Reliability of Biomarkers of Physiological Stress at Rest and Post-exertional Heat Stress.

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.

The effect of water temperature on orthostatic tolerance: a randomised crossover trial.

PURPOSE: Bolus water drinking, at room temperature, has been shown to improve orthostatic tolerance (OT), probably via sympathetic activation; however, it is not clear whether the temperature of the water bolus modifies the effect on OT or the cardiovascular responses to orthostatic stress. The aim of this study was to assess whether differing water temperature of the water bolus would alter time to presyncope and/or cardiovascular parameters during incremental orthostatic stress. METHODS: Fourteen participants underwent three head-up tilt (HUT) tests with graded lower body negative pressure (LBNP) continued until presyncope. Fifteen minutes prior to each HUT, participants drank a 500 mL bolus of water which was randomised, in single-blind crossover fashion, to either room temperature water (20 °C) (ROOM), ice-cold water (0-3 °C) (COLD) or warm water (45 °C) (WARM). Cardiovascular parameters were monitored continuously. RESULTS: There was no significant difference in OT in the COLD (33 ± 3 min; p = 0.3321) and WARM (32 ± 3 min; p = 0.6764) conditions in comparison to the ROOM condition (31 ± 3 min). During the HUT tests, heart rate and cardiac output were significantly reduced (p < 0.0073), with significantly increased systolic blood pressure, stroke volume, cerebral blood flow velocity and total peripheral resistance (p < 0.0054), in the COLD compared to ROOM conditions. CONCLUSIONS: In healthy controls, bolus cold water drinking results in favourable orthostatic cardiovascular responses during HUT/LBNP without significantly altering OT. Using a cold water bolus may result in additional benefits in patients with orthostatic intolerance above those conferred by bolus water at room temperature (by ameliorating orthostatic tachycardia and enhancing vascular resistance responses). Further research in patients with orthostatic intolerance is warranted.

Cerebral, cardiac and skeletal muscle stress associated with a series of static and dynamic apnoeas.

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 min after each protocol to determine S100ß, neuron-specific enolase (NSE), myoglobin, and high sensitivity cardiac troponin T (hscTNT) concentrations. RESULTS: S100ß and myoglobin concentrations were elevated following both apnoeic interventions (p < 0.001; p ≤ 0.028, respectively) but not after CTL (p ≥ 0.348). S100ß increased from baseline (0.024 ± 0.005 µg/L) at 30 (STA, +149%, p < 0.001; DYN, +166%, p < 0.001) and 90 min (STA, +129%, p < 0.001; DYN, +132%, p = 0.008) following the last apnoeic repetition. Myoglobin was higher than baseline (22.3 ± 2.7 ng/ml) at 30 (+42%, p = 0.04), 90 (+64%, p < 0.001) and 180 min (+49%, p = 0.013) post-STA and at 90 min (+63%, p = 0.016) post-DYN. Post-apnoeic S100ß 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. 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.

Reproductive and metabolic adaptation to multistressor training in women.

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.

Marching to the Beet: The effect of dietary nitrate supplementation on high altitude exercise performance and adaptation during a military trekking expedition.

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.

Echocardiographic changes following active heat acclimation.

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.

Copeptin reflects physiological strain during thermal stress.

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.

Phaeochromocytoma and ACTH-dependent cushing's syndrome: tumour crf secretion can mimic pituitary cushing's disease.

INTRODUCTION: 10% of corticotrophin (ACTH)-dependent Cushing's syndrome arises from secretion by extrapituitary tumours, with phaeochromocytoma implicated in a few cases. Ectopic secretion by phaeochromocytoma of corticotropin-releasing hormone (CRF), with secondary corticotroph hyperplasia, is even rarer, with only five cases in the literature hitherto. However, such cases may be classified as 'ectopic ACTH' due to incomplete verification. CLINICAL CASES: We describe three patients with phaeochromocytoma and ACTH-dependent Cushing's syndrome in whom biochemical cure was achieved following unilateral adrenalectomy. Although unable to access a validated CRF assay within the timeframe for sample storage, we nevertheless inferred CRF secretion in 2 of 3 cases by tumour immunostaining (positive for CRF; negative for ACTH), supported in one case by pre-operative inferior petrosal sinus sampling (IPSS) indicative of pituitary ACTH source. Both cases were characterized by rapid postoperative wean off glucocorticoids, presumed to reflect the pituitary stimulatory-effect of CRF outweighing central negative feedback inhibition by hypercortisolaemia. By contrast, the tumour excised in a third case exhibited positive immunostaining for ACTH - negative for CRF - and postoperative recovery of hypothalamic-pituitary-adrenal axis took significantly longer. DISCUSSION: Ectopic CRF production is biochemically indistinguishable from ectopic ACTH secretion, except that IPSS mimics pituitary Cushing's disease and cortisol dynamics may normalize rapidly postadrenalectomy. CRF secretion can be inferred through tumour immunohistochemistry, even if no CRF assay is available. Unrecognized phaeochromocytoma ACTH secretion may underpin some cases of cardiovascular collapse postadrenalectomy through acute hypocortisolaemia. Despite advances in phaeochromocytoma genetics since previous reports, we were unable to identify somatic DNA defects associated with either ACTH or CRF secretion.

Rating of perceived exertion and acute mountain sickness during a high-altitude trek.

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.

Improvements in Orthostatic Tolerance with Exercise Are Augmented by Heat Acclimation: A Randomized Controlled Trial.

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 effects of prolonged acute hypobaric hypoxia on novel measures of biventricular performance.

BACKGROUND: There are limited data on the effects of prolonged acute hypoxia on individual and global measures of biventricular function. AIMS: The aim of this study was to assess its effects on conventional and novel measures of biventricular function, including the recently defined E'/(A'×S') (EAS) index, obtained using pulsed-wave tissue Doppler Imaging (PWTDI) and associated blood brain natriuretic peptide (BNP) levels. METHODS: In this study, 14 healthy subjects aged 30.5 years were assessed at baseline and at >150 minutes following hypobaric hypoxia (HH) to the equivalent altitude of 4800 m for a total of 180 minutes. The combined EAS index (E'/(A' × S')) was calculated at the mitral and tricuspid annulus using data from the peak systolic (S') early (E') and late (A') diastolic filling. RESULTS: It was seen that HH increased resting heart rate (63.4 ± 8.4 vs. 85.2 ± 10.2/min; P < 0.0001), cardiac output (4.6 ± 0.7 L/min vs. 6.1 ± 1.2 L/min; P < 0.0001), peak pulmonary artery systolic pressure (PASP) (26.3 ± 2.0 mmHg vs. 37.2 ± 6.3 mmHg; P < 0.0001), and reduced SpO2 (98.5 ± 1.1 vs. 72.9 ± 8.1%; P < 0.0001). There was a significant reduction in mitral (0.19 ± 0.06 vs. 0.11 ± 0.03; P < 0.0001) and tricuspid (0.12 ± 0.04 vs. 0.09 ± 0.03; P = 0.03) EAS indices, but no change in left or right ventricular myocardial performance (Tei) indices, global left ventricular (LV) longitudinal systolic strain, BNP levels, or estimated filling pressures (E/E'). Only reducing SpO2 remained as an independent predictor of PASP on multivariate analysis (overall R(2) = 0.77; P < 0.0001). The right and LV EAS indices were significantly correlated (r = 0.45; 95% CI: 0.07-0.7; P = 0.02). CONCLUSION: The conclusion from this study was that acute prolonged HH does not adversely affect resting global biventricular function and there is evidence of linked right and LV responses.

Managing endocrine dysfunction following blast injury to the male external genitalia.

Blast injury to the external genitalia is associated with considerable morbidity, including the risk of primary hypogonadism due to insufficient testosterone. It is of the utmost importance that, prior to any testosterone replacement being commenced, serious consideration is given to sperm retrieval. The clinical and biochemical picture of hypogonadism allows a relatively straightforward diagnosis in most cases although it is important to be alert to the possibility of hypogonadism in the context of partial testicular tissue preservation. It is also prudent to consider the possibility of secondary hypogonadism especially in patients with chronic pain or those on opiate medication. Therapeutic options for testosterone replacement are diverse but relatively simple. This article aims to give guidance to the non-specialist in the consideration, diagnosis, and treatment of hypogonadism, with particular reference to blast injury of the external genitalia.

Associations of Bioavailable Serum Testosterone With Cognitive Function in Older Men: Results From the National Health and Nutrition Examination Survey.

BACKGROUND: Age-associated cognitive decline may be influenced by testosterone status. However, studies evaluating the impact of bioavailable testosterone, the active, free testosterone, on cognitive function are scarce. Our study determined the relationship between calculated bioavailable testosterone and cognitive performance in older men. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. This study consisted of 208 men aged ≥60 years. Bioavailable serum testosterone was calculated based on the total serum testosterone, sex hormone-binding globulin, and albumin levels, whereas cognitive performance was assessed through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning Test (WLLT), Word List Recall Test (WLRT), and Intrusion Word Count Test (WLLT-IC and WLRT-IC), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Multiple linear regression analyses were performed upon adjustment for age, ethnicity, socioeconomic status, education level, medical history, body mass index, energy, alcohol intake, physical activity levels, and sleep duration. RESULTS: A significant positive association between bioavailable testosterone and DSST (ß: 0.049, p = .002) score was detected, with no signs of a plateau effect. No significant associations with CERAD WLLT (p = .132), WLRT (p = .643), WLLT-IC (p = .979), and WLRT-IC (p = .387), and AFT (p = .057) were observed. CONCLUSION: Calculated bioavailable testosterone presented a significant positive association with processing speed, sustained attention, and working memory in older men above 60 years of age. Further research is warranted to elucidate the impact of the inevitable age-related decline in testosterone on cognitive function in older men.

Relative changes in brain and kidney biomarkers with Exertional Heat Illness during a cool weather marathon.

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, S100ß) 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.

Capsaicin 8% Patch Treatment in Non-Freezing Cold Injury: Evidence for Pain Relief and Nerve Regeneration.

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.

Tibial Macrostructure and Microarchitecture Adaptations in Women During 44 Weeks of Arduous Military Training.

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. © 2021 Crown copyright. Journal of Bone and Mineral Research © 2021 American Society for Bone and Mineral Research (ASBMR). This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

Measuring the Exercise Component of Energy Availability during Arduous Training in Women.

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 labeled water in women. The secondary aim was to determine the relationship of EA with physical fitness, body composition by dual-energy x-ray absorptiometry, heart rate variability (HRV), and eating behavior (Brief Eating Disorder in Athletes Questionnaire [BEDA-Q]). METHODS: This was a prospective, repeated-measures study, assessing EA measures and training adaptation during 11-month basic military training. Forty-seven women (23.9 ± 2.6 yr) completed three 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, HRV, 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 (R2 = 0.76, r = 0.87, P < 0.001) and was higher by 10 kcal·kg-1 FFM·d-1. However, EA was low in absolute terms because of 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 doubly labeled water during multistressor training, the difference representing 10 kcal·kg-1 FFM·d-1 EEE from nonexercise activity. Beneficial physical but not autonomic adaptations were associated with higher EA. EAmvpa and BEDA-Q warrant consideration for low EA assessment and screening.

The Effects of Apnea Training, Using Voluntary Breath Holds, on High Altitude Acclimation: Breathe-High Altitude Study.

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.

Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study.

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.