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Importance: More than 109,000 Americans died of drug overdose in 2022, with 81,231 overdose deaths involving opioids. Methadone, buprenorphine and naltrexone are the most widely used medications for opioid use disorders (MOUD) and the most effective intervention for preventing overdose deaths. However, there is a concern that methadone results in long QT syndrome, which increases the risk for fatal cardiac arrythmias. Currently few studies have systematically evaluated both the short‐term and long‐term differences in cardiac and mortality outcomes between MOUD. Objectives: To compare the risks of cardiac arrythmias, long QT syndrome and overall mortality between patients with opioid use disorders (OUD) who were prescribed methadone, buprenorphine or naltrexone. Design, Setting, and Participants: Retrospective cohort study based on a multicenter and nationwide database of electronic health records (EHRs) in the United States. The study population was comprised of 144,141 patients who had medical encounters for OUD in 2016‐2022, were prescribed MOUD within 1 month following a medical encounter for OUD diagnosis and had no diagnosis of cardiac arrythmias or long QT syndrome before any MOUD prescription. The study population was divided into three cohorts: (1) Methadone cohort (n = 40,938)—who were only prescribed methadone. (2) Buprenorphine cohort (n = 80,055)—who were only prescribed buprenorphine. (3) Naltrexone cohort (n = 5,738)—who were only prescribed naltrexone. Exposures: methadone, buprenorphine, or naltrexone. Main Outcomes and Measures: Cardiac arrythmias, long QT syndrome, and death. Hazard ratio (HR) and 95% confidence interval (CI) of outcomes at six different follow‐up time frames (1‐month, 3‐month, 6‐month, 1‐year, 3‐year, and 5‐year) by comparing propensity‐score matched cohorts using Kaplan‐Meier survival analysis. Results: Patients with OUD who were prescribed methadone had significantly higher risks of cardiac arrhythmias, long QT syndrome and death compared with propensity‐score matched patients with OUD who were prescribed buprenorphine or naltrexone. For the 1‐month follow‐up, the overall risk for cardiac arrythmias was 1.03% in the Methadone cohort, higher than the 0.87% in the matched Buprenorphine cohort (HR: 1.20, 95% CI: 1.04−1.39); The overall risk for long QT syndrome was 0.35% in the Methadone cohort, higher than the 0.15% in the matched Buprenorphine cohort (HR: 2.40, 95% CI: 1.75−3.28); The overall mortality was 0.59% in the Methadone cohort, higher than the 0.41% in the matched Buprenorphine cohort (HR: 1.48, 95% CI: 1.21−1.81). The increased risk persisted for 5 years: cardiac arrhythmias (HR: 1.31, 95% CI: 1.23−1.38), long QT syndrome (HR: 3.14, 95% CI: 2.76−3.58), death (HR: 1.50, 95% CI: 1.41−1.59). Conclusions and Relevance: Methadone was associated with a significantly higher risk for cardiac and mortality outcomes than buprenorphine and naltrexone. These findings are relevant to the development of guidelines for medication selection when initiating MOUD treatment and inform future medication development for OUD that minimizes risks while maximizing benefits. [ABSTRACT FROM AUTHOR]

Background and aims: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost‐effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA‐approved drugs for CUD treatment. Design: Our drug repurposing strategy combines artificial intelligence (AI)‐based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI‐based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non‐ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD. Setting The study utilized TriNetX to access EHRs from more than 90 million patients world‐wide. Genetic‐ and functional‐level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases. Participants: A total of 7742 CUD patients who received anesthesia (3871 ketamine‐exposed and 3871 anesthetic‐controlled) and 7910 CUD patients with depression (3955 ketamine‐exposed and 3955 antidepressant‐controlled) were identified after propensity score‐matching. Measurements EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription. Findings Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42–2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89–6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD‐associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand‐receptor interaction, cAMP signaling and cocaine abuse/dependence. Conclusions: Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a heterogeneous condition with high individual variabilities in clinical outcomes driven by patient demographics, genetics, brain structure features, blood biomarkers, and comorbidities. Multi‐modality data‐driven approaches have been used to discover MCI subtypes; however, disease comorbidities have not been included as a modality though multiple diseases including hypertension are well‐known risk factors for Alzheimer's disease (AD). The aim of this study was to examine MCI heterogeneity in the context of AD‐related comorbidities along with other AD‐relevant features and biomarkers. Methods: A total of 325 MCI subjects with 32 AD‐relevant comorbidities and features were considered. Mixed‐data clustering is applied to discover and compare MCI subtypes with and without including AD‐related comorbidities. Finally, the relevance of each comorbidity‐driven subtype was determined by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. Results: We identified four (five) MCI subtypes: poor‐, average‐, good‐, and best‐AD prognosis by including comorbidities (without including comorbidities). We demonstrated that comorbidity‐driven MCI subtypes differed from those identified without comorbidity information. We further demonstrated the clinical relevance of comorbidity‐driven MCI subtypes. Among the four comorbidity‐driven MCI subtypes there were substantial differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. The groups showed different behaviors, having significantly different MCI to AD prognosis, significantly different means for cognitive test‐related and plasma features, and by the proportion of comorbidities. Conclusions: Our study indicates that AD comorbidities should be considered along with other diverse AD‐relevant characteristics to better understand MCI heterogeneity. [ABSTRACT FROM AUTHOR]

Introduction: There is lack of data on COVID‐19 breakthrough infections in vaccinated patients with dementia in the United States. Methods: This is a retrospective cohort study of 262,847 vaccinated older adults (age 73.8 ± 6.81 years old) between December 2020 and August 2021. Results: Among the fully vaccinated patients with dementia, the overall risk of COVID‐19 breakthrough infections ranged from 8.6% to 12.4%. Patients with dementia were at increased risk for breakthrough infections compared with patients without dementia, with the highest odds for patients with Lewy body dementia (LBD) (adjusted odds ratio or AOR: 3.06, 95% confidence interval or CI [1.45 to 6.66]), followed by vascular dementia (VD) (AOR: 1.99, 95% CI [1.42 to 2.80]), Alzheimer's disease (AD) (1.53, 95% CI [1.22 to 1.92]), and mild cognitive impairment (MCI) (AOR: 1.78, 95% CI [1.51 to 2.11]). The incidence rate of breakthrough infections among fully vaccinated patients with dementia increased since December 2020 and accelerated after May 2021. The overall risk for hospitalization after breakthrough infections in patients with dementia was 39.5% for AD, 46.2% for VD, and 30.4% for MCI. Discussion: These results highlight the need to continuously monitor breakthrough severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections and outcomes in vaccinated patients with dementia. [ABSTRACT FROM AUTHOR]

Introduction: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long‐term effects on the dementia/AD risk remain unknown. Methods: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health‐care system from 2000 to 2020. Results: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52–0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long‐term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39–0.83) during the 20 years of follow‐up. Conclusion: TNF inhibitor use is associated with lower long‐term risk of dementia/AD among US veterans with RA. [ABSTRACT FROM AUTHOR]

Introduction: At present, there is limited data on the risks, disparity, and outcomes for COVID‐19 in patients with dementia in the United States. Methods: This is a retrospective case‐control analysis of patient electronic health records (EHRs) of 61.9 million adult and senior patients (age ≥ 18 years) in the United States up to August 21, 2020. Results: Patients with dementia were at increased risk for COVID‐19 compared to patients without dementia (adjusted odds ratio [AOR]: 2.00 [95% confidence interval (CI), 1.94–2.06], P <.001), with the strongest effect for vascular dementia (AOR: 3.17 [95% CI, 2.97–3.37], P <.001), followed by presenile dementia (AOR: 2.62 [95% CI, 2.28–3.00], P <.001), Alzheimer's disease (AOR: 1.86 [95% CI, 1.77–1.96], P <.001), senile dementia (AOR: 1.99 [95% CI, 1.86–2.13], P <.001) and post‐traumatic dementia (AOR: 1.67 [95% CI, 1.51–1.86] P <.001). Blacks with dementia had higher risk of COVID‐19 than Whites (AOR: 2.86 [95% CI, 2.67–3.06], P <.001). The 6‐month mortality and hospitalization risks in patients with dementia and COVID‐19 were 20.99% and 59.26%, respectively. Discussion: These findings highlight the need to protect patients with dementia as part of the strategy to control the COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

The FXYD family, which contains seven members, are tissue specific regulators of the Na,K-ATPase. Increased expression of FXYD5, a cancer–cell-associated membrane glycoprotein, has been associated with increased cell motility and metastatic potential. To better understand how FXYD5 may modulate cell motility, we analyzed S163, a conserved residue in all FXYD family members located in the C-terminus. Ectopic expression of human FXYD5 S163 mutants in HEK 293 cells showed that negative charge at S163 (S163D) decreased membrane localization, assessed by immunofluorescence. Coimmunoprecipitation studies revealed decreased FXYD5/Na,K-ATPase interaction for S163D compared with wild-type or S163A mutants. Interestingly, FXYD5 overexpression induced expression of vimentin, a marker of epithelial–mesenchymal transition, in murine airway epithelial cells. Because Na,K-ATPase expression is decreased in some forms of cancer and is critical for establishing cell polarity and suppressing cell motility, we analyzed S163 mutants in an epithelial cell scratch-wound model as a measure of cell migration. Wild-type FXYD5 overexpression increased reepithelialization ( p<0.0001), which was further increased in S163D mutants ( p<0.005). However, S163A mutants inhibited epithelial cell migration compared with wild-type FXYD5 overexpression ( p<0.0001). We conclude that negative charge at S163 regulates FXYD5/Na,K-ATPase interaction and that this interaction modulates cell migration across a wound in airway epithelial cells. [ABSTRACT FROM AUTHOR]