Plain Language Summary of the PAISLEY study: deucravacitinib as a treatment for people with systemic lupus erythematosus.

What is this summary about?This plain language summary describes the results of the phase 2 study called PAISLEY which tested deucravacitinib, a new medicine under investigation before approval, in people living with lupus. In this trial, researchers wanted to find out if deucravacitinib would be safe and reduce the symptoms and disease activity in people living with lupus. PAISLEY looked at the type of lupus known as systemic lupus erythematosus, shortened to SLE.What happened in the study?The study included 363 people from 17 countries who had SLE and were between 18 and 75 years of age. The participants were divided into 4 groups at random. One group was given placebo (a fake or dummy pill that contains no medicine) and the other 3 groups took deucravacitinib, a pill taken by mouth. Each of the groups taking deucravacitinib took a different dose, either 3 milligrams (mg) twice daily, 6 mg twice daily, or 12 mg once daily. After 32 and 48 weeks, researchers measured the number of people in each group who had improvements in their SLE symptoms and disease activity, as measured by different tests. They also looked at any side effects people experienced, which may or may not have been caused by the medicine.What do the results mean?After 32 weeks of treatment, SLE symptoms and disease activity improved in more people in each of the deucravacitinib dose groups compared with the people taking placebo (the dummy pill). After 48 weeks of treatment, SLE symptoms and disease activity were still improved in more people taking deucravacitinib compared with people taking placebo, and this was measured in several different ways. The best results were seen in people taking deucravacitinib 3 mg twice daily. The number of serious side effects was similar for people taking deucravacitinib and those taking placebo. The most common side effects that were seen in people taking deucravacitinib were infections such as sore throat, cough, or bronchitis (upper respiratory tract), infltion in the nose (nasopharyngitis), headaches, and urinary tract infections. More people taking deucravacitinib than placebo had acne, rash, and cold sores (oral herpes). These were not serious and did not have any long-term effects on patient health or lead to patients stopping treatment.How to say (double click sound icon to play sound)… Systemic lupus erythematosus: SIS-teh-MIC LOO-puhs Eh-RE-the-ma-TOE-susDeucravacitinib: doo-KRAV-a-sih-ti-nibEnzyme: EN-zimeInterferon: in-tur-FER-onPlacebo: pluh-SEE-bohTyrosine kinase: TY-ruh-seen KY-naysTYK2: TIK-tu.

Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). METHODS: Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. RESULTS: At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. CONCLUSION: Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.

Estimation of the cumulative incidence function under multiple dependent and independent censoring mechanisms.

Competing risks occur in a time-to-event analysis in which a patient can experience one of several types of events. Traditional methods for handling competing risks data presuppose one censoring process, which is assumed to be independent. In a controlled clinical trial, censoring can occur for several reasons: some independent, others dependent. We propose an estimator of the cumulative incidence function in the presence of both independent and dependent censoring mechanisms. We rely on semi-parametric theory to derive an augmented inverse probability of censoring weighted (AIPCW) estimator. We demonstrate the efficiency gained when using the AIPCW estimator compared to a non-augmented estimator via simulations. We then apply our method to evaluate the safety and efficacy of three anti-HIV regimens in a randomized trial conducted by the AIDS Clinical Trial Group, ACTG A5095.

Towards best practice in physical and physiological employment standards.

While the scope of the term physical employment standards is wide, the principal focus of this paper is on standards related to physiological evaluation of readiness for work. Common applications of such employment standards for work are in public safety and emergency response occupations (e.g., police, firefighting, military), and there is an ever-present need to maximize the scientific quality of this research. Historically, most of these occupations are male-dominated, which leads to potential sex bias during physical demands analysis and determining performance thresholds. It is often assumed that older workers advance to positions with lower physical demand. However, this is not always true, which raises concerns about the long-term maintenance of physiological readiness. Traditionally, little attention has been paid to the inevitable margin of uncertainty that exists around cut-scores. Establishing confidence intervals around the cut-score can reduce for this uncertainty. It may also be necessary to consider the effects of practise and biological variability on test scores. Most tests of readiness for work are conducted under near perfect conditions, while many emergency responses take place under far more demanding and unpredictable conditions. The potential impact of protective clothing, respiratory protection, load carriage, environmental conditions, nutrition, fatigue, sensory deprivation, and stress should also be considered when evaluating readiness for work. In this paper, we seek to establish uniformity in terminology in this field, identify key areas of concern, provide recommendations to improve both scientific and professional practice, and identify priorities for future research.

Nivolumab in previously untreated melanoma without BRAF mutation.

BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

Supplemental feedings increase self-selected work output during wildfire suppression.

PURPOSE: The purpose of this study was to determine the impact of supplemental feeding strategies on self-selected activity during wildland fire suppression. METHODS: Seventy-six wildland firefighters were studied in three experiments for three fire seasons. During the first two seasons, subjects consumed, in addition to their sack lunch, 1) liquid carbohydrate (CHO) (200 mL.h, 20% CHO (40 g.h, 160 kcal.h)) or placebo (PLA) every hour, or 2) liquid CHO (200 mL.h, 20% CHO (40 g.h, 160 kcal.h) every even hour and solid CHO (25 g of CHO, 10 g of protein, 2 g of fat, and 160 kcal.h) every odd hour, or PLA, using counterbalanced crossover designs. During the third season, subjects consumed their sack lunch halfway through their workday, or shift food items of approximately 150-400 kcal at 90-min intervals after breakfast in a randomized crossover design (isocaloric intake, 1534+/-265 kcal per workday). Work output was monitored using CSA and MiniMitter actigraphy units. RESULTS: During the liquid CHO trials, subjects consuming CHO demonstrated significantly higher average activity counts throughout the day compared with PLA (50,262+/-36,560 and 40,159+/-35,969 counts per hour for 12 h for the CHO and PLA trials, respectively; P<0.05). For the liquid+solid CHO trials, subjects consuming CHO demonstrated higher average activity counts per minute 2 h before lunch and the last 4 h of the workday compared with PLA (P<0.05). For the sack lunch and shift food trials, subjects consuming shift foods demonstrated higher average counts per minute during the final 2 h compared with those consuming sack lunch (521+/-421 vs 366+/-249 counts per minute during 2 h; P<0.05). CONCLUSION: Liquid and/or solid supplemental CHO and regular feedings increased self-selected work rates during wildland fire suppression, particularly during the latter hours of the workday.

Water turnover and changes in body composition during arduous wildfire suppression.

INTRODUCTION: Our lab has recently documented the total energy expenditure during arduous wildfire suppression using the doubly labeled water methodology. The elevated rates of isotopic elimination indicate an arduous working environment that may often compromise energy balance and overall hydration. PURPOSE: The purpose of this investigation was to determine the effects of arduous wildfire suppression on water turnover and changes in body composition in wildland firefighters (WLFF). METHODS: WLFF (N = 14) were studied during a 5-d period of arduous fire suppression work. A comparison group (N = 13) of recreationally active college students (RACS) was also studied. Water turnover was measured from rates of 2H elimination (rH2O). Urine osmolality, specific gravity, and skinfold measures were also collected. RESULTS: WLFF demonstrated a decrease in nude body weight (pre = 71.9 +/- 10.4 kg, post = 70.9 +/- 10.2 kg, P = 0.0001) and total body water (pre = 42.9 +/- 7.2 kg, post = 42.0 +/- 6.7 kg, P = 0.0046). RACS maintained total body water and body weight during the experimental period. Isotope (2H2O) dilution demonstrated that rH2O was significantly higher for the WLFF (rH2O = 6.7 +/- 1.4 and 3.8 +/- 1.0 L.24 h-1 for the WLFF and RACS, respectively). CONCLUSION: These results demonstrate an arduous work environment that threatens hydration, energy balance, and perhaps normal glycogen status.

Total energy expenditure during arduous wildfire suppression.

PURPOSE: The purpose of this investigation was to determine the total energy expenditure (TEE) by using the doubly labeled water (DLW) methodology during 5 d of wildfire suppression in Montana, California, Florida, Washington, and Idaho. METHODS: Seventeen wildland firefighters (from three Interagency Hot Shot crews, N = 8 men, height = 177 +/- 7 cm, weight = 74.6 +/- 6.4 kg, age = 24.5 +/- 1.8 yr; N = 9 women, height = 170 +/- 7 cm, weight = 65.2 +/- 8.0 kg, age = 25.0 +/- 1.3 yr) served as subjects. Before wildland fire suppression, each subject was given an oral dose of 2H2O and H218O (approximately 0.23 g 2H2O.kg estimated TBW-1 and 0.39 g H218O.kg estimated TBW-1). Urine samples were collected between 0400 and 0600 daily. TEE was calculated using the two-point method for days 1-3 and 1-5, with the TEE for days 4-5 calculated by extrapolation. Urine samples from other crew members not participating in the DLW protocol were collected at the same times and used to adjust calculations of isotopic elimination for background shifts. RESULTS: TEE was 17.4 +/- 3.7 and 17.5 +/- 6.9 MJ.d-1 during days 1-3 and 4-5, respectively. The energy expenditure associated with physical activity (EEA) was 8.8 +/- 3.0 and 8.9 +/- 6.1 MJ.d-1 for days 1-3 and 4-5, respectively. CONCLUSION: The current data demonstrate consistently high daily energy expenditure in the wildland firefighter. These data also demonstrate that the doubly labeled water methodology is an appropriate methodology for the measure of TEE during unpredictable field operations if adjustments are made for changes in background enrichment and elevated water turnover.