Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. Objective: To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. Design, Setting, and Participants: This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Interventions: Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. Main Outcomes and Measures: The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Results: Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. Conclusions and Relevance: In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. Trial Registration: ISRCTN Identifier: 16108482.

Need for recovery and physician well-being in emergency departments: national survey findings.

BACKGROUND AND IMPORTANCE: Need for recovery (NFR) describes an individual's need to physically and psychologically recuperate following a period of work. Physicians working in emergency departments (EDs) have higher NFR scores than other occupational groups. Increased NFR may precede occupational burnout and identification provides opportunities for early interventions. OBJECTIVE: To identify the incidence of well-being characteristics for ED physicians and to determine if NFR score is associated with these characteristics, whilst adjusting for potential confounders. DESIGN: This is a secondary analysis of a survey study. Responses to 11 items were summated into the NFR score, from 0 (lowest NFR) to 100. Additional items (n = 44) explored well-being, demographic and occupational characteristics. SETTING AND PARTICIPANTS: Physicians working within 112 EDs in the UK and Ireland were surveyed in June-July 2019. OUTCOME MEASURE AND ANALYSIS: The outcome measure was self-perceptions of well-being including; current burnout, risk of future burnout and feeling overwhelmed at work. Descriptive statistics are presented alongside findings of a multiple regression analysis. MAIN RESULTS: In 4365 participants, the self-perceived incidence of current burnout, high risk of future burnout and feeling overwhelmed at work more than once a week was 24.8, 62.7 and 45.1%, respectively. For every unfavourable response of the NFR scale there was an increase in odds of 34.0% (95% CI, 31.0-37.1) for frequency of feeling overwhelmed; 53.8% (95% CI, 47.5-60.4) for current burnout; 56.2% (95% CI, 51.1-61.6) for high risk of future burnout. CONCLUSION: This study confirms an association between increased NFR score and self-perceived well-being characteristics. Factors previously reported to reduce NFR could therefore be important initiatives to improve well-being of the ED workforce.

The Use of Tranexamic Acid to Reduce the Need for Nasal Packing in Epistaxis (NoPAC): Randomized Controlled Trial.

STUDY OBJECTIVE: Epistaxis is a common emergency department (ED) presentation and, if simple first aid measures fail, can lead to a need for anterior nasal packing. Tranexamic acid is an agent that contributes to blood clot stability. The aim of this study is to investigate the effectiveness of topical intranasal tranexamic acid in adult patients presenting to the ED with persistent epistaxis, and whether it reduces the need for anterior nasal packing. METHODS: From May 5, 2017, to March 31, 2019, a double-blind, placebo-controlled, multicenter, 1:1, randomized controlled trial was conducted across 26 EDs in the United Kingdom. Participants with spontaneous epistaxis, persisting after simple first aid and the application of a topical vasoconstrictor, were randomly allocated to receive topical tranexamic acid or placebo. The primary outcome was the need for anterior nasal packing of any kind during the index ED attendance. Secondary outcome measures included hospital admission, need for blood transfusion, recurrent epistaxis, and any thrombotic events requiring any hospital reattendance within 1 week. RESULTS: The study sample consisted of 496 participants with spontaneous epistaxis, persisting after simple first aid and application of a topical vasoconstrictor. In total, 211 participants (42.5%) received anterior nasal packing during the index ED attendance, including 111 of 254 (43.7%) in the tranexamic acid group versus 100 of 242 (41.3%) in the placebo group. The difference was not statistically significant (odds ratio 1.107; 95% confidence interval 0.769 to 1.594; P=.59). Furthermore, there were no statistically significant differences between tranexamic acid and placebo for any of the secondary outcome measures. CONCLUSION: In patients presenting to an ED with atraumatic epistaxis that is uncontrolled with simple first aid measures, topical tranexamic acid applied in the bleeding nostril on a cotton wool dental roll is no more effective than placebo at controlling bleeding and reducing the need for anterior nasal packing.

The Use of Postoperative Antibiotics Following Endoscopic Sinus Surgery for Chronic Rhinosinusitis: A Systematic Review and Meta-analysis.

BACKGROUND: Endoscopic sinus surgery is performed for medically recalcitrant chronic rhinosinusitis. There is no universally accepted strategy regarding post-operative antibiotics despite the high rates of usage worldwide. The aim of this study was to analyse patient-reported and objective outcomes behind antibiotic use following endoscopic sinus surgery. METHODS: A search of electronic databases was performed. Eligible randomised controlled trials (RCTs) and observational trials were included. The primary outcome was patient reported outcome measures. Secondary outcomes were local infections, endoscopy scores and adverse events. Meta-analysis was performed. RESULTS: Of 1045 publications identified, 7 were included in the qualitative synthesis and 5 RCTs were included in meta-analysis. Antibiotic regimens varied between studies in terms of antibiotic selection, timing commenced and duration of use. Meta-analysis suggested no significant difference between placebo and antibiotics in patient reported outcome measures (standardised mean difference (SMD) -0.215, 95% confidence interval (CI) -0.637 to 0.207) or endoscopic scores (SMD -2.86, 95% CI -0.846 to 0.273). There was no consistent definition in reporting of infection; therefore, this outcome cannot be comprehensively considered. No severe adverse events were attributable to antibiotics. CONCLUSIONS: From the studies analysed, there is no level 1 evidence to suggest that antibiotics improved patient outcomes following sinus surgery. However, there was significant heterogeneity in outcome measures and no clear data exists regarding the effects of antibiotics on postoperative infections. The available evidence at present is not enough to make a recommendation in either direction. Further designed larger RCTs are required to investigate these questions in more detail.

Transmural unipolar electrogram change occurs within 7 s at the left atrial posterior wall during pulmonary vein isolation.

BACKGROUND: To assess occurrence of a histologically validated measure of transmural (TM) atrial ablation-pure R unipolar electrogram (UE) morphology change-at first-ablated left atrial posterior wall (LAPW) sites during contact force (CF)-guided pulmonary vein isolation (PVI). METHODS: Objectively annotated VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc., Diamond Bar, CA, USA) UE morphology data were retrospectively analyzed in 23 consecutive patients undergoing PVI under general anesthesia. RESULTS: PVI without spontaneous/dormant recovery was achieved in all, employing 16.3 (3.2) min of radiofrequency (RF; 30 W) energy. All first-ablated LAPW sites demonstrated RS UE morphology preablation, with RF-induced pure R UE morphology change in 98%. Time to pure R UE morphology was significantly shorter at left-sided LAPW sites (4.9 [2.1] vs 6.7 [2.5] s; P = .02), with significantly greater impedance drop (median 13.5 vs 9.9 Ω; P = .003). Importantly, neither first-site RF duration (14.9 vs 15.0 s) nor maximum ablation catheter tip distance moved (during RF) was significantly different, yet the mean CF was significantly higher at right-sided sites (16.5 vs 11.2 g; P = .002). Concurrent impedance and objectively annotated bipolar electrogram (BE) data demonstrated ∼6-8 Ω impedance drop and ∼30% BE decrease at the time of first pure R UE morphology change. CONCLUSIONS: Using objective ablation site annotation, UE morphology evidence of TM RF effect was demonstrated far sooner than considered biologically possible according to the "conventional" 20-40 s RF per-site approach, with significantly greater ablative effect evident at left-sided sites. This novel methodology represents a scientifically more rigorous foundation toward future research into the biological effects of RF ablation in vivo.

Epidemiology of balance and dizziness in a national population: findings from the English Longitudinal Study of Ageing.

OBJECTIVE: to identify socio-economic, behavioural and disease status risks for impaired balance or self-reported dizziness in older people from a large population-based study. METHODS: data were from the English Longitudinal Study of Ageing (ELSA), for 2,925 participants, aged 65+. Multivariate models were used to assess the associations between balance and dizziness and disease status, health behaviours, grip strength and socio-economic markers. RESULTS: there were 21.5% (n = 619) participants with impaired balance and 11.1% (n = 375) reported dizziness. Impaired balance was statistically significantly associated with age, diabetes (OR = 1.53), arthritis (OR = 1.33), eyesight (OR = 1.94) and grip strength. The wealthiest 20% of participants were less likely to have impaired balance than the poorest 20% (OR = 0.46). Dizziness problems were not associated with age, gender or wealth, but were significantly associated with an abnormal heart rhythm (OR = 1.85), hearing (OR = 1.81), eyesight (OR = 1.72) and grip strength. CONCLUSION: the epidemiology of impaired balance differs from that of dizziness, and risk assessment approaches to prevent falls may need to elicit information on different problem-specific factors. Impaired balance test performance in older people may be added to the many outcomes showing strong socio-economic gradients.