Professor David Woods

Energy deficits are common in military training and can result in endocrine and metabolic disturbances. This study provides first investigation of sex differences in energy balance, body composition, and endocrine and metabolic markers in response to prolonged and arduous military training. Men experienced greater energy deficits than women due to higher energy expenditure, which was not compensated for by increased energy intake. These energy deficits were not associated with decreases in fat or lean mass or metabolic or endocrine 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.

Summary

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.

Introduction: Hypoxia induces an inflammatory response, which is enhanced by exercise. High altitude (HA) leads to endothelial activation and may be proinflammatory. The relationship between endothelial activation, inflammation, and acute mountain sickness (AMS) and its severity has never been examined. Methods: Forty-eight trekkers were studied during a progressive trek at 3833, 4450, and 5129 m at rest postascent (exercise), and then again at rest 24 hours later. Twenty of the subjects were also tested at rest pre- and postexercise at sea level (SL) at 6 weeks preascent. We examined plasma levels of the interleukin 6 (IL-6), 17a (IL-17a), and endothelin-1 (ET-1) along with oxygen saturation (SpO2) and Lake Louise scores (LLS). Results: ET-1 (5.7 ± 2.1 vs. 4.3 ± 1.9 pg/mL; p < 0.001), IL-6 (3.3 ± 3.3 vs. 2.4 ± 2.3 pg/mL; p = 0.007), and IL-17a (1.3 ± 3.0 vs. 0.46 ± 0.4 pg/mL; p < 0.001) were all overall significantly higher at HA versus SL. There was a paired increase in ET-1 and IL-6 with exercise versus rest at SL, 3833, 4450, and 5129 m (p < 0.05). There was a negative correlation between LLS and SpO2 (r = -0.32; 95% confidence interval [CI] -0.21 to -0.42; p < 0.001) and a positive correlation between LLS and IL-6 (r = 0.16; 0.0-0.27; p = 0.007) and ET-1 levels (r = 0.29; 0.18-0.39; p < 0.001. Altitude, ET-1, IL-6, and SpO2 were all univariate predictors of AMS. On multivariate analysis, ET-1 (p = 0.002) and reducing SpO2 (p = 0.02) remained as the only independent predictors (overall r2 = 0.16; p < 0.001) of AMS. ET-1 (p = 03) and SpO2 were (p = 0.01) also independent predictors of severe AMS (overall r2 = 0.19; p < 0.001). Conclusions: HA leads to endothelial activation and an inflammatory response. The rise in ET-1 and IL-6 is heavily influenced by the degree of exercise and hypoxia. ET-1 is an independent predictor of both AMS and its severity.

Heat illness in the Armed Forces is considered preventable. The UK military relies upon dual Command and Medical reporting for case ascertainment, investigation of serious incidents and improvement of preventive practices and policy. This process could be vulnerable to under-reporting.To establish whether heat illness in the British Army has been under-reported, by reviewing concordance of reporting to the Army Incident Notification Cell (AINC) and the Army Health Unit (AHU) and to characterise the burden of heat illness reported by these means.Analysis of anonymised reporting databases held by the AHU and AINC, for the period 2009-2013.565 unique cases of heat illness were identified. Annual concordance of reporting ranged from 9.6% to 16.5%. The overall rate was 13.3%. July was the month with the greatest number of heat illness reports (24.4% of total reporting) and the highest concordance rate (30%). Reports of heat illness from the UK (n=343) exceeded overseas notifications (n=221) and showed better concordance (17.1% vs 12.8%). The annual rate of reported heat illness varied widely, being greater in full-time than reservist personnel (87 vs 23 per100 000) and highest in full-time untrained personnel (223 per100 000).The risk of heat illness was global, year-round and showed dynamic local variation. Failure to dual-report casualties impaired case ascertainment of heat illness across Command and Medical chains. Current preventive guidance, as applied in training and on operations, should be critically evaluated to ensure that risk of heat illness is reduced as low as possible. Clear procedures for casualty notification and surveillance are required in support of this and should incorporate communication within and between the two reporting chains.

BACKGROUND: Acute mountain sickness (AMS) is a common problem of trekkers to high altitude. The UK military train at high altitude through adventurous training (AT) or as exercising troops. The ascent of Point Lenana at 4985 m on Mount Kenya is frequently attempted on AT. This study sought to establish the incidence of AMS within this population, to aid future planning for military activities at altitude. METHODS: A voluntary questionnaire was distributed to all British Army Training Unit Kenya based expeditions attempting to ascend Mount Kenya during the period from February to April 2014. The questionnaire included twice daily Lake Louise and Borg (perceived exertion scale) self-scoring. All expeditions were planned around a 5-day schedule, which included reserve time for acclimatisation, illness and inclement weather. RESULTS: Data were collected on 47 participants, 70% of whom reached the summit of Point Lenana. 62% (29/47) self-reported AMS (defined as Lake Louise score (LLS) ≥3) on at least one occasion during the ascent, and 34% (10/29) suffered severe AMS (LLS ≥6). Those who attempted the climb within 2 weeks of arrival in Kenya had a higher incidence of AMS (12/15 (80%) vs 17/32 (53%), p=0.077). Participants recording a high Borg score were significantly more likely to develop AMS (16/18 vs 9/21, p=0.003). CONCLUSIONS: This represents the first informative dataset for Mount Kenya ascents and altitude. The incidence of AMS during AT on Mount Kenya using this ascent profile is high. Adapting the current ascent profile, planning the ascent after time in country and reducing perceived exertion during the trek may reduce the incidence of AMS.

The military has always had an important role in high altitude research. This is due to the fact that mountainous regions often span borders and provide a safe haven to enemies. Deploying troops rapidly into high altitude environments presents major problems in terms of the development of high altitude illness. This paper examines the rationale for carrying out research at high altitude and the opportunities within the UK Defence Medical Services for carrying out this research.

Purpose: A diuresis is a key part of acclimatisation to high altitude (HA). Arginine vasopressin (AVP) is a hormone involved in salt and water balance and may potentially have a role in the development of altitude illness. ProAVP (copeptin) is more stable than AVP and is assayed by a straightforward, automated method. We investigated the relationship of AVP to copeptin and the copeptin response to exercise and altitude illness in a large cohort during a field study at HA. Methods: 48 subjects took part in a 10-day trek at HA. Venous blood samples were taken at 3,833, 4,450 and 5,129 m post-trek (exercise) and the following day at rest. Daily recordings of symptoms of altitude illness, oxygen saturations and perceived exertion were carried out. Results: AVP and copeptin levels increased with exercise and correlated closely (ρ 0.621 p < 0.001), this was strongest in the stressed state when AVP secretion was highest, at 5,129 m post-exercise (ρ 0.834 p < 0.001). On two-way ANOVA, both altitude (F = 3.5; p = 0.015) and exercise (F = 10.2; p = 0.002) influenced copeptin levels (interaction F = 2.2; p = 0.08). AVP levels were influenced by exercise (F = 14.4; p = 0.0002) but not altitude (F = 2.0; p = 0.12) with no overall group interactions (F = 1.92.6; p = 0.06). There was no association between copeptin or arginine vasopressin and altitude illness. Copeptin correlated with the Borg RPE score and was significantly higher in the group with a Borg score ≥15 (7.9 vs. 3.7 p < 0.001). Conclusion: We have shown that arginine vasopressin and copeptin levels correlate and are suppressed below 5,129 m. Furthermore, we have demonstrated that exertion, rather than altitude illness or increasing osmolality, is the stimulus for increases in copeptin.

Background: High altitude (HA) exposure can lead to changes in resting heart rate variability (HRV), which may be linked to acute mountain sickness (AMS) development. Compared with traditional HRV measures, non-linear HRV appears to offer incremental and prognostic data, yet its utility and relationship to AMS have been barely examined at HA. This study sought to examine this relationship at terrestrial HA. Methods: Sixteen healthy British military servicemen were studied at baseline (800 m, first night) and over eight consecutive nights, at a sleeping altitude of up to 3600 m. A disposable cardiac patch monitor was used, to record the nocturnal cardiac inter-beat interval data, over 1 h (0200-0300 h), for offline HRV assessment. Non-linear HRV measures included Sample entropy (SampEn), the short (α1, 4-12 beats) and long-term (α2, 13-64 beats) detrend fluctuation analysis slope and the correlation dimension (D2). The maximal rating of perceived exertion (RPE), during daily exercise, was assessed using the Borg 6-20 RPE scale. Results: All subjects completed the HA exposure. The average age of included subjects was 31.4 ± 8.1 years. HA led to a significant fall in SpO2 and increase in heart rate, LLS and RPE. There were no significant changes in the ECG-derived respiratory rate or in any of the time domain measures of HRV during sleep. The only notable changes in frequency domain measures of HRV were an increase in LF and fall in HFnu power at the highest altitude. Conversely, SampEn, SD1/SD2 and D2 all fell, whereas α1 and α2 increased (p < 0.05). RPE inversely correlated with SD1/SD2 (r = -0.31; p = 0.002), SampEn (r = -0.22; p = 0.03), HFnu (r = -0.27; p = 0.007) and positively correlated with LF (r = 0.24; p = 0.02), LF/HF (r = 0.24; p = 0.02), α1 (r = 0.32; p = 0.002) and α2 (r = 0.21; p = 0.04). AMS occurred in 7/16 subjects (43.8%) and was very mild in 85.7% of cases. HRV failed to predict AMS. Conclusion: Non-linear HRV is more sensitive to the effects of HA than time and frequency domain indices. HA leads to a compensatory decrease in nocturnal HRV and complexity, which is influenced by the RPE measured at the end of the previous day. HRV failed to predict AMS development.

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.

Introduction The UK military operates a Heat Illness Clinic (HIC) to aid the return to exercise, training and occupational duty recommendations for individuals who have suffered exertional heat illness or heatstroke. This paper describes the process of assessment and reports representative data from n=22 patients referred to the HIC. Method The assessment included clinical consultation, and measurement of maximal oxygen consumption (V̇O2max) and a heat tolerance test (HTT) conducted on a treadmill in an environmental chamber with an air temperature of 34°C and 44% relative humidity. Patients began the HTT wearing military clothing, carrying a rucksack (mass 15 kg) and walking at 60% V̇O2max, at 30 min the rucksack and jacket were removed and the T-shirt at 45 min, individuals continued walking for 60–90 min. Patients were considered heat tolerant if rectal temperature achieved a plateau. Results N=14 patients were heat tolerant on the first assessment and of the n=8 patients required to return for repeat assessment, five were heat tolerant on the second assessment and the remaining three on the third assessment. Conclusions In conjunction with patient history and clinical evaluation, the HTT provides a physiological basis to assist with decisions concerning patient management and return to duty following an episode of heat illness.

The article Histamine, mast cell tryptase and post-exercise hypotension in healthy and collapsed marathon runners, written by I. T. Parsons, M. J. Stacey, L. Faconti, N. Hill, J. O’Hara, E. Walter, B. Farukh, R. McNally, H. Sharp, A. Patten, R. Grimaldi, N. Gall, P. Chowienczyk and D. R. Woods, was originally published Online First without Open Access. After publication in volume 121, issue 5, pages 1451–1459 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2021 and this article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The original article has been corrected.

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.

High altitude (HA) exposure affects heart rate variability (HRV). The influence of increasing HA altitude exposure on ultra-short HRV and its relationship to gold-standard HRV measures at HA has not been examined. Methods This was a prospective observational study of adults aged >18 years undertaking a HA trek in the Dhaulagiri region of the Himalayas. Cardiac inter-beat-intervals were obtained from a 10-second (s) recording of supra-systolic blood pressure (Uscom BP+ device) and simultaneously from a 300s single lead ECG recording (CheckMyHeart device). HRV was quantified using the RMSSD (root mean square of successive differences of successive NN intervals) at sea level (SL) in the UK and at 3619m, 4600m and 5140m at HA. Oxygen saturations (SpO2) were measured using finger-based pulse oximetry. Agreements in the 10s vs 300s HRV scores were examined using correlation coefficients and Bland-Altman analyses. Results Overall 89 participants aged 32.2±8.8 years (range 18-56) were included of which 70.8% were men. HA exposure (SL vs 3619m) was associated with an initial increase in both 10s (45.0 [31.0-82.0]) vs 58.0 [33.0-119.0] ms) and 300s (45.67 [33.24-70.32] vs 56.48 [36.98-102.0] ms) in RMSSD. Thereafter at 4600m and 5140m both 10s and 300s RMSSD values were significantly lower than SL. From a total of 316 paired HRV measures the 10s and 300s RMSSD measures were moderately, yet significantly, correlated (Spearman r=0.66; 95% CI: 0.59 to 0.72: p<0.0001). RMSSD tended to be higher with the 10s vs 300s (median [bias] difference 2.6; p=0.72) with 92.7% of the 316 paired readings were within the 95% CI of agreement. Neither HRV method was predictive of AMS. Conclusions Increasing HA affects ultra-short HRV in a similar manner to gold-standard 300s measures. Ultra-short HRV has a modest agreement with 300s measurements. HRV did not predict AMS.

Extreme environments present medical and occupational challenges that extend beyond generic resuscitation, to formulating bespoke diagnoses and prognoses and embarking on management pathways rarely encountered in civilian practice. Pathophysiological complexity and clinical uncertainty call for military physicians of all kinds to balance intuition with pragmatism, adapting according to the predominant patterns of care required. In an era of smaller operational footprints and less concentrated clinical experience, proposals aimed at improving the systematic care of Service Personnel incapacitated at environmental extremes must not be lost to corporate memory. These general issues are explored in the particular context of thermal stress and metabolic disruption. Specific focus is given to the accounts of military physicians who served on large-scale deployments into the heat of Iraq and Kuwait (Operation TELIC) and Oman (Exercise SAIF SAREEA). Generalisable insights into the enduring character of military medicine and future clinical requirements result.

The National Patient Safety Alert supporting early recognition and treatment of adrenal crisis is a vital new component of care for adults affected by primary adrenal insufficiency. Benefits for patients with secondary and tertiary adrenal insufficiency need to be weighed alongside other considerations such as security of the diagnosis, relative likelihood of adrenal crisis and potential for anxiety and distress from assigning 'physical dependency' in relation to glucocorticoid therapy. All clinicians must be vigilant for and responsive to managing risks of adrenal crisis in at-risk patients, while avoiding diagnostic anchoring in the context of acute illness. More research is required to help define who is at greatest risk of adverse outcomes (including avoidance of therapeutic glucocorticoid therapy for fear of adrenal insufficiency) and a cross-specialty approach is advocated.

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.

Urinary concentrations of the major progesterone (P4) metabolite pregnanediol-3-glucuronide (PDG) are used to confirm ovulation. We aimed to determine whether automated immunoassay of urinary P4 was as efficacious as PDG to confirm ovulation. Daily urine samples from 20 cycles in 14 healthy women in whom ovulation was dated by ultrasound, and serial weekly samples from 21 women in whom ovulation was unknown were analysed. Daily samples were assayed by two automated P4 immunoassays (Roche Cobas and Abbott Architect) and PDG ELISA. Serial samples were assayed for P4 by Architect and PDG by ELISA. In women with detailed monitoring of ovulation, median (95% CI) luteal phase increase was greatest for PDG, 427% (261–661), 278% (187–354) for P4 Architect and least for P4 Cobas, 146% (130–191), p < 0.0001. Cobas P4 also showed marked inaccuracy in serial dilution. Similar ROC AUCs were observed for individual threshold values and two-sample percent rise analyses for P4 Architect and PDG (both >0.92). In serial samples classified as (an)ovulatory by PDG, P4 Architect gave ROC AUC 0.95 (95% CI 0.89 to 1.01), with sensitivity and specificity for confirmation of ovulation of 0.90 and 0.91 at a cutoff of 1.67 μmol/mol. Automated P4 may potentially be as efficacious as PDG ELISA but research from a range of clinical settings is required.

Purpose: To investigate the skeletal effects of the first all-female trans-Antarctic traverse. Methods: Six women (mean ± SD, age 32 ±3 years, height 1.72 ± 0.07m, body mass 72.8 ± 4.0kg) hauled 80kg sledges over 1700km in 61days from coast-to-coast across the Antarctic. Whole-body areal bone mineral density (aBMD) (dual-energy X-ray absorptiometry) and tibial volumetric BMD (vBMD), geometry, microarchitecture and estimated mechanical properties (high-resolution peripheral quantitative computed tomography) were assessed 39 days before (pre-expedition) and 15 days after the expedition (post-expedition). Serum and plasma markers of bone turnover were assessed pre-expedition, and 4 and 15 days after the expedition. Results: There were reductions in trunk (−2.6%), ribs (−5.0%) and spine (−3.4%) a BMD from pre-to post-expedition (all P≤0.046); arms, legs, pelvis and total body a BMD were not different (all P≥0.075). Tibial v BMD, geometry, microarchitecture and estimated mechanical properties at the metaphysis (4% site) and diaphysis (30% site) were not different between pre-and post-expedition (all P≥0.082). Bone-specific alkaline phosphatase was higher 15days post-than 4 days post-expedition (1.7 μg∙l⁠−1, P=0.028). Total 25(OH) D decreased from pre-to 4 dayspost expedition (−36nmol∙l⁠−1,P=0.008).Sclerostin,procollagen1N-terminal propeptide, C-telopeptide cross-links of type 1 collagen and adjusted calcium were unchanged (allP≥0.154). Conclusion: Adecline in a BMD of the axial skeleton maybe due to indirect and direct effects of prolonged energy deficit. We propose that weight-bearing exercise was protective against the effects of energy deficit on tibial v BMD, geometry, microarchitecture and strength.

Objective Abnormal biochemical measurements have previously been described in runners following marathons. The incidence of plasma sodium levels outside the normal range has been reported as 31%, and the incidence of raised creatinine at 30%. This study describes the changes seen in electrolytes and creatinine in collapsed (2010–2019 events) and noncollapsed (during the 2019 event) runners during a UK marathon. Methods Point-of-care sodium, potassium, urea and creatinine estimates were obtained from any collapsed runner treated by the medical team during the Brighton Marathons, as part of their clinical care, and laboratory measurements from control subjects. Results Results from 224 collapsed runners were available. Serum creatinine was greater than the normal range in 68.9%. About 6% of sodium results were below, and 3% above the normal range, with the lowest 132 mmol/l. Seventeen percent of potassium readings were above the normal range; the maximum result was 8.4 mmol/l, but 97% were below 6.0 mmol/l. In the control group, mean creatinine was significantly raised in both the collapse and control groups, with 55.4% meeting the criteria for acute kidney injury, but had resolved to baseline after 24 h. Sodium concentration but not the potassium was significantly raised after the race compared with baseline, but only 15% were outside the normal range. Conclusion In this study, incidence of a raised creatinine was higher than previously reported. However, the significance of such a rise remains unclear with a similar rise seen in collapsed and noncollapsed runners, and resolution noted within 24 h. Abnormal sodium concentrations were observed infrequently, and severely abnormal results were not seen, potentially reflecting current advice to drink enough fluid to quench thirst.

Objectives Running a marathon has been equivocally associated with acute changes in cardiac performance. First-phase ejection fraction is a novel integrated echocardiographic measure of left ventricular contractility and systo-diastolic coupling which has never been studied in the context of physical activity. The aim of this study was to assess first-phase ejection fraction following recreational marathon running along with standard echocardiographic indices of systolic and diastolic function. Design and participants: Runners (n = 25, 17 males), age (mean ± standard deviation) 39 ± 9 years, were assessed before and immediately after a marathon race which was completed in 4 h, 10 min ± 47 min. Main outcome measures Central hemodynamics were estimated with applanation tonometry; cardiac performance was assessed using standard M-mode two-dimensional Doppler, tissue-doppler imaging and speckle-tracking echocardiography. First-phase ejection fraction was calculated as the percentage change in left ventricular volume from end-diastole to the time of peak aortic blood flow. Results Conventional indices of systolic function and cardiac performance were similar pre- and post-race while aortic systolic blood pressure decreased by 9 ± 8 mmHg (P < 0.001) and first-phase ejection fraction increased by approximately 48% from 16.3 ± 3.9% to 22.9 ± 2.5% (P < 0.001). The ratio of left ventricular transmitral Doppler early velocity (E) to tissue-doppler imaging early annular velocity (e′) increased from 5.1 ± 1.8 to 6.2 ± 1.3 (P < 0.01). Conclusion In recreational marathon runners, there is a marked increase in first-phase ejection fraction after the race despite no other significant change in cardiac performance or conventional measure of systolic function. More detailed physiological studies are required to elucidate the mechanism of this increase.

This paper reports the metabolic energy changes in six women who made the first unsupported traverse of Antarctica, covering a distance of 1,700 km in 61 days, hauling sledges weighing up to 80 kg. Pre- and postexpedition, measurements of energy expenditure and substrate utilization were made on all six members of the expedition over a 36-h period in a whole body calorimeter. During the study, subjects were fed an isocaloric diet: 50% carbohydrate, 35% fat, and 15% protein. The experimental protocol contained pre- and postexpedition measurement, including periods of sleep, rest, and three periods of standardized stepping exercise at 80, 100, and 120 steps/min. A median (interquartile range) decrease in the lean and fat weight of the subjects of 1.4 (1.0) and 4.4 (1.8) kg, respectively (P < 0.05) was found, using air-displacement plethysmography. No statistically significant difference was found between pre- and postexpedition values for sleeping or resting metabolic rate, nor for diet-induced thermogenesis. A statistically significant difference was found in energy expenditure between the pre- and postexpedition values for exercise at 100 [4.7 (0.23) vs. 4.4 (0.29), P < 0.05] and 120 [5.7 (0.46) vs. 5.5 (0.43), P < 0.05] steps/min; a difference that disappeared when the metabolic rate values were normalized to body weight. The group was well matched for the measures studied. Whereas a physiological change in weight was seen, the lack of change in metabolic rate measures supports a view that women appropriately nourished and well prepared can undertake polar expeditions with a minimal metabolic energy consequence. NEW & NOTEWORTHY This is the first study on the metabolic energy consequences for women undertaking expeditionary polar travel. The results show that participant selection gave a "well-matched" group, particularly during exercise. Notwithstanding this, individual differences were observed and explored. The results show that appropriately selected, trained, and nourished women can undertake such expeditions with no change in their metabolic energy requirements during rest or while undertaking moderate exercise over a sustained period of time.

Objectives: To investigate changes in renal status from exercise in the heat with acclimatisation and to evaluate surrogates markers of Acute Kidney Injury. Design: Prospective observational cohort study. Methods: 20 male volunteers performed 60 min standardised exercise in the heat, at baseline and on four subsequent occasions during a 23-day acclimatisation regimen. Blood was sampled before and after exercise for serum creatinine, copeptin, interleukin-6, normetanephrine and cortisol. Fractional excretion of sodium was calculated for corresponding urine samples. Ratings of Perceived Exertion were reported every 5 min during exercise. Acute Kidney Injury was defined as serum creatinine rise ≥26.5 μmol L

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This study investigates differences in pre- to post-expedition energy expenditure, substrate utilisation and body composition, between the all-male Spear17 (SP-17) and all-female Ice Maiden (IM) transantarctic expeditions (IM: N = 6, 61 days, 1700 km; SP-17: N = 5, 67 days, 1750 km). Energy expenditure and substrate utilisation were measured by a standardised 36 h calorimetry protocol; body composition was determined using air displacement plethysmography. Energy balance calculation were used to assess the physical challenge. There was difference in the daily energy expenditure (IM: 4,939 kcal day−1; SP-17: 6,461 kcal day−1, p = 0.004); differences related to physical activity were small, but statistically significant (IM = 2,282 kcal day−1; SP-17 = 3,174 kcal day−1; p = 0.004). Bodyweight loss was modest (IM = 7.8%, SP-17 = 6.5%; p > 0.05) as was fat loss (IM = 30.4%, SP-17 = 40.4%; p > 0.05). Lean tissue weight change was statistically significant (IM = − 2.5%, SP-17 = + 1.0%; p = 0.05). No difference was found in resting or sleeping energy expenditure, normalised to lean tissue weight (p > 0.05); nor in energy expenditure when exercising at 80, 100 and 120 steps min−1, normalised to body weight (p > 0.05). Similarly, no difference was found in the change in normalised substrate utilisation for any of the activities (p > 0.05). Analysis suggested that higher daily energy expenditures for the men in Spear-17 was the result of higher physical demands resulting in a reduced demand for energy to thermoregulate compared to the women in Ice Maiden. The lack of differences between men and women in the change in energy expenditure and substrate utilisation, suggests no sex difference in response to exposure to extreme environments.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Introduction: Expedition ICE MAIDEN (Ex IM) was the first all-female unsupported crossing of Antarctica. We describe the prerequisite selection and training, comparing those who formed the final team with other participants, and discuss how the expedition diet was established. Methods: All women serving in the British Army were invited to participate. Following initial assessments, successful women completed three training/selection ski expeditions. Between expeditions 1 and 2, participants completed 6 months rigorous UK-based training. Weight was measured before and after the 6 months UK-based training, expeditions 2 and 3, and body composition by skinfold before and after expedition 2. Participant feedback, body composition and weight changes were applied to modify the expedition diet and provide weight gain targets prior to Ex IM. Results: Following 250 applications, 50 women were assessed and 22, 12 and seven women attended training expeditions 1, 2 and 3, respectively. The final team of six women lost more weight than other participants during UK-based training (mean (SD) change -1.3 (1.5) kg vs -0.5 (1.6) kg, respectively, p=0.046) and during training expedition 2 (-2.8 (0.8) kg vs -1.7 (0.4) kg, respectively, p=0.048), when they also gained more lean mass (+2.1 (0.8) kg vs +0.4 (0.7) kg, respectively, p=0.004). The Ex IM diet provided 5000 kCal/day, comprising approximately 45% carbohydrate, 45% fat and 10% protein. Median (range) weight change between expedition 3 and Ex IM was +8.7 (-1.9 to +14.3) kg. Conclusions: The selected Ex IM team demonstrated favourable training-associated body composition changes. Training-associated weight loss informed the expeditionary diet design.

© 2019 Background: Basic military training (BMT) is a useful model of prolonged exposure to multiple stressors. 8–12 week BMT is associated with perturbations in the hypothalamic-pituitary-adrenal (HPA) axis which could predispose recruits to injury and psychological strain. However, characterisations of HPA axis adaptations during BMT have not been comprehensive and most studies included few if any women. Methods: We studied women undertaking an arduous, 44-week BMT programme in the UK. Anxiety, depression and resilience questionnaires, average hair cortisol concentration (HCC), morning and evening saliva cortisol and morning plasma cortisol were assessed at regular intervals throughout. A 1-h dynamic cortisol response to 1 μg adrenocorticotrophic hormone-1-24 was performed during weeks 1 and 29. Results: Fifty-three women (aged 24 ± 2.5 years) completed the study. Questionnaires demonstrated increased depression and reduced resilience during training (F 6.93 and F 7.24, respectively, both p < 0.001). HCC increased from 3 months before training to the final 3 months of training (median (IQR) 9.63 (5.38, 16.26) versus 11.56 (6.2, 22.45) pg/mg, p = 0.003). Morning saliva cortisol increased during the first 7 weeks of training (0.44 ± 0.23 versus 0.59 ± 0.24 μg/dl p < 0.001) and decreased thereafter, with no difference between the first and final weeks (0.44 ± 0.23 versus 0.38 ± 0.21 μg/dl, p = 0.2). Evening saliva cortisol did not change. Fasting cortisol decreased during training (beginning, mid and end-training concentrations: 701 ± 134, 671 ± 158 and 561 ± 177 nmol/l, respectively, p < 0.001). Afternoon basal cortisol increased during training while there was a trend towards increased peak stimulated cortisol (177 ± 92 versus 259 ± 13 nmol/l, p = 0.003, and 589 ± 164 versus 656 ± 135, p = 0.058, respectively). Discussion: These results suggest a normal stress response in early training was followed quickly by habituation, despite psychological and physical stress evidenced by questionnaire scores and HCC, respectively. There was no evidence of HPA axis maladaptation. These observations are reassuring for women undertaking arduous employment.

© 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.

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.

Intravenous iron supplementation at sea level is associated with enhanced stroke volume and higher SpO2 on ascent to very high altitude (5100 m). These effects appear to result from reduced pulmonary vascular resistance and improved right heart function. https://bit.ly/2VQX5fR

Since the advent of women in ground close combat (WGCC) roles, the impact on women of the attendant risk of heat stress and heat illness has been considered. Much emphasis has been placed on sex differences in thermal physiology. This article considers the application of evidence of sex-associated thermoregulatory variation to the occupational and environmental setting of WGCC, and weighs the relative importance of physiological differences arising from biological sex, and behaviour associated with gender normatives. Quantifying the risk of heat illness to WGCC should draw on data from their real-world occupational context.

Background Heat illness (HI) is a growing global concern; its incidence has risen dramatically across the world in recent years. The individual factors whereby elevated core temperature produces HI are not well-understood. Given known physiological differences between men and women pertaining to temperature regulation, we hypothesized that women would be at increased risk of HI than men. Objectives We aimed to determine the relative risk of HI in women compared with men through an exhaustive literature review and meta-analysis. Methods We search PubMed and Ovid Medline databases from inception to Apr 2017. Search terms included all permutations of sex and heat illness (including heatstroke and exertional heat illness) with no language restrictions. We included adult or adolescent human data reporting comparable male and female HI rates. One reviewer identified and screened titles and abstracts. Two independent reviewers applied eligibility criteria. Disagreements were resolved with a third reviewer. Results Of 5888 articles identified by searches, 36 were included in the systematic review and 22 in the meta-analysis. The mean (standard deviation) quality score was 3.31(1.25)/5. Overall the rate among women was consistently lower than men across the lifespan. The male: female pooled IRR was 2.28 (p<0.001, 95% CI: 1.66-3.16). There was modest heterogeneity (between-studies variance (τ2) = 0.02). The rates did not differ significantly when corrected for severity or occupation. Discussion The rate of HI was significantly increased in men compared with women. Risk for HI might be conferred by psychological and behavioral factors rather than physiological ones. Further research is required to delineate which groups are at greatest risk, leading to the development of mitigation strategies against HI.

Purpose To explore the effects of the first all-female transantarctic expedition on hormonal axes pertinent to reproductive and metabolic function. Methods Six females (age, 28–36 yr; body mass index, 24.2 ± 0.97 kg·m−2) hauled 80-kg sledges 1700 km in 61 d. Estimated average energy intake was 20.8 ± 0.1 MJ·d−1 (4970 ± 25 kcal·d−1). Whole and regional body composition was measured by dual-energy x-ray absorptiometry 1 and 2 months before and 15 d after, the expedition. Body fat was also estimated by skinfold and bioimpedance immediately before and after the expedition. Basal metabolic and endocrine blood markers and, after 0.25 mg dexamethasone suppression, 1-h 10-μg gonadorelin and 1.0 μg adrenocortiocotrophin-(1–24) tests were completed, 39–38 d preexpedition and 4 to 5 d and 15 to 16 d postexpedition. Cortisol was assessed in hair (monthly average concentrations) and saliva (five-point day curves and two-point diurnal sampling). Results Average body mass loss was 9.37 ± 2.31 kg (P < 0.0001), comprising fat mass only; total lean mass was maintained. Basal sex steroids, corticosteroids, and metabolic markers were largely unaffected by the expedition except leptin, which decreased during the expedition and recovered after 15 d, a proportionately greater change than body fat. Luteinizing hormone reactivity was suppressed before and during the expedition, but recovered after 15 d, whereas follicle-stimulating hormone did not change during or after the expedition. Cortisol reactivity did not change during or after the expedition. Basal (suppressed) cortisol was 73.25 ± 45.23 mmol·L−1 before, 61.66 ± 33.11 mmol·L−1 5 d postexpedition and 54.43 ± 28.60 mmol·L−1 16 d postexpedition (P = 0.7). Hair cortisol was elevated during the expedition. Conclusions Maintenance of reproductive and hypothalamic-pituitary-adrenal axis function in women after an extreme physical endeavor, despite energy deficiency, suggests high female biological capacity for extreme endurance exercise.

The relationship between autonomic function and recovery following prolonged arduous exercise in women has not been examined. We undertook an exploratory study that aimed to examine the temporal change in linear and nonlinear measures of heart rate variability (HRV) following prolonged arduous exercise in the form of first all-female (mean age 32.7 ± 3.1 years) team to attempt an unassisted Antarctic traverse. HRV analysis was performed before and 1, 4, and 15 days postexpedition. The traverse was completed in 61 days. There was a significant paired reduction in heart rate, LnLF, LF:HF, DFAα1 between baseline and 15 days postexercise in the same environment. Conversely, RMSSD, LnHF and HFnu, SD1:SD2, and SampEn significantly increased. DFAα2 levels significantly fell from baseline to Day 1 postexercise. In conclusion, we observed a significant latent increase in relative parasympathetic dominance and RR interval irregularity at 15 days post prolonged arduous exercise, versus pre-exercise baseline, in a group of very fit and healthy adult women.

Acclimatization favors greater extracellular tonicity from lower sweat sodium, yet hyperosmolality may impair thermoregulation during heat stress. Enhanced secretion or action of vasopressin could mitigate this through increased free water retention. Aims were to determine responses of the vasopressin surrogate copeptin to dehydrating exercise and investigate its relationships with tonicity during short and long-term acclimatization. Twenty-three participants completed a structured exercise programme following arrival from a temperate to a hot climate. A Heat Tolerance Test (HTT) was conducted on Day-2, 6, 9 and 23, consisting of 60-min block-stepping at 50% VO2 peak, with no fluid intake. Resting sweat [Na+ ] was measured by iontophoresis. Changes in body mass (sweat loss), core temperature, heart rate, osmolality (serum and urine) and copeptin and aldosterone (plasma) were measured with each Test. From Day 2 to Day 23, sweat [Na+ ] decreased significantly (adjusted P < 0.05) and core temperature and heart rate fell. Over the same interval, HTT-associated excursions were increased for serum osmolality (5 [-1, 9] vs. 9 [5, 12] mosm·kg-1 ), did not differ for copeptin (9.6 [6.0, 15.0] vs. 7.9 [4.3, 14.7] pmol·L-1 ) and were reduced for aldosterone (602 [415, 946] vs. 347 [263, 537] pmol·L-1 ). Urine osmolality was unchanging and related consistently to copeptin at end-exercise, whereas the association between copeptin and serum osmolality was right-shifted (P = 0.0109) with acclimatization. Unchanging urine:serum osmolality argued against increased renal action of vasopressin. In conclusion, where exercise in the heat is performed without fluid replacement, heat acclimatization does not appear to enhance AVP-mediated free water retention in humans.

Purpose Endurance exercise and hyperthermia are associated with compromised intestinal permeability and endotoxaemia. The presence of intestinal fatty acid-binding protein (I-FABP) in the systemic circulation suggests intestinal wall damage, but this marker has not previously been used to investigate intestinal integrity after marathon running. Methods Twenty-four runners were recruited as controls prior to completing a standard marathon and had sequential I-FABP measurements before and on completion of the marathon, then at four and 24 h later. Eight runners incapacitated with exercise-associated collapse (EAC) with hyperthermia had I-FABP measured at the time of collapse and 1 hour later. Results I-FABP was increased immediately on completing the marathon (T0; 2593 ± 1373 ng·l−1) compared with baseline (1129 ± 493 ng·l−1; p < 0.01) in the controls, but there was no significant difference between baseline and the levels at four hours (1419 ± 1124 ng·l−1; p = 0.7), or at 24 h (1086 ± 302 ng·l−1; p = 0.5). At T0, EAC cases had a significantly higher I-FABP concentration (15,389 ± 8547 ng.l−1) compared with controls at T0 (p < 0.01), and remained higher at 1 hour after collapse (13,951 ± 10,476 ng.l−1) than the pre-race control baseline (p < 0.05). Conclusion I-FABP is a recently described biomarker whose presence in the circulation is associated with intestinal wall damage. I-FABP levels increase after marathon running and increase further if the endurance exercise is associated with EAC and hyperthermia. After EAC, I-FABP remains high in the circulation for an extended period, suggesting ongoing intestinal wall stress.

For most individuals residing in Northwestern Europe, maintaining replete vitamin D status throughout the year is unlikely without vitamin D supplementation and deficiency remains common. Military studies have investigated the association with vitamin D status, and subsequent supplementation, with the risk of stress fractures particularly during recruit training. The expression of nuclear vitamin D receptors and vitamin D metabolic enzymes in immune cells additionally provides a rationale for the potential role of vitamin D in maintaining immune homeostasis. One particular area of interest has been in the prevention of acute respiratory tract infections (ARTIs). The aims of this review were to consider the evidence of vitamin D supplementation in military populations in the prevention of ARTIs, including SARS-CoV-2 infection and consequent COVID-19 illness. The occupational/organisational importance of reducing transmission of SARS-CoV-2, especially where infected young adults may be asymptomatic, presymptomatic or paucisymptomatic, is also discussed.

PURPOSE: To prevent heat-related illnesses, guidelines recommend limiting core body temperature (T c) ≤ 38 °C during thermal stress. Copeptin, a surrogate for arginine vasopressin secretion, could provide useful information about fluid balance, thermal strain and health risks. It was hypothesised that plasma copeptin would rise with dehydration from occupational heat stress, concurrent with sympathoadrenal activation and reduced glomerular filtration, and that these changes would reflect T c responses. METHODS: Volunteers (n = 15) were recruited from a British Army unit deployed to East Africa. During a simulated combat assault (3.5 h, final ambient temperature 27 °C), T c was recorded by radiotelemetry to differentiate volunteers with maximum T c > 38 °C versus ≤ 38 °C. Blood was sampled beforehand and afterwards, for measurement of copeptin, cortisol, free normetanephrine, osmolality and creatinine. RESULTS: There was a significant (P < 0.05) rise in copeptin from pre- to post-assault (10.0 ± 6.3 vs. 16.7 ± 9.6 pmol L(-1), P < 0.001). Although osmolality did not increase, copeptin correlated strongly with osmolality after the exposure (r = 0.70, P = 0.004). In volunteers with maximum T c > 38 °C (n = 8) vs ≤ 38 °C (n = 7) there were significantly greater elevations in copeptin (10.4 vs. 2.4 pmol L(-1)) and creatinine (10 vs. 2 μmol L(-1)), but no differences in cortisol, free normetanephrine or osmolality. CONCLUSIONS: Changes in copeptin reflected T c response more closely than sympathoadrenal markers or osmolality. Dynamic relationships with tonicity and kidney function may help to explain this finding. As a surrogate for integrated physiological strain during work in a field environment, copeptin assay could inform future measures to prevent heat-related illnesses.

Introduction: A lack of knowledge among laypersons about the hazards of high-altitude exposure contributes to morbidity and mortality from acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) among high-altitude travelers. There are guidelines regarding the recognition, prevention, and treatment of acute-altitude illness for experts, but essential knowledge for laypersons traveling to high altitudes has not been defined. We sought expert consensus on the essential knowledge required for people planning to travel to high altitudes. Methods: The Delphi method was used. The panel consisted of two moderators, a core expert group and a plenary expert group. The moderators made a preliminary list of statements defining the desired minimum knowledge for laypersons traveling to high altitudes, based on the relevant literature. These preliminary statements were then reviewed, supplemented, and modified by a core expert group. A list of 33 statements was then presented to a plenary group of experts in successive rounds. Results: It took three rounds to reach a consensus. Of the 10 core experts invited, 7 completed all the rounds. Of the 76 plenary experts, 41 (54%) participated in Round 1, and of these 41 a total of 32 (78%) experts completed all three rounds. The final list contained 28 statements in 5 categories (altitude physiology, sleeping at altitude, AMS, HACE, and HAPE). This list represents an expert consensus on the desired minimum knowledge for laypersons planning high-altitude travel. Conclusion: Using the Delphi method, the STrengthening Altitude Knowledge initiative yielded a set of 28 statements representing essential learning objectives for laypersons who plan to travel to high altitudes. This list could be used to develop educational interventions.

Reproductive endocrine function adapts to psychological, environmental, and energy-associated stressors. Multistressor environments upregulate hypothalamic-pituitary-adrenal (HPA) axis, causing suppression of the hypothalamic-pituitary-gonadal (HPG) axis, but it is not known if this pattern or its magnitude is sex biased. We compared HPG and HPA axis activity in 9 men and 34 women undergoing Army training. One-hour low-dose gonadorelin and Synacthen tests were conducted at 1 and 29 wk, measuring gonadotrophins and cortisol. Cortisol was measured from hair every 3 mo. Morning and evening salivary cortisol and psychometric questionnaires were measured at six timepoints. Sexes were compared over time by two-way ANOVA. Gonadotrophin responses were significantly higher in women than men in week 1, but no sex difference was seen at week 29 (no significant sex × time interaction). Week 1 cortisol response was higher among men, but week 29 cortisol response was higher among women (sex × time F(1,44) = 18.0, P < 0.001). Hair cortisol was higher among women than men beforehand, not different between sexes during the first 3 mo, and significantly higher among women during training months 5–11 (F(3,15) = 3.25, P = 0.024). Morning salivary cortisol was higher among women in weeks 8 and 14, but higher among men in week 29 (F(4,76) = 4.0, P = 0.005). No differences were seen in evening salivary cortisol. Psychometrics did not change or differ between sexes. HPA axis responses to military training were greater among women than men. HPG axis responses suggest greater downregulation among women. These findings will enable equitable and individualized management of people undergoing periods of intensive physical stress. NEW & NOTEWORTHY We conducted a comprehensive comparison of adrenal and reproductive function in men and women undergoing 11-mo military training. We found progressively elevated cortisol levels and dynamic cortisol response to stress among women, but not men, and suppression of reproductive function among women. The physiological impact of stressful military training was greater among women than men; this could not be explained by energy balance, and sex-specific effects of sleep, socio-ethnographic, or other stressors may be responsible.

PURPOSE: Heat adaptation (HA) is critical to performance and health in a hot environment. Transition from short-term heat acclimatisation (STHA) to long-term heat acclimatisation (LTHA) is characterised by decreased autonomic disturbance and increased protection from thermal injury. A standard heat tolerance test (HTT) is recommended for validating exercise performance status, but any role in distinguishing STHA from LTHA is unreported. The aims of this study were to (1) define performance status by serial HTT during structured natural HA, (2) evaluate surrogate markers of autonomic activation, including heart rate variability (HRV), in relation to HA status. METHODS: Participants (n = 13) were assessed by HTT (60-min block-stepping, 50% VO2peak) during STHA (Day 2, 6 and 9) and LTHA (Day 23). Core temperature (Tc) and heart rate (HR) were measured every 5 min. Sampling for HRV indices (RMSSD, LF:HF) and sympathoadrenal blood measures (cortisol, nephrines) was undertaken before and after (POST) each HTT. RESULTS: Significant (P < 0.05) interactions existed for Tc, logLF:HF, cortisol and nephrines (two-way ANOVA; HTT by Day). Relative to LTHA, POST results differed significantly for Tc (Day 2, 6 and 9), HR (Day 2), logRMSSD (Day 2 and Day 6), logLF:HF (Day 2 and Day 6), cortisol (Day 2) and nephrines (Day 2 and Day 9). POST differences in HRV (Day 6 vs. 23) were + 9.9% (logRMSSD) and - 18.6% (logLF:HF). CONCLUSIONS: Early reductions in HR and cortisol characterised STHA, whereas LTHA showed diminished excitability by Tc, HRV and nephrine measures. Measurement of HRV may have potential to aid real-time assessment of readiness for activity in the heat.

Evidence from civilian athletes raises the question of whether reproductive dysfunction may be seen in female soldiers as a result of military training. Such reproductive dysfunction consists of impaired ovulation with or without long term subfertility. We critically review pertinent evidence, which points towards reduced energy availability as the most likely explanation for exercise-induced reproductive dysfunction. Evidence also suggests reproductive dysfunction is mediated by activation of the hypothalamic-pituitary-adrenal axis and suppression of the hypothalamic-pituitary-gonadal axis, with elevated ghrelin and reduced leptin likely to play an important role. The observed reproductive dysfunction exists as part of a female athletic triad, together with osteopenia and disordered eating. If this phenomenon was shown to exist with UK military training this would be of significant concern. We hypothesise that the nature of military training and possibly field exercises may contribute to greater risk of reproductive dysfunction among female military trainees compared with exercising civilian controls. We discuss the features of military training and its participants, such as energy availability, age at recruitment, body phenotype, type of physical training, psychogenic stressors, altered sleep pattern and elemental exposure as contributors to reproductive dysfunction. We identify lines of future research to more fully characterise reproductive dysfunction in military women, and suggest possible interventions which, if indicated, could improve their future wellbeing.

Bone adapts to unaccustomed, high-impact loading but loses mechanosensitivity quickly. Short periods of military training (≤12 weeks) increase the density and size of the tibia in women. The effect of longer periods of military training, where the incidence of stress fracture is high, on tibial macrostructure and microarchitecture in women is unknown. This observational study recruited 51 women (age 19 to 30 years) at the start of 44 weeks of British Army Officer training. Tibial volumetric bone mineral density (vBMD), geometry, and microarchitecture were measured by high-resolution peripheral quantitative computed tomography (HRpQCT). Scans of the right tibial metaphysis (4% site) and diaphysis (30% site) were performed at weeks 1, 14, 28, and 44. Measures of whole-body areal bone mineral density (aBMD) were obtained using dual-energy X-ray absorptiometry (DXA). Blood samples were taken at weeks 1, 28, and 44, and were analyzed for markers of bone formation and resorption. Trabecular vBMD increased from week 1 to 44 at the 4% site (3.0%, p < .001). Cortical vBMD decreased from week 1 to 14 at the 30% site (−0.3%, p < .001). Trabecular area decreased at the 4% site (−0.4%); trabecular bone volume fraction (3.5%), cortical area (4.8%), and cortical thickness (4.0%) increased at the 4% site; and, cortical perimeter increased at the 30% site (0.5%) from week 1 to 44 (p ≤ .005). Trabecular number (3.5%) and thickness (2.1%) increased, and trabecular separation decreased (−3.1%), at the 4% site from week 1 to 44 (p < .001). Training increased failure load at the 30% site from week 1 to 44 (2.5%, p < .001). Training had no effect on aBMD or markers of bone formation or resorption. Tibial macrostructure and microarchitecture continued to adapt across 44 weeks of military training in young women. Temporal decreases in cortical density support a role of intracortical remodeling in the pathogenesis of stress fracture.

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.

Hypothalamic-pituitary-gonadal (HPG) axis suppression in exercising women can be caused by low energy availability (EA), but the impact of a real-world, multistressor training environment on reproductive and metabolic function is unknown. This study aimed to characterize reproductive and metabolic adaptation in women undertaking basic military training. A prospective cohort study in women undertaking 11-month initial military training (n = 47) was carried out. Dynamic low-dose 1-h gonadotrophin-releasing hormone (GnRH) tests were completed after 0 and 7 mo of training. Urine progesterone was sampled weekly throughout. Body composition (dual X-ray absorptiometry), fasting insulin resistance (homeostatic modeling assessment 2, HOMA2), leptin, sex steroids, anti-Müllerian hormone (AMH), and inhibin B were measured after 0, 7, and 11 mo with an additional assessment of body composition at 3 mo. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses were suppressed after 7 mo (both P < 0.001). Among noncontraceptive users (n = 20), 65% had regular (23–35 days) cycles preenrollment, falling to 24% by 7 mo of training. Of women in whom urine progesterone was measured (n = 24), 87% of cycles showed no evidence of ovulation. There was little change in AMH, LH, and estradiol, although inhibin B and FSH increased (P < 0.05). Fat mass fluctuated during training but at month 11 was unchanged from baseline. Fat-free mass did not change. Visceral adiposity, HOMA2, and leptin increased (all P < 0.001). HPG axis suppression with anovulation occurred in response to training without evidence of low EA. Increased insulin resistance may have contributed to the observed pituitary and ovarian dysfunction. Our findings are likely to represent an adaptive response of reproductive function to the multistressor nature of military training. NEW & NOTEWORTHY We characterized reproductive endocrine adaptation to prolonged arduous multistressor training in women. We identified marked suppression of hypothalamic-pituitary-gonadal (HPG) axis function during training but found no evidence of low energy availability despite high energy requirements. Our findings suggest a complex interplay of psychological and environmental stressors with suppression of the HPG axis via activation of the hypothalamic-pituitary adrenal (HPA) axis. The neuroendocrine impact of nonexercise stressors on the HPG axis during arduous training should be considered.

We queried whether adrenal insufficiency attributable to non-classic congenital adrenal hyperplasia (21 hydroxylase deficiency, 21OHD) might contribute to heat illness susceptibility. Patients referred to a specialist heat illness clinic (n=2 with prior hyponatraemia; n=16 lacking documentary evidence) and controls (n=16) underwent laboratory Heat Tolerance Assessment (HTA: 60-90 min walking, 60% relative intensity, 34 ° C heat), synthetic adrenocorticotrophic hormone stimulation (heat illness only) and CYP21A2 genotyping (hyponatraemic heat illness only). Copeptin, cortisol, 17-hydroxyprogesterone and 21 deoxycortisol were assayed from blood at baseline and post-HTA, with precursor product [17-hydroxyprogesterone + 21 deoxycortisol] expressed relative to cortisol. Saliva and urine were assayed for free cortisol (one hyponatraemic case, controls). Versus controls, normonatraemic heat illness exhibited greater (P<0.05) serum cortisol across HTA, while hyponatraemic heat illness showed blunted responses in aldosterone, and free cortisol (salivary cortisol 1.6 and 1.6 vs 6.0 [4.2, 19.4] and 4.2 [3.8, 19.2] nmol.L-1; urine cortisol 19 vs 117 +/- 71 nmol.L-1). Hyponatraemic heat illness demonstrated elevated precursor product consistent with 21OHD, and multiple CYP21A2 mutations. One normonatraemic case of heat illness also showed elevated precursor product. These data support potential for 21OHD to precipitate heat illness under sustained physical stress and advance a case for targeted genetic screening.

Polar expeditions have been associated with changes in the hypothalamic-pituitary-testicular axis consistent with central hypogonadism (i.e., decreased testosterone, luteinising hormone (LH), and follicle stimulating hormone (FSH)). These changes are typically associated with body mass loss. Our aim was to evaluate whether maintenance of body mass during a polar expedition could mitigate against the development of central hypogonadism. Male participants (n = 22) from a 42-day expedition (British Services Antarctic Expedition 2012) volunteered to take part in the study. Body mass, body composition, and strength data were recorded pre- and postexpedition in addition to assessment of serum testosterone, LH, FSH, thyroid hormones, insulin-like growth factor 1 (IGF-1), and trace elements. Energy provision and energy expenditure were assessed at mid- and end-expedition. Daily energy provision was 6335 ± 149 kcal·day(-1). Estimated energy expenditure midexpedition was 5783 ± 1690 kcal·day(-1). Body mass and percentage body fat did not change between pre- and postexpedition. Total testosterone (nmol·L(-1)) (14.0 ± 4.9 vs. 17.3 ± 4.0, p = 0.006), calculated free testosterone (pmol·L(-1)) (288 ± 82 vs. 350 ± 70, p = 0.003), and sex hormone binding globulin (nmol·L(-1)) (33 ± 12 vs. 36 ± 11, p = 0.023) concentrations increased. LH and FSH remained unchanged. Thyroid stimulating hormone (TSH; IU·L(-1)) (2.1 ± 0.8 vs. 4.1 ± 2.1, p < 0.001) and free triiodothyronine (FT3; IU·L(-1)) (5.4 ± 0.4 vs. 6.1 ± 0.8, p < 0.001) increased while free thyroxine, IGF-1, and trace elements remained unchanged. Hand-grip strength was reduced postexpedition but static lift strength was maintained. Maintenance of body mass and nutritional status appeared to negate the central hypogonadism previously reported from polar expeditions. The elevated TSH and free FT3 were consistent with a previously reported "polar T3 syndrome".

Background: Gradual ascent to high altitude is typically associated with reduced resting aldosterone and unchanged cortisol, features that may facilitate acclimatization but are poorly understood. Aims: To investigate the cortisol and aldosterone response to adrenocorticotrophic hormone at altitude. Methods: Eleven subjects underwent a 250 µg short synacthen test at sea-level and again after trekking to 3600 m in Nepal. Cortisol and aldosterone were measured by conventional assay from blood samples taken immediately prior to the administration of synacthen (T0) and then 30 (T30) and 60 (T60) minutes later. Results: At 3600 m resting basal cortisol and aldosterone levels were both significantly lower than they were at sea-level (p=0.004, p=0.003 respectively). Cortisol values at T30 and T60 were no different between sea-level and 3600 m but the increment after synacthen was significantly (p=0.041) greater at 3600 m due to a lower basal value. Aldosterone at T30 and T60 was significantly lower (p=0.003 for both) at 3600 m than at sea-level and the increment following synacthen was also significantly (p=0.003) less at 3600 m. Conclusions: At 3600 m there appears to be a divergent adrenal response to synthetic adrenocorticotrophic hormone with an intact cortisol response but a reduced aldosterone response, relative to sea-level. This may reflect a specific effect of hypoxia on aldosterone synthesis and may be beneficial to acclimatization.

© 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.

Background It has been consistently shown that heavy exercise leads to cardiac troponin (cTn) release and variable changes in post exercise cardiac function. This relationship has not been explored at increasing or significant high altitude (HA). This study assessed the effects of exercise at progressively increasing HA on high-sensitivity (hs)-cTnT levels and their relationship to biventricular cardiac function and severity of acute mountain sickness (AMS). Methods Transthoracic echocardiograms, hs-cTnT levels and AMS scores were measured at rest at 1,300 m then repeated post exercise and 12 h later after progressive trekking to 3,440, 4,270 m and at 5,150 m (after trekking to 5,643 m) on 19 healthy subjects (age 35.4 ± years, 52.6 % males). Results There was a detectable increase (>5 ng/L) in post exercise hs-cTnT with exercise at HA which became significant at 5,150 m (5.84 % at 3,440 m, 5.2 % at 4,270 m and 56.3 % at 5,150 m; p = 0.0005). Compared with baseline, HA to 5,150 m led to a significant rise in post exercise Lake Louis AMS scores (p < 0.001) pulmonary artery systolic pressure (PASP) (23.7 ± 3.8 vs 37.9 ± 11.7 mmHg: p < 0.001), cardiac output (5.2 ± 1.2 vs 7.5 ± 1.3 l/min; p < 0.001) and a fall in SpO2 (96.1 ± vs 77.4 ± 12.0 %; p < 0.001). There was no change in stroke volume (p = 0.10) or estimated filling pressures (E/E’) of the left (p = 0.50) and right ventricles (p = 0.4). On multivariate analysis increasing cardiac output (p = 0.02) and PASP (p = 0.04) and decreasing SpO2 (p = 0.01) were the only independent predictors of increasing cTnT levels (overall R2 = 0.23, p < 0.0001). Conclusions Moderate intensity exercise at significant HA influences the post exercise increase in hs-cTnT without overt deleterious effects on cardiac function.

Purpose To study the relationship between serum neutrophil gelatinase-associated lipocalin (NGAL) and military blast and gunshot wound (GSW) to establish whether potential exists for NGAL as a biomarker for blast lung injury (BLI). Method Patients from the intensive care unit (ICU) of the Role 3 Medical Treatment Facility at Camp Bastion, Helmand Province, Afghanistan were studied over a five month period commencing in 2012. Age, mechanism, trauma injury severity score (TRISS) and serum NGAL were recorded on ICU admission (NGAL1). Serum NGAL (NGAL2) and PaO2/FiO2 ratio (P/F ratio2) were recorded at 24 h. Results 33 patients were injured by blast and 23 by GSW. NGAL1 inversely correlated with TRISS (p = 0.020), pH (p = 0.002) and P/F ratio 2 (p = 0.009) overall. When data was stratified into blast and GSW, NGAL1 also inversely correlated with P/F ratio 2 in the blast injured group (p = 0.008) but not GSW group (p = 0.27). Conclusion Raised NGAL correlated with increased severity of injury (worse survival probability i.e. TRISS and low pH) in both patient groups. There was an inverse correlation between admission NGAL and a marker of blast lung injury (low P/F ratio) at 24 h in blast injured group but not GSW group that warrants further investigation.

Objectives To assess how biomarkers indicating central nervous system insult (neurobiomarkers) vary in peripheral blood with exertional-heat stress from prolonged endurance exercise. Design Observational study of changes in neuron specific enolase (NSE), S100 calcium-binding protein B (S100β), Glial Fibrillary Acid Protein (GFAP) and Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) at Brighton Marathon 2022. Methods In 38 marathoners with in-race core temperature (Tc) monitoring, exposure (High, Intermediate or Low) was classified by cumulative hyperthermia – calculated as area under curve of Time × Tc > 38 °C – and also by running duration (finishing time). Blood was sampled for neurobiomarkers, cortisol and fluid-regulatory stress surrogates, including copeptin and creatinine (at rested baseline; within 30 min of finishing; and at 24 h). Results Finishing in 236 ± 40 min, runners showed stable GFAP and UCH-L1 across the marathon and next-day. Significant (P < 0.05) increases from baseline were shown post-marathon and at 24 h for S100β (8.52 [3.65, 22.95] vs 39.0 [26.48, 52.33] vs 80.3 [49.1, 99.7] ng·L−1) and post-marathon only for NSE (3.73 [3.30, 4.32] vs 4.85 [4.45, 5.80] μg·L−1, P < 0.0001). Whilst differential response to hyperthermia was observed for cortisol, copeptin and creatinine, neurobiomarker responses did not vary. Post-marathon, only NSE differed by exercise duration (High vs Low, 5.81 ± 1.77 vs. 4.69 ± 0.73 μg·L−1, adjusted P = 0.0358). Conclusions Successful marathon performance did not associate with evidence for substantial neuronal insult. To account for variation in neurobiomarkers with prolonged endurance exercise, factors additional to hyperthermia, such as exercise duration and intensity, should be further investigated.

Heart rate variability (HRV) is a useful index of autonomic function and has been linked to the development of high altitude (HA) related illness. However, its assessment at HA has been undermined by the relative expense and limited portability of traditional HRV devices which have mandated at least a minute heart rate recording. In this study, the portable ithlete(™) HRV system, which uses a 55 s recording, was compared with a reference method of HRV which utilizes a 5 min electrocardiograph recording (CheckMyHeart(™) ). The root mean squares of successive R-R intervals (RMSSD) for each device was converted to a validated HRV score (lnRMSSD × 20) for comparison. Twelve healthy volunteers were assessed for HRV using the two devices across seven time points at HA over 10 days. There was no significant change in the HRV values with either the ithlete (P = 0·3) or the CheckMyHeart(™) (P = 0·19) device over the seven altitudes. There was also a strong overall correlation between the ithlete(™) and CheckMyHeart(™) device (r = 0·86; 95% confidence interval: 0·79-0·91). The HRV was consistently, though non-significantly higher with ithlete(™) than with the CheckMyHeart(™) device [mean difference (bias) 1·8 l; 95% CI -12·3 to 8·5]. In summary, the ithlete(™) and CheckMyHeart(™) system provide relatively similar results with good overall agreement at HA.

Summary: Fluid retention is a recognized feature of acute mountain sickness. However, accurate assessment of hydration, including the quantification of body water, has traditionally relied on expensive and non-portable equipment limiting its utility in the field setting. We compared the assessment of total body water (TBW) and their relationship to total body weight using two non-invasive methods using the NICas single-frequency bioimpedance analysis (SF-BIA) system and the BodyStat QuadScan 4000 multifrequency BIA system (MF-BIA). TBW measurements were performed at rest at sea level and at high altitude (HA) at 3833 m postexercise and at rest and thereafter at rest at 4450 m and 5129 m on 47 subjects. The average age was 34·5 ± 9·3 years with an age range of 21-54 years (70·2% male). There were strong correlations between TBW assessment with both methods at sea level (r = 0·90; 95% CI 0·78-0·95: P<0·0001) and at HA (r = 0·92; 0·89-0·94: P<0·0001), however, TBW readings were 0·2 l and 1·91 l lower, respectively, with the NICaS. There was a stronger correlation between TBW and body weight with the QuadScan (r = 0·91; P<0·0001) than with the NICaS (r = 0·83; P<0·0001). The overall agreement between the two TBW methods was good, but the 95% confidence intervals around these agreements were relatively wide. We conclude that there was reasonable agreement between the two methods of BIA for TBW, but this agreement was lower at HA.

Summary

Fluid retention is a recognized feature of acute mountain sickness. However, accurate assessment of hydration, including the quantification of body water, has traditionally relied on expensive and non‐portable equipment limiting its utility in the field setting. We compared the assessment of total body water (TBW) and their relationship to total body weight using two non‐invasive methods using the NICas single‐frequency bioimpedance analysis (SF‐BIA) system and the BodyStat QuadScan 4000 multifrequency BIA system (MF‐BIA). TBW measurements were performed at rest at sea level and at high altitude (HA) at 3833 m postexercise and at rest and thereafter at rest at 4450 m and 5129 m on 47 subjects. The average age was 34·5 ± 9·3 years with an age range of 21–54 years (70·2% male). There were strong correlations between TBW assessment with both methods at sea level (r = 0·90; 95% CI 0·78–0·95: P<0·0001) and at HA (r = 0·92; 0·89–0·94: P<0·0001), however, TBW readings were 0·2 l and 1·91 l lower, respectively, with the NICaS. There was a stronger correlation between TBW and body weight with the QuadScan (r = 0·91; P<0·0001) than with the NICaS (r = 0·83; P<0·0001). The overall agreement between the two TBW methods was good, but the 95% confidence intervals around these agreements were relatively wide. We conclude that there was reasonable agreement between the two methods of BIA for TBW, but this agreement was lower at HA.

Mellor, Adrian, Christopher Boos, David Holdsworth, Joe Begley, David Hall, Andrew Lumley, Anne Burnett, Amanda Hawkins, John O'Hara, Stephen Ball, and David Woods. Cardiac biomarkers at high altitude. High Alt Med Biol 15:452-458, 2014. - Background: Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT-proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS. Methods: 48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded. Results: Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (≥40 mm Hg) was associated with higher NPs, NT-proBNP: 137±195 vs. 71.8±68 (p=0.001); BNP 15.3±18.1 vs. 8.7±6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2±264 vs. 76.4±82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8±21 vs. 7.8±6.5, p=0.018). Conclusion: The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS.

Background: There is a widely held belief that strenuous exercise should be avoided on arrival at high altitude (HA) and during acclimatization. Data from chamber studies are contradictory and the studies are usually of short duration, therefore differing from the " real world. " Methods: We studied 48 trekkers during a 10-d ascent to 16,827 ft (5129 m) in the Cordillera Real area of Bolivia. Borg Rating of Perceived Exertion (RPE) scores were recorded for the hardest perceived exertion during the day after ascents to 12,576, 14,600, and 16,827 ft (3833, 4450, and 5129 m). Heart rate, SpO2 , and Lake Louise Score (LLS) were recorded simultaneously. Statistical testing was performed using SPSS 21 software. A P - value of ≤ 0.05 was deemed significant. Results: Acute mountain sickness (AMS) rates were higher after trekking days with higher levels of perceived exertion. The LLS was higher in those with a Borg RPE score ≥ 15 both following exercise (mean LLS 2.6 vs. 1.7) and at rest the following day (mean LLS 2.7 vs. 1.7). Heart rate was higher in those with high Borg RPE scores (80 vs. 87) and oxygen saturations lower at rest (86 vs. 83) the following morning. Discussion: This data lends weight to the advice of moderate exertion during a trek to HA and suggests that reducing perceived exertion may reduce AMS.

Our objective was to evaluate the utility of the natriuretic peptides BNP (brain natriuretic peptide) and NT-proBNP as markers of pulmonary artery systolic pressure (PASP) in trekkers ascending to high altitude (HA). 20 participants had BNP and NT-proBNP assayed and simultaneous echocardiographic assessment of PASP performed during a trek to 5150 m. PASP increased significantly (p=0.006) with ascent from 24+/-4 to 39+/-11 mm Hg at 5150 m. At 5150 m those with a PASP>/=40 mm Hg (n=8) (versus those with PASP<40 mm Hg) had higher post-exercise BNP (pg/ml): 54.5+/-36 vs. 13.4+/-17 (p=0.012). Their resting BNP at 5150 m was also higher: 57.3+/-43.4 vs. 12.6+/-13 (p=0.017). In those with a pathological (>/=400 pg/ml) rise in NT-proBNP at 5150 m (n=4) PASP was significantly higher: 45.9+/-7.5 vs. 32.2+/-6.2 mm Hg (p=0.015). BNP and NT-proBNP may reflect elevated PASP, a central feature of high altitude pulmonary oedema, at HA.

Intense exercise is an integral part of high altitude (HA) exposure and is linked to an increased risk of acute mountain sickness (AMS)1. Quantification of exercise intensity at HA is challenging and prone to marked inter-individual variability due to subjectivity in reporting. The Borg rating of perceived exertion (RPE) scale allows for a quantitative measure of exercise intensity2 however its relationship to heart rate (HR) during exercise at HA is not well established3. This study aimed to assess the relationship between HR and Borg RPE scale during exercise at HA. Seventeen healthy and physically active adults (11 male, 6 female), with median age 32 (range 25-54 years) were studied at terrestrial HA during unacclimatised ascent from 1180 to 5140m over 11 separate trekking days. Subjects were issued with individual Polar watches (RS400) which were linked to a Polar (H1) chest worn heart rate monitor and set to record continuously throughout the trek. The overall RPE was quantified using Borg 6-20 scale and was collected at random intervals during the trek. HR data was subsequently analysed and paired to the corresponding RPE, although HR between these intervals was not analysed. 419 paired observations of HR and RPE were recorded. The median RPE score was 10.0 (IQR 9.0-11.0) with an average HR (mean ± SD) of 110 ± 18bpm. There was a significant increase in HR with increasing RPE category: 100 ± 17bpm (RPE 6-9), 114 ± 14bpm (RPE 10-13) and 131 ± 12bpm (RPE >14; ANOVA p <0.0001). HR and RPE significantly correlated across all altitudes (Spearman’s rho =0 49: 95% CI 0.41-0.56: p<0.001) and at each altitude range rho=0.44 at 1200-3500m (n=221; p<0.01,), 0.34 at 3600-4600m (n=36; p=0.043) and 0.57 at 4600-5140m (n=162; p<0.01). The Borg 6-20 RPE scale significantly correlated with HR at HA and appears to be an effective method for monitoring exercise intensity at HA. RPE monitoring should be considered as a useful prevention and risk stratification tool for the development of AMS.

PURPOSE: Heat stress exacerbates post-exercise hypotension (PEH) and cardiovascular disturbances from elevated body temperature may contribute to exertion-related incapacity. Mast cell degranulation and muscle mass are possible modifiers, though these hypotheses lack practical evidence. This study had three aims: (1) to characterise pre-post-responses in histamine and mast cell tryptase (MCT), (2) to investigate relationships between whole body muscle mass (WBMM) and changes in blood pressure post-marathon, (3) to identify any differences in incapacitated runners. METHODS: 24 recreational runners were recruited and successfully completed the 2019 Brighton Marathon (COMPLETION). WBMM was measured at baseline. A further eight participants were recruited from incapacitated runners (COLLAPSE). Histamine, MCT, blood pressure, heart rate, body temperature and echocardiographic measures were taken before and after exercise (COMPLETION) and upon incapacitation (COLLAPSE). RESULTS: In completion, MCT increased by nearly 50% from baseline (p = 0.0049), whereas histamine and body temperature did not vary (p > 0.946). Systolic (SBP), diastolic (DBP) and mean (MAP) arterial blood pressures and systemic vascular resistance (SVR) declined (p < 0.019). WBMM negatively correlated with Δ SBP (r = - 0.43, p = 0.046). For collapse versus completion, there were significant elevations in MCT (1.77 ± 0.25 μg/L vs 1.18 ± 0.43 μg/L, p = 0.001) and body temperature (39.8 ± 1.3 °C vs 36.2 ± 0.8 °C, p < 0.0001) with a non-significant rise in histamine (9.6 ± 17.9 μg/L vs 13.7 ± 33.9 μg/L, p = 0.107) and significantly lower MAP, DBP and SVR (p < 0.033). CONCLUSION: These data support the hypothesis that mast cell degranulation is a vasodilatory mechanism underlying PEH and exercise associated collapse. The magnitude of PEH is inversely proportional to the muscle mass and enhanced by concomitant body heating.

BACKGROUND: Medical personnel may find it challenging to distinguish severe Exertional Heat Illness (EHI), with attendant risks of organ-injury and longer-term sequalae, from lesser forms of incapacity associated with strenuous physical exertion. Early evidence for injury at point-of-incapacity could aid the development and application of targeted interventions to improve outcomes. We aimed to investigate whether biomarker surrogates for end-organ damage sampled at point-of-care (POC) could discriminate EHI versus successful marathon performance. METHODS: Eight runners diagnosed as EHI cases upon reception to medical treatment facilities and 30 successful finishers of the same cool weather marathon (ambient temperature 8 rising to 12 ºC) were recruited. Emerging clinical markers associated with injury affecting the brain (neuron specific enolase, NSE; S100 calcium-binding protein B, S100β) and renal system (cystatin C, cysC; kidney-injury molecule-1, KIM-1; neutrophil gelatinase-associated lipocalin, NGAL), plus copeptin as a surrogate for fluid-regulatory stress, were sampled in blood upon marathon collapse/completion, as well as beforehand at rest (successful finishers only). RESULTS: Versus successful finishers, EHI showed significantly higher NSE (10.33 [6.37, 20.00] vs. 3.17 [2.71, 3.92] ug.L-1, P<0.0001), cysC (1.48 [1.10, 1.67] vs. 1.10 [0.95, 1.21] mg.L-1, P = 0.0092) and copeptin (339.4 [77.0, 943] vs. 18.7 [7.1, 67.9] pmol.L-1, P = 0.0050). Discrimination of EHI by ROC (Area-Under-the-Curve) showed performance that was outstanding for NSE (0.97, P<0.0001) and excellent for copeptin (AUC = 0.83, P = 0.0066). CONCLUSIONS: As novel biomarker candidates for EHI outcomes in cool-weather endurance exercise, early elevations in NSE and copeptin provided sufficient discrimination to suggest utility at point-of-incapacity. Further investigation is warranted in patients exposed to greater thermal insult, followed up over a more extended period.

Introduction: High-altitude (HA) exposure affects heart rate variability (HRV) and has been inconsistently linked to acute mountain sickness (AMS). The influence of increasing HA exposure on ultra-short HRV and its relationship to gold standard HRV measures at HA has not been examined. Methods: This was a prospective observational study of adults aged ≥ 18 years undertaking a HA trek in the Dhaulagiri region of the Himalayas. Cardiac inter-beatintervals were obtained from a 10-s recording of supra-systolic blood pressure (Uscom BP+ device) immediately followed by 300 s single lead ECG recording (CheckMyHeart device). HRV was measured using the RMSSD (root mean square of successive differences of NN intervals) at sea level (SL) in the United Kingdom and at 3,619, 4,600, and 5,140 m at HA. Oxygen saturations (SpO2) were measured using finger-based pulse oximetry. The level of agreement between the 10 and 300 s RMSSD values were examined using a modified Bland–Altman relative-difference analysis. Results: Overall, 89 participants aged 32.2 ± 8.8 years (range 18–56) were included of which 70.8% were men. HA exposure (SL vs. 3,619 m) was associated with an initial increase in both 10 s (45.0 [31.0–82.0]) vs. 58.0 [33.0–119.0] ms) and 300 s (45.67 [33.24–70.32] vs. 56.48 [36.98–102.0] ms) in RMSSD. Thereafter at 4,600 and 5,140 m both 10 and 300 s RMSSD values were significantly lower than SL. From a total of 317 paired HRV measures the 10 and 300 s RMSSD measures were moderately correlated (Spearman = 0.66; 95% CI: 0.59–0.72; p < 0.0001). The median difference (bias) in RMSSD values (300 s − 10 s) was −2.3 ms with a lower and upper limit of agreement of −107.5 and 88.61 ms, respectively with no differences with altitude. Overall, 293/317 (92.4%) of all paired HRV values fell within the 95% CI limits of agreement. Neither HRV method was predictive of AMS. Conclusion: Increasing HA affects ultra-short HRV in a similar manner to gold-standard 300 s. Ultra-short HRV has a moderate agreement with 300 s measurements. HRV did not predict AMS.

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.

The binding of high-mobility group box-1 (HMGB-1) to the membrane receptor for advanced glycation end-products (mRAGE) is a key early mediator of non-infectious inflammation and its triggers include ischaemia/hypoxia. The effects of acute hypoxia on soluble RAGE (sRAGE) are unknown. Fourteen healthy adults (50% women; 26.6±3.8 years) were assessed at baseline normoxia (T0), followed by four time-points (T90, 95, 100 and 180 minutes) over three hours of continuous normobaric hypoxia (NH, 4450m equivalent) and again 60 minutes after return to normoxia (T240). A 5-minute exercise step-test was performed during NH at T90. Plasma concentrations of HMGB-1, sRAGE VCAM-1, ICAM-1, VEGF IL-8 and IL-13 were measured using venous blood. Arterial and tissue oxygen saturations were measured using pulse oximetry (SpO2) and near-infrared spectroscopy (StO2) respectively. NH led to a significant reduction in SpO2, StO2, sRAGE and VEGF, which was compounded by exercise, before increasing to baseline values with normoxic restoration (T240). NH-Exercise led to a paired increase in HMGB-1. sRAGE inversely correlated with HMGB-1 (r=-0.32; p=0.006), heart rate (r=-0.43; p=0.004) but was not linked to SpO2 or StO2. In conclusion short-term NH leads to a fall in sRAGE and VEGF concentrations with a transient rise post NH-exercise in HMGB-1.

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.

Introduction: There is evidence that intermittent hypoxic exposure (IHE) may improve high altitude (HA) performance. In this study, the effects of short-term IHE through voluntary apnea training on HA-related symptoms, including acute mountain sickness (AMS), were examined for the first time. Methods: Forty healthy adults were randomized to a self-administered apnea training (n = 19) or control (n = 21 no apnea training) group before ascent to an altitude of 5100 m in the Himalayas over 14 days. The apnea training was conducted at sea level (SL) and consisted of five breath holds per day in week 1, seven in week 2, followed by 10 per day from weeks 3 to 6 and until HA exposure. Saturation of arterial oxygen (SpO2), heart rate, sleep quality (Insomnia Severity Index [ISI]), rating of perceived exertion (RPE), blood pressure, and Lake Louise scores were measured at SL (in the United Kingdom) and at HA at 1400, 2700, 3400–3700, 4050–4200, 4800, and 5100–5200 m. Anxiety (Generalized Anxiety Disorder-7 [GAD-7]) scores were examined at SL, 1400, and 5100–5200 m. Results: Apnea training led to a significant increase in the mean longest breath-hold times from baseline (80.42 ± 32.49 [median 87.00] seconds) to the end of week 6 (107.02 ± 43.65 [113.00] seconds), respectively (p = 0.009). There was no significant difference in the prevalence of AMS (8/19 = 42.1% vs. 11/21 = 52.4%; RR 0.80; 95% confidence interval 0.41–1.57: p = 0.80) or in GAD-7, ISI and RPE, SpO2, heart rate, or blood pressure among the apnea versus control groups, respectively, at HA. Conclusions: Apnea training does not lessen HA-related symptoms in healthy adults traveling up to 5200 m. Larger studies using more challenging apnea protocols and at higher altitudes should be considered.

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.

Acute Mountain Sickness (AMS) is a common clinical challenge at high altitude (HA). A point-of-care biochemical marker for AMS could have widespread utility. Neutrophil gelatinase-associated lipocalin (NGAL) rises in response to renal injury, inflammation and oxidative stress. We investigated whether NGAL rises with HA and if this rise was related to AMS, hypoxia or exercise. NGAL was assayed in a cohort (n = 22) undertaking 6 hours exercise at near sea-level (SL); a cohort (n = 14) during 3 hours of normobaric hypoxia (FiO2 11.6%) and on two trekking expeditions (n = 52) to over 5000 m. NGAL did not change with exercise at SL or following normobaric hypoxia. During the trekking expeditions NGAL levels (ng/ml, mean ± sd, range) rose significantly (P < 0.001) from 68 ± 14 (60-102) at 1300 m to 183 ± 107 (65-519); 143 ± 66 (60-315) and 150 ± 71 (60-357) at 3400 m, 4270 m and 5150 m respectively. At 5150 m there was a significant difference in NGAL between those with severe AMS (n = 7), mild AMS (n = 16) or no AMS (n = 23): 201 ± 34 versus 171 ± 19 versus 124 ± 12 respectively (P = 0.009 for severe versus no AMS; P = 0.026 for mild versus no AMS). In summary, NGAL rises in response to prolonged hypobaric hypoxia and demonstrates a relationship to the presence and severity of AMS.

Purpose-This study sought to explore, for the first time, the effects of repeated maximal static and dynamic apnoeic attempts on the physiological milieu by assessing cerebral, cardiac and striatal muscle stress-related biomarkers in a group of elite breath-hold divers (EBHD). Methods-Sixteen healthy males were recruited (EBHD=8; controls=8). On two separate occasions EBHD performed two sets of five repeated maximal static apnoeas (STA) or five repeated maximal dynamic apnoeas (DYN). Controls performed a static eupnoeic protocol to negate any effects of water immersion and diurnal variation on haematology (CTL). Venous blood samples were drawn at 30, 90, and 180-mins after each protocol to determine S100β, neuron-specific enolase (NSE), myoglobin and high sensitivity cardiac troponin T (hscTNT) concentrations. Results-S100β and myoglobin concentrations were elevated following both apnoeic interventions (p<0.001; p≤0.028, respectively) but not after CTL (p≥0.348). S100β increased from baseline (0.024±0.005µg/L) at 30 (STA, +149%, p<0.001; DYN, +166%, p<0.001) and 90 mins (STA, +129%, p<0.001; DYN, +132%, p=0.008) following the last apnoeic repetition. Myoglobin was higher than baseline (22.3±2.7ng/mL) at 30 (+42%, p=0.04), 90 (+64%, p<0.001) and 180 mins (+49%, p=0.013) post-STA and at 90 mins (+63%, p=0.016) post-DYN. Post-apnoeic S100β and myoglobin concentrations were higher than CTL (STA, p<0.001; DYN, p≤0.004). NSE and hscTNT did not change from basal concentrations after the apnoeic (p≥0.146) nor following the eupnoeic (p≥0.553) intervention. from basal concentrations after the apnoeic (p≥0.146) nor following the eupnoeic (p≥0.553) intervention. Conclusions-This study suggests that a series of repeated maximal static and dynamic apnoeas transiently disrupt the blood-brain barrier and instigate muscle injury but do not induce neuronal-parenchymal damage or myocardial damage.

This study investigated how exercise and heat stress may affect the neurobiomarkers Glial fibrillary acid protein (GFAP) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Both are assayed in plasma by a semiquantitative cartridge-based system (Abbott iSTAT Alinity®) that is FDA-approved to ‘rule in’ mild Traumatic Brain Injury (mTBI) following head trauma. We hypothesised that healthy volunteers would show unchanging levels across exercise bouts differing by mode, duration, environmental conditions and heat acclimation (HA) status. We further investigated the frequency with which the manufacturer’s decision thresholds for suspecting more severe brain injury might be breached by neurobiomarker response to exercise-heat stress. Twenty endurance trained volunteers (five females, 15 males; age 30 ± 7 years, VO2max 56 ± 10 ml.kg.min-1) were sampled for blood before and after cycle ergometry in a heated chamber (45 min at 2.0 to 2.5 W.kg-1 in 32°C), at un-adapted baseline and again following eight days of HA or control activity (combined exercise-hot water immersion regimen, n=10 vs. matched temperate exercise, n=10). Separately, 50 unacclimatised runners (nine females, 39 males; age 31 ± 5 years) gave blood at rested baseline and after running the Brighton marathon 2022 (finishing time 3 h 59 min ± 49 min; peak ambient temperature 11 °C). In each study, body core temperature (Tc) was recorded (rectal thermistor vs BodyCap® telemetry pill), change in body mass (BM) was measured and blood collected and centrifuged within 30 min post-exposure. A single accredited laboratory received frozen samples for analysis of thawed plasma by both benchtop ELISA (BENCH) and iSTAT Alinity (CARTRIDGE). Cycling in the heat resulted in significant (P<0.05) overall ΔBM (–1.41 ± 0.39 kg) and ΔTc (+1.5 ± 0.4 °C). No change in neurobiomarkers was observed by BENCH or CARTRIDGE, neither did HA status influence levels (P=0.94) despite reduced Tc and increased sweat losses. CARTRIDGE decision thresholds for GFAP (30 pg.mL-1) and UCHL1 (360 30 pg.mL-1) were not exceeded. In the marathon, significant ΔBM (-1.39 ± 1.72 kg) and ΔTc (+1.8 ± 0.6 °C) were observed. Versus baseline, GFAP did not vary, whereas UCH-L1 increased for both BENCH (64.9 [39.1, 578.1] vs 91.0 [39.1, 570.0] pg.mL-1, P=0.0018) and CARTRIDGE (200 [200, 200] vs 448 [302.8, 756.0 pg.mL-1, P<0.0001). The CARTRIDGE decision threshold was not breached for GFAP, but was exceeded for UCHL1 in 32/50 runners (highest value 2261 pg.mL-1, reportable range 200 to 3200 pg.mL-1). In summary, neurobiomarkers used in mTBI assessment were unaffected by moderate intensity and duration cycling in the heat, with HA status having no discernible impact. However, prolonged running in cool weather conditions elevated UCHL1 above the decision threshold used in mTBI assessment. These results suggest caution in interpreting elevated UCHL1 after prolonged exercise.

Introduction. Aldosterone decreases at high altitude (HA) but the effect of hypoxia on angiotensin converting-enzyme (ACE), a key step in the renin-angiotensin-aldosterone system, is unclear. Materials and Methods. We investigated the effects of exercise and acute normobaric hypoxia (NH, ~11.0% FiO2) on nine participants and six controls undertaking the same exercise at sea-level (SL). NH exposure lasted 5 hours with 90 min of submaximal treadmill walking. Blood samples for aldosterone, ACE and cortisol were taken throughout exposure and at rest during a trek to HA (5140 m) in eight separate participants. Results. There was no difference in cortisol or aldosterone between groups pre-exercise. Aldosterone rose with exercise to a greater extent at SL than in NH (post-exercise: 700±325 vs 335±238 pmol/L, mean ± SD, p=0.044). Conversely, cortisol rose to a greater extent in NH (post-exercise: 734±165 vs 344±159 nmol/L, mean ± SD, p=0.001). There were no differences in ACE activity. During the trek to HA resting aldosterone and cortisol reduced with no change in ACE. Conclusion. Acute NH subdues the exercise-associated rise in aldosterone but stimulates cortisol, whereas prolonged exposure at HA reduces both resting aldosterone and cortisol. As ACE activity was unchanged in both environments this is not the mechanism underlying the fall in aldosterone.

Introduction: The British Service Dhaulagiri Research Expedition (BSDMRE) took place from 27th March to 31st May 2016. The expedition involved 129 personnel, with voluntary participation in 9 different study protocols. Studies were conducted in three research camps established at 3600m, 4600m and 5140m and involved taking and storing blood samples, cardiac echocardiography and investigations involving a balance plate. Research in this remote environment requires careful planning in order to provide a robust and resilient power plan. In this paper we aim to report the rationale for the choices we made in terms of power supply, the equipment used and potential military applicability. Methods: This is a descriptive account from the expedition members involved in planning and conducting the medical research. Results: Power calculations were used to determine estimates of requirement prior to the expedition. The primary sources used to generate power were internal combustion engine (via petrol fueled electric generators), and solar panels. Having been generated, power was stored using lithium-ion batteries. Special consideration was given to the storage of samples taken in the field, for which electric freezers and dry-shippers were used. All equipment used functioned well during the expedition, with the challenges of altitude, temperature, and transport all overcome due to extensive prior planning. Conclusions: Power was successfully generated, stored, and delivered during the BSDMRE, allowing extensive medical research to be undertaken. The challenges faced and overcome are directly applicable to delivering military medical care in austere environments, and lessons learned can help with the planning and delivery of future operations, training exercises, or expeditions.

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.

The purpose of this study was to assess the reliability of blood biomarkers that can signify exercise-induced heat stress in hot conditions. Fourteen males completed two heat stress tests separated by 5-7 days. Venous blood was drawn pre- and post- heat stress for the concentration of normetanephrine, metanephrine, serum osmolality, copeptin, kidney-injury molecule 1 and neutrophil gelatinase-associated lipocalin. No biomarker, except copeptin, displayed systematic trial order bias (p ≥ 0.05). Normetanephrine, copeptin and neutrophil gelatinase-associated lipocalin presented acceptable reliability (CV range: 0.9-14.3%), while greater variability was present in metanephrine, osmolality and kidney-injury molecule 1 (CV range: 28.6-43.2%). Normetanephrine exhibited the largest increase (p <0.001) in response to heat stress (trial 1 = 1048 ± 461 pmol. L-1; trial 2 = 1067 ± 408 pmol. L-1), whilst kidney-injury molecule 1 presented trivial changes (trial 1 = -4 ± 20 ng. L-1; trial 2 = 2 ± 16 ng. L-1, p >0.05). Normetanephrine, copeptin and neutrophil gelatinase-associated lipocalin demonstrated good reliability and sensitivity to an acute bout of heat stress. These biomarkers may be suitable for application in laboratory and field research to understand the efficacy of interventions that can attenuate the risk of thermal injury whilst exercising in the heat.

Heat adaption through acclimatisation or acclimation improves cardiovascular stability by maintaining cardiac output due to compensatory increases in stroke volume. The main aim of this study was to assess whether 2D transthoracic echocardiography (TTE) could be used to confirm differences in resting echocardiographic parameters, before and after active heat acclimation (HA). Thirteen male endurance trained cyclists underwent a resting blinded TTE before and after randomisation to either 5 consecutive daily exertional heat exposures of controlled hyperthermia at 32◦C with 70% relative humidity (RH) (HOT) or 5-days of exercise in temperate (21◦C with 36% RH) environmental conditions (TEMP). Measures of HA included heart rate, gastrointestinal temperature, skin temperature, sweat loss, total non-urinary fluid loss (TNUFL), plasma volume and participant’s ratings of perceived exertion (RPE). Following HA, the HOT group demonstrated increased sweat loss (p = 0.01) and TNUFL (p = 0.01) in comparison to the TEMP group with a significantly decreased RPE (p = 0.01). On TTE, post exposure, there was a significant comparative increase in the HOT group in left ventricular end diastolic volume (p = 0.029), SV (p = 0.009), left atrial volume (p = 0.005), inferior vena cava diameter (p = 0.041), and a significant difference in mean peak diastolic mitral annular velocity (e’) (p = 0.044).Cardiovascular adaptations to HA appear to be predominantly mediated by improvements in increased preload and ventricular compliance. TTE is a useful tool to demonstrate and quantify cardiac HA.

Nitrate-rich beetroot juice (BRJ) increases plasma nitrite concentrations, lowers the oxygen cost (V̇O2) of steady-state exercise and improves exercise performance in sedentary and moderately-trained, but rarely in well-trained individuals exercising at sea-level. BRJ supplementation may be more effective in a hypoxic environment, where the reduction of nitrite into nitric oxide (NO) is potentiated, such that well-trained and less well-trained individuals may derive a similar ergogenic effect. We conducted a randomised, counterbalanced, double-blind placebo controlled trial to determine the effects of BRJ on treadmill running performance in moderate normobaric hypoxia (equivalent to 2500 m altitude) in participants with a range of aerobic fitness levels. Twelve healthy males (V̇O2max ranging from 47.1 to 76.8 ml kg(-1)·min(-1)) ingested 138 ml concentrated BRJ (∼15.2 mmol nitrate) or a nitrate-deplete placebo (PLA) (∼0.2 mmol nitrate). Three hours later, participants completed steady-state moderate intensity running, and a 1500 m time-trial (TT) in a normobaric hypoxic chamber (FIO2 ∼15%). Plasma nitrite concentrations were significantly greater following BRJ versus PLA 1 h post supplementation, and remained higher in BRJ throughout the testing session (p < 0.01). Average V̇O2 was significantly lower (BRJ: 18.4 ± 2.0, PLA: 20.4 ± 12.6 ml kg(-1)·min(-1); p = 0.002), whilst arterial oxygen saturation (SpO2) was significantly greater (BRJ: 88.4 ± 2.7, PLA: 86.5 ± 3.3%; p < 0.001) following BRJ. BRJ improved TT performance in all 12 participants by an average of 3.2% (BRJ: 331.1 ± 45.3 vs. PL: 341.9 ± 46.1 s; p < 0.001). There was no apparent relationship between aerobic fitness and the improvement in performance following BRJ (r(2) = 0.05, p > 0.05). These findings suggests that a high nitrate dose in the form of a BRJ supplement may improve running performance in individuals with a range of aerobic fitness levels conducting moderate and high-intensity exercise in a normobaric hypoxic environment.

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: Dietary nitrate supplementation increases nitric oxide (NO) bioavailability, and has been shown to improve exercise performance in hypoxia (i.e. a low-oxygen environment) in some (e.g. Muggeridge et al., 2014, Med Sci Sports Exerc, 46:143-150) but not all (e.g. Arnold et al., 2015, Appl. Physiol. Nutr. Metab., 40: 590-595) studies. The precise conditions under which nitrate consumption is ergogenic remains to be established. The aim of this study was to assess the effects of nitrate-rich beetroot juice on the physiological response to steady-state exercise, and 1500 m time-trial (TT) performance in trained runners exercising in moderate normobaric hypoxia (equivalent to 2500 m altitude). METHODS: Six trained runners (age: 23.3 ± 1.9 years; sea-level V̇O2max: 64.6 ± 10.2 ml·kg-1·min-1; altitude V̇O2max: 53.1 ± 7.9 ml·kg-1·min-1) visited the laboratory on five separate occasions, including incremental running tests in normoxia (1) and hypoxia (2) to determine V̇O2max; a familiarization trial (3); and two performance trials (4 + 5). On the morning of the performance trials, participants consumed 138 ml concentrated nitrate-rich (reported to contain ~12.5 mmol nitrate) or a nitrate-deplete (~0 mmol nitrate) beetroot juice. Three hours later, participants completed two, 15 minute steady-state bouts of running at 45 and 65 % of altitude V̇O2max, respectively, and a 1500 m TT in a normobaric hypoxic chamber (PIO2 107.5 mmHg, FIO2 ~15 %). Exhaled NO was measured pre-supplementation, pre-hypoxic exposure, pre-exercise and post-TT. VO2 was monitored during steady-state exercise, and arterial oxygen saturation (SaO2) was monitored pre-hypoxic exposure, pre-exercise, during steady-state exercise, and post-TT. RESULTS: Nitrate supplementation significantly elevated exhaled NO versus placebo (Placebo: 20.5 ± 20.5 vs. Nitrate: 45.5 ± 30.6 p.p.b., p = 0.044). Average VO2 was significantly lower during steady-state exercise (Placebo: 27.6 ± 5.4 vs. Nitrate: 25.0 ± 4.5 ml·kg-1·min-1, p = 0.029), whilst average SaO2 was significantly greater (Placebo: 85.9 ± 2.6 vs. Nitrate: 88.2 ± 2.8 %, p = 0.02) with nitrate ingestion. TT performance was significantly faster (Placebo: 346.8 ± 43.3 s vs. Nitrate: 335.1 ± 42.3 s, p = 0.01, Cohen’s d = 0.272) following nitrate supplementation. CONCLUSION: Dietary nitrate supplementation increases exhaled NO, reduces steady-state VO2, and elevates SaO2 during steady-state exercise, and results in a small (3.4 %) but significant improvement in 1500 m TT performance relative to a placebo. Therefore, nitrate-rich beetroot juice may represent a viable ergogenic aid for enhancing 1500 m running performance in trained athletes exercising in moderate normobaric hypoxia.

Purpose: Exposure to high altitude has been shown to enhance both glucose and lipid utilization depending on experimental protocol. In addition, high and low blood glucose levels have been reported at high altitude. We hypothesized that gradual ascent to high altitude results in changes in glucose levels in healthy young adults. Methods: 25 adult volunteers, split into two teams, took part in the British Services Dhaulagiri Medical Research Expedition completing 14 days of trekking around the Dhaulagiri circuit in Nepal reaching a peak altitude of 5300m on Day 11 of the trek. Participants wore blinded continuous glucose monitors (CGM) throughout. Blood samples for c-peptide, pro-insulin and triacylglycerides were taken at sea level (UK) and in acclimatisation camps at 3600m, 4650m and 5120m. Energy intake was determined from food diaries. Results: There was no difference in time spent in hypoglycemia stratified by altitude. Nocturnal CGM readings (22.00-06.00 hrs) were chosen to reduce the short-term impact of physical activity and food intake and showed a significant (p<0.0001) increase at 3600m (5.53±0.22mmol/L), 4650m (4.77±0.30mmol/L) and 5120m (4.78±0.24mmol/L) compared to baseline altitude 1100m (vs 4.61±0.25mmol/L). Energy intake did not differ by altitude. Insulin resistance and B-cell function, calculated by homeostatic model assessment, was reduced at 3600m compared to sea level. Conclusions: We observed a significant increase in nocturnal CGM glucose at 3600m and above despite gradual ascent from 1100m. Taken with the changes in insulin resistance and B-cell function, it is possible that the stress response to high altitude dominates exercise enhanced insulin sensitivity, resulting in relative hyperglycemia.

There is evidence to suggest that high altitude (HA) exposure leads to a fall in heart rate variability (HRV) that is linked to the development of acute mountain sickness (AMS). The effects of sex on changes in HRV at HA and its relationship to AMS are unknown. HRV (5-minute single lead ECG) was measured in 63 healthy adults (41 men and 22 women) aged 18-56 years at sea level (SL) and during a HA trek at 3619m, 4600m and 5140m respectively. The main effects of altitude (SL, 3619, 4600 and 5140m) and sex (men vs women) and their potential interaction were assessed using a Factorial Repeated Measures ANOVA. Logistic regression analyses were performed to assess the ability of HRV to predict AMS. Men and women were of similar age (31.2 ±9.3 vs 31.7±7.5 years), ethnicity, body and mass index. There was main effect for altitude on heart rate, SDNN (standard deviation [SD] of normal-to-normal [NN] intervals), RMSSD (Root mean square of successive differences), NN50 (number of pairs of successive NNs differing by >50 ms), pNN50 (NN50 / total number of NNs), very low frequency (VLF), low frequency (LF), high frequency (HF) and total power (TP). The most consistent effect on post hoc analysis was reduction in these HRV measures between 3619 and 5140m at HA. Heart rate was significantly lower and SDNN, RMSSD, LF, HF and TP were higher in men compared with women at HA. There was no interaction between sex and altitude for any of the HRV indices measured. HRV was not predictive of AMS development. Increasing HA leads to a reduction in HRV. Significant differences between men and women emerge at HA. HRV was not predictive of AMS.

Exposure to altitude results in multiple physiological consequences. These include, but are not limited to, a reduced maximal oxygen consumption, drop in arterial oxygen saturation, and increase in muscle metabolic perturbations at a fixed sub-maximal work rate. Exercise capacity during fixed work rate or incremental exercise and time-trial performance are also impaired at altitude relative to sea-level. Recently, dietary nitrate (NO3-) supplementation has attracted considerable interest as a nutritional aid during altitude exposure. In this review, we summarise and critically evaluate the physiological and performance effects of dietary NO3- supplementation during exposure to simulated and terrestrial altitude. Previous investigations at simulated altitude indicate that NO3- supplementation may reduce the oxygen cost of exercise, elevate arterial and tissue oxygen saturation, improve muscle metabolic function, and enhance exercise capacity/ performance. Conversely, current evidence suggests that NO3- supplementation does not augment the training response at simulated altitude. Few studies have evaluated the effects of NO3- at terrestrial altitude. Current evidence indicates potential improvements in endothelial function at terrestrial altitude following NO3- supplementation. No effects of NO3- supplementation have been observed on oxygen consumption or arterial oxygen saturation at terrestrial altitude, although further research is warranted. Limitations of the present body of literature are discussed, and directions for future research are provided.

Introduction Heat adaptation is protective against heat illness; however, its role in heat syncope, due to reflex mechanisms, has not been conclusively established. The aim of this study was to evaluate if heat acclimation (HA) was protective against heat syncope and to ascertain underlying physiological mechanisms. Methods Twenty (15 males, 5 females) endurance-trained athletes were randomized to either 8 d of mixed active and passive HA (HEAT) or climatically temperate exercise (CONTROL). Before, and after, the interventions participants underwent a head up tilt (HUT) with graded lower body negative pressure (LBNP), in a thermal chamber (32.0 ± 0.3°C), continued until presyncope with measurement of cardiovascular parameters. Heat stress tests (HST) were performed to determine physiological and perceptual measures of HA. Results There was a significant increase in orthostatic tolerance (OT), as measured by HUT/LBNP, in the HEAT group (preintervention; 28 ± 9 min, postintervention; 40 ± 7 min) compared with CONTROL (preintervention; 30 ± 8 mins, postintervention; 33 ± 5 min) (P = 0.01). Heat acclimation resulted in a significantly reduced peak and mean rectal and skin temperature (P < 0.01), peak heat rate (P < 0.003), thermal comfort (P < 0.04), and rating of perceived exertion (P < 0.02) during HST. There was a significantly increased plasma volume (PV) in the HEAT group in comparison to CONTROL (P = 0.03). Conclusions Heat acclimation causes improvements in OT and is likely to be beneficial in patients with heat exacerbated reflex syncope. Heat acclimation–mediated PV expansion is a potential physiological mechanism underlying improved OT.

The purpose of this study was to assess the reliability of a pre-loaded 1500 m treadmill time-trial, conducted in moderate normobaric hypoxia. Eight trained runners/ triathletes (24 ± 3 years, 73.2 ± 8.1 kg, 182.5 ± 6.5 cm, altitude specific V̇O2max: 52.9 ± 5.5 ml·kg-1·min-1) completed three trials (the first as a familiarisation), involving two, 15 minute running bouts at 45 % and 65 % V̇O2max, respectively, and a 1500 m time-trial in moderate normobaric hypoxia equivalent to a simulated altitude of 2500 m (FiO2 ~ 15 %). Heart rate, arterial oxygen saturation, skeletal muscle and cerebral tissue oxygenation (StO2), expired gas (V̇O2 and V̇CO2), and ratings of perceived exertion were monitored. Running performance (Trial 1: 352.7 ± 40; Trial 2: 353.9 ± 38.2 s) demonstrated a low CV (0.9 %) and high ICC (1). All physiological variables demonstrated a global CV ≤ 4.2 %, and ICC ≥ 0.87, with the exception of muscle (CV 10.4 %; ICC 0.70) and cerebral (CV 4.1 %; ICC 0.82) StO2. These data demonstrate good reliability of the majority of physiological variables, and indicate that a pre-loaded 1500 m time-trial conducted in moderate normobaric hypoxia is a highly reliable test of performance.

Purpose This study evaluated the effects of dietary nitrate (NO3-) supplementation on physiological functioning and exercise performance in trained runners/ triathletes conducting short and longer distance treadmill running time-trials (TT). Method Eight trained male runners or triathletes completed four exercise performance tests comprising a 10 minute warm up followed by either a 1500 m or 10,000 m treadmill TT. Exercise performance tests were preceded 3 hours before the exercise by supplementation with either 140 ml concentrated nitrate-rich (~ 12.5 mmol nitrate) (BRJ) or nitrate-deplete (~ 0.01 mmol nitrate) (PLA) beetroot juice. Results BRJ supplementation significantly elevated plasma [NO2-] (P < 0.05). Resting blood pressure and exercise V̇O2 were not significantly different between BRJ and PLA (P > 0.05). However, post-exercise blood [lactate] was significantly greater in BRJ following the 1500 m TT (6.6 ± 1.2 vs. 6.1 ± 1.5 mM; P < 0.05), but not significantly different between conditions in the 10,000 m TT (P > 0.05). Performance in the 1500 m TT was significantly faster in BRJ versus PLA (319.6 ± 36.2 vs. 325.7 ± 38.8 s; P < 0.05). Conversely, there was no significant difference in 10,000 m TT performance between conditions (2643.1 ± 324. 1 vs. 2649.9 ± 319.8 s, P > 0.05). Conclusion Acute BRJ supplementation significantly enhanced 1500 m but not 10,000 m TT performance. These findings suggest that BRJ might be ergogenic during shorter-distance TTs which allow for a high work rate, but not during longer-distance TTs, completed at a lower work rate.

Central arterial systolic blood pressure (SBP) and arterial stiffness are known to be better predictors of adverse cardiovascular outcomes than brachial SBP. The effect of progressive high altitude (HA) on these parameters has not been examined. Ninety healthy adults were included. Central BP and the augmentation index (AI) were measured at the level of the brachial artery (Uscom BP + device) at <200 m and at 3619, 4600 and 5140 m. The average age of the subjects (70% men) were 32.2±8.7 years. Compared with central arterial pressures, brachial SBP (+8.1±6.4 mm Hg; P<0.0001) and pulse pressure (+10.9±6.6 mm Hg; P<0.0001) were significantly higher and brachial diastolic BP was lower (-2.8±1.6 mm Hg; P<0.0001). Compared with <200 m, HA led to a significant increase in brachial and central SBP. Central SBP correlated with AI (r=0.50; 95% confidence interval (CI): 0.41-0.58; P<0.0001) and age (r=0.32; 95% CI: 21-0.41; P<0.001). AI positively correlated with age (r=0.39; P<0.001) and inversely with subject height (r=-0.22; P<0.0001), weight (r=-0.19; P=0.006) and heart rate (r=-0.49; P<0.0001). There was no relationship between acute mountain sickness scores (Lake Louis Scoring System (LLS)) and AI or central BP. The independent predictors of central SBP were male sex (coefficient, t=4.7; P<0.0001), age (t=3.6; P=0.004) and AI (t=7.5; P<0.0001; overall r 2 =0.40; P<0.0001). Subject height (t=2.4; P=0.02), age (7.4; P<0.0001) and heart rate (t=11.4; P<0.0001) were the only independent predictors of AI (overall r 2 =0.43; P<0.0001). Central BP and AI significantly increase at HA. This rise was influenced by subject-related factors and heart rate but not independently by altitude, LLS or SpO 2.

Postural control and joint position sense are essential for safely undertaking leisure and professional activities, particularly at high altitude. We tested whether exposure to a 12-day trek with a gradual ascent to high altitude impairs postural control and joint position sense. This was a repeated measures observational study of 12 military service personnel (28±4 years). Postural control (sway velocity measured by a portable force platform) during standing balance, a Sharpened Romberg Test and knee joint position sense were measured, in England (113m elevation) and at 3 research camps (3619m, 4600m and 5140m) on a 12-day high altitude trek in the Dhaulagiri region of Nepal. Pulse oximetry, and Lake Louise scores were also recorded on the morning and evening of each trek day. Data were compared between altitudes and relationships between pulse oximetry, Lake Louise score, and sway velocity were explored. Total sway velocity during standing balance with eyes open (p = 0.003, d = 1.9) and during Sharpened Romberg test with eyes open (p = 0.007, d = 1.6) was significantly greater at altitudes of 3619m and 5140m when compared with sea level. Anterior-posterior sway velocity during standing balance with eyes open was also significantly greater at altitudes of 3619m and 5140m when compared with sea level (p = 0.001, d = 1.9). Knee joint position sense was not altered at higher altitudes. There were no significant correlations between Lake Louise scores, pulse oximetry and postural sway. Despite a gradual ascent profile, exposure to 3619 m was associated with impairments in postural control without impairment in knee joint position sense. Importantly, these impairments did not worsen at higher altitudes of 4600 m or 5140 m. The present findings should be considered during future trekking expeditions when developing training strategies targeted to manage impairments in postural control that occur with increasing altitude.

The purpose of this study was to investigate changes in postural control and knee joint position sense (KJPS)during a trek to high altitude. Postural control during standing balance and KJPS were measured in 12 participants at sea-level, 3619m, 4600m and 5140m. Total (p = 0.003, d=1.9) and anterior-posterior sway velocity (p= 0.001, d=1.9) during standing balance with eyes open velocity was significantly greater at altitudes of 3619m and 5140m when compared with sea level. Despite a gradual ascent profile, exposure to 3619 m was associated with impairments in postural control. Importantly, these impairments did not worsen at higher altitudes. The present findings should be considered during future trekking expeditions when considering specific strategies to manage impairments in postural control that occur with increasing altitude.

The purpose of this study was to investigate changes in postural control and knee joint position sense (KJPS) during a trek to high altitude. Postural control during standing balance and KJPS were measured in 12 participants at sea-level, 3619m, 4600m and 5140m. Total (p = 0.003, d=1.9) and anterior-posterior sway velocity (p= 0.001, d=1.9) during standing balance with eyes open velocity was significantly greater at altitudes of 3619m and 5140m when compared with sea level. Despite a gradual ascent profile, exposure to 3619 m was associated with impairments in postural control. Importantly, these impairments did not worsen at higher altitudes. The present findings should be considered during future trekking expeditions when considering specific strategies to manage impairments in postural control that occur with increasing altitude.

Purpose To investigate whether there is a differential response at rest and following exercise to conditions of genuine high altitude (GHA), normobaric hypoxia (NH), hypobaric hypoxia (HH) and normobaric normoxia (NN). Method Markers of sympathoadrenal and adrenocortical function (plasma normetanephrine [PNORMET], metanephrine [PMET], cortisol), myocardial injury (highly sensitive cardiac troponin T [hscTnT]) and function (N-terminal brain natriuretic peptide [NT-proBNP]) were evaluated at rest and with exercise under NN, at 3375 m in the Alps (GHA) and at equivalent simulated altitude under NH and HH. Participants cycled for 2 hours {15 minute warm-up, 105 minutes at 55% Wmax (maximal workload)} with venous blood samples taken prior (T0), immediately following (T120) and 2 hours post-exercise (T240). Results Exercise in the three hypoxic environments produced a similar pattern of response with the only difference between environments being in relation to PNORMET. Exercise in NN only induced a rise in PNORMET and PMET. Conclusion Biochemical markers that reflect sympathoadrenal, adrenocortical and myocardial responses to physiological stress demonstrate significant differences in the response to exercise under conditions of normoxia versus hypoxia while NH and HH appear to induce broadly similar responses to GHA and may therefore be reasonable surrogates.

Purpose: This study compared the co-ingestion of glucose and fructose on exogenous and endogenous substrate oxidation during prolonged exercise at terrestrial high altitude (HA) versus sea level, in women. Method: Five women completed two bouts of cycling at the same relative workload (55% Wmax) for 120 minutes on acute exposure to HA (3375m) and at sea level (~113m). In each trial, participants ingested 1.2 g.min-1 of glucose (enriched with 13C glucose) and 0.6 g.min-1 of fructose (enriched with 13C fructose) before and every 15 minutes during exercise. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total and exogenous carbohydrate oxidation, plasma glucose oxidation and endogenous glucose oxidation derived from liver and muscle glycogen. Results: The rates and absolute contribution of exogenous carbohydrate oxidation was significantly lower at HA compared with sea level (ES>0.99, P<0.024), with the relative exogenous carbohydrate contribution approaching significance (32.6±6.1 vs. 36.0±6.1%, ES=0.56, P=0.059) during the second hour of exercise. In comparison, no significant differences were observed between HA and sea level for the relative and absolute contributions of liver glucose (3.2±1.2 vs. 3.1±0.8%, ES=0.09, P=0.635 and 5.1±1.8 vs. 5.4±1.7 grams, ES=0.19, P=0.217), and muscle glycogen (14.4±12.2% vs. 15.8±9.3%, ES=0.11, P=0.934 and 23.1±19.0 vs. 28.7±17.8 grams, ES=0.30, P=0.367). Furthermore, there was no significant difference in total fat oxidation between HA and sea level (66.3±21.4 vs. 59.6±7.7 grams, ES=0.32, P=0.557). Conclusion: In women, acute exposure to HA reduces the reliance on exogenous carbohydrate oxidation during cycling at the same relative exercise intensity.

This study compared the effects of co-ingesting glucose and fructose on exogenous and endogenous substrate oxidation during prolonged exercise at altitude and sea level, in men. Seven male British military personnel completed two bouts of cycling at the same relative workload (55% Wmax) for 120 minutes on acute exposure to altitude (3375m) and at sea level (~113m). In each trial, participants ingested 1.2 g.min-1 of glucose (enriched with 13C glucose) and 0.6 g.min-1 of fructose (enriched with 13C fructose) directly before and every 15 minutes during exercise. Indirect calorimetry and isotope ratio mass spectrometry were used to calculate fat oxidation, total and exogenous carbohydrate oxidation, plasma glucose oxidation and endogenous glucose oxidation derived from liver and muscle glycogen. Total carbohydrate oxidation during the exercise period was lower at altitude (157.7±56.3 grams) than sea level (286.5±56.2 grams, P=0.006, ES=2.28), whereas fat oxidation was higher at altitude (75.5±26.8 grams) than sea level (42.5±21.3 grams, P=0.024, ES=1.23). Peak exogenous carbohydrate oxidation was lower at altitude (1.13±0.2 g.min-1) than sea level (1.42±0.16 g.min-1, P=0.034, ES=1.33). There were no differences in rates, or absolute and relative contributions of plasma or liver glucose oxidation between conditions during the second hour of exercise. However, absolute and relative contributions of muscle glycogen during the second hour were lower at altitude (29.3±28.9 grams, 16.6±15.2%) than sea level (78.7±5.2 grams (P=0.008, ES=1.71), 37.7±13.0% (P=0.016, ES=1.45). Acute exposure to altitude reduces the reliance on muscle glycogen and increases fat oxidation during prolonged cycling in men, compared with sea level.

The British Service Dhaulagiri Research Expedition took place in March-May 2016. A total of 129 personnel took part in the expedition and were invited to consent to a variety of study protocols investigating adaptation to high altitudes and diagnosis of altitude illness. The study took place in a remote and inhospitable environment at altitudes up to 7500m. This paper gives an overview of the challenges involved, the research protocols investigated and the execution of the expedition in Nepal.

Purpose Circulating acylated ghrelin concentrations are associated with altitude-induced anorexia in laboratory environments, but have never been measured at terrestrial altitude. This study examined time course changes in appetite, energy intake, body composition, and ghrelin constituents during a high-altitude trek. Methods Twelve participants [age: 28(4) years, BMI 23.0(2.1) kg m−2] completed a 14-day trek in the Himalayas. Energy intake, appetite perceptions, body composition, and circulating acylated, des-acylated, and total ghrelin concentrations were assessed at baseline (113 m, 12 days prior to departure) and at three fixed research camps during the trek (3619 m, day 7; 4600 m, day 10; 5140 m, day 12). Results Relative to baseline, energy intake was lower at 3619 m (P = 0.038) and 5140 m (P = 0.016) and tended to be lower at 4600 m (P = 0.056). Appetite perceptions were lower at 5140 m (P = 0.027) compared with baseline. Acylated ghrelin concentrations were lower at 3619 m (P = 0.046) and 4600 m (P = 0.038), and tended to be lower at 5140 m (P = 0.070), compared with baseline. Des-acylated ghrelin concentrations did not significantly change during the trek (P = 0.177). Total ghrelin concentrations decreased from baseline to 4600 m (P = 0.045). Skinfold thickness was lower at all points during the trek compared with baseline (P ≤ 0.001) and calf girth decreased incrementally during the trek (P = 0.010). Conclusions Changes in plasma acylated and total ghrelin concentrations may contribute to the suppression of appetite and energy intake at altitude, but differences in the time course of these responses suggest that additional factors are also involved. Interventions are required to maintain appetite and energy balance during trekking at terrestrial altitudes.

Purpose: Nitric oxide (NO) bioavailability is reduced during acute altitude exposure, contributing towards the decline in physiological and cognitive function in this environment. This study evaluated the effects of nitrate (NO3-) supplementation on NO bioavailability, physiological and cognitive function, and exercise performance at moderate and very-high simulated altitude. Methods: Ten males (mean (SD): V̇O2max: 60.9 (10.1) ml·kg-1·min-1) rested and performed exercise twice at moderate (~14.0 % O2; ~3000 m) and twice at very-high (~11.7% O2; ~4300 m) simulated altitude. Participants ingested either 140 ml concentrated NO3--rich (BRJ; ~12.5 mmol NO3-) or NO3--deplete (PLA; 0.01 mmol NO3-) beetroot juice 2 hours before each trial. Participants rested for 45 minutes in normobaric hypoxia prior to completing an exercise task. Exercise comprised a 45 minute walk at 30 % V̇O2max and a 3 km time-trial (TT), both conducted on a treadmill at a 10 % gradient whilst carrying a 10 kg backpack to simulate altitude hiking. Plasma nitrite concentration ([NO2-]), peripheral oxygen saturation (SpO2), pulmonary oxygen uptake (V̇O2), muscle and cerebral oxygenation, and cognitive function were measured throughout. Results: Pre-exercise plasma [NO2-] was significantly elevated in BRJ compared with PLA (p = 0.001). Pulmonary V̇O2 was reduced (p = 0.020), and SpO2 was elevated (p = 0.005) during steady-state exercise in BRJ compared with PLA, with similar effects at both altitudes. BRJ supplementation enhanced 3 km TT performance relative to PLA by 3.8 % (1653.9 (261.3) vs. 1718.7 (213.0) s) and 4.2 % (1809.8 (262.0) vs. 1889.1 (203.9) s) at 3000 m and 4300 m, respectively (p = 0.019). Oxygenation of the gastrocnemius was elevated during the TT consequent to BRJ (p = 0.011). The number of false alarms during the Rapid Visual Information Processing Task tended to be lower with BRJ compared with PLA prior to altitude exposure (p = 0.056). Performance in all other cognitive tasks did not differ significantly between BRJ and PLA at any measurement point (p ≥ 0.141). Conclusion: This study suggests that BRJ improves physiological function and exercise performance, but not cognitive function, at simulated moderate and very-high altitude