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Introduction: Neuropathic pain associated with Non-freezing Cold Injury (NFCI) is a major burden to military service personnel. A key feature of NFCI is reduction of the intra-epidermal nerve fibre density in skin biopsies, in keeping with painful neuropathy. Current oral treatments are generally ineffective and have undesirable side effects. Capsaicin 8% patch (Qutenza) has been shown to be well-tolerated and effective for reducing neuropathic pain, for up to 3 months after a single 30-minute application. Methods: In this single-centre open label study, 16 military participants with NFCI (mean duration 49 months) received 30-minute Capsaicin 8% patch treatment to the feet and distal calf. Pain symptoms were assessed using a pain diary (with the 11-point Numerical Pain Rating Scale, NPRS) and questionnaires, the investigations included skin biopsies, performed before and three months after treatment. Results: Participants showed significant decrease in spontaneous pain (mean NPRS: -1.1, 95% CI: 0.37 to 1.90; p = 0.006), and cold-evoked pain (-1.2, 95% CI: 0.40 to 2.04; p = 0.006). The time-course of pain relief over 3 months was similar to other painful neuropathies. Patient Global Impression of Change showed improvement (p = 0.0001). Skin punch biopsies performed 3 months after the patch application showed significant increase of nerve fibres with structural marker PGP9.5 (intra-epidermal nerve fibres [IENFs], p < 0.0001; sub-epidermal nerve fibres [SENFs]; p =< 0.0001), and of regenerating nerve fibres with their selective marker GAP43 (p = 0.0001). The increase of IENFs correlated with reduction of spontaneous (p = 0.027) and cold-evoked pain (p = 0.019). Conclusions: Capsaicin 8% patch provides an exciting new prospect for treatment of NFCI, with regeneration and restoration of nerve fibres, for the first time, in addition to pain relief.

PURPOSE: The aim was to investigate the effect of dietary nitrate supplementation (in the form of beetroot juice, BRJ) for 20 days on salivary nitrite (a potential precursor of bioactive nitric oxide), exercise performance and high altitude (HA) acclimatisation in field conditions (hypobaric hypoxia). METHODS: This was a single-blinded randomised control study of 22 healthy adult participants (12 men, 10 women, mean age 28 ± 12 years) across a HA military expedition. Participants were randomised pre-ascent to receive two 70 ml dose per day of either BRJ (~12.5 mmol nitrate per day; n = 11) or non-nitrate calorie matched control (n = 11). Participants ingested supplement doses daily, beginning 3 days prior to departure and continued until the highest sleeping altitude (4800 m) reached on day 17 of the expedition. Data were collected at baseline (44 m altitude), at 2350 m (day 9), 3400 m (day 12) and 4800 m (day 17). RESULTS: BRJ enhanced the salivary levels of nitrite (p = 0.007). There was a significant decrease in peripheral oxygen saturation and there were increases in heart rate, diastolic blood pressure, and rating of perceived exertion with increasing altitude (p=<0.001). Harvard Step Test fitness scores significantly declined at 4800 m in the control group (p = 0.003) compared with baseline. In contrast, there was no decline in fitness scores at 4800 m compared with baseline (p = 0.26) in the BRJ group. Heart rate recovery speed following exercise at 4800 m was significantly prolonged in the control group (p=<0.01) but was unchanged in the BRJ group (p = 0.61). BRJ did not affect the burden of HA illness (p = 1.00). CONCLUSIONS: BRJ increases salivary nitrite levels and ameliorates the decline in fitness at altitude but does not affect the occurrence of HA illness.

Introduction Specific patterns of blood test results are associated with COVID-19 infection. The aim of this study was to identify which blood tests could be used to assist in diagnosing COVID-19. Method A retrospective review was performed on consecutive patients referred to hospital with a clinical suspicion of COVID-19 over a period of four weeks. The patient’s clinical presentation and severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (SARS-CoV-2 RT-PCR) were recorded. The patients were divided by diagnosis into COVID (COVID-19 infection) or CONTROL (an alternate diagnosis). A retrospective review of consecutive patients over a further two-week period was used for the purposes of validation. Results Overall, 399 patients (53% COVID, 47% CONTROL) were analysed. White cell count, neutrophils and lymphocytes were significantly lower, while lactate dehydrogenase and ferritin were significantly higher, in the COVID group in comparison to CONTROL. Combining the white cell count, lymphocytes and ferritin results into a COVID Combined Blood Test (CCBT) had an area under the curve of 0.79. Using a threshold CCBT of –0.8 resulted in a sensitivity of 0.85 and a specificity of 0.63. Analysing this against a further retrospective review of 181 suspected COVID-19 patients, using the same CCBT threshold, resulted in a sensitivity of 0.73 and a specificity of 0.75. The sensitivity was comparable to the SARS-CoV-2 RT PCR. Discussion Mathematically combining the blood tests has the potential to assist clinical acumen allowing for rapid streaming and more accurate patient flow pending definitive diagnosis. This may be of particular use in low-resource settings.

INTRODUCTION: Low energy availability (EA) may impede adaptation to exercise, suppressing reproductive function and bone turnover. Exercise energy expenditure (EEE) measurements lack definition and consistency. This study aimed to compare EA measured from moderate and vigorous physical activity from accelerometry (EEEmpva) with EA from total physical activity (EEEtpa) from doubly-labelled water in women. The secondary aim was to determine the relationship of EA with physical fitness, body composition by DXA, heartrate variability (HRV) and eating behavior (brief eating disorder in athletes-questionnaire, BEDA-Q). METHODS: Prospective, repeated measures study, assessing EA measures and training adaptation during 11-month basic military training. 47 women (23.9 ±2.6 years) completed 3 consecutive 10-d assessments of EEEmvpa, EEEtpa and energy intake (EI). EA measures were compared using linear regression and Bland-Altman analyses; relationships of EA with fat mass, heartrate variability, 1.5-mile run times and BEDA-Q were evaluated using partial correlations. RESULTS: EA from EEEmvpa demonstrated strong agreement with EA from EEEtpa across the measurement range (R=0.76, r=0.87, p<0.001) and was higher by 10 kcal/kg FFM/d. However, EA was low in absolute terms due to underreported EI. Higher EA was associated with improved 1.5 mile run time (r=0.28, p<0.001) fat mass loss (r=0.38, p<0.001) and lower BEDA-Q score (r=-0.37, p<0.001) but not HRV (all p>0.10). CONCLUSION: Accelerometry-based EEE demonstrated validity against DLW during multi-stressor training, the difference representing 10 kcal/kg FFM/d EEE from non-exercise activity. Beneficial physical but not autonomic adaptations were associated with higher EA. EAmvpa and BEDA-Q warrant consideration for low EA assessment and screening.

CONTEXT: Survival rates after severe injury are improving, but complication rates and outcomes are variable. OBJECTIVE: This cohort study addressed the lack of longitudinal data on the steroid response to major trauma and during recovery. DESIGN: We undertook a prospective, observational cohort study from time of injury to 6 months postinjury at a major UK trauma centre and a military rehabilitation unit, studying patients within 24 hours of major trauma (estimated New Injury Severity Score (NISS) > 15). MAIN OUTCOME MEASURES: We measured adrenal and gonadal steroids in serum and 24-hour urine by mass spectrometry, assessed muscle loss by ultrasound and nitrogen excretion, and recorded clinical outcomes (ventilator days, length of hospital stay, opioid use, incidence of organ dysfunction, and sepsis); results were analyzed by generalized mixed-effect linear models. FINDINGS: We screened 996 multiple injured adults, approached 106, and recruited 95 eligible patients; 87 survived. We analyzed all male survivors <50 years not treated with steroids (N = 60; median age 27 [interquartile range 24-31] years; median NISS 34 [29-44]). Urinary nitrogen excretion and muscle loss peaked after 1 and 6 weeks, respectively. Serum testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate decreased immediately after trauma and took 2, 4, and more than 6 months, respectively, to recover; opioid treatment delayed dehydroepiandrosterone recovery in a dose-dependent fashion. Androgens and precursors correlated with SOFA score and probability of sepsis. CONCLUSION: The catabolic response to severe injury was accompanied by acute and sustained androgen suppression. Whether androgen supplementation improves health outcomes after major trauma requires further investigation.

© Copyright © 2019 Parsons, Stacey and Woods. The study of heat adaptation in military personnel offers generalizable insights into a variety of sporting, recreational and occupational populations. Conversely, certain characteristics of military employment have few parallels in civilian life, such as the imperative to achieve mission objectives during deployed operations, the opportunity to undergo training and selection for elite units or the requirement to fulfill essential duties under prolonged thermal stress. In such settings, achieving peak individual performance can be critical to organizational success. Short-notice deployment to a hot operational or training environment, exposure to high intensity exercise and undertaking ceremonial duties during extreme weather may challenge the ability to protect personnel from excessive thermal strain, especially where heat adaptation is incomplete. Graded and progressive acclimatization can reduce morbidity substantially and impact on mortality rates, yet individual variation in adaptation has the potential to undermine empirical approaches. Incapacity under heat stress can present the military with medical, occupational and logistic challenges requiring dynamic risk stratification during initial and subsequent heat stress. Using data from large studies of military personnel observing traditional and more contemporary acclimatization practices, this review article (1) characterizes the physical challenges that military training and deployed operations present (2) considers how heat adaptation has been used to augment military performance under thermal stress and (3) identifies potential solutions to optimize the risk-performance paradigm, including those with broader relevance to other populations exposed to heat stress.

© 2018, Journal of Clinical and Diagnostic Research. All rights reserved. Introduction: There is conflicting data at sea-level to suggest that Paced Breathing (PB) versus Spontaneous Breathing (SB) during short-term Heart Rate Variability (HRV) measurement improves data reliability. Aim: This study sought to examine the effects of SB versus PB on HRV, at High Altitude (HA). Materials and Methods: This was a prospective observational study on thirty healthy adult men who were investigated over nine days at altitudes of 800-4107 m. Cardiac inter-beat interval data were measured over 55 seconds, twice daily, using an ithlete finger sensor linked to a mobile phone to generate a HRV score. Agreements in the paired (SB vs PB) HRV scores were examined using paired t-tests, correlation coefficients and F-Testing. A factorial repeated measures ANOVA was used to examine the main effect of altitude and breathing method on the paired differences in HRV scores. Results: HA led to a significant reduction in SpO2 and increase in Acute Mountain Sickness (AMS) Scores. HRV scores (511 paired scores) were consistently higher with PB versus SB (mean difference +6.0; 96.1% within 95% agreement limit), though the variance was lower (F=1.2; p=0.04) and the scores strongly correlated (r=0.78; p<0.0001). HRV scores were lower with AMS (versus without AMS), but this difference was only significant with SB (68.1±12.1 vs. 74.3±11.4 vs; p=0.03) but not PB (76.3±11.8 vs. 80.3±10.4 vs; p=0.13). There was a significant main-effect for altitude (F=5.3; p<0.0001) and breathing (F=262.1; p<0.0001) on HRV scores but no altitude-x-breathing interaction (F=1.2; p=0.30). Conclusion: Ithlete HRV scores obtained with PB and SB strongly correlate at moderate HA but are consistently higher and the variance lower with PB. Whilst the actual per se does not affect this difference, the presence of AMS may be an important confounder.

INTRODUCTION: Whilst the link between physical factors and risk of high altitude (HA)-related illness and acute mountain sickness (AMS) have been extensively explored, the influence of psychological factors has been less well examined. In this study we aimed to investigate the relationship between 'anxiety and AMS risk during a progressive ascent to very HA. METHODS: Eighty health adults were assessed at baseline (848m) and over 9 consecutive altitudes during a progressive trek to 5140m. HA-related symptoms (Lake Louise [LLS] and AMS-C Scores) and state anxiety (State-Trait-Anxiety-Score [STAI Y-1]) were examined at each altitude with trait anxiety (STAI Y-2) at baseline. RESULTS: The average age was 32.1 ± 8.3 years (67.5% men). STAI Y-1 scores fell from 848m to 3619m, before increasing to above baseline scores (848m) at ≥4072m (p = 0.01). STAI Y-1 scores correlated with LLS (r = 0.31; 0.24-0.3; P<0.0001) and AMS-C Scores (r = 0.29; 0.22-0.35; P<0.0001). There was significant main effect for sex (higher STAI Y-1 scores in women) and altitude with no sex-x-altitude interaction on STAI Y-1 Scores. Independent predictors of significant state anxiety included female sex, lower age, higher heart rate and increasing LLS and AMS-C scores (p<0.0001). A total of 38/80 subjects (47.5%) developed AMS which was mild in 20 (25%) and severe in 18 (22.5%). Baseline STAI Y-2 scores were an independent predictor of future severe AMS (B = 1.13; 1.009-1.28; p = 0.04; r2 = 0.23) and STAI Y-1 scores at HA independently predicted AMS and its severity. CONCLUSION: Trait anxiety at low altitude was an independent predictor of future severe AMS development at HA. State anxiety at HA was independently associated with AMS and its severity.

INTRODUCTION: The autonomic system and sympathetic activation appears integral in the pathogenesis of acute mountain sickness (AMS) at high altitude (HA), yet a link between heart rate variability (HRV) and AMS has not been convincingly shown. In this study we investigated the utility of the smartphone-derived HRV score to predict and diagnose AMS at HA. METHODS: Twenty-one healthy adults were investigated at baseline at 1400 m and over 10 days during a trek to 5140 m. HRV was recorded using the ithlete HRV device. RESULTS: Acute mountain sickness occurred in 11 subjects (52.4%) at >2650 m. HRV inversely correlated with AMS Scores (r = -0.26; 95% CI, -0.38 to -0.13: P < 0.001). HRV significantly fell at 3700, 4100, and 5140 m versus low altitude. HRV scores were lower in those with both mild (69.7 ± 14.0) and severe AMS (67.1 ± 13.1) versus those without AMS (77.5 ± 13.1; effect size n = 0.043: P = 0.007). The HRV score was weakly predictive of severe AMS (AUC 0.74; 95% CI, 0.58-0.89: P = 0.006). The change (delta) in the HRV Score (compared with baseline at 1400 m) was a moderate diagnostic marker of severe AMS (AUC 0.80; 95% CI, 0.70-0.90; P = 0.0004). A fall in the HRV score of >5 had a sensitivity of 83% and specificity of 60% to identify severe AMS (likelihood ratio 1.9). Baseline HRV at 1400 m was not predictive of either AMS at higher altitudes. CONCLUSIONS: The ithlete HRV score can be used to help in the identification of severe AMS; however, a baseline score is not predictive of future AMS development at HA.

Background: Acute hypoxia leads to a number of recognized changes in cardiopulmonary function, including acute increase in pulmonary artery systolic pressure. However, the comparative responses between men and women have been barely explored.Fourteen young healthy adult Caucasian subjects were studied at sea-level rest and then after >150-minute exposure to acute normobaric hypoxia (NH) equivalent to 4800 m and again at sea-level rest at 2 hours post-NH exposure. Cardiac function, using transthoracic echocardiography, physiological variables, and Lake Louise Scores for acute mountain sickness (AMS) were collected.All subjects completed the study, and there was an equal balance of men (n = 7) and women (n = 7) who were well matched for age (25.9 ± 3.2 vs. 27.3 ± 4.4; p = 0.51). NH exposure led to a significant increase in AMS scores and heart rate, as well as a fall in oxygen saturation, systolic blood pressure, and stroke volume. Stroke volumes and cardiac output were overall significantly higher in men than in women, and acute NH heart rate was higher in women (80.3 ± 10.2 vs. 69.7 ± 10.7/min; p < 0.05). NH led to a significant fall in the estimated left ventricular filling pressure (E/E'), an increase in the septal A' and S' and septal and lateral isovolumic contractile velocities (ICVs), and a fall in the E'A'S' ratio. The mitral E, lateral ICV, and E' velocities were all higher in men. Acute NH led to a significant increase in right ventricular systolic pressure and pulmonary vascular resistance. There was no interaction between NH exposure and sex for any parameters measured.Despite several baseline differences between men and women, the cardiopulmonary effects of acute NH are consistent between men and women.

There has been considerable debate as to whether different modalities of simulated hypoxia induce similar cardiac responses.This was a prospective observational study of 14 healthy subjects aged 22-35 years. Echocardiography was performed at rest and at 15 and 120 minutes following two hours exercise under normobaric normoxia (NN) and under similar PiO2 following genuine high altitude (GHA) at 3,375m, normobaric hypoxia (NH) and hypobaric hypoxia (HH) to simulate the equivalent hypoxic stimulus to GHA.All 14 subjects completed the experiment at GHA, 11 at NN, 12 under NH, and 6 under HH. The four groups were similar in age, sex and baseline demographics. At baseline rest right ventricular (RV) systolic pressure (RVSP, p = 0.0002), pulmonary vascular resistance (p = 0.0002) and acute mountain sickness (AMS) scores were higher and the SpO2 lower (p<0.0001) among all three hypoxic groups (GHA, NH and HH) compared with NN. At both 15 minutes and 120 minutes post exercise, AMS scores, Cardiac output, septal S', lateral S', tricuspid S' and A' velocities and RVSP were higher and SpO2 lower with all forms of hypoxia compared with NN. On post-test analysis, among the three hypoxia groups, SpO2 was lower at baseline and 15 minutes post exercise with GHA (89.3±3.4% and 89.3±2.2%) and HH (89.0±3.1 and (89.8±5.0) compared with NH (92.9±1.7 and 93.6±2.5%). The RV Myocardial Performance (Tei) Index and RVSP were significantly higher with HH than NH at 15 and 120 minutes post exercise respectively and tricuspid A' was higher with GHA compared with NH at 15 minutes post exercise.GHA, NH and HH produce similar cardiac adaptations over short duration rest despite lower SpO2 levels with GHA and HH compared with NH. Notable differences emerge following exercise in SpO2, RVSP and RV cardiac function.

BACKGROUND: Susceptibility to exertional heat illness (EHI) is considered multifactorial in nature. The aims of this study were to (1) review traditional susceptibility factors identified in cases of EHI and (2) determine how they are related to risk of hospitalisation. METHODS: Review of an electronic database of EHI reported in the British Army between 1 September 2007 and 31 December 2014. Cases were categorised by demographic, situational and susceptibility variables. Univariate and multivariate logistic regression was performed for the OR for hospitalisation by risk factor. RESULTS: 361 reports were included in the analysis. 33.5% of cases occurred in hot climates, 34.6% in temperate climates during summer months and 31.9% in temperate climates outside of summer months. Traditional susceptibility factors were reported in 193 but entirely absent from 168 cases. 137 cases (38.0%) were admitted to hospital. Adjusted OR for hospitalisation was lower for recruits (OR 0.42, 95% CI 0.18 to 0.99, p<0.05) and for personnel wearing occlusive dress (OR 0.56, 95% CI 0.34 to 0.93, p<0.05) or unacclimatised to heat (OR 0.31, 95% CI 0.15 to 0.66, p<0.01). CONCLUSIONS: The global, year-round threat of EHI is highlighted. Absence of susceptibility factors in nearly half of reports highlights the challenge of identifying EHI-prone individuals. Paradoxical association of traditional susceptibility factors with reduced hospitalisation risk may reflect the contemporary contexts in which severe EHI occurs. These findings also suggest a need for better evidence to inform guidelines that aim to prevent severe EHI concurrent to reducing overall morbidity.

BACKGROUND: Heat illness is a preventable disorder in military populations. Measures that protect vulnerable individuals and contribute to effective Immediate Treatment may reduce the impact of heat illness, but depend upon adequate understanding and awareness among Commanders and their troops. OBJECTIVE: To assess risk factors for heat illness in British soldiers deployed to the hot Collective Training Environment (CTE) and to explore awareness of Immediate Treatment responses. METHODS: An anonymous questionnaire was distributed to British soldiers deployed in the hot CTEs of Kenya and Canada. Responses were analysed to determine the prevalence of individual (Intrinsic) and Command-practice (Extrinsic) risk factors for heat illness and the self-reported awareness of key Immediate Treatment priorities (recognition, first aid and casualty evacuation). RESULTS: The prevalence of Intrinsic risk factors was relatively low in comparison with Extrinsic risk factors. The majority of respondents were aware of key Immediate Treatment responses. The most frequently reported factors in each domain were increased risk by body composition scoring, inadequate time for heat acclimatisation and insufficient briefing about casualty evacuation. CONCLUSIONS: Novel data on the distribution and scale of risk factors for heat illness are presented. A collective approach to risk reduction by the accumulation of 'marginal gains' is proposed for the UK military. This should focus on limiting Intrinsic risk factors before deployment, reducing Extrinsic factors during training and promoting timely Immediate Treatment responses within the hot CTE.

Military training has been associated with changes in the hypothalamic-pituitary-gonadal axis consistent with central hypogonadism. Often such changes have been associated with body mass loss, though sleep deprivation and other psychological stress may also contribute. The effects of deployment in a combat zone on the hypothalamic-pituitary-gonadal axis in military personnel are not known. The objective was to investigate the hypothalamic-pituitary-gonadal axis in male military personnel deployed in Afghanistan. Eighty-nine Royal Marines were investigated pre-deployment, following 3 months in Afghanistan and following 2 weeks mid-tour leave. Testosterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinising hormone (LH), 17-hydroxyprogesterone, androstenedione (AD) and insulin were assayed and body mass recorded. The results showed that body mass (kg) dropped from 83.2 ± 9.2 to 79.2 ± 8.2 kg during the first 3 months of deployment (p < 0.001). Total testosterone did not change, but SHBG increased (30.7 ± 9.7 vs. 42.3 ± 14.1 nmol/L, p < 0.001), resulting in a significant (p < 0.001) fall in calculated free testosterone (435.2 ± 138 vs. 375.1 ± 98 pmol/L). Luteinising hormone and FSH increased by 14.3% (p < 0.001) and 4.9% (p = 0.003) respectively. Free testosterone, SHBG, LH and FSH returned to baseline following 2 weeks of mid-tour leave. Androstenedione (AD) decreased by 14.5% (p = 0.024), and insulin decreased by 26% (p = 0.039), over the course of deployment. In this study of lean Royal Marines, free testosterone decreased during operational deployment to Afghanistan. There was no evidence to suggest major stress-induced central hypogonadism. We postulate that reduced body mass, accompanied by a decrease in insulin and AD synthesis, may have contributed to an elevated SHBG, leading to a decrease in free testosterone.