Association of Terazosin, Doxazosin, or Alfuzosin Use and Risk of Dementia With Lewy Bodies in Men.

BACKGROUND AND OBJECTIVES: Terazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are α-1 adrenergic receptor antagonists that also bind to and activate a key adenosine triphosphate (ATP)-producing enzyme in glycolysis. It is hypothesized that the increase in energy availability in the brain may slow or prevent neurodegeneration, potentially by reducing the accumulation of alpha-synuclein. Recent work has suggested a potentially neuroprotective effect of the use of Tz/Dz/Az in Parkinson disease in both animal and human studies. We investigated the neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB). METHODS: We used a new-user active comparator design in the Merative Marketscan database to identify men with no history of DLB who were newly started on Tz/Dz/Az or 2 comparator medications. Our comparator medications were other drugs commonly used to treat benign prostatic hyperplasia that do not increase ATP: the α-1 adrenergic receptor antagonist tamsulosin or 5α-reductase inhibitor (5ARI). We matched the cohorts on propensity scores and duration of follow-up. We followed up the matched cohorts forward to estimate the hazard of developing DLB using Cox proportional hazards regression. RESULTS: Men who were newly started on Tz/Dz/Az had a lower hazard of developing DLB than matched men taking tamsulosin (n = 242,716, 728,256 person-years, hazard ratio [HR] 0.60, 95% CI 0.50-0.71) or 5ARI (n = 130,872, 399,316 person-years, HR 0.73, 95% CI 0.57-0.93). while the hazard in men taking tamsulosin was similar to that of men taking 5ARI (n = 159,596, 482,280 person-years, HR 1.17, 95% CI 0.96-1.42). These results were robust to several sensitivity analyses. DISCUSSION: We find an association in men who are taking Tz/Dz/Az and a lower hazard of DLB compared with similar men taking other medications. When combined with the literature of Tz/Dz/Az on Parkinson disease, our findings suggest that glycolysis-enhancing drugs may be broadly protective in neurodegenerative synucleinopathies. A future randomized trial is required to assess these associations for causality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that Tz/Dz/Az use reduces the rate of developing DLB in adult men.

Association of Appendicitis Incidence With Warmer Weather Independent of Season.

Importance: Acute appendicitis is a common cause of abdominal pain and the most common reason for emergency surgery in several countries. Increased cases during summer months have been reported. Objective: To investigate the incidence of acute appendicitis by considering local temperature patterns in geographic regions with different climate over several years. Design, Setting, and Participants: This cohort study used insurance claims data from the MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental and Coordination of Benefits Database from January 1, 2001, to December 31, 2017. The cohort included individuals at risk for appendicitis who were enrolled in US insurance plans that contribute data to the MarketScan databases. Cases of appendicitis in the inpatient, outpatient, and emergency department settings were identified using International Classification of Diseases, Ninth Revision, Clinical Modification or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. Local weather data were obtained for individuals living in a metropolitan statistical area (MSA) from the Integrated Surface Database. Associations were characterized using a fixed-effects generalized linear model based on a negative binomial distribution. The model was adjusted for age, sex, and day of week and included fixed effects for year and MSA. The generalized linear model was fit with a piecewise linear model by searching each 0.56 °C in temperature for change points. To further isolate the role of temperature, observed temperature was replaced with the expected temperature and the deviation of the observed temperature from the expected temperature for a given city on a given day of year. Data were analyzed from October 1, 2021, to July 31, 2022. Main Outcomes and Measures: The primary outcome was the daily number of appendicitis cases in a given city stratified by age and sex, with mean temperature in the MSA over the previous 7 days as the independent variable. Results: A total of 450 723 744 person-years at risk and 689 917 patients with appendicitis (mean [SD] age, 35 [18] years; 347 473 male [50.4%] individuals) were included. Every 5.56 °C increase in temperature was associated with a 1.3% increase in the incidence of appendicitis (incidence rate ratio [IRR], 1.01; 95% CI, 1.01-1.02) when temperatures were 10.56 °C or lower and a 2.9% increase in incidence (IRR, 1.03; 95% CI, 1.03-1.03) for temperatures higher than 10.56 °C. In terms of temperature deviations, a higher-than-expected temperature increase greater than 5.56 °C was associated with a 3.3% (95% CI, 1.0%-5.7%) increase in the incidence of appendicitis compared with days with near-0 deviations. Conclusions and Relevance: Results of this cohort study observed seasonality in the incidence of appendicitis and found an association between increased incidence and warmer weather. These results could help elucidate the mechanism of appendicitis.

Use of Glycolysis-Enhancing Drugs and Risk of Parkinson's Disease.

BACKGROUND: Terazosin (TZ) and closely related α1-adrenergic receptor antagonists (doxazosin [DZ] and alfuzosin [AZ]) enhance glycolysis and reduce neurodegeneration in animal models. Observational evidence in humans from several databases supports this finding; however, a recent study has suggested that tamsulosin, the comparator medication, increases the risk of Parkinson's disease. AIMS: We consider a different comparison group of men taking 5α-reductase inhibitors (5ARIs) as a new, independent comparison allowing us to both obtain new estimates of the association between TZ/DZ/AZ and Parkinson's disease outcomes and validate tamsulosin as an active comparator. METHODS: Using the Truven Health Analytics Marketscan database, we identified men without Parkinson's disease, newly started on TZ/DZ/AZ, tamsulosin, or 5ARIs. We followed these matched cohorts to compare the hazard of developing Parkinson's disease. We conducted sensitivity analyses using variable duration of lead-in to mitigate biases introduced by prodromal disease. RESULTS: We found that men taking TZ/DZ/AZ had a lower hazard of Parkinson's disease than men taking tamsulosin (hazard ratio (HR) = 0.71, 95% CI [confidence interval]: 0.65-0.77, n = 239,888) and lower than men taking 5ARIs (HR = 0.84, 95% CI: 0.75-0.94, n = 129,116). We found the TZ/DZ/AZ versus tamsulosin HR to be essentially unchanged with up to 5 years of lead-in time; however, the TZ/DZ/AZ versus 5ARI effect became attenuated with longer lead-in durations. CONCLUSIONS: These data suggest that men using TZ/DZ/AZ have a somewhat lower risk of developing Parkinson's disease than those using tamsulosin and a slightly lower risk than those using 5ARIs. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A pilot to assess target engagement of terazosin in Parkinson's disease.

BACKGROUND: Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD. METHODS: We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with 31P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events. RESULTS: Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of ßATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01). CONCLUSIONS: This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.

Continuous in-home PM2.5 concentrations of smokers with and without a history of respiratory exacerbations in Iowa, during and after an air purifier intervention.

BACKGROUND: Americans spend most of their time indoors. Indoor particulate matter (PM) 2.5 µm and smaller (PM2.5) concentrations often exceed ambient concentrations. Therefore, we tested whether the use of an air purifying device (electrostatic precipitator, ESP) could reduce PM2.5 in homes of smokers with and without respiratory exacerbations, compared with baseline. METHODS: We assessed PM2.5 concentrations in homes of subjects with and without a recent (≤3 years) history of respiratory exacerbation. We compared PM2.5 concentrations during 1 month of ESP use with those during 1 month without ESP use. RESULTS: Our study included 19 subjects (53-80 years old), nine with a history of respiratory exacerbation. Geometric mean (GM) PM2.5 and median GM daily peak PM2.5 were significantly lower during ESP deployment compared with the equivalent time-period without the ESP (GSD = 0.50 and 0.37 µg/m3, respectively, p < 0.001). PM2.5 in homes of respiratory exacerbators tended (p < 0.14) to be higher than PM2.5 in homes of those without a history of respiratory exacerbation. CONCLUSIONS: Subjects with a history of respiratory exacerbation tended to have higher mean, median, and mean peak PM2.5 concentrations compared with homes of subjects without a history of exacerbations. The ESP intervention reduced in-home PM2.5 concentrations, demonstrating its utility in reducing indoor exposures. NOVELTY OF STUDY: Our work characterizes PM air pollution concentrations in homes of study subjects with and without respiratory exacerbations. We demonstrate that PM concentrations tend to be higher in homes of participants with respiratory exacerbations, and that the use of an inexpensive air purifier resulted in significantly lower daily average PM concentrations than when the purifier was not present. Our results provide a helpful intervention strategy for purifying indoor air and may be useful for susceptible populations.

Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases.

Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

The Seasonal Variability of Surgical Site Infections in Knee and Hip Arthroplasty.

BACKGROUND: Surgical site infections (SSIs) after total knee (TKA) and total hip (THA) arthroplasty are devastating to patients and costly to healthcare systems. The purpose of this study is to investigate the seasonality of TKA and THA SSIs at a national level. METHODS: All data were extracted from the National Readmission Database for 2013 and 2014. Patients were included if they had undergone TKA or THA. We modeled the odds of having a primary diagnosis of SSI as a function of discharge date by month, payer status, hospital size, and various patient co-morbidities. SSI status was defined as patients who were readmitted to the hospital with a primary diagnosis of SSI within 30 days of their arthroplasty procedure. RESULTS: There were 760,283 procedures (TKA 424,104, THA 336,179) in our sample. Our models indicate that SSI risk was highest for patients discharged from their surgery in June and lowest for December discharges. For TKA, the odds of a 30-day readmission for SSI were 30.5% higher at the peak compared to the nadir time (95% confidence interval [CI] 20-42). For THA, the seasonal increase in SSI was 19% (95% CI 9-30). Compared to Medicare, patients with Medicaid as the primary payer had a 49% higher odds of 30-day SSI after TKA (95% CI 32-68). CONCLUSION: SSIs following TKA and THA are seasonal peaking in summer months. Payer status was also a significant risk factor for SSIs. Future studies should investigate potential factors that could relate to the associations demonstrated in this study.