Falls and Fractures in Patients with Parkinson's Disease-Related Psychosis Treated with Pimavanserin vs Atypical Antipsychotics: A Cohort Study.

BACKGROUND: Parkinson's disease-related psychosis increases patients' risk of falls. Pimavanserin is an atypical antipsychotic approved in the USA in 2016 for the treatment of hallucinations and delusions associated with Parkinson's disease-related psychosis. OBJECTIVE: We aimed to compare the risk of falls/fractures among patients with Parkinson's disease-related psychosis treated with pimavanserin vs other atypical antipsychotics. PATIENTS AND METHODS: We identified a cohort of patients with Parkinson's disease-related psychosis aged ≥ 40 years initiating either pimavanserin or a comparator antipsychotic (clozapine, quetiapine, risperidone, olanzapine, aripiprazole, brexpiprazole) in US commercial insurance and supplementary Medicare claims (2015-2019). Comparators were propensity score matched 2:1 with pimavanserin initiators; incidence rates of falls/fractures were compared using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS: We identified 112 eligible pimavanserin initiators and 982 comparators. Pimavanserin initiators were younger and had fewer severe comorbidities, indicators of impairment, and healthcare encounters, though they had higher Parkinson's disease medication use. The crude incidence rates [cases/100 person-years] (95% CI) for composite falls/fractures were 17.8 (7.7-35.0) for pimavanserin and 40.8 (35.0-47.4) for comparators. Matching retained 108 pimavanserin initiators and 216 comparators-all characteristics were well balanced after matching-with a matched IRR (pimavanserin vs comparator) of 0.71 (95% CI 0.27-1.67). Sensitivity analysis IRR estimates were consistently below 1.00, with a sensitivity analysis not requiring a diagnosis of psychosis resulting in an IRR estimate of 0.55 (95% CI 0.34-0.86). CONCLUSIONS: The results of this study do not suggest an increase in the risk of falls or fractures associated with pimavanserin compared with other antipsychotics in patients with Parkinson's disease-related psychosis. Sensitivity analyses suggest a decreased risk.

Darolutamide and health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the phase III ARAMIS trial.

BACKGROUND: In the ARAMIS trial, darolutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT significantly improved metastasis-free survival (MFS), overall survival (OS) and time to pain progression in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Herein, we present analyses of patient-reported health-related quality of life (HRQoL) outcomes. PATIENTS AND METHODS: This double-blind, placebo-controlled, phase III trial randomised patients with nmCRPC and prostate-specific antigen doubling time ≤10 months to darolutamide 600 mg (n = 955) twice daily or matched placebo (n = 554) while continuing ADT. The primary end-point was MFS; the secondary end-points included OS and time to pain progression. In this analysis, HRQoL was assessed by the time to deterioration using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale (PCS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer Module (EORTC QLQ-PR25) subscales. RESULTS: Darolutamide significantly prolonged time to deterioration of FACT-P PCS versus placebo (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.70-0.91; P = 0.0005) at the primary analysis (cut-off date: 3rd September 2018). Time to deterioration of EORTC QLQ-PR25 outcomes showed statistically significant delays with darolutamide versus placebo for urinary (HR 0.64, 95% CI 0.54-0.76; P < 0.0001) and bowel (HR 0.78, 95% CI 0.66-0.92; P = 0.0027) symptoms. Time to worsening of hormonal treatment-related symptoms was similar between the two groups. CONCLUSION: In patients with nmCRPC who are generally asymptomatic, darolutamide maintained HRQoL by significantly delaying time to deterioration of prostate cancer-specific quality of life and disease-related symptoms versus placebo.

Effect of Regorafenib in Delaying Definitive Deterioration in Health-Related Quality of Life in Patients with Advanced Cancer of Three Different Tumor Types.

PURPOSE: The efficacy and safety of regorafenib have been demonstrated in phase 3 trials for multiple tumor types, including metastatic colorectal cancer (mCRC) (CORRECT [NCT01103323]; CONCUR [NCT01584830]), advanced gastrointestinal stromal tumor (GIST) (GRID [NCT01271712]), and hepatocellular carcinoma (HCC) (RESORCE [NCT01774344]). The objective of this post hoc exploratory analysis was to explore the impact of regorafenib on delaying health-related quality of life (HRQOL) deterioration across these tumor types. PATIENTS AND METHODS: HRQOL data (assessed with EORTC QLQ-C30 and EQ-5D questionnaires) were pooled for all trials to determine time until definitive deterioration (TUDD), defined as the patient's first minimal clinically important deterioration in HRQOL score from baseline that does not resolve, using stratified Kaplan-Meier estimators and Cox proportional hazards models adjusted for relevant trial, cancer type, and baseline covariates. Additional analyses based on cancer type were conducted by pooling mCRC trials (CORRECT and CONCUR) and pooling the two mCRC trials with the HCC trial (RESORCE). RESULTS: A total of 1699 patients with HRQOL data were pooled across the four trials. The results showed that regorafenib significantly delayed TUDD compared with placebo across all three tumor types. Median time to deterioration across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and 8.6 to 12.1 weeks for placebo. The results from the individual studies, the pooled mCRC trials, and the pooled mCRC and HCC trials were similar to the overall pooled results. CONCLUSION: A pooled analysis of four phase 3 trials demonstrated that regorafenib delayed a clinically relevant exploratory endpoint, defined as TUDD, compared with placebo across three different tumor types (mCRC, GIST, and HCC), which supports a novel benefit of the impact of regorafenib with respect to patients with these three types of cancers by allowing initial declines in HRQOL to resolve and patients the opportunity to continue treatment.

Increased risk of falls and fractures in patients with psychosis and Parkinson disease.

OBJECTIVE: Evaluate whether the risk of falls and fractures differs between patients with Parkinson disease with psychosis (PDP) and patients with Parkinson disease (PD) without psychosis at similar disease stages. METHODS: Patients with PD without psychosis were identified in the Medicare claims databases (2008-2018) and followed from the first PD diagnosis date during the study period. Patients with a subsequent diagnosis of psychosis were included in the PDP group. Patients with PDP and PD without psychosis were propensity score-matched based on characteristics within blocks of time since cohort entry. The incidence rates (IRs), expressed per 100 person-years, and 95% confidence intervals (CIs) of falls and fractures were evaluated as composite and separate outcomes. Incidence rate ratios (IRRs) were used to compare patients with PDP and PD without psychosis in the matched cohort. RESULTS: 154,306 patients had PD without psychosis and no falls or fractures before cohort entry; the IR for falls and fractures was 11.41 events (95% CI, 11.29-11.53). 12,127 patients (7.8%) had a subsequent PDP diagnosis. PDP patients had a higher prevalence of most comorbidities and risk factors for falls and fractures than those without psychosis. The crude IR for falls and fractures among PDP patients was 29.03 events (95% CI, 28.27-29.81). PD without psychosis and PDP groups had more falls than fractures. After matching, 24,144 PD patients without psychosis (15.6%) and 12,077 PDP patients (99.6%) were retained. Matched PDP patients had a higher incidence of falls and fractures than PD patients without psychosis (IRR = 1.44; 95% CI, 1.39-1.49). The higher increased rate was noted separately for falls (IRR = 1.48; 95% CI, 1.43-1.54) and any fractures (IRR = 1.17; 95% CI, 1.08-1.27) as well as within specific types of fracture, including pelvis and hip fractures. CONCLUSIONS: Our findings suggest a modest but consistently higher increased risk of falls and fractures in PDP patients compared with PD patients without psychosis.

Design of the Association of Uterine Perforation and Expulsion of Intrauterine Device study: a multisite retrospective cohort study.

BACKGROUND: Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006-2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration-mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device-related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion. OBJECTIVE: We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up. STUDY DESIGN: APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights. RESULTS: The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74-177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m2, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record. CONCLUSION: Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.

Variation in Cardiovascular Risk Related to Individual Antimuscarinic Drugs Used to Treat Overactive Bladder: A UK Cohort Study.

BACKGROUND: Blocking muscarinic receptors could have an effect on cardiac function, especially among elderly patients with overactive bladder (OAB). STUDY OBJECTIVE: To investigate the risk of cardiovascular (CV) events in users of antimuscarinic drugs to treat OAB. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium, 18 years or older, in the United Kingdom's Clinical Practice Research Datalink (CPRD), 2004-2012. OUTCOME MEASUREMENTS AND MAIN RESULTS: Using tolterodine as the reference, we estimated propensity-score-stratified incidence rate ratios (IRRs) for acute myocardial infarction, stroke, CV mortality, major adverse cardiac events (MACE, a combined end point of the previous three), and all-cause death for individual antimuscarinic drugs. The study cohort included 119,912 new users of OAB drugs. The mean age at cohort entry was 62 years, 70% were female, and the mean follow-up was 3.3 years. The adjusted IRR for MACE and current use of oxybutynin compared with current use of tolterodine was 1.14 (95% confidence interval [CI] 1.01-1.30). In contrast, the IRR was 0.65 (CI 0.56-0.76) for current use of solifenacin compared with tolterodine. In this study, performed with health care data, the distribution of risk factors was relatively similar across users of different OAB drugs and, although our analyses controlled for a range of measured potential confounders, residual confounding cannot be ruled out. CONCLUSIONS: In an observational comparative study of users of medications to treat OAB conducted in routine clinical practice, the risk for CV side effects was increased in users of oxybutynin and decreased in users of solifenacin compared with users of tolterodine.

Cancer Incidence after Initiation of Antimuscarinic Medications for Overactive Bladder in the United Kingdom: Evidence for Protopathic Bias.

STUDY OBJECTIVE: To estimate the incidence of 10 common cancers among patients treated with antimuscarinic medications for overactive bladder (AMOABs). DESIGN: Retrospective cohort study. DATA SOURCE: United Kingdom's Clinical Practice Research Datalink. PATIENTS: A total of 119,912 adults with no previous cancer diagnosis who were new users of AMOABs-darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium-between January 2004 and December 2012. MEASUREMENTS AND MAIN RESULTS: Sex-specific incidence rates per 1000 person-years and 95% confidence intervals (CIs) were estimated for each study cancer (bladder, breast, colorectal, lung, melanoma, non-Hodgkin lymphoma, pancreatic, prostate, renal, and uterine cancer) overall and stratified by time since cohort entry and by cumulative AMOAB dose. Among the 119,912 patients followed for 399,365 person-years, 4117 incident study cancers occurred. The incidence rate of prostate cancer was 14.2 (95% CI 12.9-15.5) in the year after cohort entry and decreased markedly thereafter. The incidence rate of bladder cancer was also higher in the year after cohort entry than subsequently (men: 5.5, 95% CI 4.8-6.4; women: 1.2, 95% CI 1.0-1.5). The incidence rates of both prostate and bladder cancer decreased with increasing cumulative dose of AMOAB. We observed no similar relations between incidence rates of other study cancers and time since cohort entry. CONCLUSION: High incidence rates of bladder and prostate cancer soon after AMOAB initiation and a negative correlation between incidence and cumulative AMOAB dose suggest that protopathic bias is a more likely explanation for these findings than causality. (Protopathic bias in this context means patients' urinary symptoms prompted treatment with an AMOAB, but the symptoms were actually due to a cancer that was already present, although not yet diagnosed or not yet recorded.) To avoid unnecessary delays in the diagnosis of prostate and bladder cancer, physicians should consider these diseases in patients for whom treatment with AMOABs is indicated.

Characterisation of the impact of open biomass burning on urban air quality in Brisbane, Australia.

Open biomass burning from wildfires and the prescribed burning of forests and farmland is a frequent occurrence in South-East Queensland (SEQ), Australia. This work reports on data collected from 10 to 30 September 2011, which covers the days before (10-14 September), during (15-20 September) and after (21-30 September) a period of biomass burning in SEQ. The aim of this project was to comprehensively quantify the impact of the biomass burning on air quality in Brisbane, the capital city of Queensland. A multi-parameter field measurement campaign was conducted and ambient air quality data from 13 monitoring stations across SEQ were analysed. During the burning period, the average concentrations of all measured pollutants increased (from 20% to 430%) compared to the non-burning period (both before and after burning), except for total xylenes. The average concentration of O3, NO2, SO2, benzene, formaldehyde, PM10, PM2.5 and visibility-reducing particles reached their highest levels for the year, which were up to 10 times higher than annual average levels, while PM10, PM2.5 and SO2 concentrations exceeded the WHO 24-hour guidelines and O3 concentration exceeded the WHO maximum 8-hour average threshold during the burning period. Overall spatial variations showed that all measured pollutants, with the exception of O3, were closer to spatial homogeneity during the burning compared to the non-burning period. In addition to the above, elevated concentrations of three biomass burning organic tracers (levoglucosan, mannosan and galactosan), together with the amount of non-refractory organic particles (PM1) and the average value of f60 (attributed to levoglucosan), reinforce that elevated pollutant concentration levels were due to emissions from open biomass burning events, 70% of which were prescribed burning events. This study, which is the first and most comprehensive of its kind in Australia, provides quantitative evidence of the significant impact of open biomass burning events, especially prescribed burning, on urban air quality. The current results provide a solid platform for more detailed health and modelling investigations in the future.

Analysis of odour compounds from scented consumer products using gas chromatography-mass spectrometry and gas chromatography-olfactometry.

Scented consumer products are being bought in increasing amounts and gaining more popularity. There is, however, relatively little information available about their ingredients, emissions and allergenic potential. Frequently, a mixture of different fragrance substances and not solely an individual substance contributes to the overall desired smell. The aim of this study was to investigate the odorous volatile organic compounds (OVOCs) in consumer products containing fragrances. Over 44 products were selected: various scented candles, printing products with different scent types and other products types particularly meant to be used indoors. Measurements were carried out in a desiccator. Air samples were collected on thermal desorption tubes to determine the released fragrance substances by means of gas chromatography-mass spectrometry (GC-MS). Moreover, gas chromatography-olfactometry (GC-O) was used to obtain sensory data and to ensure no important odorant was overlooked. Using both methods it was possible to distinguish between odour active and inactive compounds and subsequently to identify almost 300 different odorants across all scented products. Besides the advantage of differentiation, as the human nose is a very sensitive detector, GC-O was found to be a useful tool for detecting traces and chosen target compounds. One focus in this study lay on the 26 EU-regulated fragrance allergens to prove their relevance in scented consumer goods. In total, 18 of them were identified, with at least one substance being present in almost every product. Benzyl alcohol, cinnamaldehyde, citronellol, eugenol, linalool and limonene were the prevalently detected allergens. Particularly linalool and limonene were observed in over 50% of the products. In addition, eugenol appeared to be one of the most frequently detected compounds in trace-level concentrations in the candle emissions.

Anaphylaxis in Schools: Results of the EPIPEN4SCHOOLS Survey Combined Analysis.

A pilot survey described the characteristics of anaphylactic events occurring in an initial set of participating U.S. schools during the 2013-2014 school year. This survey was subsequently readministered to large school districts, which were underrepresented in initial results. A cross-sectional survey was administered to the U.S. schools that were participating in the EPIPEN4SCHOOLS® program (Mylan Specialty L.P., Canonsburg, PA) to assess characteristics of anaphylactic events. Data from large school districts were added to initial findings in this comprehensive combined analysis. A total of 1,140 anaphylactic events were reported among 6,574 responding schools. Of 1,063 anaphylactic events with data on who experienced the event, it was observed that it occurred mostly in students (89.5%, 951/1,063). For students, anaphylactic events were reported across all grades, with 44.9% (400/891) occurring in high school students, 18.9% (168/891) in middle school students, and 32.5% (290/891) in elementary school students. Food was identified as the most common trigger (60.1%, 622/1,035). A majority of schools (55.0%, 3,332/6,053) permitted only the school nurse and select staff to administer epinephrine to treat anaphylaxis. The unpredictability of anaphylaxis is emphasized by its high occurrence in individuals with no known allergies (25.0%). A majority of schools permitted only the school nurse and select staff to treat anaphylaxis. Thus, individuals experiencing an anaphylactic event may frequently encounter staff members not being permitted to administer potentially life-saving epinephrine. Epinephrine auto-injectors provided by the EPIPEN4SCHOOLS program were used to treat 38.0% of events. Anaphylaxis can occur in children with no previously known allergies, illustrating the importance of public access to epinephrine.