Search

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 = 0.055; 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.

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). 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. 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)). 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.

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.

Summary 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.

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.

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.

We sought to evaluate the relationship between acute liver injury (ALI) and statins utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database. 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. 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. 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: Sulfamethoxazole-trimethoprim (SXT) therapy is commonly used in HIV-infected patients and is associated with hyperkalemia and elevated serum creatinine (SCr). Objective: The purpose of this study was to examine the frequency of hyperkalemia and elevated SCr in hospitalized, HIV-infected patients receiving SXT. Methods: This was a retrospective, single-center cohort study. HIV-infected hospitalized patients receiving a minimum of 3 consecutive days of SXT were included. Patients were grouped according to high dose (≥10 mg/kg/d) and low dose (

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.

Background Deer mice (genus Peromyscus) are the most common rodents in North America. Despite the availability of reference genomes for some species, a comprehensive database of polymorphisms, especially in those maintained as living stocks and distributed to academic investigators, is missing. In the present study we surveyed two populations of P. maniculatus that are maintained at the Peromyscus Genetic Stock Center (PGSC) for polymorphisms across their 2.5 × 109 bp genome. Results High density of variation was identified, corresponding to one SNP every 55 bp for the high altitude stock (SM2) or 207 bp for the low altitude stock (BW) using snpEff (v4.3). Indels were detected every 1157 bp for BW or 311 bp for SM2. The average Watterson estimator for the BW and SM2 populations is 248813.70388 and 869071.7671 respectively. Some differences in the distribution of missense, nonsense and silent mutations were identified between the stocks, as well as polymorphisms in genes associated with inflammation (NFATC2), hypoxia (HIF1a) and cholesterol metabolism (INSIG1) and may possess value in modeling pathology. Conclusions This genomic resource, in combination with the availability of P. maniculatus from the PGSC, is expected to promote genetic and genomic studies with this animal model.

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.

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.

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.

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.The purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE.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)).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.

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.

Significance Alu elements, comprising more than 10% of the human genome, propagate via retrotransposition. This genomic expansion requires enzymatic activity of L1 that reverse transcribes Alu RNA into Alu cDNA in the nucleus. We report Alu also undergoes L1-mediated reverse transcription via self-priming in the cytoplasm independent of retrotransposition, providing evidence of human DNA synthesis in this cellular compartment. This newly discovered shunt molecule in the Alu replication cycle also induces death of the retinal pigmented epithelium, a hallmark of atrophic age-related macular degeneration. A Big Data Archeology analysis of multiple health insurance databases reveals that use of FDA-approved nucleoside reverse transcriptase inhibitors is associated with protection against macular degeneration, identifying a repurposing candidate for this blinding disease.

The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no FDA-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 years 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 that it inhibits activation of the NLRP3-ASC inflammasome in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other anti-depressant 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 triangulate to link fluoxetine as a potential drug repurposing candidate for a major unmet medical need that causes blindness in millions of people in the United States and across the world.Significance StatementDry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no FDA-approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents the assembly and activation of the NLRP3-ASC inflammasome. As a result, it also blocks the degeneration of retinal pigmented epithelium (RPE) cells in an animal model of dry AMD. Furthermore, we demonstrate through an analysis of health insurance databases that use of this FDA-approved anti-depressant drug is associated with reduced incidence of dry AMD. These studies identify that fluoxetine is a potential repurposing candidate for AMD, a prevalent cause of blindness.

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.

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.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.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.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.

Expanding pharmacist-driven antimicrobial stewardship efforts in the emergency department (ED) can improve antibiotic management for both admitted and discharged patients. We piloted a pharmacist-driven culture and rapid diagnostic technology (RDT) follow-up program in patients discharged from the ED. This was a single-center, pre- and post-implementation, cohort study examining the impact of a pharmacist-driven culture/RDT follow-up program in the ED. Adult patients discharged from the ED with subsequent positive cultures and/or RDT during the pre- (21 August 2018&ndash, 18 November 2018) and post-implementation (19 November 2018&ndash, 15 February 2019) periods were screened for inclusion. The primary endpoints were time from ED discharge to culture/RDT review and completion of follow-up. Secondary endpoints included antimicrobial agent prescribed during outpatient follow-up, repeat ED encounters within 30 days, and hospital admissions within 30 days. Baseline characteristics were analyzed using descriptive statistics. Time-to-event data were analyzed using the Wilcoxon signed-rank test. One-hundred-and-twenty-seven patients were included, 64 in the pre-implementation group and 63 in the post-implementation group. There was a 36.3% reduction in the meantime to culture/RDT data review in the post-implementation group (75.2 h vs. 47.9 h, p &lt, 0.001). There was a significant reduction in fluoroquinolone prescribing in the post-implementation group (18.1% vs. 5.4%, p = 0.036). The proportion of patients who had a repeat ED encounter or hospital admission within 30 days was not significantly different between the pre- and post-implementation groups (15.6 vs. 19.1%, p = 0.78 and 9.4% vs. 7.9%, p = 1.0, respectively). Introduction of a pharmacist culture and RDT follow-up program in the ED reduced time to data review, time to outpatient intervention and outpatient follow-up of fluoroquinolone prescribing.

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 United States Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 hours 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% CI, 1.16 to 2.89; P=0.009) but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80 to 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 to 1.82; P=0.42 and aHR, 2.11; 95% CI, 0.96 to 4.62; P=0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72 to 1.66; P=0.69 and aHR, 1.25; 95% CI, 0.59 to 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., Graphical Abstract, Highlights • Hydroxychloroquine (HC) use did not reduce the risk of ventilation or death • HC with azithromycin (AZ) did not reduce the risk of ventilation or death • HC, with or without AZ, was associated with longer length of hospital stay, In this nationwide retrospective analysis of 807 patients hospitalized with COVID-19, Magagnoli et al. report that, after adjusting for several COVID-19-relevant clinical and demographic characteristics, hydroxychloroquine use, with or without azithromycin, did not improve mortality or reduce the need for mechanical ventilation compared to no hydroxychloroquine use.

We sought to evaluate the relationship between acute liver injury (ALI) and statins utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database.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.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.Statin initiators had a lower risk of any ALI outcome compared with non-users within 18 months regardless of HIV and/or HCV status.

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.

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.

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.

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.

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.

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, Inflammasome activation may contribute to type 2 diabetes, but whether targeting inflammasome is beneficial is unclear. Here the authors show that repurposing nucleoside reverse transcriptase inhibitors for inhibiting inflammasome activation is associated with reduced diabetes development in people and improves insulin sensitivity in experimental settings.

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.

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 Ve...

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.

Objectives: To evaluate the association between human immunodeficiency virus (HIV) patients and medical costs (inpatient, outpatient, pharmacy, total) using a national cohort of HIV-infected Veterans and non-HIV matched controls within the Veteran’s Affairs (VA) Administration system. Design: This study used claims (January 2000 to December 2016) extracted from the VA Informatics and Computing Infrastructure and VA Health Economics Resource Center. Cases included Veterans with an International Classification of Diseases, Ninth Revision/International Classification of Diseases, Tenth Revision for HIV with at least 1 prescription for a complete antiretroviral therapy regimen (January 2000 to September 2016). Two non-HIV controls were exact matched on race, sex, month, and year of birth. All patients were followed until the earliest of the following: last date of VA activity, death, or December 31, 2016. 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. Adjusted multivariable logistic regression models demonstrated that HIV was associated with higher odds of incurring a pharmacy cost (odds ratio = 2286.45, 95% confidence interval: 322.79-16 195.82), 4-fold, and 2-fold higher odds of incurring both outpatient and inpatient costs compared to the matched controls, respectively. In adjusted multivariable gamma generalized linear models, HIV-positive patients had an almost 4-fold, 17-fold, and almost 2-fold higher cost than matched controls in total, pharmacy, and outpatient costs, respectively. Conclusions: This study found an association between HIV-positive patients having higher odds of incurring a medical cost as well as higher medical costs compared to non-HIV controls.

tudy Objective To evaluate the odds of achieving viral suppression in human immunodeficiency virus (HIV) patients using antiretroviral therapy as a single-tablet regimen (STR) or multiple-tablet regimen (MTR). Design Retrospective cohort study. Data Sources South Carolina Medicaid medical and pharmacy paid claims data were obtained from the South Carolina Revenue and Fiscal Affairs Office; laboratory data were obtained from the South Carolina Department of Health and Environmental Control. Patients A total of 1536 patients who were dispensed a complete STR (477 patients) or MTR (1059 patients) regimen lasting at least 60 days between January 1, 2006, and December 31, 2013. Measurements and Main Results The analysis examined adherence levels and regimen type on odds of viral load suppression. Regimen adherence levels (90–94%, 85–89%, 80–84%, and less than 80%) were compared with the gold standard adherence for HIV of 95% or greater. Patients were followed from index date until the earliest date of regimen discontinuation, treatment switch, end of study period, last date of eligibility, or death. Differences in outcomes were evaluated by χ2, Wilcoxon rank sum statistical tests, and multivariate regression models controlling for covariates. For STR regimens we find that, when compared with 95% or greater adherence, there is no statistical difference in the odds of viral suppression with adherence levels greater than or equal to 80%. However, adherence levels greater than or equal to 95% were associated with a greater odds of viral suppression when compared with less than 80% STR adherence (odds ratio [OR] 2.57, Dunnett 95% confidence interval [CI] 1.04–6.32). For MTR regimens, there was no statistical difference in the odds of viral suppression for the adherence level 90–94% compared with the 95% or greater adherence (OR 3.59, Dunnett 95% CI 0.805–16.043). However, the 95% or greater adherence has greater odds of viral suppression compared with all other MTR adherence levels. In addition, no difference was found in the odds of viral suppression between STR and MTR for all adherence levels. Conclusions Compared with 95% or greater adherence, STR regimens achieve viral suppression with adherence levels of 80% or greater, whereas MTR regimens require adherence levels of 90% or greater to achieve viral suppression in South Carolina Medicaid patients with HIV/AIDS.

Antiretroviral therapy (ART) is a combination treatment involving three or more antiretroviral agents for patients with HIV. ART has reduced HIV-related morbidity and mortality via single-tablet or multiple-tablet regimens. Single-tablet regimens, with their lower pill burdens, have demonstrated higher adherence rates, improved viral suppression, and reduced resource use compared with multiple-tablet regimens. In addition, select newer ARTs do not require the high levels of adherence for viral load suppression required by older ART formulations.

STUDY OBJECTIVE To evaluate the impact of pill burden on outcomes in patients with human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) receiving antiretroviral therapy (ART) as a single-tablet regimen (STR) or multiple-tablet regimen (MTR). DESIGN Retrospective cohort study. DATA SOURCES South Carolina Medicaid medical and pharmacy paid claims data were obtained from the South Carolina Revenue and Fiscal Affairs Office; laboratory data were obtained from the South Carolina Department of Health and Environmental Control. PATIENTS A total of 2174 patients covered by South Carolina Medicaid who were dispensed a complete ART STR (580 patients) or MTR (1594 patients) lasting at least 60 days between January 1, 2006, and December 31, 2013. MEASUREMENTS AND MAIN RESULTS Outcomes were ART adherence; risk of, time to, and total number of hospitalizations; and viral load suppression. Patients were followed from the index date (start date of their complete ART regimen) until the earliest date of one of the following: treatment discontinuation; treatment switch from MTR to STR, or vice versa; end of study period; last date of Medicaid eligibility; or death. Differences in outcomes were evaluated by using bivariate χ(2) and Wilcoxon rank sum tests, as well as multivariate regression models controlling for covariates measured during a 6-month baseline period. The STR and MTR cohorts were, on average, similar in terms of age at index date, Charlson Comorbidity Index score, sex, drug abuse, and mental health diagnoses, but they differed significantly in racial composition, index year of regimen, previous treatment, baseline viral load, and CD4 measures. The bivariate analysis revealed that the STR cohort was more adherent (p