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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.
Subject(s)
Bilirubin , Influenza, Human , Venous Thromboembolism , Humans , Venous Thromboembolism/blood , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology , Bilirubin/blood , Male , Female , Influenza, Human/blood , Influenza, Human/complications , Middle Aged , Retrospective Studies , Aged , Risk Factors , Cohort Studies , IncidenceABSTRACT
Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.
Subject(s)
Cisplatin , Fluoxetine , Fluvoxamine , Hearing Loss , Tinnitus , Humans , Cisplatin/adverse effects , Hearing Loss/chemically induced , Retrospective Studies , Male , Tinnitus/chemically induced , Female , Fluoxetine/adverse effects , Fluoxetine/therapeutic use , Middle Aged , Fluvoxamine/adverse effects , Fluvoxamine/therapeutic use , AgedABSTRACT
Importance: Age-related macular degeneration (AMD) is a serious and common ophthalmologic disorder that is hypothesized to result, in part, from inflammatory reactions in the macula. Alzheimer disease (AD) treatment, acetylcholinesterase inhibitors (AChEIs), have anti-inflammatory effects and it remains unclear if they modify the risk of AMD. Objective: To investigate the association between AChEI medications and the incidence of AMD. Design, Setting, and Participants: This propensity score-matched retrospective cohort study took place at health care facilities within the US Department of Veterans Affairs (VA) health care system from January 2000 through September 2023. Participants included patients diagnosed with AD between ages 55 and 80 years with no preexisting diagnosis of AMD in the VA database. Exposure: AChEIs prescription dispensed as pharmacologic treatments for AD. Main Outcomes and Measure: The first diagnosis of AMD. Results: A total of 21â¯823 veterans with AD (mean [SD] age, 72.3 [6.1] years; 21â¯313 male participants [97.7%] and 510 female participants [2.3%]) were included. Propensity score-matched Cox model reveals each additional year of AChEI treatment was associated with a 6% lower hazard of AMD (hazard ratio, 0.94; 95% CI, (0.89-0.99). Conclusions and Relevance: This observational study reports a small reduction in the risk of AMD among veterans with AD receiving AChEIs. Randomized clinical trials would be needed to determine if there is a cause-and-effect relationship and further research is required to validate these findings across diverse populations.
Subject(s)
Alzheimer Disease , Macular Degeneration , Humans , Male , Female , Aged , Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Alzheimer Disease/epidemiology , Cholinesterase Inhibitors/therapeutic use , Acetylcholinesterase/therapeutic use , Retrospective Studies , Macular Degeneration/diagnosis , Macular Degeneration/drug therapy , Macular Degeneration/epidemiologyABSTRACT
More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.
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Haloperidol is an anti-psychotic used for the treatment of schizophrenia or Tourette disorder. Here we report, by studying three large administrative health insurance databases, that haloperidol use is associated with a reduced risk of developing rheumatoid arthritis. A meta-analysis revealed a 31% reduced hazard of incident rheumatoid arthritis among individuals with schizophrenia or Tourette disorder treated with haloperidol compared to those treated with other anti-psychotic drugs. These findings suggest a potential benefit of haloperidol in rheumatoid arthritis and provide a rationale for randomized controlled trials to provide causal insights.
ABSTRACT
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.
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Oral factor Xa (FXa) inhibitors significantly reduce incidence of stroke and thromboembolic events in patients with atrial fibrillation or venous thromboembolism. Due to various factors and the lack of a randomized controlled trial comparing andexanet alfa to usual care, non-specific replacement agents including 4 F-PCC are still used off-label for FXa inhibitor bleed management. Clinical and mortality data were extracted from the inpatient medical data and Veteran Affairs (VA) vital status files over the time of March 2014 through December 2020. Propensity score-weighted models were used for this retrospective cohort study using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). The study included 255 patients (85-andexanet alfa and 170-4 F-PCC) exposed to an oral factor Xa inhibitor and hospitalized with an acute major, gastrointestinal (GI), intracranial (ICH) or other bleed. In-hospital mortality was significantly lower in the andexanet alfa cohort compared to the 4 F-PCC cohort (10.6% vs. 25.3%, p = 0.01). Propensity score-weighted Cox models reveal a 69% lower hazard of in-hospital mortality for those treated with andexanet alfa (HR 0.31, 95% CI 0.14-0.71) compared to those treated with 4 F-PCC. Additionally, those treated with andexanet alfa had a lower 30-day mortality rate and lower 30-day hazard of mortality in the weighted Cox model (20.0% vs. 32.4%, p = 0.039; HR 0.54, 95% CI 0.30-0.98) compared to those treated with 4 F-PCC. Among 255 US veterans with major bleeding in the presence of an oral factor Xa inhibitor, treatment with andexanet alfa was associated with lower in-hospital and 30-day mortality than treatment with 4 F-PCC.
Subject(s)
Factor Xa , Veterans , Humans , Factor Xa/pharmacology , Factor Xa Inhibitors/adverse effects , Retrospective Studies , Blood Coagulation Factors/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/drug therapy , Antithrombin III , Factor IX/therapeutic use , Recombinant Proteins/adverse effects , Anticoagulants/adverse effectsABSTRACT
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.
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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.
Subject(s)
Gout , Uric Acid , Humans , Uric Acid/therapeutic use , Gout Suppressants/therapeutic use , Cohort Studies , Treatment Outcome , Gout/drug therapyABSTRACT
Innate immune signaling through the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia. We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B infections, also inhibit inflammasome activation. Here we report that in humans, NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States. Treatment of aged 5xFAD mice (a mouse model of amyloid-ß deposition that expresses five mutations found in familial AD) with Kamuvudine-9 (K-9), an NRTI-derivative with enhanced safety profile, reduced Aß deposition and reversed their cognitive deficit by improving their spatial memory and learning performance to that of young wild-type mice. These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of NRTIs or K-9 in AD.
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BACKGROUND: By inhibiting xanthine oxidase, subsequent inflammatory cytokine release and the resulting breakdown of the blood-retina barrier, allopurinol may limit the inflammation-driving diabetic macular edema (DME). METHODS: We examined the relationship between allopurinol and DME among type 2 diabetic United States veterans using a retrospective cohort study. We used propensity score matching and Cox hazard models to estimate the risk of DME. RESULTS: Propensity score-matched Cox models revealed allopurinol was associated with a 24.6% reduction in the risk of DME (HR = 0.754; 95% CI = (0.684-0.831)). CONCLUSION: Allopurinol could reduce the risk of DME, one of the major causes of visual disturbance among diabetic patients. Further research into the effects of allopurinol on DME is warranted.
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Medicare Annual Wellness Visits (AWVs) are annual appointments with the primary care team to prepare personalized prevention plans and focus on gaps in care. Although beneficial, AWVs are often difficult for providers to schedule and complete due to the increased time commitments compared to other visits. The purpose of this study was to assess the clinical, economic and patient-level value of newly implemented pharmacist-led AWVs within a rural Federally Qualified Health Center (FQHC). This retrospective, cohort study included patients who completed an AWV between 1 October 2021, and 14 February 2022. The primary objective was to compare the per clinician rate of completed AWVs between pharmacists and providers. The secondary objectives were to compare revenue generated, interventions made, and patient satisfaction between pharmacist- and provider-led AWVs. During the study period, nine providers completed 139 AWVs (15.4/provider) and two pharmacists completed 116 AWVs (58/pharmacist). Proportions of interventions ordered among those due in eligible patients were similar between pharmacists and providers (47.6% vs. 44.5%; p = 0.356). Patient satisfaction was overall positive with no difference between groups. Pharmacist-led AWVs increased completion of AWVs by 83% over a 20-week period, including significantly more initial, compared to subsequent, AWVs than providers. Sustainability of pharmacist-led AWVs at this FQHC is supported by study outcomes.
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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.
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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.
Subject(s)
Melatonin , Sepsis , Veterans , Hospitalization , Humans , Male , Melatonin/therapeutic use , Retrospective Studies , Sepsis/drug therapyABSTRACT
BACKGROUND: Arachidonic acid (AA), which is metabolized via the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways, was found to be associated with venous thromboembolism (VTE). Metabolites of the LOX pathway include cysteinyl (Cys) Leukotrienes (LT), potent proinflammatory mediators, which have also been implicated in cardiovascular disease. OBJECTIVE: The purpose of this study was to examine if cysteinyl leukotriene receptor blockade by montelukast, lowers the risk of VTE. METHODS: We conducted a retrospective cohort study examining VTE risk among COPD patients from the United States Department of Veterans Affairs. We use propensity score matching and Cox survival models to estimate the hazard ratio comparing montelukast exposure to non-exposure. Montelukast exposure was associated with a 15.9% reduction in risk of VTE compared to those unexposed (HR= 0.841; 95% CI= (0.758-0.934)). CONCLUSION: The results of this study demonstrate that targeting LTs might be beneficial for VTE prophylaxis using the clinically available LT inhibitor, montelukast. Importantly, further research on LTs is warranted to fully understand and validate this relationship.
Subject(s)
Quinolines , Venous Thromboembolism , Acetates/pharmacology , Acetates/therapeutic use , Cyclopropanes , Humans , Leukotriene Antagonists/pharmacology , Leukotriene Antagonists/therapeutic use , Leukotrienes , Quinolines/pharmacology , Quinolines/therapeutic use , Receptors, Leukotriene/metabolism , Retrospective Studies , Sulfides , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & controlABSTRACT
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.
ABSTRACT
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.