Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or without evidence of allergic asthma.

BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.

Delineating the impacts of air temperature and humidity for endurance exercise.

NEW FINDINGS: What is the central question of this study? What are the independent effects of air temperature and humidity on performance, physiological and perceptual responses during endurance exercise? What is the main finding and its importance? When examined independently, elevated air temperature increased heat strain and impaired aerobic exercise performance, but to a lesser extent than has been reported previously. These findings highlight the importance of absolute humidity relative to temperature when exercising or working under severe heat stress. ABSTRACT: Many studies have reported that ambient heat stress increases physiological and perceptual strain and impairs endurance exercise, but effects of air temperature per se remain almost unexamined. Most studies have used matched relative humidity, thereby exponentially increasing absolute humidity (water content in air) concurrently with temperature. Absolute (not relative) humidity governs evaporative rate and is more important at higher work rates and air temperatures. Therefore, we examined the independent effects of air temperature and humidity on performance, thermal, cardiovascular and perceptual measures during endurance exercise. Utilizing a crossover design, 14 trained participants (7 females) completed 45 min fixed-intensity cycling (70% V ̇ O 2 peak ${\dot V_{{{\rm{O}}_{\rm{2}}}{\rm{peak}}}}$ ) followed by a 20-km time trial in each of four environments: three air temperatures at matched absolute humidity (Cool, 18°C; Moderate, 27°C; and Hot, 36°C; at 1.96 kPa, air velocity ∼4.5 m/s), and one at elevated humidity (Hot Humid, 36°C at 3.92 kPa). Warmer air caused warmer skin (0.5°C/°C; P < 0.001), higher heart rate (1 bpm/°C; P < 0.001), sweat rate (0.04 l/h/°C; P < 0.001) and thermal perceptions during fixed-intensity exercise, but minimally affected core temperature (<0.01°C/°C; P = 0.053). Time-trial performance was comparable between Cool and Moderate (95% CI: -1.4, 5.9%; P = 0.263), but 3.6-6% slower in Hot (95% CI: ±2.4%; P ≤ 0.006). Elevated humidity increased core temperature (P < 0.001), perceived temperature and discomfort but not skin temperature or heart rate, and reduced mean blood pressure (P = 0.046) during fixed-intensity exercise. Elevated humidity impaired time-trial performance by 3.4% (95% CI: ±2.2%; P = 0.006). In conclusion, these findings quantify the importance of absolute humidity alongside air temperature when exercising under severe heat stress.

Workplace absenteeism due to COVID-19 and influenza across Canada: A mathematical model.

The continual distress of COVID-19 cannot be overemphasized. The pandemic economic and social costs are alarming, with recent attributed economic loss amounting to billions of dollars globally. This economic loss is partly driven by workplace absenteeism due to the disease. Influenza is believed to be a culprit in reinforcing this phenomenon as it may exist in the population concurrently with COVID-19 during the influenza season. Furthermore, their joint infection may increase workplace absenteeism leading to additional economic loss. The objective of this project will aim to quantify the collective impact of COVID-19 and influenza on workplace absenteeism via a mathematical compartmental disease model incorporating population screening and vaccination. Our results indicate that appropriate PCR testing and vaccination of both COVID-19 and seasonal influenza may significantly alleviate workplace absenteeism. However, with COVID-19 PCR testing, there may be a critical threshold where additional tests may result in diminishing returns. Regardless, we recommend on-going PCR testing as a public health intervention accompanying concurrent COVID-19 and influenza vaccination with the added caveat that sensitivity analyses will be necessary to determine the optimal thresholds for both testing and vaccine coverage. Overall, our results suggest that rates of COVID-19 vaccination and PCR testing capacity are important factors for reducing absenteeism, while the influenza vaccination rate and the transmission rates for both COVID-19 and influenza have lower and almost equal affect on absenteeism. We also use the model to estimate and quantify the (indirect) benefit that influenza immunization confers against COVID-19 transmission.

Expected Impact of Universal Immunization With Nirsevimab Against RSV-Related Outcomes and Costs Among All US Infants in Their First RSV Season: A Static Model.

BACKGROUND: Respiratory syncytial virus (RSV) is associated with substantial morbidity in the United States, especially among infants. Nirsevimab, an investigational long-acting monoclonal antibody, was evaluated as an immunoprophylactic strategy for infants in their first RSV season and for its potential impact on RSV-associated, medically attended lower respiratory tract illness (RSV-MALRTI) and associated costs. METHODS: A static decision-analytic model of the US birth cohort during its first RSV season was developed to estimate nirsevimab's impact on RSV-related health events and costs; model inputs included US-specific costs and epidemiological data. Modelled RSV-related outcomes included primary care and emergency room visits, hospitalizations including intensive care unit admission and mechanical ventilations, and RSV-related mortality. RESULTS: Under current standard of care, RSV caused 529 915 RSV-MALRTIs and 47 281 hospitalizations annually, representing $1.2 billion (2021 US dollars [USD]) in costs. Universal immunization of all infants with nirsevimab is expected to reduce 290 174 RSV-MALRTI, 24 986 hospitalizations, and expenditures of $612 million 2021 USD. CONCLUSIONS: An all-infant immunization strategy with nirsevimab could substantially reduce the health and economic burden for US infants during their first RSV season. While this reduction is driven by term infants, all infants, including palivizumab-eligible and preterm infants, would benefit from this strategy.

Exertional heat stroke: nutritional considerations.

NEW FINDINGS: What is the topic of this review? The potential role of nutrition in exertional heat stroke. What advances does it highlight? Certain nutritional and dietary strategies used by athletes and workers may exert a protective effect the pathophysiological processes of exertional heat stroke, whereas others may be detrimental. While current evidence suggests that some of these practices may be leveraged as a potential countermeasure to exertional heat stroke, further research on injury-related outcomes in humans is required. ABSTRACT: Exertional heat stroke (EHS) is a life-threatening illness and an enduring problem among athletes, military servicemen and -women, and occupational labourers who regularly perform strenuous activity, often under hot and humid conditions or when wearing personal protective equipment. Risk factors for EHS and mitigation strategies have generally focused on the environment, health status, clothing, heat acclimatization and aerobic conditioning, but the potential role of nutrition is largely underexplored. Various nutritional and dietary strategies have shown beneficial effects on exercise performance and health and are widely used by athletes and other physically active populations. There is also evidence that some of these practices may dampen the pathophysiological features of EHS, suggesting possible protection or abatement of injury severity. Promising candidates include carbohydrate ingestion, appropriate fluid intake and glutamine supplementation. Conversely, some nutritional factors and low energy availability may facilitate the development of EHS, and individuals should be cognizant of these. Therefore, the aims of this review are to present an overview of EHS along with its mechanisms and pathophysiology, discuss how selected nutritional considerations may influence EHS risk focusing on their impact on the key pathophysiological processes of EHS, and provide recommendations for future research. With climate change expected to increase EHS risk and incidence in the coming years, further investigation on how diet and nutrition may be optimized to protect against EHS would be highly beneficial.

The Impact of MHC Class I Dose on Development and Maintenance of the Polyclonal Naive CD8+ T Cell Repertoire.

Naive CD8+ T cell survival in the periphery is critically dependent on tonic TCR signaling through peptide + MHC class I (MHCI) recognition; however, little is known about how natural variation in MHCI levels impacts the naive CD8+ T cell repertoire. Using mice that are hemizygous or homozygous for a single MHCI allele, we showed that despite a reduction in peripheral CD8+ T cell numbers of ∼50% in MHCI hemizygous mice, MHCI levels had no notable impact on the rate of thymic generation or emigration of CD8 single-positive T cells. Moreover, the peripheral T cell repertoire in hemizygous mice showed selective retention of T cell clonotypes with a greater competitive advantage as evidenced by increased expression of CD5 and IL-7Rα. The qualitative superiority of CD8+ T cells retained in hemizygous mice was also seen during influenza A virus infection, in which epitope-specific CD8+ T cells from hemizygous mice had a higher avidity for pMHCI and increased cytokine polyfunctionality, despite a reduced response magnitude. Collectively, this study suggests that natural variation in MHCI expression levels has a notable and biologically relevant impact on the maintenance, but not generation, of the naive CD8+ T cell repertoire.

The use of sun-shade on safe heat exposure limit on a sunny summer day: a modelling study in Japan.

Sustainable methods are required to reduce the risks of thermal strain and heat-related illness without exacerbating greenhouse gas emissions. We investigated the effects of sun-shade use on safe heat exposure limit on a sunny summer day using historical climate data in Japan. We simulated a heat-acclimatised person standing at rest (metabolic heat production, 70 W·m-2) and during light work (100 W·m-2) on an asphalt pavement in the sun and sun-shade. Japan has three Köppen climate regions: tropical, temperate and cold. We analysed one city in the tropical region (24°N), three cities in the temperate region (31°N, 35°N and 39°N) and one city in the cold region (40°N). Hourly data were collected from 7 AM to 6 PM, June to September, from 2010 to 2019. The day with the longest daylight hours and the greatest solar radiation intensity was used for analysis. With sun-shade (a white polyester tarpaulin/awning), ambient temperature, global solar radiation and ground surface temperature were assumed to be 0.5°C, 45% and 6°C lower than in the sun, respectively. Sun-shade use eliminated the days with at least 1 hour exceeding safe heat exposure limit at rest in all cities. The same was observed for light work in the temperate and cold cities, although the tropical city had 2 days exceeding safe heat exposure limit during the decade. Sun-shade use on a sunny summer day can be an effective and sustainable method to reduce heat exposure hazard at rest and during light work in tropical, temperate and cold climate regions.

Assessing the prior event rate ratio method via probabilistic bias analysis on a Bayesian network.

BACKGROUND: Unmeasured confounders are commonplace in observational studies conducted using real-world data. Prior event rate ratio (PERR) adjustment is a technique shown to perform well in addressing such confounding. However, it has been demonstrated that, in some circumstances, the PERR method actually increases rather than decreases bias. In this work, we seek to better understand the robustness of PERR adjustment. METHODS: We begin with a Bayesian network representation of a generalized observational study, which is subject to unmeasured confounding. Previous work evaluating PERR performance used Monte Carlo simulation to calculate joint probabilities of interest within the study population. Here, we instead use a Bayesian networks framework. RESULTS: Using this streamlined analytic approach, we are able to conduct probabilistic bias analysis (PBA) using large numbers of combinations of parameters and thus obtain a comprehensive picture of PERR performance. We apply our methodology to a recent study that used the PERR in evaluating elderly-specific high-dose (HD) influenza vaccine in the US Veterans Affairs population. That study obtained an HD relative effectiveness of 25% (95% CI: 2%-43%) against influenza- and pneumonia-associated hospitalization, relative to standard-dose influenza vaccine. In this instance, we find that the PERR-adjusted result is more like to underestimate rather than to overestimate the relative effectiveness of the intervention. CONCLUSIONS: Although the PERR is a powerful tool for mitigating the effects of unmeasured confounders, it is not infallible. Here, we develop some general guidance for when a PERR approach is appropriate and when PBA is a safer option.

Effect of regular precooling on adaptation to training in the heat.

PURPOSE: This study investigated whether regular precooling would help to maintain day-to-day training intensity and improve 20-km cycling time trial (TT) performed in the heat. Twenty males cycled for 10 day × 60 min at perceived exertion equivalent to 15 in the heat (35 °C, 50% relative humidity), preceded by no cooling (CON, n = 10) or 30-min water immersion at 22 °C (PRECOOL, n = 10). METHODS: 19 participants (n = 9 and 10 for CON and PRECOOL, respectively) completed heat stress tests (25-min at 60% [Formula: see text] and 20-km TT) before and after heat acclimation. RESULTS: Changes in mean power output (∆MPO, P = 0.024) and heart rate (∆HR, P = 0.029) during heat acclimation were lower for CON (∆MPO - 2.6 ± 8.1%, ∆HR - 7 ± 7 bpm), compared with PRECOOL (∆MPO + 2.9 ± 6.6%, ∆HR - 1 ± 8 bpm). HR during constant-paced cycling was decreased from the pre-acclimation test in both groups (P < 0.001). Only PRECOOL demonstrated lower rectal temperature (Tre) during constant-paced cycling (P = 0.002) and lower Tre threshold for sweating (P = 0.042). However, skin perfusion and total sweat output did not change in either CON or PRECOOL (all P > 0.05). MPO (P = 0.016) and finish time (P = 0.013) for the 20-km TT were improved in PRECOOL but did not change in CON (P = 0.052 for MPO, P = 0.140 for finish time). CONCLUSION: Precooling maintains day-to-day training intensity and does not appear to attenuate adaptation to training in the heat.

Solar radiation and the validity of infrared tympanic temperature during exercise in the heat.

We investigated the validity of infrared tympanic temperature (IR-Tty) during exercise in the heat with variations in solar radiation. Eight healthy males completed stationary cycling trials at 70% peak oxygen uptake until exhaustion in an environmental chamber maintained at 30°C with 50% relative humidity. Three solar radiation conditions, 0, 250 and 500 W/m2, were tested using a ceiling-mounted solar simulator (metal-halide lamps) over a 3 × 2 m irradiated area. IR-Tty and rectal temperature (Tre) were similar before and during exercise in each trial (P > 0.05). Spearman's rank correlation coefficient (rs) demonstrated very strong (250 W/m2, rs = 0.87) and strong (0 W/m2, rs = 0.73; 500 W/m2, rs = 0.78) correlations between IR-Tty and Tre in all trials (P < 0.001). A Bland-Altman plot showed that mean differences (SD; 95% limits of agreement; root mean square error) between IR-Tty and Tre were - 0.11°C (0.46; - 1.00 to 0.78°C; 0.43 ± 0.16°C) in 0 W/m2, - 0.13°C (0.32; - 0.77 to 0.50°C; 0.32 ± 0.10°C) in 250 W/m2 and - 0.03°C (0.60; - 1.21 to 1.14°C; 0.46 ± 0.27°C) in 500 W/m2. A positive correlation was found in 500 W/m2 (rs = 0.51; P < 0.001) but not in 250 W/m2 (rs = 0.04; P = 0.762) and 0 W/m2 (rs = 0.04; P = 0.732), indicating a greater elevation in IR-Tty than Tre in 500 W/m2. Percentage of target attainment within ± 0.3°C between IR-Tty and Tre was higher in 250 W/m2 (100 ± 0%) than 0 (93 ± 7%) and 500 (90 ± 10%; P < 0.05) W/m2. IR-Tty is acceptable for core temperature monitoring during exercise in the heat when solar radiation is ≤ 500 W/m2, and its accuracy increases when solar radiation is 250 W/m2 under our study conditions.

Reconciling temperature-dependent factors affecting mass transport losses in polymer electrolyte membrane electrolyzers.

In this work, we investigated the impact of temperature on two-phase transport in low temperature (LT)-polymer electrolyte membrane (PEM) electrolyzer anode flow channels via in operando neutron imaging and observed a decrease in mass transport overpotential with increasing temperature. We observed an increase in anode oxygen gas content with increasing temperature, which was counter-intu.itive to the trends in mass transport overpotential. We attributed this counterintuitive decrease in mass transport overpotential to the enhanced reactant distribution in the flow channels as a result of the temperature increase, determined via a one-dimensional analytical model. We further determined that gas accumulation and fluid property changes are competing, temperature-dependent contributors to mass transport overpotential; however, liquid water viscosity changes led to the dominate enhancement of reactant water distributions in the anode. We present this temperature-dependent mass transport overpotential as a great opportunity for further increasing the voltage efficiency of PEM electrolyzers.

Relative Vaccine Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among Veterans Health Administration Patients.

Background: We examined whether a high-dose inactivated influenza vaccine was more efficacious in preventing hospitalizations than a standard-dose vaccine in the Veterans Health Administration (VHA) senior population. Methods: This study estimated the relative vaccine effectiveness (rVE) of high dose versus standard dose using a retrospective cohort of VHA patients 65 years of age or older in the 2015-2016 influenza season. To adjust for measured confounders, we matched each high-dose recipient with up to 4 standard-dose recipients vaccinated at the same location within a 2-week period and having 2 or more pre-existing medical comorbidities. We used the previous event rate ratio method (PERR), a type of difference-in-differences analysis, to adjust for unmeasured confounders. Results: We evaluated 104965 standard-dose and 125776 high-dose recipients; matching decreased the population to 49091 standard-dose and 24682 high-dose recipients. The matched, PERR-adjusted rVE was 25% (95% confidence interval [CI], 2%-43%) against influenza- or pneumonia-associated hospitalization, 7% (95% CI, -2% to 14%) against all-cause hospitalization, 14% (95% CI, -8% to 32%) against influenza- or pneumonia-associated outpatient visit, 5% (95% CI, 2%-8%) against all-cause outpatient visit, and 38% (95% CI, -5% to 65%) against laboratory-confirmed influenza. Conclusions: In protecting senior VHA patients against influenza- or pneumonia-associated hospitalization, a high-dose influenza vaccine is more effective than a standard-dose vaccine.

Novel Cooling Strategies for Military Training and Operations.

The deleterious effects of environmental heat stress, combined with high metabolic loads and protective clothing and equipment of the modern Warfighter, impose severe heat strain, impair task performance, and increase risk of heat illness, thereby reducing the chance for mission success. Despite the implementation of heat-risk mitigation procedures over the past decades, task performance still suffers and exertional heat illness remains a major military problem. We review 3 novel heat mitigation strategies that may be implemented in the training or operational environment to reduce heat strain and the risk of exertional heat illness. These strategies include ingestion of ice slurry, arm immersion cooling, and microclimate cooling. Each of these strategies is suitable for use in different scenarios and the choice of cooling strategy is contingent on the requirements, circumstances, and constraints of the training and operational scenario. Ingestion of ice slurry and arm immersion cooling are practical strategies that may be implemented during training scenarios; ice slurry can be ingested before and during exercise, whereas arm immersion cooling can be administered after exercise-heat exposure. In the operational environment, existing microclimate cooling can be implemented with retrofitted vehicles and as an unmounted system, and it has the potential for use in many military occupational scenarios. This review will discuss the efficacy, limitations, and practical considerations for field implementation of each strategy.

Cleavage of the JunB transcription factor by caspases generates a carboxyl-terminal fragment that inhibits activator protein-1 transcriptional activity.

The activator protein-1 (AP-1) family transcription factor, JunB, is an important regulator of proliferation, apoptosis, differentiation, and the immune response. In this report, we show that JunB is cleaved in a caspase-dependent manner in apoptotic anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma cell lines and that ectopically expressed JunB is cleaved in murine RAW 264.7 macrophage cells treated with the NALP1b inflammasome activator, anthrax lethal toxin. In both cases, we identify aspartic acid 137 as the caspase cleavage site and demonstrate that JunB can be directly cleaved in vitro by multiple caspases at this site. Cleavage of JunB at aspartic acid 137 separates the N-terminal transactivation domain from the C-terminal DNA binding and dimerization domains, and we show that the C-terminal cleavage fragment retains both DNA binding activity and the ability to interact with AP-1 family transcription factors. Furthermore, this fragment interferes with the binding of full-length JunB to AP-1 sites and inhibits AP-1-dependent transcription. In summary, we have identified and characterized a novel mechanism of JunB post-translational modification and demonstrate that the C-terminal JunB caspase cleavage product functions as a potent inhibitor of AP-1-dependent transcription.