Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study.

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide's potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42-0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46-0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29-0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42-1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.

Association of semaglutide with risk of suicidal ideation in a real-world cohort.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

Risk for diagnosis or treatment of mood or anxiety disorders in adults after SARS-CoV-2 infection, 2020-2022.

COVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06-1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01-1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13-1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30-1.40]).

Liver abnormalities following SARS-CoV-2 infection in children 1 to 10 years of age.

OBJECTIVE: Beginning in October 2021 in the USA and elsewhere, cases of severe paediatric hepatitis of unknown aetiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading aetiological suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities. DESIGN: We conducted a study using retrospective cohorts of deidentified, aggregated data from the electronic health records of over 100 million patients contributed by US healthcare organisations. RESULTS: Compared with propensity score matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (HR (95% CI) 2.16 (1.74 to 2.69)) or total bilirubin (HR (95% CI) 3.02 (1.91 to 4.78)), or new diagnoses of liver diseases (HR (95% CI) 1.67 (1.21 to 2.30)) from 1 to 6 months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years) or illness requiring hospitalisation all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections. CONCLUSION: These results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare (~1 in 1000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver.

Ischemic stroke after COVID-19 bivalent vaccine administration in patients aged 65 years and older in the United States.

The Centers for Disease Control and Prevention announced in January 2023 a potential connection between administration of the Pfizer novel coronavirus disease-2019 (COVID-19) bivalent vaccine booster and ischemic stroke (IS). A retrospective cohort study was conducted to compare the hazard of IS in patients aged 65 years and over administered the Pfizer bivalent booster versus those administered the Pfizer/Moderna monovalent or Moderna bivalent boosters. De-identified patient electronic health data were collected from TriNetX, a cloud-based analytics platform that includes data from over 90 million unique patients in the United States. Patients aged 65 years and over at the time of administration of a Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent booster were included for analysis. Cohorts were propensity-score matched. The hazard ratios (HR) and 95% confidence intervals (CI) for IS between matched cohorts at 1-21 and 22-42 days after booster administration were calculated. There was reduced hazard of IS in the Pfizer bivalent cohort compared to the monovalent cohort at both timepoints: 1-21 days after vaccination (HR: 0.54, 95% CI: 0.47-0.62), and 22-42 days after vaccination (HR: 0.62, 95% CI: 0.54-0.72) (n = 79,036 patients per cohort). There was reduced hazard of IS in the Pfizer bivalent cohort compared to the Moderna bivalent cohort at 1-21 days after vaccination (HR: 0.75, 95% CI: 0.58-0.96) (n = 26,962 patients per cohort). This analysis provides no evidence that the Pfizer bivalent vaccine is associated with increased hazard of IS compared to the monovalent or Moderna bivalent vaccines.

Time trend and seasonality in medically attended respiratory syncytial virus (RSV) infections in US children aged 0-5 years, January 2010-January 2023.

OBJECTIVE: The long-term time trend and seasonality variations of first-time medically attended respiratory syncytial virus (RSV) infections among young children are unknown. We aim to examine the time trend of medically attended first-time RSV infections among young children in the USA from January 2010 through January 2023. DESIGN: This is a population-based cohort study using electronic health records (EHRs). Monthly incidence rate of medically attended first-time RSV infection (cases per 10 000 000 person-days). A time-series regression model was used to model and predict time trends and seasonality. SETTING: Multicenter and nationwide TriNetX Network in the USA. PARTICIPANTS: The study population comprised children aged 0-5 years who had medical visits during the period of January 2010 to January 2023. RESULTS: The data included 29 013 937 medical visits for children aged 0-5 years (46.5% girls and 53.5% boys) from January 2010 through January 2023. From 2010 through 2019, the monthly incidence rate of first-time medically attended RSV infection in children aged 0-5 years followed a consistent seasonal pattern. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. In 2020, the seasonal variation disappeared with a peak incidence rate of 20 cases per 1 000 000 person-days, a decrease of 97.4% from the expected peak rate (rate ratio or RR: 0.026, 95% CI 0.017 to 0.040). In 2021, the seasonality returned but started 4 months earlier, lasted for 9 months, and peaked in August at a rate of 753 cases per 1 000 000 person-days, a decrease of 9.6% from the expected peak rate (RR: 0.90, 95% CI 0.82 to 0.99). In 2022, the seasonal pattern is similar to prepandemic years but reached a historically high rate of 2182 cases per 10 000 000 person-days in November, an increase of 143% from the expected peak rate (RR: 2.43, 95% CI 2.25 to 2.63). The time trend and seasonality of the EHR-based medically attended RSV infections are consistent with those of RSV-associated hospitalisations from the Centers for Disease Control and Prevention (CDC) survey-based surveillance system. CONCLUSION: The findings show the disrupted seasonality during the COVID-19 pandemic and a historically high surge of paediatric RSV cases that required medical attention in 2022. Our study demonstrates the potential of EHRs as a cost-effective alternative for real-time pathogen and syndromic surveillance of unexpected disease patterns including RSV infection.

Association of COVID-19 with respiratory syncytial virus (RSV) infections in children aged 0-5 years in the USA in 2022: a multicentre retrospective cohort study.

OBJECTIVE: To investigate whether COVID-19 infection was associated with increased risk for incident respiratory syncytial virus (RSV) infections and associated diseases among young children that might have contributed to the 2022 surge of severe paediatric RSV cases in the USA. DESIGN: This is a retrospective population-based cohort study. Five outcomes were examined, including overall RSV infection, positive lab test-confirmed RSV infection, clinically diagnosed RSV diseases, RSV-associated bronchiolitis and unspecified bronchiolitis. Risk ratio (RR) and 95% CI of the outcomes that occurred during the 2022 and 2021 RSV seasons were calculated by comparing propensity-score matched cohorts. SETTING: Nationwide multicentre database of electronic health records (EHRs) of 61.4 million patients in the USA including 1.7 million children 0-5 years of age, which was accessed through TriNetX Analytics that provides web-based and secure access to patient EHR data from hospitals, primary care and specialty treatment providers. PARTICIPANTS: The study population consisted of 228 940 children of 0-5 years with no prior RSV infection who had medical encounters in October 2022. Findings were replicated in a separate study population of 370 919 children of 0-5 years with no prior RSV infection who had medical encounters in July 2021-August 2021 during a non-overlapping time period. RESULTS: For the 2022 study population (average age 2.4 years, 46.8% girls, 61% white, 16% black), the risk for incident RSV infection during October 2022-December 2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (RR 1.40, 95% CI 1.27 to 1.55); and among children aged 0-1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR 1.40, 95% CI 1.21 to 1.62). For the 2021 study population (average age 2.2 years, 46% girls, 57% white, 20% black), the risk for incident RSV infection during July 2021-December 2021 was 4.85% for children with prior COVID-19 infection, higher than 3.68% for the matched children without COVID-19 (RR 1.32, 95% CI 1.12 to 1.56); and 7.30% for children aged 0-1 year with prior COVID-19 infection, higher than 4.98% for matched children without (RR 1.47, 95% CI 1.18 to 1.82). CONCLUSION: COVID-19 was associated with a significantly increased risk for RSV infections among children aged 0-5 years in 2022. Similar findings were replicated for a study population of children aged 0-5 years in 2021. Our findings suggest that COVID-19 contributed to the 2022 surge of RSV cases in young children through the large buildup of COVID-19-infected children and the potential long-term adverse effects of COVID-19 on the immune and respiratory system.

Liver abnormalities following SARS-CoV-2 infection in children under 10 years of age.

Objective: Beginning in October 2021 in the US and elsewhere, cases of severe pediatric hepatitis of unknown etiology were identified in young children. While the adenovirus and adenovirus-associated virus have emerged as leading etiologic suspects, we attempted to investigate a potential role for SARS-CoV-2 in the development of subsequent liver abnormalities. Design: We conducted a study utilizing retrospective cohorts of de-identified, aggregated data from the electronic health records of over 100 million patients contributed by US health care organizations. Results: Compared to propensity-score-matched children with other respiratory infections, children aged 1-10 years with COVID-19 had a higher risk of elevated transaminases (Hazard ratio (HR) (95% Confidence interval (CI)) 2.16 (1.74-2.69)) or total bilirubin (HR (CI) 3.02 (1.91-4.78)), or new diagnoses of liver diseases (HR (CI) 1.67 (1.21-2.30)) from one to six months after infection. Patients with pre-existing liver abnormalities, liver abnormalities surrounding acute infection, younger age (1-4 years), or illness requiring hospitalization all had similarly elevated risk. Children who developed liver abnormalities following COVID-19 had more pre-existing conditions than those who developed abnormalities following other infections. Conclusion: These results indicate that SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. While rare (~1 in 1,000), SARS-CoV-2 is a risk for subsequent abnormalities in liver function or the diagnosis of diseases of the liver. What is already known on this topic: Clusters of severe hepatitis in children in 2022 coincident with the increase in COVID-19 infections in children raised the question of the contribution of SARS-CoV-2 to the hepatitis outbreak, though it was soon determined that SARS-CoV-2 was not the primary etiologic agent. What this study adds: SARS-CoV-2 may prime the patient for subsequent development of liver infections or non-infectious liver diseases. How this study might affect research practice or policy: Despite the mild initial disease in children, there may be longer term consequences of COVID-19, such as liver abnormalities, that warrants further investigation.

Potential effect of antidepressants on remission from cocaine use disorder - A nationwide matched retrospective cohort study.

BACKGROUND: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration-approved pharmacotherapy. Depressive disorders are common psychiatric comorbidity amongst individuals with CUD. METHODS: A retrospective cohort study was conducted among 161,544 patients diagnosed with CUD and depression to evaluate the effectiveness of 13 antidepressants on CUD remission. For any antidepressant found to be associated with CUD remission that had an additional indication, we conducted an additional analysis to evaluate the effectiveness of the candidate drug in patients with CUD with that indication. We then analyzed publicly genomic and functional databases to identify potential explanatory mechanisms of action of the candidate drug in the treatment of CUD. RESULTS: Among these antidepressants, bupropion was associated with higher rates of CUD remission compared to propensity-score matched patients prescribed other antidepressants: hazard ratio (HR) and 95% confidence interval (CI) 1.57 (95% CI: 1.27-1.94). Bupropion is also approved for smoking cessation. We identified CUD patients with co-occurring nicotine dependence and observed that patients prescribed bupropion displayed a higher rate of CUD remission compared to matched individuals prescribed other drugs for nicotine dependence: 1.38 (95% CI: 1.11-1.71). Genetic and functional analyses revealed that bupropion interacts with four protein-encoding genes (COMT, DRD2, SLC6A3, and SLC6A4) which are also associated with CUD and targets CUD-associated pathways including serotonergic synapses, cocaine addiction, and dopaminergic synapses. CONCLUSIONS: Our findings suggest that bupropion might be considered a treatment for improving CUD remission in patients with CUD and co-occurring depression or nicotine dependence.

Suicidal ideation and suicide attempt following ketamine prescription in patients with treatment-resistant depression: a nation-wide cohort study.

Ketamine, including esketamine, is an effective treatment for patients with treatment-resistant depression (TRD); however, its long-term efficacy in real-world populations remains poorly characterized. This is a retrospective cohort study using TriNetX US Collaborative Network, a platform aggregating electronic health records (EHRs) data from 93 million patients from 56 health care organizations in the US, and the study population includes 321,367 patients with a diagnosis of TRD who were prescribed relevant treatment in their EHRs. The prescription of ketamine (including esketamine) was associated with significant decreased risk of suicidal ideation compared to prescription of other common antidepressants: HR = 0.65 (95% CI: 0.53 - 0.81) at 1 day - 7 days, 0.78 (95% CI: 0.66 - 0.92) at 1 day - 30 days, 0.81 (95% CI: 0.70 - 0.92) at 1 day - 90 days, 0.82 (95% CI: 0.72 - 0.92) at 1 day - 180 days, and 0.83 (95% CI: 0.74 - 0.93) at 1 day - 270 days. This trend was especially robust among adults over 24 years of age, males, and White patients with TRD. No significant difference was observed for suicide attempts, except significantly increased risk for adolescents (aged 10-24) at 1 day - 30 days with HR = 2.22 (95% CI: 1.01-4.87). This study provides real-world evidence that ketamine has long-term benefits in mitigating suicidal ideation in patients with treatment-resistant depression. Future work should focus on optimizing dosage regimens for ketamine, understanding the mechanism, and the difference in various demographic subpopulations.

Cardiac and mortality outcome differences between methadone, buprenorphine and naltrexone prescriptions in patients with an opioid use disorder.

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.

Disrupted seasonality and association of COVID-19 with medically attended respiratory syncytial virus infections among young children in the US: January 2010-January 2023.

Respiratory syncytial virus (RSV) infections and hospitalizations surged sharply in 2022 among young children. To assess whether COVID-19 contributed to this surge, we leveraged a real-time nation-wide US database of electronic health records (EHRs) using time series analysis from January 1, 2010 through January 31, 2023, and propensity-score matched cohort comparisons for children aged 0-5 years with or without prior COVID-19 infection. Seasonal patterns of medically attended RSV infections were significantly disrupted during the COVID-19 pandemic. The monthly incidence rate for first-time medically attended cases, most of which were severe RSV-associated diseases, reached a historical high rate of 2,182 cases per 1,0000,000 person-days in November 2022, corresponding to a related increase of 143% compared to expected peak rate (rate ratio: 2.43, 95% CI: 2.25-2.63). Among 228,940 children aged 0-5 years, the risk for first-time medically attended RSV during 10/2022-12/2022 was 6.40% for children with prior COVID-19 infection, higher than 4.30% for the matched children without COVID-19 (risk ratio or RR: 1.40, 95% CI: 1.27-1.55); and among 99,105 children aged 0-1 year, the overall risk was 7.90% for those with prior COVID-19 infection, higher than 5.64% for matched children without (RR: 1.40, 95% CI: 1.21-1.62). These data provide evidence that COVID-19 contributed to the 2022 surge of severe pediatric RSV cases.

Repurposing ketamine to treat cocaine use disorder: integration of artificial intelligence-based prediction, expert evaluation, clinical corroboration and mechanism of action analyses.

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.

Ischemic stroke after COVID-19 bivalent vaccine administration in patients aged 65 years and older: analysis of nation-wide patient electronic health records in the United States.

Importance: The Centers for Disease Control and Prevention (CDC) announced in January 2023 that they were investigating a potential connection between administration of the Pfizer novel coronavirus disease-2019 (COVID-19) bivalent vaccine booster and ischemic stroke (IS). Objective: To explore the relationship between Pfizer bivalent booster administration and IS in older patients in the United States and compare it to other COVID-19 vaccines. Design: A retrospective cohort study was conducted to compare hazard of IS among patients aged 65 years or over who received the Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent COVID-19 booster vaccine 1-21 and 22-42 days after vaccination. Setting: Patient data were collected from TriNetX, a cloud-based analytics platform that includes electronic health record data from over 90 million unique patients in the United States. Participants: Patients in the United States aged 65 years or over at the time of administration of a Pfizer bivalent (n = 43,216), Moderna bivalent (n = 4,267), or Pfizer/Moderna monovalent (n = 100,583) booster were included for analysis. Cohorts were propensity-score matched by demographic factors and risk factors for IS and severe COVID-19. Exposures: Pfizer bivalent, Moderna bivalent, or Pfizer/Moderna monovalent COVID-19 booster administration. Main outcomes: The hazard ratio (HR) and 95% confidence interval (CI) for IS in the cohorts at 1-21 and 22-42 days after administration. Results: After matching, the Pfizer bivalent cohort included 4,267 patients, with an average age of 73.7 years (44.43% male, 76.59% white). The Moderna bivalent cohort included 4,267 patients, with an average age of 74.0 years (44.08% male, 77.39% white). There was no significant difference in the hazard of IS encounters between the Pfizer bivalent versus Moderna bivalent cohorts at 1-21- or 22-42-days post-administration: HR = 0.59 (0.31, 1.11), 0.73 (0.33, 1.60). The hazard for IS was lower in the Pfizer bivalent cohort than in the Pfizer/Moderna monovalent cohort at both timepoints: HR = 0.24 (0.19, 0.29), 0.25 (0.20, 0.31). Conclusions and relevance: Older adults administered the Pfizer bivalent booster had similar hazard for IS encounters compared to those administered the Moderna bivalent booster vaccine, but lower hazard than those administered the Pfizer/Moderna monovalent boosters.

Association of Recent SARS-CoV-2 Infection With New-Onset Alcohol Use Disorder, January 2020 Through January 2022.

Importance: The COVID-19 pandemic affects many diseases, including alcohol use disorders (AUDs). As the pandemic evolves, understanding the association of a new diagnosis of AUD with COVID-19 over time is required to mitigate negative consequences. Objective: To examine the association of COVID-19 infection with new diagnosis of AUD over time from January 2020 through January 2022. Design, Setting, and Participants: In this retrospective cohort study of electronic health records of US patients 12 years of age or older, new diagnoses of AUD were compared between patients with COVID-19 and patients with other respiratory infections who had never had COVID-19 by 3-month intervals from January 20, 2020, through January 27, 2022. Exposures: SARS-CoV-2 infection or non-SARS-CoV-2 respiratory infection. Main Outcomes and Measures: New diagnoses of AUD were compared in COVID-19 and propensity score-matched control cohorts by hazard ratios (HRs) and 95% CIs from either 14 days to 3 months or 3 to 6 months after the index event. Results: This study comprised 1 201 082 patients with COVID-19 (56.9% female patients; 65.7% White; mean [SD] age at index, 46.2 [18.9] years) and 1 620 100 patients with other respiratory infections who had never had COVID-19 (60.4% female patients; 71.1% White; mean [SD] age at index, 44.5 [20.6] years). There was a significantly increased risk of a new diagnosis of AUD in the 3 months after COVID-19 was contracted during the first 3 months of the pandemic (block 1) compared with control cohorts (HR, 2.53 [95% CI, 1.82-3.51]), but the risk decreased to nonsignificance in the next 3 time blocks (April 2020 to January 2021). The risk for AUD diagnosis increased after infection in January to April 2021 (HR, 1.30 [95% CI, 1.08-1.56]) and April to July 2021 (HR, 1.80 [95% CI, 1.47-2.21]). The result became nonsignificant again in blocks 7 and 8 (COVID-19 diagnosis between July 2021 and January 2022). A similar temporal pattern was seen for new diagnosis of AUD 3 to 6 months after infection with COVID-19 vs control index events. Conclusions and Relevance: Elevated risk for AUD after COVID-19 infection compared with non-COVID-19 respiratory infections during some time frames may suggest an association of SARS-CoV-2 infection with the pandemic-associated increase in AUD. However, the lack of excess hazard in most time blocks makes it likely that the circumstances surrounding the pandemic and the fear and anxiety they created also were important factors associated with new diagnoses of AUD.

Association of COVID-19 with endocarditis in patients with cocaine or opioid use disorders in the US.

The incidence of endocarditis in the US is increasing, driven in part by the rise in intravenous drug use, mostly opioids and stimulant drugs (cocaine and methamphetamine). Recent reports have documented that individuals with COVID-19 are at increased risk for cardiovascular diseases. However, it is unknown whether COVID-19 is associated with increased risk for endocarditis in patients with opioid or stimulant use disorders. This is a retrospective cohort study based on a nationwide database of electronic health records (EHRs) of 109 million patients in the US, including 736,502 patients with a diagnosis of opioid use disorder (OUD) and 379,623 patients with a diagnosis of cocaine use disorder (CocaineUD). Since Metamphetamine use disorder is not coded we could not analyze it. We show that the incidence rate of endocarditis among patients with OUD or CocaineUD significantly increased from 2011 to 2022 with acceleration during 2021-2022. COVID-19 was associated with increased risk of new diagnosis of endocarditis among patients with OUD (HR: 2.23, 95% CI: 1.92-2.60) and with CocaineUD (HR: 2.24, 95% CI: 1.79-2.80). Clinically diagnosed COVID-19 was associated with higher risk of endocarditis than lab-test confirmed COVID-19 without clinical diagnosis. Hospitalization within 2 weeks following COVID-19 infection was associated with increased risk of new diagnosis of endocarditis. The risk for endocarditis did not differ between patients with and without EHR-recorded vaccination. There were significant racial and ethnic differences in the risk for COVID-19 associated endocarditis, lower in blacks than in whites and lower in Hispanics than in non-Hispanics. Among patients with OUD or CocaineUD, the 180-day hospitalization risk following endocarditis was 67.5% in patients with COVID-19, compared to 58.7% in matched patients without COVID-19 (HR: 1.21, 95% CI: 1.07-1.35). The 180-day mortality risk following the new diagnosis of endocarditis was 9.2% in patients with COVID-19, compared to 8.0% in matched patients without COVID-19 (HR: 1.16, 95% CI: 0.83-1.61). This study shows that COVID-19 is associated with significantly increased risk for endocarditis in patients with opioid or cocaine use disorders. These results highlight the need for endocarditis screening and for linkage to infectious disease and addiction treatment in patients with opioid or cocaine use disorders who contracted COVID-19. Future studies are needed to understand how COVID-19 damages the heart and the vascular endothelium among people who misuse opioids or cocaine (presumably also methamphetamines).

Sex-Specific Heterogeneity of Mild Cognitive Impairment Identified Based on Multi-Modal Data Analysis.

BACKGROUND: Mild cognitive impairment (MCI), a prodromal phase of Alzheimer's disease (AD), is heterogeneous with different rates and risks of progression to AD. There are significant gender disparities in the susceptibility, prognosis, and outcomes in patients with MCI, with female being disproportionately negatively impacted. OBJECTIVE: The aim of this study was to identify sex-specific heterogeneity of MCI using multi-modality data and examine the differences in the respective MCI subtypes with different prognostic outcomes or different risks for MCI to AD conversion. METHODS: A total of 325 MCI subjects (146 women, 179 men) and 30 relevant features were considered. Mixed-data clustering was applied to women and men separately to discover gender-specific MCI subtypes. Gender differences were compared in the respective subtypes of MCI by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. RESULTS: We identified three MCI subtypes: poor-, good-, and best-prognosis for women and for men, separately. The subtype-wise comparison (for example, poor-prognosis subtype in women versus poor-prognosis subtype in men) showed significantly different means for brain volumetric, cognitive test-related, also for the proportion of comorbidities. Also, there were substantial gender differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. CONCLUSION: Analyzing sex-specific heterogeneity of MCI offers the opportunity to advance the understanding of the pathophysiology of both MCI and AD, allows stratification of risk in clinical trials of interventions, and suggests gender-based early intervention with targeted treatment for patients at risk of developing AD.

Association of Aspirin Use with Reduced Risk of Developing Alzheimer's Disease in Elderly Ischemic Stroke Patients: A Retrospective Cohort Study.

BACKGROUND: Currently there are no effective therapies to prevent or halt the development of Alzheimer's disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD. OBJECTIVE: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients. METHODS: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders. RESULTS: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.81 [0.70,0.94], and 0.76 [0.70,0.92]. CONCLUSION: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease.