Clinical Burden of Chronic Obstructive Pulmonary Disease in Patients with Suboptimal Peak Inspiratory Flow.

Introduction: Many patients with chronic obstructive pulmonary disease (COPD) may derive inadequate benefit from dry powder inhalers (DPIs) because of suboptimal peak inspiratory flow (sPIF). Objectives: To assess the clinical burden of COPD by characterizing the clinical characteristics of participants with sPIF against medium-low resistance DPIs versus those with optimal PIF (oPIF) from two phase 3 clinical trials. Methods: Baseline data were collected from two randomized, controlled, phase 3 trials (NCT03095456; NCT02518139) in participants with moderate-to-severe COPD. oPIF (60 L/min) against the medium-low resistance DPIs was used as the threshold for defining the PIF subgroups (<60 L/min (sPIF) vs ≥60 L/min (oPIF)). Results: Most participants included in this analysis were White (92%) and male (63%); the mean (range) age was 65 (43-87) years. Participants with sPIF had significantly greater dyspnea than those with oPIF as measured using the modified Medical Research Council scoring (mean (95% CI): 2.1 (2.0-2.2) vs 1.6 (1.4-1.7); P < 0.001) and baseline dyspnea index (mean (95% CI): 5.1 (4.9-5.4) vs 6.1 (5.8-6.3); P < 0.001). Based on COPD Assessment Test scores, participants with sPIF had a higher COPD symptom burden than those with oPIF (mean (95% CI): 21.5 (19.7-23.3) vs 19.5 (18.6-20.4); P = 0.05). Conclusion: In these trials, participants with COPD who had sPIF against the medium-low resistance DPIs had more dyspnea and worse health status than those with oPIF. These results demonstrate that sPIF is associated with a higher clinical burden as measured by patient-reported outcomes.

Post Hoc Analysis of Lung Function Improvement and Patient-Reported Outcomes With Revefenacin in Adults With Moderate-to-Very Severe COPD and Comorbid Anxiety or Depression.

Background: Revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist approved in the United States for the maintenance of chronic obstructive pulmonary disease (COPD), significantly improves lung function and quality of life versus placebo in patients with moderate-to-very severe COPD. Comorbid anxiety and/or depression may alter patients' symptom perception and response to bronchodilators. The impact of revefenacin in patients with COPD with comorbid anxiety and/or depression has not been previously investigated. Methods: This post hoc subgroup analysis examined data from two 12-week, randomized, phase 3 trials in patients with moderate-to-very severe COPD with the following self-reported subgroups: anxiety only (A), depression only (D), anxiety and depression (+A/+D), and neither anxiety nor depression (-A/-D). We assessed change from baseline in trough forced expiratory volume in 1 second (FEV1) at Day 85 and health status by the St George's Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT). Results: Of 812 patients, 90 (11%), 110 (14%), 141 (17%), and 471 (58%) had A, D, +A/+D, and -A/-D respectively. In revefenacin versus placebo, trough FEV1 significantly improved from baseline at Day 85 across all subgroups as well as the SGRQ and CAT scores in patients with A, +A/+D, and -A/-D. Revefenacin was well tolerated regardless of A/D status, with a minimal incidence of treatment-emergent antimuscarinic adverse events across subgroups. Conclusion: In this analysis, revefenacin versus placebo significantly improved health outcomes in patients with moderate-to-very severe COPD with A, +A/+D, and -A/-D, but not in patients with D. The safety profile of revefenacin was not affected by comorbid anxiety/depression status.

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Efficacy and safety of an inhaled pan-Janus kinase inhibitor, nezulcitinib, in hospitalised patients with COVID-19: results from a phase 2 clinical trial.

BACKGROUND: The inhaled lung-selective pan-Janus kinase inhibitor nezulcitinib had favourable safety and potential efficacy signals in part 1 of a phase 2 trial in patients with severe COVID-19, supporting progression to part 2. METHODS: Part 2 was a randomised, double-blind phase 2 study (NCT04402866). Hospitalised patients aged 18-80 years with confirmed symptomatic COVID-19 requiring supplemental oxygen (excluding baseline invasive mechanical ventilation) were randomised 1:1 to nebulised nezulcitinib 3 mg or placebo for up to 7 days with background standard-of-care therapy (including corticosteroids). Efficacy endpoints included respiratory failure-free (RFF) days through day 28 as the primary endpoint. Secondary endpoints included safety and change from baseline oxygen saturation (SaO2)/fraction of inspired oxygen (FiO2) ratio on day 7, and 28-day mortality rate was a prespecified exploratory endpoint. RESULTS: Between June 2020 and April 2021, 205 patients were treated (nezulcitinib, 103; placebo, 102). There was no statistically significant difference between nezulcitinib versus placebo in the primary endpoint (RFF days; median, 21.0 vs 21.0; p=0.6137) or secondary efficacy endpoints. Nezulcitinib was generally well tolerated with a favourable safety profile. CONCLUSIONS: Although the prespecified primary, secondary and exploratory efficacy endpoints, including RFF through day 28, change from baseline SaO2/FiO2 ratio on day 7, and 28-day mortality rate, were not met, nezulcitinib was generally well tolerated and had a favourable safety profile. Further studies are required to determine if treatment with nezulcitinib confers clinical benefit in specific inflammatory biomarker-defined populations of patients with COVID-19.

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial.

Importance: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence. Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks. Design, Setting, and Participants: This phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry. Interventions: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI. Main Outcomes and Measures: The main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population. Results: Of 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]). Conclusions and Relevance: In this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI. Trial Registration: ClinicalTrials.gov identifier: NCT03183141.

Improvements in health status with revefenacin, a once-daily, nebulized, long-acting muscarinic antagonist for chronic obstructive pulmonary disease.

BACKGROUND: Replicate, 12-week, phase 3 trials (0126 and 0127) of once-daily nebulized revefenacin 175 µg vs placebo demonstrated significant bronchodilation and improvements in health status in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). This post hoc analysis evaluated improvement in patient-reported outcomes (PROs), including the St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Clinical COPD Questionnaire (CCQ) in both women and men. METHODS: Participants were pooled from the two 12-week studies (411 [51%] women and 401 [49%] men). Changes in PROs were assessed overall and separately in men and women. RESULTS: Revefenacin improved SGRQ and CAT total scores from baseline in both studies; improvement in CCQ total score reached significance only in 0126. In pooled data, a greater proportion of patients achieved clinically meaningful response in SGRQ score (≥4-unit decrease from baseline) with revefenacin vs placebo (odds ratio, 1.5; 95% confidence interval, 1.1-2.1; P = 0.012). Clinically meaningful responses were also seen in CAT (≥2-unit decrease from baseline) and CCQ (≥0.4-unit decrease from baseline) scores with revefenacin vs placebo. When stratified by sex, improvements from baseline in SGRQ, CAT, and CCQ scores following revefenacin vs placebo reached statistical significance only in women. CONCLUSIONS: Maintenance treatment with revefenacin improved health status in patients with moderate to very severe COPD; however, the effect was more pronounced for women than men. CLINICALTRIALS: GOV: NCT02459080; NCT02512510.

Chronotypes in the US: Influence of longitude position in a time zone.

The availability of electrical light has altered modern light exposure, affecting the synchronization process ('entrainment') of the circadian clock to the natural light-dark cycle. The discrepancy between the natural light-dark cycle and self-selected light exposure has raised the question whether humans entrain to sun time (as most organisms do) vs. social time. None of the studies addressing this question have been conducted in the US in a large-scale, nationally representative sample. In this brief report, we aimed at estimating the relationship between individual chronotype (the result of the entrainment process) and longitude position in a time zone, using 12 years (2003-2014) of pooled diary data (n = 50,753) from the American Time Use Survey (ATUS). Chronotype was estimated based on mid-sleep time on weekends (MSFWe), a proxy that was previously shown to replicate known age and sex differences in chronotype in the ATUS. Longitude position was derived from state-level information (e.g., average state border outline). Regression results showed a progressive delay in MSFWe from east to west within three of the four US continental time zones (delay per degree of longitude): Eastern, 1.8 min; Central, 1.2 min; Mountain, 2.4 min (all p < .01). The findings suggest that humans entrain to sun time, leading to an increasing discrepancy between social time and biological time ("circadian misalignment") towards the west of a time zone. Such a misalignment induced by where people live within a time zone may affect a large share of the population, with implications for health and safety.

Real-World Clinical Use and Outcomes of Telavancin for the Treatment of Bone and Joint Infections: Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Additional antibiotic options are needed to treat bone and joint infections caused by penicillin-resistant Gram-positive pathogens. OBJECTIVE: This subanalysis of the Telavancin Observational Use Registry (TOUR™) aimed to record real-world telavancin usage patterns in patients with bone and joint infections treated with telavancin. METHODS: TOUR was a multicenter observational-use registry study conducted at 45 US sites between January 2015 and March 2017. Patient characteristics, infection type, infecting pathogen(s), previous treatment, telavancin dosing and duration, clinical response, and adverse event data were collected by retrospective medical chart reviews. As such, inclusion/exclusion criteria were limited, and any patient receiving at least one dose of telavancin at the discretion of the treating physician was eligible. Patients were assessed as either positive clinical response, failed treatment, or indeterminate outcome. RESULTS: Of the 1063 patients enrolled in TOUR, 27.4% (291/1063) were patients with bone and joint infections including osteomyelitis (with or without prosthetic material), acute septic arthritis, and prosthetic joint infections. Most of these patients had osteomyelitis without prosthetic material (191/291; 66.0%). Among patients assessed at the end of treatment, 211/268 (78.7%) achieved a positive clinical response, 26/268 (9.7%) failed treatment, and 31/268 (11.6%) had an indeterminate outcome. The most frequent pathogen was methicillin-resistant Staphylococcus aureus (110/291; 37.8%). The median (interquartile range [IQR as Q1, Q3]) telavancin dose was 750.0 mg (IQR, 750, 750 mg) or 8.2 mg/kg (IQR, 6.8, 9.7 mg/kg) administered for a median of 26 days (IQR, 12, 42 days). These assessments were recorded in the registry ≥ 30 days after the last dose of telavancin was administered. CONCLUSIONS: Real-world data from the TOUR study show that clinicians are using once-daily telavancin with positive clinical outcomes for the treatment of bone and joint infections caused by Gram-positive pathogens. CLINICAL TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02288234) on 11 November, 2014.

Characteristics of working hours and the risk of occupational injuries among hospital employees: a case-crossover study.

Objectives We investigated the association of working hours with occupational injuries in hospital shift work. Methods Registry data of occupational injuries of hospital employees from 11 towns and 6 hospital districts were linked to daily payroll data to obtain working hours for 37 days preceding the first incidence of the injury (N=18 700). A case-crossover design and associated matched-pair interval analysis were used to compare working hour characteristics for three separate hazard windows among the same subjects. Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Results We found an elevated risk of an occupational injury for workdays with evening shifts (OR 1.09, 95% CI 1.03-1.14) and workdays following night shifts (OR 1.33, 95% CI 1.17-1.52). After excluding commuting injuries, the risk increased during the evening shifts (OR 1.15, 95% CI 1.09-1.23) and the work days following night shifts (OR 1.44, 95% CI 1.24-1.69), but was no more significant during the morning shifts. Injury risk increased following a week of ≥5 morning shifts or ≥3 evening shifts, but did not increase according to the number of preceding night shifts or quick returns. The length of the work shift (OR 1.22, CI 1.06-1.42) - not the length of the weekly working hours - was associated with an increased risk. Conclusions The results indicate an increased occupational injury risk during the evening shifts and during work days following night shifts, with the risk increasing according to the number of evening but not night shifts.

Clinical Experience with Telavancin for the Treatment of Patients with Bacteremia and Endocarditis: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Bacteremia and endocarditis caused by Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), are challenging to treat and are associated with high morbidity and mortality. Telavancin is a lipoglycopeptide antibacterial active against susceptible Gram-positive pathogens, including MRSA. OBJECTIVE: This registry study assessed the real-world use and clinical outcomes of telavancin in patients with bacteremia or endocarditis enrolled in the Telavancin Observation Use Registry (TOUR™). METHODS: The subset of patients enrolled in TOUR who were diagnosed with endocarditis and/or bacteremia with a known or unknown primary source (N = 151) were analyzed. Data including demographics, infection type, baseline pathogens, prior or concomitant antimicrobial therapy, dosing regimen, clinical response, treatment-emergent adverse events (TEAEs) of interest, and mortality were collected by retrospective medical chart review. RESULTS: Telavancin was primarily used as a second-line or greater therapy (n = 132, 87.4%). MRSA was present in 87 (57.6%) patients. Median telavancin dose was 740.6 mg (interquartile range (IQR) 206.0 mg) and median duration of therapy was 9.0 days (IQR 24.0 days). Of the 132/151 (87.4%) patients with an available assessment at the end of telavancin therapy, a positive clinical response was achieved in 98/132 (74.2%), while 14/132 (10.6%) failed therapy and 20/132 (15.2%) had an indeterminant outcome. TEAEs occurred in 24 (15.9%) patients. The most frequent TEAE was renal failure (n = 12, 7.9%); seven of these patients were receiving concomitant nephrotoxic medications. There was no change in creatinine clearance for 67/89 (75.3%) patients with values recorded at the beginning and the end of telavancin therapy. CONCLUSIONS: In real-world clinical practice, overall positive clinical outcomes are observed in patients with bacteremia or endocarditis treated with telavancin, including in those patients infected with MRSA or another S. aureus pathogen. Telavancin may be an alternative treatment option for these patients. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (NCT02288234) on 11 November 2014.

Peak Inspiratory Flows: Defining Repeatability Limits and a Predictive Equation for Different Inhalers.

BACKGROUND: Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking. RESEARCH QUESTIONS: What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIFD) and HandiHaler (Boehringer Ingelheim; PIFHH) resistances? STUDY DESIGN AND METHODS: Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIFD and PIFHH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149). RESULTS: In study 0128, the mean values (SD) for PIF at zero resistance and PIFHH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIFD and PIFHH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIFD and PIFHH was small, < 5 and < 3 L/min, respectively. The repeatability limit was determined as 10 and 5 L/min for PIFD and PIFHH, respectively. Modeling the relationship between PIFD and PIFHH, after controlling for significant covariates, demonstrated that a PIFD value of 60 L/min was approximately equivalent to PIFHH of 40 L/min. INTERPRETATIONS: This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov.

Evolution of a US County System for Acute Comprehensive Stroke Care.

BACKGROUND AND PURPOSE: In Orange County, California, patients with suspected acute stroke are taken to stroke neurology receiving centers that are designated by County Emergency Medical Services authorities as either hubs or spokes based on endovascular treatment capability. We examined relationships between stroke details, reperfusion therapies, hospital transfers, and their change over time. METHODS: All patients from January 1, 2013, to December 31, 2015, for whom 911 was called within 7 hours of onset in whom Emergency Medical Services personnel suspected acute stroke were evaluated. RESULTS: Among 6132 patients, 3924 (64%) had confirmed diagnosis of stroke (74% ischemic/26% hemorrhagic), yielding diagnostic precision of 64% in the field. Of the 2892 patients with acute ischemic stroke, acute reperfusion therapy was given to 29.2% (21.7% intravenous tPA [tissue-type plasminogen activator] only and 7.5% endovascular treatment). Rates of endovascular treatment of patients with ischemic stroke increased over time, more than doubling from 5.6% in 2013 to 12.5% (odds ratio per 3-month quarter=1.09; 95% confidence interval, 1.04-1.14; P<0.0001). Only 3.4% of patients with acute ischemic stroke were transferred from a spoke to a hub hospital; transfer rates were inversely related to age (P<0.0001), and reperfusion therapy rates did not vary according to transfer status. CONCLUSIONS: Favorable features of this acute stroke care system include reperfusion therapy in 29.2% of patients with ischemic stroke and substantial increases in endovascular treatment rates over time. Continued efforts to optimize acute stroke systems of care can be directed toward improving access to best acute stroke therapies.

Updating the "Risk Index": A systematic review and meta-analysis of occupational injuries and work schedule characteristics.

Fatigue is a major risk factor for occupational 'accidents' and injuries, and involves dimensions of physical, mental, and muscular fatigue. These dimensions are largely influenced by temporal aspects of work schedules. The "Risk Index" combines four fatigue-related components of work schedules to estimate occupational 'accident' and injury risk based on empirical trends: shift type (morning, afternoon/evening, night), length and consecutive number, and on-shift rest breaks. Since its first introduction in 2004, several additional studies have been published that allow the opportunity to improve the internal and external validity of the "Risk Index". Thus, we updated the model's estimates by systematically reviewing the literature and synthesizing study results using meta-analysis. Cochrane Collaboration directives and MOOSE guidelines were followed. We conducted systematic literature searches on each model component in Medline. An inverse variance approach to meta-analysis was used to synthesize study effect sizes and estimate between-studies variance ('heterogeneity'). Meta-regression models were conducted to explain the heterogeneity using several effect modifiers, including the sample age and sex ratio. Among 3,183 initially identified abstracts, after screening by two independent raters (95-98% agreement), 29 high-quality studies were included in the meta-analysis. The following trends were observed: Shift type. Compared to morning shifts, injury risk significantly increased on night shifts (RR = 1.36 [95%CI = 1.15-1.60], n = 14 studies), while risk was slightly elevated on afternoon/evening shifts, although non-significantly (RR = 1.12 [0.76-1.64], n = 9 studies). Meta-regressions revealed worker's age as a significant effect modifier: adolescent workers (≤ 20 y) showed a decreased risk on the afternoon/evening shift compared to both morning shifts and adult workers (p < 0.05). Number of consecutive shifts. Compared to the first shift in a block of consecutive shifts, risk increased exponentially for morning shifts (e.g., 4th: RR = 1.09 [0.90-1.32]; n = 6 studies) and night shifts (e.g., 4th: RR = 1.36 [1.14-1.62]; n = 8 studies), while risk on afternoon/evening shifts appeared unsystematic. Shift length. Injury risk rose substantially beyond the 9th hour on duty, a trend that was mirrored when looking at shift lengths (e.g., >12 h: RR = 1.34 [1.04-1.51], n = 3 studies). Rest breaks. Risk decreased for any rest break duration (e.g., 31-60 min: RR = 0.35 [0.29-0.43], n = 2 studies). With regards to time between breaks, risk increased with every additional half hour spent on the work task compared to the first 30 min (e.g., 90-119 min: RR = 1.62 [1.00-2.62], n = 3 studies). Rest break duration and interval seem to interact such that with increasing duration, the time between breaks becomes irrelevant. The updated "Risk Index". All four components were combined to form the updated model and the relative risk values estimated for a variety of work schedules. The resulting "Risk Map" shows regions of highest risk when rest breaks are not taken frequently enough (i.e. <4 h) or are too short (i.e. <30 min), when shift length exceeds 11 h, and when work takes place during the night (particularly for >3 consecutive night shifts). The "Risk Index" is proposed as an empirical model to predict occupational 'accident' and injury risk based on the most recent data in the field, and can serve as a tool to evaluate hazards and maximize safety across different work schedules.

Chronotypes in the US - Influence of age and sex.

An individual's chronotype reflects how the circadian system embeds itself into the 24-h day with rhythms in physiology, cognition and behavior occurring accordingly earlier or later. In view of an increasing number of people working at unusual times and linked health and safety risks, the wide range in human chronotypes may provide opportunities to allow people to work (and sleep) at times that are in synch with their circadian physiology. We aimed at estimating the distribution of chronotypes in the US population by age and sex. Twelve years (2003-2014) of pooled diary data from the American Time Use Survey were used to calculate chronotype based on mid-point of sleep on weekends (MSFWe, n = 53,689). We observed a near-normal distribution overall and within each age group. The distribution's mean value is systematically different with age, shifting later during adolescence, showing a peak in 'lateness' at ~19 years, and shifting earlier thereafter. Men are typically later chronotypes than women before 40, but earlier types after 40. The greatest differences are observed between 15 and 25 for both sexes, equaling more than 50% of the total chronotype difference across all age groups. The variability in chronotype decreases with age, but is generally higher in males than females. This is the first study to estimate the distribution and prevalence of individual chronotypes in the US population based on a large-scale, nationally representative sample. Our finding that adolescents are on average the latest chronotypes supports delaying school start times to benefit their sleep and circadian alignment. The generally wide range in chronotypes may provide opportunities for tailored work schedules by matching external and internal time, potentially decreasing long- and short-term health and safety risks.

Circumstances of fall-related injuries by age and gender among community-dwelling adults in the United States.

INTRODUCTION: Falls are the leading cause of injury in almost all age-strata in the U.S. However, fall-related injuries (FI) and their circumstances are under-studied at the population level, particularly among young and middle-aged adults. This study examined the circumstances of FI among community-dwelling U.S. adults, by age and gender. METHODS: Narrative texts of FI from the National Health Interview Survey (1997-2010) were coded using a customized taxonomy to assess place, activity, initiating event, hazards, contributing factors, fall height, and work-relatedness of FI. Weighted proportions and incidence rates of FI were calculated across six age-gender groups (18-44, 45-64, 65+ years; women, men). RESULTS: The proportion of FI occurring indoors increased with age in both genders (22%, 30%, and 48% among men, and 40%, 49% and 62% among women for 18-44, 45-64, 65+ age-groups, respectively). In each age group the proportion of indoor FI was higher among women as compared to men. Among women, using the stairs was the second leading activity (after walking) at the time of FI (19%, 14% and 10% for women in 18-44, 45-64, 65+ age groups, respectively). FI associated with tripping increased with age among both genders, and women were more likely to trip than men in every age group. Of all age-gender groups, the rate of FI while using ladders was the highest among middle-aged men (3.3 per 1000 person-year, 95% CI 2.0, 4.5). Large objects, stairs and steps, and surface contamination were the three most common hazards noted for 15%, 14% and 13% of fall-related injuries, respectively. CONCLUSIONS: The rate and the circumstances of FI differ by age and gender. Understanding these differences and obtaining information about circumstances could be vital for developing effective interventions to prevent falls and FI.

Developing a job-exposure matrix with exposure uncertainty from expert elicitation and data modeling.

Job exposure matrices (JEMs) are tools used to classify exposures for job titles based on general job tasks in the absence of individual level data. However, exposure uncertainty due to variations in worker practices, job conditions, and the quality of data has never been quantified systematically in a JEM. We describe a methodology for creating a JEM which defines occupational exposures on a continuous scale and utilizes elicitation methods to quantify exposure uncertainty by assigning exposures probability distributions with parameters determined through expert involvement. Experts use their knowledge to develop mathematical models using related exposure surrogate data in the absence of available occupational level data and to adjust model output against other similar occupations. Formal expert elicitation methods provided a consistent, efficient process to incorporate expert judgment into a large, consensus-based JEM. A population-based electric shock JEM was created using these methods, allowing for transparent estimates of exposure.

Age-related differences in fatal intersection crashes in the United States.

OBJECTIVE: Given the aging U.S. population and resulting number of older drivers in the coming years, it is important to understand the factors leading to their involvement in vehicle crashes and develop counter-measures to reduce their frequency and severity. This is also useful for helping older adults "age in place" in terms of accessibility, mobility, quality of life and safety. Thus, the objective of this study was to provide up-to-date data on differences in age-related risks and rates for involvement in fatal intersection motor-vehicle crashes in the US. METHODS: Pooled data for the years 2011-2014 from the FARS, a census of fatal traffic crashes within the 50 States, the District of Columbia, and Puerto Rico, created by the US National Highway Traffic Safety Administration (NHTSA) were used to calculate summary statistics including annualized crash rates. Multivariate logistic regression models were used to evaluate age and gender-related differences in fatal intersection crash risk, controlling for covariates. An induced exposure analysis was conducted to calculate crash involvement ratios (CIRs) for all two-vehicle fatal intersection crashes. Older and younger drivers were compared with respect to the presence of factors related to intersection crashes using a multivariate Poisson regression model. RESULTS: During the period of 2011-2014, among the reported 120,809 fatal accidents in the US involving 178,489 drivers of vehicles, 48,733 (28%) were drivers involved in fatal intersection crashes. Age-adjusted annualized fatal intersection crash rates per 100,000 licensed drivers were highest for drivers aged 85 or older (9.89/100,000), followed by 20 years of age (8.93/100,000). Teen and older drivers (55+ years of age) were over-involved in fatal intersection crashes, drivers from 20 to 54 years old were under-involved. Male and female drivers, 70-74 years of age, were 20% and 21%, respectively, more likely to be involved in a fatal intersection crash than 20-24year olds (of same gender). By age 85, fatal intersection crash risk for all drivers was almost doubled. Significant differences in factors related to crashes involving younger (<65) and older (65+ years) drivers were time of day, lighting and weather conditions, day of week, roadway type and number of lanes, presence of visible traffic controls, speed limit and estimated driving speed, and whether the driver was deemed at fault for the crash CONCLUSION: The results provide the most up-to-date analysis of aging and fatal intersection crash risk in the US, and underscore several trends worthy of further investigation. Older adults face a number of challenges associated with natural aging, including sensory, perceptual, cognitive and motor declines that may impact their driving. As with younger drivers, expanded or renewed approaches to driver training at licensing renewals, as well as safety-based technological advances are viable avenues toward improving the safety outlook for older adults.

Effect of Body Mass Index on Left Ventricular Mass in Career Male Firefighters.

Left ventricular (LV) mass is a strong predictor of cardiovascular disease (CVD) events; increased LV mass is common among US firefighters and plays a major role in firefighter sudden cardiac death. We aim to identify significant predictors of LV mass among firefighters. Cross-sectional study of 400 career male firefighters selected by an enriched randomization strategy. Weighted analyses were performed based on the total number of risk factors per subject with inverse probability weighting. LV mass was assessed by echocardiography (ECHO) and cardiac magnetic resonance, and normalized (indexed) for height. CVD risk parameters included vital signs at rest, body mass index (BMI)-defined obesity, obstructive sleep apnea risk, low cardiorespiratory fitness, and physical activity. Linear regression models were performed. In multivariate analyses, BMI was the only consistent significant independent predictor of LV mass indexes (all, p <0.001). A 1-unit decrease in BMI was associated with 1-unit (g/m1.7) reduction of LV mass/height1.7 after adjustment for age, obstructive sleep apnea risk, and cardiorespiratory fitness. In conclusion, after height-indexing ECHO-measured and cardiac magnetic resonance-measured LV mass, BMI was found to be a major driver of LV mass among firefighters. Our findings taken together with previous research suggest that reducing obesity will improve CVD risk profiles and decrease on-duty CVD and sudden cardiac death events in the fire service. Our results may also support targeted noninvasive screening for LV hypertrophy with ECHO among obese firefighters.