Warm hands, cold heart: progressive whole-body cooling increases warm thermosensitivity of human hands and feet in a dose-dependent fashion

While inhibitory/facilitatory central modulation of vision and pain has been investigated, contextual modulation of skin temperature integration has been unexplored. Hence, we tested whether progressive decreases in whole-body mean skin temperature (Tsk) (a large conditioning stimulus) alter the magnitude estimation of local warming and cooling stimuli applied to hairy and glabrous skin. On 4 separate occasions, 8 males (27 ± 5y) underwent a 30-min whole-body cooling protocol (water-perfused-suit; temperature: 5 C), during which a quantitative thermosensory test, consisting of reporting perceived magnitude of warming and cooling stimuli (±8°C from 30°C baseline) applied to the hand (palm/dorsum) and foot (sole/dorsum), was performed before cooling and every 10 min thereafter. The cooling protocol resulted in large progressive reductions in whole-body Tsk (10 min: -3.36 C (95% CI: -2.62, -4.10); 20 min: −5.21°C (−4.47, -5.95); 30 min: −6.32°C ( −5.58, -7.05); P < 0.001), with minimal changes (∼0.08 C) in rectal temperature. While thermosensitivity to local skin cooling remained unchanged (P = 0.831), sensitivity to skin warming increased significantly at each level of whole-body Tsk for all skin regions (10 min: +4.9% (−1.1, +11.0); 20 min: +6.1% (+0.1, 12.2); 30 min: +7.9% (+1.9, +13.9); P = 0.009). Linear regression indicated a 1.2%.°C−1 increase in warm thermosensitivity with whole-body skin cooling. Overall, large decreases in whole-body Tsk significantly facilitated warm, but not cold, sensory processing of local thermal stimuli, in a dose-dependent fashion. In highlighting a novel feature of human temperature integration, these findings point to the existence of an endogenous thermosensory system that could modulate local skin thermal sensitivity in relation to whole-body thermal states

Temperature in the hot spot: oesophageal temperature and whole body thermal status in patent foramen ovale

Temperature in the hot spot: oesophageal temperature and whole body thermal status in patent foramen oval

Evidence of viscerally-mediated cold-defence thermoeffector responses in man

Sudomotor activity is modified by both warm and cold fluid ingestion during heat stress, independently of differences in core and skin temperatures, suggesting independent viscerally-mediated modification of thermoeffectors. The purpose of the present study was to determine whether visceral thermoreceptors modify shivering responses to cold stress. Ten males (27 ± 5y, 1.73 ± 0.06 m, 78.4 ± 10.7 kg) underwent whole-body cooling via 5 °C water perfusion-suit, on four occasions, to induce a steady-state shivering response, at which point two aliquots of 1.5 ml/kg (SML) and 3.0 ml/kg (LRG), separated by 20- min, of either 7°C, 22°C, 37°C or 52°C water were ingested. Rectal, mean skin and mean body temperature (Tb), electromyographic activity (EMG), metabolic rate (M) and whole-body thermal sensation on a visual analogue scale (WBTS) ranging from 0 mm [very cold] to 200 mm [very hot] were all measured throughout. Tb was not different between all fluid temperatures following SML (7°C:35.7 ± 0.5°C, 22°C:35.6 ± 0.5°C, 37°C:35.5 ± 0.4°C, 52°C:35.5 ± 0.4°C; P = 0.27) or LRG (7°C:35.3 ± 0.6°C, 22°C:35.3 ± 0.5°C, 37°C:35.2 ± 0.5°C, 52°C:35.3 ± 0.5°C; P = 0.99) fluid ingestion. With SML ingestion, greater metabolic rate and cooler thermal sensations were observed with 7°C (M:179 ± 55 W, WBTS:29 ± 21 mm) compared to 52°C (M:164 ± 34 W, WBTS:51 ± 28 mm; all P < 0.05) ingestion. With LRG ingestion, compared to shivering and thermal sensations with 37 °C ingestion (M:215 ± 47 W, EMG:3.9 ± 2.5%MVC, WBTS:33 ± 2 mm) values were different (all P < 0.05) following 7°C (M:269 ± 77 W, EMG:5.5 ± 0.9%MVC, WBTS:14 ± 12 mm), 22°C (M:270 ± 86 W, EMG:5.6 ± 1.0%MVC, WBTS:18 ± 19 mm) and 52°C (M:179 ± 34 W, EMG:3.3 ± 2.1%MVC, WBTS:53 ± 28 mm) ingestion. In conclusion, ingesting 52°C fluids decreased shivering and the sensation of coolness, whereas 22°C and 7°C fluids increased shivering and sensations of coolness to similar levels, independently of core and skin temperature

Safety Recommendations for Evaluation and Surgery of the Head and Neck During the COVID-19 Pandemic

Importance The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists–head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19

Sustainable solutions to mitigate occupational heat strain – an umbrella review of physiological effects and global health perspectives

Background: Climate change is set to exacerbate occupational heat strain, the combined effect of environmental and internal heat stress on the body, threatening human health and wellbeing. Therefore, identifying effective, affordable, feasible and sustainable solutions to mitigate the negative effects on worker health and productivity, is an increasingly urgent need. Objectives: To systematically identify and evaluate methods that mitigate occupational heat strain in order to provide scientific-based guidance for practitioners.Methods: An umbrella review was conducted in biomedical databases employing the following eligibility criteria: 1) ambient temperatures > 28 °C or hypohydrated participants, 2) healthy adults, 3) reported psychophysiological (thermal comfort, heart rate or core temperature) and/or performance (physical or cognitive) outcomes, 4) written in English, and 5) published before November 6, 2019. A second search for original research articles was performed to identify interventions of relevance but lacking systematic reviews. All identified interventions were independently evaluated by all co-authors on four point scales for effectiveness, cost, feasibility and environmental impact. Results: Following screening, 36 systematic reviews fulfilled the inclusion criteria. The most effective solutions at mitigating occupational heat strain were wearing specialized cooling garments, (physiological) heat acclimation, improving aerobic fitness, cold water immersion, and applying ventilation. Although air-conditioning and cooling garments in ideal settings provide best scores for effectiveness, the limited applicability in certain industrial settings, high economic cost and high environmental impact are drawbacks for these solutions. However, (physiological) acclimatization, planned breaks, shading and optimized clothing properties are attractive alternative solutions when economic and ecological sustainability aspects are included in the overall evaluation.Discussion: Choosing the most effective solution or combinations of methods to mitigate occupational heat strain will be scenario-specific. However, this paper provides a framework for integrating effectiveness, cost, feasibility (indoors and outdoor) and ecologic sustainability to provide occupational health and safety professionals with evidence-based guidelines.<br

Evaluating methods for the analysis of rare variants in sequence data

A number of rare variant statistical methods have been proposed for analysis of the impending wave of next-generation sequencing data. To date, there are few direct comparisons of these methods on real sequence data. Furthermore, there is a strong need for practical advice on the proper analytic strategies for rare variant analysis. We compare four recently proposed rare variant methods (combined multivariate and collapsing, weighted sum, proportion regression, and cumulative minor allele test) on simulated phenotype and next-generation sequencing data as part of Genetic Analysis Workshop 17. Overall, we find that all analyzed methods have serious practical limitations on identifying causal genes. Specifically, no method has more than a 5% true discovery rate (percentage of truly causal genes among all those identified as significantly associated with the phenotype). Further exploration shows that all methods suffer from inflated false-positive error rates (chance that a noncausal gene will be identified as associated with the phenotype) because of population stratification and gametic phase disequilibrium between noncausal SNPs and causal SNPs. Furthermore, observed true-positive rates (chance that a truly causal gene will be identified as significantly associated with the phenotype) for each of the four methods was very low (<19%). The combination of larger than anticipated false-positive rates, low true-positive rates, and only about 1% of all genes being causal yields poor discriminatory ability for all four methods. Gametic phase disequilibrium and population stratification are important areas for further research in the analysis of rare variant data

Evaluating methods for combining rare variant data in pathway-based tests of genetic association

Analyzing sets of genes in genome-wide association studies is a relatively new approach that aims to capitalize on biological knowledge about the interactions of genes in biological pathways. This approach, called pathway analysis or gene set analysis, has not yet been applied to the analysis of rare variants. Applying pathway analysis to rare variants offers two competing approaches. In the first approach rare variant statistics are used to generate p-values for each gene (e.g., combined multivariate collapsing [CMC] or weighted-sum [WS]) and the gene-level p-values are combined using standard pathway analysis methods (e.g., gene set enrichment analysis or Fisher’s combined probability method). In the second approach, rare variant methods (e.g., CMC and WS) are applied directly to sets of single-nucleotide polymorphisms (SNPs) representing all SNPs within genes in a pathway. In this paper we use simulated phenotype and real next-generation sequencing data from Genetic Analysis Workshop 17 to analyze sets of rare variants using these two competing approaches. The initial results suggest substantial differences in the methods, with Fisher’s combined probability method and the direct application of the WS method yielding the best power. Evidence suggests that the WS method works well in most situations, although Fisher’s method was more likely to be optimal when the number of causal SNPs in the set was low but the risk of the causal SNPs was high

Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA

The HEAT-SHIELD project - Perspectives from an inter-sectoral approach to occupational heat stress

Objectives: To provide perspectives from the HEAT-SHIELD project (www.heat-shield.eu): a multinational, inter-sectoral, and cross-disciplinary initiative, incorporating twenty European research institutions, as well as occupational health and industrial partners, on solutions to combat negative health and productivity effects caused by working on a warmer world. Methods: In this invited review, we focus on the theoretical and methodological advancements developed to combat occupational heat stress during the last five years of operation. Results: We outline how we created climate forecast models to incorporate humidity, wind and solar radiation to the traditional temperature-based climate projections, providing the basis for timely, policy-relevant, industry-specific and individualized information. Further, we summarise the industry-specific guidelines we developed regarding technical and biophysical cooling solutions considering effectiveness, cost, sustainability, and the practical implementation potential in outdoor and indoor settings, in addition to field-testing of selected solutions with time-motion analyses and biophysical evaluations. All recommendations were adjusted following feedback from workshops with employers, employees, safety officers, and adjacent stakeholders such as local or national health policy makers. The cross-scientific approach was also used for providing policy-relevant information based on socioeconomic analyses and identification of vulnerable regions considered to be more relevant for political actions than average continental recommendations and interventions. Discussion: From the HEAT-SHIELD experiences developed within European settings, we discuss how this inter-sectoral approach may be adopted or translated into actionable knowledge across continents where workers and societies are affected by escalating environmental temperatures.The study has received funding from the European Union’s Horizon 2020 research and innovation program under the grant agreement No 66878

Xpert MTB/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: a prospective validation study.

INTRODUCTION: Tuberculous meningitis accounts for 1-5% of tuberculosis cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/RIF Ultra (Xpert Ultra) for tuberculous meningitis diagnosis. METHODS: In this prospective validation study, we tested the cerebrospinal fluid (CSF) of adults presenting with suspected meningitis (ie, headache or altered mental status with clinical signs of meningism) to the Mulago National Referral Hospital and Mbarara Regional Referral Hospital in Uganda. We centrifuged the CSF, resuspended the cell pellet in 2 mL CSF, and tested 0·5 mL aliquots with Xpert Ultra, Xpert MTB/RIF (Xpert), and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against the uniform case definition of probable or definite tuberculous meningitis and a composite microbiological reference standard. FINDINGS: From Nov 25, 2016, to Jan 24, 2019, we screened 466 adults with suspected meningitis and tested 204 for tuberculous meningitis. Uniform clinical case definition classified 51 participants as having probable or definite tuberculous meningitis. Against this uniform case definition, Xpert Ultra had 76·5% sensitivity (95% CI 62·5-87·2; 39 of 51 patients) and a negative predictive value of 92·7% (87·6-96·2; 153 of 165), compared with 55·6% sensitivity (44·0-70·4; 25 of 45; p=0·0010) and a negative predictive value of 85·8% (78·9-91·1; 121 of 141) for Xpert and 61·4% sensitivity (45·5-75·6; 27 of 44; p=0·020) and negative predictive value of 85·2% (77·4-91·1; 98 of 115) for MGIT culture. Against the composite microbiological reference standard, Xpert Ultra had sensitivity of 92·9% (80·5-98·5; 39 of 42), higher than Xpert at 65·8% (48·6-80·4; 25 of 38; p=0·0063) and MGIT culture at 72·2% (55·9-86·2; 27 of 37; p=0·092). Xpert Ultra detected nine tuberculous meningitis cases missed by Xpert and MGIT culture. INTERPRETATION: Xpert Ultra detected tuberculous meningitis with higher sensitivity than Xpert and MGIT culture in this HIV-positive population. However, with a negative predictive value of 93%, Xpert Ultra cannot be used as a rule-out test. Clinical judgment and novel highly sensitive point-of-care tests are still required. FUNDING: Wellcome Trust, National Institute of Health, National Institute of Neurologic Diseases and Stroke, Fogarty International Center, and National Institute of Allergy and Infectious Diseases