The results demonstrate that those exposed to melatonin were associated with a 21.6% lower risk of recurrent CDI compared to patients without melatonin exposure (HR = 0.784; 95% CI = 0.674-0.912). Conclusion: Our results demonstrate a decreased rate of recurrent CDI in patients exposed to melatonin. Further research on melatonin as an antimicrobial adjuvant and anti-inflammatory is warranted for the management of recurrent CDI.

Prior research suggests melatonin has beneficial effects that could improve survival among sepsis patients. This exploratory analysis sought to compare 30-day survival among melatonin treated and untreated patients with sepsis. A retrospective cohort study was conducted among patients with a primary inpatient admission diagnosis for sepsis utilizing the International Classification of Diseases, versions 9 and 10, Clinical Modification (ICD-9-CM and ICD-10-CM) diagnosis codes between 2000 and 2021. Propensity score weighting was utilized, accounting for demographic, clinical, and laboratory factors. Weighted Cox models were estimated for 30-day in-hospital and 30-day overall survival. A total of 9386 patients were included in the study with 593 exposed to melatonin within the first day of hospitalization. Propensity score weighted Cox models reveal melatonin was associated with a 37.9% decreased risk of 30-day in-hospital mortality (HR = 0.621; 95% CI = [0.415-0.931]) and a 33.5% decreased risk of 30-day overall mortality (HR = 0.665; 95% CI = [0.493-0.897]). Factors associated with higher risk of both in-hospital and overall mortality include male sex, white race, age, higher Charlson comorbidity burden, sodium and potassium levels, intensive care unit stay, invasive ventilation, and vasopressor use. Higher serum albumin levels are associated with lower mortality risks. Among patients diagnosed with sepsis, exposure to melatonin was associated with a lower in-hospital and 30-day mortality. Additional research is warranted to fully understand the role of melatonin in sepsis., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Arachidonic acid (AA), which is metabolized via the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways, was found to be associated with venous thromboembolism (VTE). Metabolites of the LOX pathway include cysteinyl (Cys) Leukotrienes (LT), potent proinflammatory mediators, which have also been implicated in cardiovascular disease., Objective: The purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE., Methods: We conducted a retrospective cohort study examining VTE risk among COPD patients from the United States Department of Veterans Affairs. We use propensity score matching and Cox survival models to estimate the hazard ratio comparing montelukast exposure to non-exposure. Montelukast exposure was associated with a 15.9% reduction in risk of VTE compared to those unexposed (HR= 0.841; 95% CI= (0.758-0.934))., Conclusion: The results of this study demonstrate that targeting LTs might be beneficial for VTE prophylaxis using the clinically available LT inhibitor, montelukast. Importantly, further research on LTs is warranted to fully understand and validate this relationship., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Obesity is a risk factor for the development of influenza by leading to a chronic inflammatory state and T-cell dysfunction. Based upon preclinical research, metformin has influenza activity by restoring T-cell function and improving the immune response., Objective: We aimed to evaluate the potential drug repurposing of metformin for the management of influenza among patients with obesity utilizing national claims data in an electronic health record database., Methods: The VA Informatics and Computing Infrastructure (VINCI) was utilized to obtain individual-level information on demographics, administrative claims, and pharmacy dispensation. A cohort was created among individuals with laboratory confirmed diagnosis of influenza with a diagnosis of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome was death after diagnosis of influenza. Cohorts were formed using diabetes status and metformin exposure prior to a positive influenza diagnosis. Hazard ratios for mortality were estimated using a cox proportional hazards model adjusting for baseline covariates and a sub-analysis was conducted utilizing propensity score matching. A greedy nearest neighbor algorithm was utilized to match 1 to 1 non-metformin diabetic controls and non-diabetic controls to diabetic patients receiving metformin., Results: A total of 3551 patients met the inclusion criteria and were evaluated in our study. The cohorts consisted of 1461 patients in the non-diabetic cohort, 1597 patients in the diabetic / metformin cohort, and 493 patients in the diabetic no metformin cohort. Compared to non-diabetic patients, diabetic patients with metformin had a lower rate of death (aHR 0.78, 95% CI 0.609-0.999). There was not a statistical difference between the non-diabetic patients and the diabetic patients without metformin (aHR 1.046, 95% CI 0.781-1.400). The propensity score matched cohorts revealed consistent results with the primary analysis., Conclusion: Our results demonstrated patients with obesity and a history of metformin treatment have lower influenza mortality.

Objective: To evaluate calcium channel blockers as a potential prophylactic agent for sensorineural hearing loss (SNHL).Patients: We used a retrospective cohort of US veterans treated by the Veteran's Affairs healthcare system. Patients were included in the study if 1) they were diagnosed with high blood pressure; 2) had no previous diagnosis of SNHL; 3) were prescribed a calcium channel blocker after diagnosis or as a control cohort, patients who had no antihypertensive medication use., Intervention: Patients were categorized into mutually exclusive cohorts by their antihypertensive medication exposure: calcium channel blocker exposed and no antihypertensive medication exposure., Main Outcome Measure: Incident SNHL was defined as an inpatient or outpatient record with diagnosis codes international classification of diseases (ICD)-9-CM 389.1 or ICD-10-CM H90, H90.41, H90.42, H90.A21, H90.A22. An audiology or otolaryngology clinic visit was required for patients with an outpatient diagnosis of SNHL., Results: A total of 1,338,409 patients met the inclusion criteria consisting of 292,981 patients with CCBs (25,614 with verapamil and 267,367 with other CCBs) and 1,045,428 patients with no antihypertensive medication. On average, patients were middle-aged, White men with a body mass index (BMI) of 30+. Cox proportional hazards model estimates from propensity score matched data revealed CCB users had a 23.6% decreased risk of SNHL compared with those with no antihypertensive medication use (hazard ratios [HR] = 0.764; 95% confidence interval = [0.752-0.777])., Conclusion: This analysis found evidence supporting the theory that calcium channel blockers might be a potential prophylactic agent for sensorineural hearing loss. Additional research is warranted., Competing Interests: Conflict of Interest: S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics unrelated to this work. The other authors declare no competing interests. This work was not funded., (Copyright © 2021, Otology & Neurotology, Inc.)

Evidence suggests that Ras-related C3 botulinum toxin substrate 1 (Rac1) might be a target in atherosclerotic disease (AD). We hypothesize that due to their ability to inhibit Rac1, thiopurines are associated with a lower risk of AD. We fit a time-dependent cox proportional hazards model estimating the hazard of AD among a national cohort of US veterans with inflammatory bowel disease. Patients exposed to thiopurines had a 7.5% lower risk of AD (HR = 0.925; 95% CI = (0.87-0.984)) compared to controls. The propensity score weighted analysis reveals thiopurine exposure reduces the risk of AD by 6.6% (HR = 0.934; 95% CI = (0.896-0.975)), compared to controls. Further exploration and evaluation of Rac1 inhibition as a target for AD is warranted.

Leukotriene inhibition, in vitro and in vivo, is found to suppress tumor growth across a variety of cancer cells. A mouse model of lung cancer revealed that the leukotriene inhibitor montelukast induced lung cancer cell death. Based on the preclinical data we hypothesize that exposure to a leukotriene inhibitor is associated with a lower risk of lung cancer. We conducted a national retrospective cohort study among U.S. Veterans with asthma to explore the relationship between leukotriene inhibition and incident lung cancer. We utilize a variety of statistical techniques, including cox proportional hazards models, propensity score matching and falsification testing to examine the association. A total of 558,466 patients met study criteria consisting of 23,730 patients with leukotriene exposure and 534,736 patients with no leukotriene medication use. Leukotriene inhibitor exposure reduced the risk of lung cancer by 17% (HR = 0.830; 95% CI = (0.757-0.911)) in the unmatched and 22.2% in the matched analysis (HR = 0.778 95% CI = (0.688-0.88)). Falsification testing with appendicitis and rotator cuff injury end points, suggest no evidence of selection bias. However, because treatment was not randomized, residual confounding cannot be ruled out. The pre-clinical data on leukotriene inhibition and lung cancer combined with our database analysis provide intriguing evidence warranting further research into the relationship between leukotrienes and lung cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate adherence after treatment switch from a multiple-tablet regimen (MTR) to a single-tablet regimen (STR) in a national cohort of human immunodeficiency virus (HIV) patients., Methods: This retrospective observational cohort, with data spanning January 1, 2000 to March 1, 2019, consisted of HIV infected patients receiving treatment from the Veterans Affairs (VA) health system. Patients were required to have a complete MTR regimen after January 1, 2006 and before December 31, 2018 with at least 60 days of treatment. Medical and pharmacy data were analyzed from the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. Statistical analyses examined differences in adherence when patients switched to a STR. Patients who switched to a STR were propensity score matched to those who never switched. Descriptive statistics and multivariable linear mixed effects models were utilized to evaluate differences in adherence between MTR and STR treatment in both the matched and unmatched samples., Results: A total of 5021 patients met the study criteria, 3906 patients in the MTR only cohort and 1115 patients in the switch to STR cohort. The unmatched cohorts were similar in terms of sex, index year, drug/alcohol abuse, and viral load but differed in terms of race, Charlson comorbidity and mental health conditions. The one to one propensity score matched cohort included 2230 patients, 1115 patients in each cohort. Among patients that switched from a MTR to STR, adherence increased on average from 65.9% to 78.12%. We find overall adherence is higher with STRs than with MTR HIV regimens in both the matched and unmatched sample and adherence declines with time for both STR and MTR regimens., Conclusions: Switching to a STR is associated with higher adherence compared to MTR among patients with HIV treated with antiretrovirals. However, adherence declines over time with both STR and MTR regimens., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA-induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD., Competing Interests: Competing interest statement: M.A., B.D.G., S.N., S.-b.W., I.A., and F.P. are named as inventors on patent applications on macular degeneration filed by the University of Virginia. S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics unrelated to this work. S.R.S. has been a consultant for 4DMT, Allergan, Amgen, Centervue, Heidelberg, Roche/Genentech, Novartis, Optos, Regeneron, and Thrombogenics and has received research funding from Carl Zeiss Meditec, all unrelated to this work. B.D.G. is a co-founder of DiceRx.

Background: Statins have a variety of pleiotropic effects that could be beneficial for patients undertaking total knee or hip arthroplasty. In vitro and in vivo models suggest the beneficial effects of statins through bone formation and modulating proinflammatory cytokines triggered by implant debris. However, statins also exhibit antimicrobial action and may reduce the risk of revision surgery via reducing the risk of infection. We sought to explore the relationship between statin use and prosthetic joint infection (PJI) after total knee or hip arthroplasty., Methods: We use a retrospective cohort of patients undergoing total knee or hip arthroplasty performed within the Department of Veterans Affairs. To minimize selection bias between the statin exposed and unexposed patients, we used 1:1 ratio propensity score matching. We fit adjusted Cox proportional hazards models to quantify the risk of PJI between the cohorts within 1 year, 3 years, and all follow-up time., Results: With a study period beginning from January 2000, a total of 60,241 patients were included. The unmatched Cox models reveal, over the entire follow-up time, a statistically significant lower risk of infection for the statin exposed patients (hazard ratio = 0.869; 95% confidence interval = [0.79-0.956]). The matched Cox model results reveal a statistically significant lower risk of PJI, only in the overall model, for the statin exposed cohort compared with the unexposed cohort (hazard ratio = 0.895, 95% confidence interval = [0.807-0.993])., Conclusion: Our analysis finds some support for the beneficial effects of statins for preventing PJI among patients undergoing total knee or hip arthroplasty., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Influenza viruses are responsible for seasonal epidemics and sporadic pandemics of varying severity in humans, and additional treatment options are needed. High-throughput siRNA screens and a pre-clinical research model demonstrated that dextromethorphan (DM) has anti-viral activity as a cellular target for treatment of influenza. This study examined DM usage and hospitalization rates among patients with laboratory-confirmed influenza in a national cohort of United States veterans. We aimed to evaluate the potential drug repurposing of DM as a cellular target for the management of influenza utilizing a large, national claims and electronic health record database., Methods: This retrospective drug-disease association cohort study was conducted using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). We used a cohort with laboratory-confirmed diagnosis of influenza and international classification of disease (ICD)-9/10 diagnosis codes of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome is inpatient hospitalization (all-cause and respiratory) within 30 days of influenza diagnosis. We estimated the relative risk for all-cause and respiratory hospitalizations using Poisson generalized linear model (GLM) and a greedy nearest neighbor propensity score 1:1 matched sub-analysis for both hospitalization models., Findings: A total of 18,677 patients met the inclusion and exclusion criteria and were evaluated in our study. The cohorts consisted of 2801 patients dispensed DM and 15,876 untreated patients (no DM). The Poisson GLM adjusted for covariates demonstrated a relative risk reduction of 34% for all-cause hospitalizations (Relative Risk (RR) 0.66, 95% Confidence Interval (CI) 0.525-0.832) and 40% for respiratory hospitalizations (RR 0.597, 95% CI 0.423-0.843) in patients with influenza treated with DM., Conclusion: Influenza viruses continue to emerge and cause infection (including pandemics) in humans, so there remains a critical need to advance the understanding of influenza treatment. Our results demonstrated reduced hospitalization rates for influenza patients treated with DM. Further research on cellular targets and/or DM is warranted for the treatment of influenza., (© Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Clinicians may prescribe antibiotics to influenza patients at high risk for bacterial complications. We explored the association between antibiotics, antivirals, and hospitalization among people with influenza., Methods: A retrospective cohort study of patients with confirmed influenza with encounters during January 2011-January 2019 was conducted using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). We compared inpatient hospitalizations (all-cause and respiratory) within 30 days of influenza diagnosis between 4 patient cohorts: (1) no treatment (n = 4228); (2) antibiotic only (n = 671); (3) antiviral only (n = 6492); and (4) antibiotic plus antiviral (n = 1415). We estimated relative risk for hospitalization using Poisson generalized linear model and robust standard errors., Results: Among 12 806 influenza cases, most were white men (mean age, 57-60 years). Those with antivirals only, antibiotic plus antiviral, and antibiotics only all had a statistically significant lower risk of all-cause and respiratory hospitalization compared to those without treatment. Comparing the antibiotic plus antiviral cohort to those who were prescribed an antiviral alone, there was a 47% lower risk for respiratory hospitalization (relative risk, 0.53 [95% confidence interval, .31-.94]), and no other statistical differences were detected., Conclusions: Those prescribed an antiviral, antibiotic, or both had a lower risk of hospitalization within 30 days compared to those without therapy. Furthermore, intervention with both an antibiotic and antiviral had a lower risk of respiratory hospitalization within 30 days compared to those with an antiviral alone. Importantly, the absolute magnitude of decreased risk with antibiotic plus antiviral therapy is small and must be interpreted within the context of the overall risk of antibiotic usage., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness., Competing Interests: Competing interest statement: J.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant for Allergan, Biogen, Boehringer-Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work. J.A., B.D.G., B.J.F., S.N., K.A., S.-b.W., I.A., M.A., F.P., N.K., and S.F. are named as inventors on patent applications on macular degeneration filed by the University of Virginia or the University of Kentucky. J.W.H. has received consulting fees from Celgene Corporation unrelated to this work. S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics unrelated to this work. J.A. and B.D.G. are co-founders of DiceRx.

Objective: We sought to evaluate the relationship between acute liver injury (ALI) and statins utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database., Methods: This retrospective cohort study, spanning January 2000-December 2018, compared ALI (aminotransferase > 200 U/L, severe ALI, and hospitalization with ALI) in statin users and non-users among uninfected, hepatitis C virus (HCV) mono-infected, human immunodeficiency virus (HIV)/HCV co-infected, and HIV mono-infected veterans within 18 months. We estimated adjusted Cox proportional hazards models comparing statin users and non-users and comparing statin intensity level with non-use; and estimate Cox proportional hazards models utilizing time-dependent coding of statin intensity. Adjusted models included restricted cubic splines of the propensity score as an adjustment variable., Results: From a total of 166,439 patients who met the study criteria, statin initiators were older, had higher values of body mass index, higher values of low-density lipoprotein cholesterol and triglycerides, and lower values of high-density lipoprotein cholesterol. HCV mono-infected and HIV/HCV co-infected cohorts had the highest rates of ALI, and statin users had lower rates across all outcomes of ALI compared with non-users in unadjusted analysis. Statin use is associated with a lower risk of all ALI outcomes compared with non-users. Patients on a high intensity are not associated with a statistically significant increase in risk for any ALI outcome. For each additional 30 days of treatment, there was a reduced risk of any ALI outcome across all cohorts., Conclusions: Statin initiators had a lower risk of any ALI outcome compared with non-users within 18 months regardless of HIV and/or HCV status.

Background: Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy., Methods: We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in US Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 h of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation., Findings: A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio [aHR], 1.83; 95% confidence interval [CI], 1.16-2.89; p = 0.009), but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80-2.15; p = 0.28). Both the propensity-score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78-1.82; p = 0.42 and aHR, 2.11; 95% CI, 0.96-4.62; p = 0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72-1.66; p = 0.69 and aHR, 1.25; 95% CI, 0.59-2.68; p = 0.56, respectively) compared to the no HC group., Conclusions: Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin., Funding: University of Virginia Strategic Investment Fund., Competing Interests: J.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics; he has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all for ophthalmic topics unrelated to COVID-19. J.A. is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work or to any ongoing COVID-19 clinical trials. S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all for projects unrelated to COVID-19. J.W.H. has received consulting fees from Celgene Corporation unrelated to this work. The other authors declare no competing interests., (© 2020 Elsevier Inc.)

Background: Tenofovir disoproxil fumarate (TDF)-based regimens have been associated with impaired kidney function and loss of bone mineral density among patients living with HIV (PLWH). We assess the association between TDF exposure and the odds of chronic kidney disease (CKD) and osteoporotic fracture in HIV patients., Methods: Demographics, administrative claims, and pharmacy dispensation were extracted from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Patients were categorized based on TDF utilization. Incidence rates for patients exposed and unexposed to TDF were calculated per 1000 patient-years (PYs). Logistic regression was used to calculate the odds of outcome after adjusting for baseline and clinical characteristics., Results: The sample included 4,630 PLWH who were currently exposed to TDF and 1,181 who were never exposed to TDF for the CKD analyses. For fracture analyses, the sample included 6,883 PLWH who were currently exposed to TDF and 1,951 who were never exposed to TDF. In adjusted models, current TDF exposure was associated with increased odds of CKD compared to never having been exposed (OR: 1.48, 95% CI: 1.18-1.85). Odds of fracture were 2.32 times higher for patients who were currently on a TDF regimen (OR: 2.32, 95% CI: 1.58-3.42) compared to those who had never been exposed to TDF in adjusted models., Conclusions: In a large cohort of US veterans with HIV, current exposure to TDF was associated with a 48% higher odds of CKD and a greater than two-fold increase in the odds of osteoporotic fracture.

Background: Ras-related C3 botulinum substrate 1 (Rac1) is a member of the small molecule family Rho guanosine triphosphate (GTP)ases. Recent findings reveal epigenetic downregulation of Rac1 is a mechanism of depression., Aims: The purpose of this study was to evaluate Rac1 as a therapeutic target for depression we examine the association between thiopurines, which inhibit Rac1, and the risk of depression among US veterans., Methods: This study uses data spanning January 2000-May 2019, comparing thiopurine exposure (no exposure, less than one year, 1-2.9 years, 3-5 years, and greater than five years) in two separate cohorts, a rheumatoid arthritis cohort and inflammatory bowel disease cohort. We estimate the hazard of depression using a time dependent cox proportional hazards model., Results: A total of 76,763 rheumatoid arthritis and 46,787 inflammatory bowel disease patients met all inclusion criteria. Patients exposed to thiopurines less than one year have a 27% (hazard ratio=1.272; 95% confidence interval=(1.038-1.559)) and 67% (hazard ratio=1.667 95% confidence interval=(1.501-1.850)) higher risk of depression in the rheumatoid arthritis and inflammatory bowel disease cohorts, respectively. In the inflammatory bowel disease cohort, we find the risk of depression is increased for up to five years of thiopurine exposure., Conclusion: These results provide evidence that Rac1 regulation is a viable therapeutic target for depression. Further research into therapeutics targeting Rac1 for the treatment of depression is warranted.

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 < 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.

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.

We sought to examine the progression from abdominal aortic aneurysm (AAA) diagnosis to surgery and death among diabetics with and without exposure to metformin as well as non-diabetics. We conducted a retrospective cohort study (January 2000 to July 2019) comparing 3 transitions (AAA surgery, death, and death after AAA surgery) among propensity score-matched metformin-exposed and unexposed diabetic veterans and non-diabetic veterans using the VA Informatics and Computing Infrastructure database. We fit an adjusted Cox proportional hazards model with transition-specific effects. There were 43,073 metformin-unexposed diabetics, 24,361 metformin-exposed diabetics and 56,006 non-diabetics. Compared with the non-diabetic cohort, both diabetic cohorts have a lower risk of surgery (no metformin (HR=0.740, 95% CI 0.706 to 0.776); with metformin (HR=0.770, 95% CI 0.730 to 0.813)). However, the non-metformin diabetic cohort has a higher risk of death (HR=1.024, 95% CI 1.004 to 1.045) and death after surgery (HR=1.086, 95% CI 1.013 to 1.165). The metformin-exposed diabetic cohort has a lower risk of death in the first 10 years after AAA diagnosis (HR=0.877, 95% CI 0.855 to 0.899), yet a higher risk of death 10 years after AAA diagnosis (HR=1.177, 95% CI 1.092 to 1.270) compared with non-diabetic cohort. Non-diabetics have the highest rate of AAA surgery compared with both diabetic cohorts. However, diabetics without metformin have the highest risk of death prior to, and after surgery. This research provides novel findings for patients diagnosed with AAA. The use of metformin after both AAA diagnosis and surgery should be further investigated., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rho-GTPase family of proteins, could be an Alzheimer's disease (AD) triggering co-factor due to its effect on both amyloid precursor protein (APP) and tau. Thiopurine medications, such as azathioprine and mercaptopurine, are immunosuppressants that suppress Rac1 activation. We hypothesize that due to their ability to suppress Rac1, thiopurines are associated with a lower risk of AD., Methods: To explore the relationship between thiopurines and incident AD diagnosis, we conducted a national retrospective cohort study among U.S. Veterans with inflammatory bowel disease (IBD), including Crohn's disease (CD) or ulcerative colitis (UC), as well as a non-IBD control. We created propensity score-matched cohorts and estimated the hazard ratio via the time-dependent Cox proportional hazards model., Results: The study sample size was 66,312 patients and consisted of 24,057 IBD patients (4354 thiopurine exposed and 19,703 unexposed) and 42,255 patients without IBD or thiopurine exposure. Patients exposed to thiopurines have the lowest rate of AD, and our results demonstrate for each additional year of thiopurine exposure risk of AD is reduced by 8.3%% (adjusted HR = 0.917; 95% CI = [0.851-0.989])., Discussion: Our results support the preclinical findings implicating Rac1 in the AD disease process. A national cohort study demonstrated that Rac1 is associated with the AD process consistent with the preclinical evidence. Further exploration and evaluation of Rac1 inhibition are needed., (© 2019 Published by Elsevier Inc. on behalf of the Alzheimer's Association.)

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., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aims/patients & methods: To evaluate the risk of acute kidney injury (AKI) in patients with HIV receiving proton pump inhibitors (PPI) a cohort study was conducted utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. Patients were followed from the index date until the earliest date of AKI, 120 days or end of study period, or death. Statistical analyses utilized a Cox proportional hazards model. Results: A total of 21,643 patients (6000 PPI and 15,643 non-PPI) met all study criteria. The PPI cohort had twice the risk of AKI compared with controls (2.12, hazard ratio: 1.46-3.1). Conclusion: A nationwide cohort study supported the relationship of an increased risk of AKI in patients receiving PPIs.

Objectives: To examine the risk of hypomagnesemia of HIV-positive patients adherent to proton pump inhibitors (PPIs)., Methods: A cohort study utilizing the Veterans Affairs Informatics and Computing Infrastructure was conducted on patients with (1) a complete antiretroviral therapy, (2) a serum magnesium measure during the study period, and (3) adherent to PPIs. Statistical analyses evaluated baseline characteristics between cohorts and a Cox proportional hazards model evaluating the association of hypomagnesemia while adjusting for baseline covariates., Results: A total of 6047 patients met the study inclusion criteria, 329 patients in the PPI cohort and 5718 patients in the non-PPI cohort. The stratified Cox proportional hazards model results revealed that the risk of hypomagnesemia for the PPI cohort is 3.16 times higher compared to the non-PPI cohort (adjusted hazard ratio = 3.16, 95% confidence interval = 2.56-3.9)., Conclusions: Proton pump inhibitors medication usage in HIV-positive patients is associated with a higher risk of hypomagnesemia compared to non-PPI patients.

Objective: To evaluate the risk of chronic kidney disease (CKD), cardiovascular disease (CVD), and osteoporotic fractures in human immunodeficiency virus (HIV) patients utilizing data within the Veteran's Affairs (VA) Administration system. Methods: A retrospective cohort study utilizing VA system claims (January 2000-December 2016) were extracted from the VA Informatics and Computing Infrastructure (VINCI). Cases included Veterans with an ICD-9/10 for HIV who had at least one prescription for a complete antiretroviral therapy (ART) regimen. Two non-HIV controls were exactly matched on race, sex, month, and year of birth. All patients were followed until the earliest of the following: first incidence of the outcome (identified based on diagnosis codes or laboratory data), last date of VA activity, death, or December 31, 2016. Relative risks (RR) and odds ratios (ORs) were estimated from multivariable Poisson regression models (CVD and osteoporotic fractures) and multivariable logistic regression models (CKD), respectively. Models were adjusted for demographic factors/comorbidities. Results: A total of 79,578 patients (26,526 HIV and 53,052 non-HIV) met all study criteria. The average age was 49.3 years, 38% were black, 32% were white, and 97% were male for both the HIV and control cohorts. The adjusted models demonstrated that HIV was associated with a 78% increased rate of CKD (OR = 1.78, 95% CI = 1.68-1.89), a 32% increased risk of CVD (RR = 1.32, 95% CI = 1.28-1.37), and a 38% increased risk of fractures (RR = 1.38, 95% CI = 1.23-1.56) compared to non-HIV controls. Conclusions: The risk/rate of the three outcomes were significantly higher in HIV patients compared to controls.