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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., Author Summary: This manuscript outlines our project involving the application of AGATHA, an AI-based literature mining tool, to discover drugs with the potential for repurposing in the context of neurocognitive disorders. The primary objective is to identify connections between approved medications and specific health conditions through advanced statistical analysis, including techniques like Partial Least Squares Discriminant Analysis (PLSDA) and unsupervised clustering. The methodology involves grouping scientific terms related to different health conditions and genes, followed by building discrimination models to extract lists of disease-specific genes. These genes are then analyzed through pathway analysis to select candidates for drug repurposing.

Genome instability is a hallmark of cancer and are driven by mutations in oncogenes and tumor suppressor genes. Despite successes seen with select targeted therapeutics, this type of personalized medicine is only beneficial for a small subpopulation of cancer patients who have one of a few actionable genetic changes. Most tumors also contain hundreds of passenger mutations that offered no fitness advantage or disadvantage during tumor evolution. Mutations in known pharmacogenetic (PGx) loci for which germline variants encode variability in drug response can cause somatically acquired drug sensitivity. The NUDT15 gene is a known PGx locus that participates in the rate-limiting metabolism of thiopurines. People with two defective germline alleles of NUDT15 are hypersensitive to the toxic effects of thiopurines. NUDT15 is located adjacent to the Retinoblastoma ( RB1 ) tumor suppressor gene, which often undergoes homozygous deletion in retinoblastomas and other epithelial cancers. We observed that RB1 undergoes homozygous deletions in 9.4% of prostate adenocarcinomas and 2.5% of ovarian cancers, and in nearly all of these cases NUDT15 is also lost. Moreover, 44% of prostate adenocarcinomas and over 60% of ovarian cancers have lost one allele of NUDT15, which predicts that a majority of all prostate and ovarian cancers have somatically acquired hypersensitivity to thiopurine treatment. We performed a retrospective analysis of >16,000 patients in the US Veterans Administration health care system and found concurrent xanthine oxidase inhibition (XOi) and thiopurine usage for non-cancer indications is significantly associated with reduced incidence of prostate cancer. The hazard ratio for the development of prostate cancer in patients treated with thiopurines and XOi was 0.562 (0.301-1.051) for the unmatched cohort and 0.389 (0.185-0.819) for the propensity score matched cohort. We experimentally depleted NUDT15 from ovarian and prostate cancer cell lines and observed a dramatic sensitization to thiopurine-induced and DNA damage-dependent toxicity. These results indicate that somatic loss of NUDT15 predicts therapeutic sensitivity to a low cost and well tolerated drug with a broad therapeutic window.

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.

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.

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.

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.

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.

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.

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.)

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.

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.

Spontaneous bacterial peritonitis (SBP) is a recognized cause of morbidity and mortality in cirrhotic patients. Enterobacteriaceae have been isolated from the majority of peritonitis cases and the gram negative aerobe Escherichia coli is the most commonly isolated organism. Anaerobic organisms are rarely isolated because of the high oxygen tension in ascetic fluid. We report a patient with a history of alcoholic cirrhosis who developed SBP and concurrent bacteremia with the anaerobe Clostridium tertium . The patient was successfully treated with intravenous antibiotics and was discharged home on oral ciprofloxacin. This case report is unique in that it is the fourth documented Clostridium tertium SBP case, utilized MALDI-TOF mass spectrometry for organism identification, and susceptibility testing for select antibiotics was performed., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To assess the association of cardiovascular mortality in patients prescribed azithromycin compared with patients prescribed alternative antibiotics in an outpatient setting., Methods: This study was a retrospective observational analysis using the South Carolina Medicaid claims and pharmacy databases over the years from 2000 to 2011 housed at the Revenue and Fiscal Affairs Office. Study antibiotics included azithromycin, amoxicillin, clindamycin, clarithromycin and quinolones (levofloxacin, ciprofloxacin and moxifloxacin), and excluded patients at a high risk of death from causes other than the study antibiotics. This study used both matching and regression adjustment with propensity scores to reduce possible bias in the estimated treatment (group) effect from confounders., Results: The total number of prescriptions evaluated in the study include: 283,743 azithromycin; 143,191 amoxicillin; 52,714 clindamycin; 38,133 clarithromycin and 49,734 for the quinolones. After propensity score weighting, cardiac deaths per million within the first 5 days were: 84.6 for azithromycin, 78.3 for clarithromycin, 69.4 for amoxicillin, 61.6 for quinolones and 15.0 for clindamycin. Our multivariate models reveal that the study antibiotics' (amoxicillin, clindamycin, clarithromycin, levofloxacin, ciprofloxacin and moxifloxacin) mortality rates are not statistically different from azithromycin in any time interval (days: 0-5, 6-10, 0-10 and 0-30). In comparison with previous studies, the results are consistent in Amoxicillin. In the first 5 and 10 days, it is associated with lower odds of cardiovascular death than azithromycin (5 days: odds ratio [OR]: 0.70 [95% CI: 0.25-1.99]; 10 days: OR: 0.92 [95% CI: 0.39-2.14]). However, we find no statistically significant difference between the two antibiotics., Conclusion: Our study shows that the odds of cardiovascular mortality between azithromycin and other antibiotics are not statistically significantly different and previous published findings may not be applicable to the general population. Additionally our results suggest that while we cannot rule out the increased risk of cardiovascular death from azithromycin in patients at low risk of death, the risk may not be as large initial studies suggest. Further research is needed to define the population at greatest risk.

Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem. Encephalopathy is a type of neurotoxicity that is defined as a diffuse disease of the brain that alters brain function or structure. We report a patient with normal renal function who developed ertapenem-induced encephalopathy manifesting as altered mental status, hallucinations, and dystonic symptoms. The patient's symptoms improved dramatically following ertapenem discontinuation, consistent with case reports describing ertapenem neurotoxicity in renal dysfunction. Since clinical evidence strongly suggested ertapenem causality, we utilized the Naranjo Scale to estimate the probability of an adverse drug reaction to ertapenem. Our patient received a Naranjo Scale score of 7, suggesting a probable adverse drug reaction, with a reasonable temporal sequence to support our conclusion., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: The objectives of the study were to measure the utilization rates of antidiabetic drugs in diabetic patients with dementia and to assess the impact of dementia on antidiabetic drug use., Materials & Methods: This study was a pooled cross-sectional study of the Medicare Current Beneficiaries Survey from 2006 to 2010., Results & Conclusion: Lower utilizations of biguanides, DPP-4 inhibitors and thiazolidinediones were observed in dementia patients. The likelihood of using antidiabetic drugs was about 30% (odds ratio: 0.69; 95% CI: 0.56-0.84) lower in dementia patients and 40% (odds ratio: 0.61; 95% CI: 0.44-0.84) lower in patients with Alzheimer's disease. Healthcare providers should be aware of underuse of antidiabetic drugs in patients with dementia.

Objectives: To evaluate the impact of antiretroviral therapy as a single-tablet regimen (STR) and multiple-tablet regimen (MTR) on outcomes in human immunodeficiency virus (HIV)/AIDS patients using electronic health records from the Veterans Healthcare Administration (VHA)., Study Design: Retrospective cohort., Methods: This study evaluated VHA patients to whom HIV medications were dispensed as STRs or MTRs during the study period (January 1, 2006, to July 30, 2012). Patients were followed from the index date (ie, start of regimen) until treatment discontinuation, end of study period, last date of healthcare-related activity, or death. Differences in outcomes of hospitalization, adherence defined as a medication possession ratio of ≥ 95%, and undetectable viral load were evaluated using a Cox-proportional hazard and logistic model controlling for covariates measured during a 6-month baseline period., Results: A total of 15,602 patients (6191 STR and 9411 MTR) met all study criteria. The study sample was, on average, aged 52 years with similar CD4 counts (mean ± SD: 432.2 ± 282.8 vs 419.3 ± 280.9; P = .287), but a significantly lower proportion of STR versus MTR patients had an undetectable viral load at baseline (42% vs 46%; P < .001). After controlling for baseline covariates, the STR cohort had twice the odds of being adherent (odds ratio [OR], 1.98; P < .001), 31% had a significantly lower hazard of having a hospitalization (hazard ratio, 0.69; P < .001), and 21% had higher odds of having an undetectable viral load during follow-up (OR, 1.21; P < .001)., Conclusions: STR is associated with higher adherence rates, decreased hospitalizations, and more patients with an undetectable viral load in VHA patients with HIV/AIDS.

Purpose: Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithromycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin., Methods: We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dispensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days., Results: During treatment days 1 to 5, patients receiving azithromycin had significantly increased risk of death (hazard ratio [HR] = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically different. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32-2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82)., Conclusions: Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

Infection with Clostridium difficile is currently the leading cause of infectious diarrhea in hospitalized patients, and recent surveillance data indicate that C. difficile has surpassed methicillin-resistant Staphylococcus aureus as the number one cause of hospital-acquired infections in some areas of the USA. In addition, concern over C. difficile has increased over the past decade due to the appearance of new hypervirulent strains. Metronidazole and vancomycin have remained the treatments of choice for initial therapy of primary infection with C. difficile for the past 25 years, but the persistence of spores leads to a recurrence of infection in an estimated 20-25% of patients. Patients who have one recurrent episode have up to a 65% chance of having additional recurrence. While the judicious use of antimicrobials in accordance with antibiotic stewardship guidelines remains the most effective method for the control of C. difficile, the high recurrence rate, increasing incidence, and changing epidemiology of C. difficile has led to an increased interest in the study of alternative strategies for the prevention and treatment of C. difficile disease. These alternative strategies attempt to eliminate C. difficile spores, replenish the normal gut flora, reduce the C. difficile toxin load in the bowel, or bolster the patient's own immune response to the C. difficile toxins. To evaluate the available evidence on these alternative strategies, we conducted a literature search of MEDLINE (1966-March 2011) and International Pharmaceutical Abstracts (1970-March 2011). Available citations from these articles were also utilized. The aim of this review is to summarize the available evidence for alternative treatment strategies for C. difficile disease and to make recommendations for their place in therapy., (Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Oppositional defiant disorder is defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., as a recurrent pattern of developmentally inappropriate, negativistic, defiant, and disobedient behavior toward authority figures. This behavior often appears in the preschool years, but initially it can be difficult to distinguish from developmentally appropriate, albeit troublesome, behavior. Children who develop a stable pattern of oppositional behavior during their preschool years are likely to go on to have oppositional defiant disorder during their elementary school years. Children with oppositional defiant disorder have substantially strained relationships with their parents, teachers, and peers, and have high rates of coexisting conditions such as attention-deficit/hyperactivity disorder and mood disorders. Children with oppositional defiant disorder are at greater risk of developing conduct disorder and antisocial personality disorder during adulthood. Psychological intervention with both parents and child can substantially improve short- and long-term outcomes. Research supports the effectiveness of parent training and collaborative problem solving. Collaborative problem solving is a psychological intervention that aims to develop a child's skills in tolerating frustration, being flexible, and avoiding emotional overreaction. When oppositional defiant disorder coexists with attention-deficit/hyperactivity disorder, stimulant therapy can reduce the symptoms of both disorders.

Reading difficulties are common and are associated with poor long-term academic achievement. Evaluation of a child's developmental, educational, and family histories in conjunction with standardized screening tests (e.g., Ages and Stages Questionnaires, Parents' Evaluation of Developmental Status, Safety Word Inventory and Literacy Screener) can increase recognition of risk factors for reading difficulties. Validated, office-based, standardized screening tests and school-administered standardized achievement tests (e.g., California Achievement Tests, Iowa Tests of Basic Skills, Metropolitan Achievement Tests, Stanford Achievement Test) can be used to assess school-age children with reading difficulties. Reading difficulties in children often are caused by environmental and organic risk factors. However, many children have reading or learning disabilities and will have lifelong difficulties with reading despite adequate intervention. Children with substantial reading difficulties should receive a full educational assessment. There is good evidence that individualized instruction emphasizing increased phonologic awareness can have a favorable long-term effect on academic achievement.

Parents and physicians often dismiss seemingly minor motor difficulties in children. Approximately 6 percent of school-aged children have coordination problems serious enough to interfere with academic performance and social integration. These problems often arise during the early school years and manifest in difficulties with such simple motor tasks as running, buttoning, or using scissors. Increasing evidence shows that rather than improving over time, these motor difficulties remain stable throughout adolescence and adulthood. While these children are initially singled out for motor difficulties, their problems are rarely limited to poor motor coordination. Many of them have a range of associated deficits, such as attention-deficit/hyperactivity disorder, learning disabilities, poor handwriting and drawing skills, and emotional immaturity. Associated problems magnify with time, and as teenagers, these children have higher rates of educational, social, and emotional problems. Diagnosis is determined by taking a careful history that includes a review of fine motor, visual, adaptive, and gross motor milestones, and performing a physical examination. Formal standardized testing may be indicated. Referral to occupational therapy that is appropriately individualized to the needs of each child appears to be effective. To aid in management, the family physician must be aware of this condition, as well as the associated coexisting deficits.