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.

Warmer Weather and the Risk of Urinary Tract Infections in Women.

PURPOSE: The incidence of urinary tract infections is seasonal, peaking in summer months. One possible mechanism for the observed seasonality of urinary tract infections is warmer weather. MATERIALS AND METHODS: We identified all urinary tract infection cases located in approximately 400 metropolitan statistical areas in the contiguous United States between 2001 and 2015 using the Truven Health MarketScan® databases. A total of 167,078,882 person-years were included in this data set and a total of 15,876,030 urinary tract infection events were identified by ICD-9 code 599.0. Weather data for each metropolitan statistical area and date were obtained from the National Centers for Environmental Information. We computed the mean temperature during the period 0 to 7 days prior to the urinary tract infection diagnosis. We used a quasi-Poisson generalized linear model. The primary outcome was the number of urinary tract infections each day in a metropolitan statistical area in each age group. Covariates considered included age group, day of week, year and the temperature during the previous 7 days. RESULTS: Warmer weather increases the risk of urinary tract infections among women treated in outpatient settings in a dose-response fashion. On days when the prior week's average temperature was between 25 and 30C, the incidence of urinary tract infections was increased by 20% to 30% relative to when the prior week's temperature was 5 to 7.5C. CONCLUSIONS: The incidence of urinary tract infections increases with the prior week's temperature. Our results indicate that warmer weather is a risk factor for urinary tract infections. Furthermore, as temperatures rise, the morbidity attributable to urinary tract infections may increase.

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.

Weather-Dependent Risk for Legionnaires' Disease, United States.

Using the Nationwide Inpatient Sample and US weather data, we estimated the probability of community-acquired pneumonia (CAP) being diagnosed as Legionnaires' disease (LD). LD risk increases when weather is warm and humid. With warm weather, we found a dose-response relationship between relative humidity and the odds for LD. When the mean temperature was 60°-80°F with high humidity (>80.0%), the odds for CAP being diagnosed with LD were 3.1 times higher than with lower levels of humidity (<50.0%). Thus, in some regions (e.g., the Southwest), LD is rarely the cause of hospitalizations. In other regions and seasons (e.g., the mid-Atlantic in summer), LD is much more common. Thus, suspicion for LD should increase when weather is warm and humid. However, when weather is cold, dry, or extremely hot, empirically treating all CAP patients for LD might contribute to excessive antimicrobial drug use at a population level.

Rurality modifies the association between symptoms and the diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: We utilized national claims-based data to identify the change in odds of diagnosis of ALS following possible-ALS-symptoms-and whether the change varies in urban/rural areas. METHODS: Insurance claims were obtained from the Merative MarketScan databases, 2001-2021 in the United States. Individuals with incident ALS were identified and matched on age, sex, and enrollment period to individuals without ALS. For all individuals, claims for 8 possible-ALS-symptoms in the time before any ALS diagnosis were identified. We then used conditional logistic regression to estimate the odds of being diagnosed with ALS following these symptoms and whether the association varied by urban/rural location. RESULTS: 19,226 individuals with ALS were matched to 96,126 controls. Patients with ALS were more likely to live in an urban area (87.0% vs 84.5%). Of those with ALS 84% had 1+ of our 8 possible-ALS-symptom compared to 51% of controls. After adjustment for confounders, having possible-ALS-symptoms increased the odds of a future ALS diagnosis by nearly 5-fold. A dose-response pattern was present with increasing odds as the number of symptoms increased. In all models, urban areas were associated with increased odds of diagnosis with ALS while the effect of having a symptom was smaller in urban places. Urban cases of ALS are diagnosed at younger ages. CONCLUSIONS: These results suggest symptoms may appear and be noted years before the diagnosis of ALS. Additionally, rural patients are diagnosed at later ages with a greater dependence on symptoms than urban patients. These results highlight potential improvements for screening for ALS.

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 between household opioid prescriptions and risk for overdose among family members not prescribed opioids.

BACKGROUND: Prescription opioids have contributed to the rise in opioid-related overdoses and deaths. The presence of opioids within households may increase the risk of overdose among family members who were not prescribed an opioid themselves. Larger quantities of opioids may further increase risk. OBJECTIVES: To determine the risk of opioid overdose among individuals who were not prescribed an opioid but were exposed to opioids prescribed to other family members in the household, and evaluate the risk in relation to the total morphine milligram equivalents (MMEs) present in the household. METHODS: We conducted a cohort study using a large database of commercial insurance claims from 2001 to 2021. For inclusion in the cohort, we identified individuals not prescribed an opioid in the prior 90 days from households with two or more family members, and determined the total MMEs prescribed to other family members. Individuals were stratified into monthly enrollment strata defined by household opioid exposure and other confounders. A generalized linear model was used to estimate incidence rate ratios (IRRs) for overdose. RESULTS: Overall, the incidence of overdose among enrollees in households where a family member was prescribed an opioid was 1.73 (95% confidence interval [CI]: 1.67-1.78) times greater than households without opioid prescriptions. The risk of overdose increased continuously with the level of potential MMEs in the household from an IRR of 1.23 (95% CI: 1.16-1.32) for 1-100 MMEs to 4.67 (95% CI: 4.18-5.22) for >12,000 MMEs. The risk of overdose associated with household opioid exposure was greatest for ages 1-2 years (IRR: 3.46 [95% CI: 2.98-4.01]) and 3-5 years (IRR: 3.31 [95% CI: 2.75-3.99]). CONCLUSIONS: The presence of opioids in a household significantly increases the risk of overdose among other family members who were not prescribed an opioid. Higher levels of MMEs, either in terms of opioid strength or quantity, were associated with increased levels of risk. Risk estimates may reflect accidental poisonings among younger family members.

Using a Fitbit-based Walking Game to Improve Physical Activity Among U.S. Veterans.

INTRODUCTION: Physical inactivity, hereafter inactivity, is a serious health problem among U.S. veterans, hereafter veterans. Inactive adults are at risk for adverse cardiac events and premature mortality. Specifically, among veterans, inactivity has been associated with a 23% increase in mortality. In order to increase physical activity among veterans, we developed Veterans Affairs (VA) MapTrek, a mobile-phone-based web app that allows users to take a virtual walk in interesting locations around the world while tracking their progress against that of others like themselves on an interactive map. Steps are counted by a commercially available Fitbit triaxial accelerometer, and users see their progress along a predefined scenic path overlaid on Google Maps. The objective of this study was to determine the effectiveness of VA MapTrek to increase physical activity in a population of veterans at risk for obesity-related morbidity. MATERIALS AND METHODS: We recruited overweight and obese veterans obtaining care at the Iowa City Veterans Affairs Health Center. Half of the veterans were assigned to participate in VA MapTrek. Each week, participants were assigned virtual walking races (Monday through Saturday), which followed a predetermined route that is displayed on Google Maps. The participant's position on the map is automatically updated each time their Fitbit syncs to their phone. In addition, challenges were issued periodically. Veterans in the control group were only given a Fitbit. We regressed daily step counts on the days of the week, the days since the start of the intervention period, whether the user was in the VA MapTrek or Control group, and an interaction between the study group and the days since the start of the intervention period. We included subject-specific random intercepts and subject-specific random slopes. This model was estimated using Bayesian Hamiltonian Monte Carlo using Stan's No-U-Turns sampler. We set vague, uniform priors on all the parameters. RESULTS: We enrolled 276 participants, but only 251 (102 in the control group and 149 in the VA MapTrek group) contributed data during the intervention period. Our analysis suggests an 86.8% likelihood that the VA MapTrek intervention led to a minimum increase of 1,000 daily steps over the 8-week period, compared to the control group. Throughout the 8-week intervention, we project that VA MapTrek participants would have taken an extra 96,627 steps, equivalent to 77.8 additional kilometers (km) (48.3 additional miles), assuming an average of 1,242 steps per km (2,000 steps per mile). CONCLUSIONS: Our study underscores the potential of VA MapTrek as an intervention for promoting walking among veterans who face elevated risks of obesity and cardiac issues. Rural veterans are a high-risk population, and new interventions like VA MapTrek are needed to improve veterans' health.

Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson's disease.

Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.

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.

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.

Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease.

Importance: Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases. Objective: To determine whether use of terazosin, doxazosin, and alfuzosin is associated with a decreased risk of developing PD. Design, Setting, and Participants: This cohort study used active comparator control and propensity score-matched data from Danish nationwide health registries, including the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Civil Registration System, from January 1996 to December 2017 and data from the Truven Health Analytics MarketScan database from January 2001 to December 2017. Men without PD who newly initiated terazosin/doxazosin/alfuzosin therapy or tamsulosin therapy, which is used for a similar indication (benign prostatic hyperplasia or unspecified urinary problems) but does not enhance glycolysis, and had at least 1 year of follow-up after medication start were included. In Denmark, the database included all residents, while the Truven database is a compilation of insurance claims across the US. Data were analyzed from February 2019 to July 2020. Exposures: Patients who used terazosin/doxazosin/alfuzosin vs tamsulosin. Additional dose-response analyses were carried out. Main Outcomes and Measures: Differences in the hazard of developing PD identified by diagnoses or use of PD-specific medications between patients who ever used terazosin/doxazosin/alfuzosin or tamsulosin. Results: A cohort of 52 365 propensity score-matched pairs of terazosin/doxazosin/alfuzosin and tamsulosin users were identified in the Danish registries, of which all were male and the mean (SD) age was 67.9 (10.4) years, and 94 883 propensity score-matched pairs were identified in the Truven database, of which all were male and the mean (SD) age was 63.8 (11.1) years. Patients in the Danish cohort who used terazosin/doxazosin/alfuzosin had a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), and patients in the Truven cohort had an HR of 0.63 (95% CI, 0.58-0.69). There was a dose-response association with short-duration, medium-duration, and long-duration use of terazosin/doxazosin/alfuzosin users having a decreasing HR in both the Danish cohort (short: HR, 0.95; 95% CI, 0.84-1.07; medium: HR, 0.88; 95% CI, 0.77-1.01; long: HR, 0.79; 95% CI, 0.66-0.95) and Truven cohort (short: HR, 0.70; 95% CI, 0.64-0.76; medium: HR, 0.58; 95% CI, 0.52-0.64; long: HR, 0.46; 95% CI, 0.36-0.57). Conclusions and Relevance: These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.

COVID-19 Case Fatality and Alzheimer's Disease.

Previous studies have identified dementia as a risk factor for death from coronavirus disease 2019 (COVID-19). However, it is unclear whether Alzheimer's disease (AD) is an independent risk factor for COVID-19 case fatality rate. In a retrospective cohort study, we identified 387,841 COVID-19 patients through TriNetX. After adjusting for demographics and comorbidities, we found that AD patients had higher odds of dying from COVID-19 compared to patients without AD (Odds Ratio: 1.20, 95%confidence interval: 1.09-1.32, p < 0.001). Interestingly, we did not observe increased mortality from COVID-19 among patients with vascular dementia. These data are relevant to the evolving COVID-19 pandemic.

Multilevel mHealth Intervention Increases Physical Activity of Older Adults Living in Retirement Community.

BACKGROUND: Regular physical activity is crucial for healthy aging, but older adults are the least active age group. This study explored the feasibility, acceptability, and efficacy of a multilevel mHealth intervention for increasing physical activity of older adults living in a retirement community. METHODS: Participants included 54 older adults (mean age = 81.2 y, 77.8% female, 98.1% white) living in a retirement community. Participants received a Fitbit Zip and access to a multilevel mHealth physical activity intervention (MapTrek Residential) for 8 weeks. Physical activity (in steps per day) and intervention compliance (days worn) were measured objectively with the Fitbit for 12 weeks (8-wk intervention plus 4-wk follow-up). Psychosocial outcomes (social support, self-efficacy, and outcome expectations) were assessed at baseline and 8 weeks. Acceptability outcomes were assessed with an open-ended process evaluation survey and focus groups. Descriptive statistics and linear mixed models were used to examine intervention effects. RESULTS: Participants increased daily steps from 5438 steps per day at baseline (95% CI, 4620 to 6256) to 6201 steps per day (95% CI, 5359 to 7042) at week 8 (P < .0001) but this was not maintained at 12 weeks (P = .92). CONCLUSIONS: Our multilevel mHealth physical activity intervention was effective for increasing physical activity older adults over 8 weeks. Additional research focused on maintaining physical activity gains with this approach is warranted.

Gamifying accelerometer use increases physical activity levels of individuals pre-disposed to type II diabetes.

Physical activity is important for preventing obesity and diabetes, but most obese and pre-diabetic patients are not physically active. We developed a Fitbit-based game called MapTrek that promotes walking. We recruited obese and pre-diabetic patients. Half were randomly assigned to the control group and given a Fitbit alone. The others were given a Fitbit plus MapTrek. The MapTrek group participated in 6 months of weekly virtual races. Each week, participants were placed in a race with 9 others who achieved a similar number of steps in the previous week's race. Participants moved along the virtual route by the steps recorded on their Fitbit and received daily walking challenges via text message. Text messages also had links to the race map and leaderboard. We used a Bayesian mixed effects model to analyze the number of steps taken during the intervention. A total of 192 (89%) participants in the control group and 196 (91%) in the MapTrek group were included in the analyses. MapTrek significantly increased step counts when it began: MapTrek participants walked almost 1,700 steps more than the control group on the first day of the intervention. We estimate that there is a 97% probability that the effect of MapTrek is at least 1,000 additional steps per day throughout the course of the 6-month intervention and that MapTrek participants would have walked an additional 81 miles, on average, before the effect ended. Our MapTrek intervention led to significant extra walking by the MapTrek participants.

The Cardiovascular Effects of Treatment with Hydroxychloroquine and Azithromycin.

Hydroxychloroquine combined with azithromycin has been investigated for activity against coronavirus disease 2019 (COVID-19), but concerns about adverse cardiovascular (CV) effects have been raised. This study evaluated claims data to determine if risks for CV events were increased with hydroxychloroquine alone or combined with azithromycin. We identified data from 43,752 enrollees that qualified for analysis. The number of CV events increased by 25 (95% confidence interval [CI]: 8, 42, p=0.005) per 1000 people per year of treatment with hydroxychloroquine alone compared with pretreatment levels and by 201 (95% CI: 145, 256, p<0.001) events per 1000 people per year when individuals took hydroxychloroquine and azithromycin. These rates translate to an additional 0.34 (95% CI: 0.11, 0.58) CV events per 1000 patients placed on a 5-day treatment with hydroxychloroquine monotherapy and 2.75 (95% CI: 1.99, 3.51) per 1000 patients on a 5-day treatment with both hydroxychloroquine and azithromycin. The rate of adverse events increased with age following exposure to hydroxychloroquine alone and combined with azithromycin. For females aged 60 to 79 years prescribed hydroxychloroquine, the rate of adverse CV events was 0.92 per 1000 patients on 5 days of therapy, but it increased to 4.78 per 1000 patients when azithromycin was added. The rate of adverse CV events did not differ significantly from zero for patients 60 years of age or younger. These data suggest that hydroxychloroquine with or without azithromycin is likely safe in individuals under 60 years of age if they do not have additional CV risks. However, the combination of hydroxychloroquine and azithromycin should be used with extreme caution in older patients.

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.

Seasonal Antimicrobial Activity of the Airway: Post-Hoc Analysis of a Randomized Placebo-Controlled Double-Blind Trial.

BACKGROUND: It is widely unknown why respiratory infections follow a seasonal pattern. Variations in ultraviolet B (UVB) light during seasons affects cutaneous synthesis of vitamin D3. Serum vitamin D concentration influences the expression of airway surface liquid (ASL) antimicrobial peptides such as LL-37. OBJECTIVE: We sought to determine the effect of seasons on serum vitamin D levels and ASL antimicrobial activity. METHODS: Forty participants, 18-60 years old, were randomized 1:1 to receive 90 days of 1000 IU vitamin D3 or placebo. We collected ASL via bronchoscopy and measured serum 25(OH) vitamin D from participants before and after intervention across seasons. We measured ASL antimicrobial activity by challenging samples with bioluminescent Staphylococcus aureus and measured relative light units (RLUs) after four minutes. We also investigated the role of LL-37 using a monoclonal neutralizing antibody. RESULTS: We found that participants, prior to any intervention, during summer-fall (n = 20) compared to winter-spring (n = 20) had (1) decreased live bacteria after challenge (5542 ± 175.2 vs. 6585 ± 279 RLU, p = 0.003) and (2) higher serum vitamin D (88.25 ± 24.25 vs. 67.5 ± 45.25 nmol/L, p = 0.026). Supplementation with vitamin D3 increased vitamin D levels and restored ASL antimicrobial activity only during the winter-spring. The increased ASL antimicrobial activity seen during the summer-fall was abrogated by adding the LL-37 neutralizing antibody. CONCLUSION: ASL kills bacteria more effectively during the summer-fall compared to the winter-spring. Supplementation of vitamin D during winter-spring restores ASL antimicrobial activity by increasing the expression of antimicrobial peptides including LL-37.