Inflammatory and Oxidant Responses to Arduous Military Training: Associations with Stress, Sleep, and Performance.

BACKGROUND: Arduous military training frequently consists of prolonged physical activity, sleep disturbance, and stress that increases musculoskeletal injury risk and performance decrements. Inflammatory and oxidative stress responses have been reported in response to arduous training, but with inconsistencies across markers and with under-representation of women. The purpose of the current report was to measure circulating inflammation and oxidative stress responses to military training and to correlate biomarkers with subjective measures of stress and sleep quality as well as military fitness test performance. METHODS: Candidates undergoing the 10-week Marine Corps Officer Candidate School (OCS; 101 men; 62 women) were monitored, with demographic and questionnaire data collected, and blood drawn before and after OCS. Blood was analyzed for six markers of inflammation and three markers of oxidative stress. Associations between biomarkers and questionnaire and fitness test performance were tested. RESULTS: All measured inflammatory markers as well as plasma antioxidant capacity were elevated following OCS. The inflammatory increase was higher in women for several markers. Sleep disturbance and stress perception were associated with IL-6, IL-10 and CRP concentrations, suggesting that low sleep disturbance and stress perception were associated with low inflammatory load. Additionally, those with the highest inflammation at each time point performed worse on fitness tests than those with low inflammation. CONCLUSIONS: Following arduous military training, the circulating environment in a significant portion of officer candidates resembled chronic low-grade inflammation. This circulating inflammatory environment appeared worse with poor sleep, high stress perception, and poor fitness test performance, with utility observed for CRP, IL-6, and IL-10 as biomarkers of these responses. Since inflammation may contribute to musculoskeletal injury and performance decrements, minimizing chronic inflammation during military training should be explored.

Micronutrient Status During Military Training and Associations With Musculoskeletal Health, Injury, and Readiness Outcomes.

OBJECTIVE: Micronutrient status, specifically vitamin D and iron, represent modifiable factors for optimizing military readiness. The primary purpose of this investigation was to determine associations between micronutrient deficiency (i.e., iron status and 25-hydroxy-vitamin D [25(OH)D]) and operationally relevant outcomes (i.e., skeletal health, musculoskeletal injury) at baseline and post-10 weeks of arduous military training. METHODS: A total of 227 (177 men, 50 women) Marine Officer Candidates School (OCS) candidates who completed OCS training with complete data sets were included in this analysis. Vitamin D and iron status indicators were collected at two timepoints, pre (baseline) and post OCS. Musculoskeletal outcomes at the mid- and proximal tibial diaphysis were assessed via peripheral quantitative computed tomography. RESULTS: Micronutrient status declined following OCS training in men and women and was associated with musculoskeletal outcomes including greater bone strength (strength strain index) at the mid-diaphysis site in those with optimal status (M = 38.26 mm3, SE = 15.59) versus those without (M = -8.03 mm3, SE = 17.27). In women (p = .037), endosteal circumference was greater in the deficient group (M = 53.26 mm, SE = 1.19) compared with the optimal group (M = 49.47 mm, SE = 1.31) at the proximal diaphysis. In men, greater baseline hepcidin concentrations were associated with an increased likelihood of suffering musculoskeletal injury during training. CONCLUSIONS: Vitamin D and iron status declined over the course of training, suggesting impaired micronutrient status. Differences in musculoskeletal outcomes by micronutrient group suggests optimal vitamin D and ferritin concentrations may exert beneficial effects on bone fatigability and fracture reduction during military training.

Physiological characteristics predictive of passing military physical employment standard tasks for ground close combat occupations in men and women.

Challenges for some women meeting the physical employment standards (PES) for ground close combat (GCC) roles stem from physical fitness and anthropometric characteristics. The purpose of this study was to identify the modifiable and nonmodifiable characteristics predictive of passing GCC-based PES tasks and determine the modifiable characteristics suitable to overcome nonmodifiable limitations. 107 adults (46 women) underwent multiday testing assessing regional and total lean mass (LM), percent body fat (BF%), aerobic capacity (V̇O2peak), strength, power, and PES performance. Predictors with p-value <0.200 were included in stepwise logistic regression analysis or binary logistic regression when outcomes among sexes were insufficient. Relative and absolute arm LM (OR: 4.617-8.522, p < 0.05), leg LM (OR: 2.463, p < 0.05), and upper body power (OR: 2.061, p < 0.05) predicted medicine ball chest throw success. Relative and absolute arm LM (OR: 3.734-11.694, p < 0.05), absolute trunk LM (OR: 2.576, p < 0.05), and leg LM (OR: 2.088, p < 0.05) predicted casualty drag success. Upper body power (OR: 3.910, p < 0.05), absolute trunk LM (OR: 2.387, p < 0.05), leg LM (OR: 2.290, p < 0.05), and total LM (OR: 1.830, p < 0.05) predicted maximum single lift success. Relative and absolute arm LM (OR: 3.488-7.377, p < 0.05), leg LM (OR: 1.965, p < 0.05), and upper body power (OR: 1.957, p < 0.05) predicted water can carry success. %BF (OR: 0.814, p = 0.007), V̇O2peak (OR: 1.160, p = 0.031), and lower body strength (OR: 1.059, p < 0.001) predicted repeated lift and carry success. V̇O2peak (OR: 1.540, p < 0.001) predicted 2-km ruck march success. Modifiable characteristics were the strongest predictors for GCC-based PES task success to warrant their improvement for enhancing PES performance for women.

Allostatic Load Is Associated with Overuse Musculoskeletal Injury during US Marine Corps Officer Candidates School.

INTRODUCTION: Overuse musculoskeletal injuries (MSKIs) remain a significant medical challenge in military personnel undergoing military training courses; a further understanding of the biological process leading to overuse MSKI development and biological signatures for injury risk are warranted. The purpose of this study was to determine the association between overuse MSKI occurrence and physiological characteristics of allostatic load (AL) characterized as maladaptive biological responses to chronic stress measured by wearable devices in US Marine Corps officer candidates during a 10-week training course. METHODS: Devices recorded energy expenditure (EE), daytime heart rate (HR), sleeping HR, and sleep architecture (time and percent of deep, light, REM sleep, awake time, total sleep). Flux was calculated as the raw or absolute difference in the average value for that day or night and the day or night beforehand. Linear mixed-effect model analysis accounting for cardiorespiratory fitness assessed the association between overuse MSKI occurrence and device metrics (α = 0.05). RESULTS: Sixty-nine participants (23 females) were included. Twenty-one participants (eight females) sustained an overuse MSKI. Overuse MSKI occurrence in male participants was positively associated with daytime HR (ß = 5.316, p = 0.008), sleeping HR (ß = 2.708, p = 0.032), relative EE (ß = 8.968, p = 0.001), absolute flux in relative EE (ß = 2.994, p = 0.002), absolute EE (ß = 626.830, p = 0.001), and absolute flux in absolute EE (ß = 204.062, p = 0.004). Overuse MSKI occurrence in female participants was positively associated with relative EE (ß = 5.955, p = 0.026), deep sleep time (ß = 0.664, p < 0.001), %deep sleep (ß = 12.564, p < 0.001) and negatively associated with absolute flux in sleeping HR (ß = -0.660, p = 0.009). CONCLUSIONS: Overuse MSKI occurrences were associated with physiological characteristics of AL including chronically elevated HR and EE and greater time in restorative sleep stages, which may serve as biological signatures for overuse MSKI risk.

Circulating extracellular vesicle characteristics differ between men and women following 12 weeks of concurrent exercise training.

Concurrent resistance and endurance exercise training (CET) has well-studied benefits; however, inherent hormonal and genetic differences alter adaptive responses to exercise between sexes. Extracellular vesicles (EVs) are factors that contribute to adaptive signaling. Our purpose was to test if EV characteristics differ between men and women following CET. 18 young healthy participants underwent 12-weeks of CET. Prior to and following CET, subjects performed an acute bout of heavy resistance exercise (AHRET) consisting of 6 × 10 back squats at 75% 1RM. At rest and following AHRET, EVs were isolated from plasma and characteristics and miRNA contents were analyzed. AHRET elevated EV abundance in trained men only (+51%) and AHRET-induced changes were observed for muscle-derived EVs and microvesicles. There were considerable sex-specific effects of CET on EV miRNAs, highlighted by larger variation following the 12-week program in men compared to women at rest. Pathway analysis based on differentially expressed EV miRNAs predicted that AHRET and 12 weeks of CET in men positively regulates hypertrophy and growth pathways more so than in women. This report highlights sex-based differences in the EV response to resistance and concurrent exercise training and suggests that EVs may be important adaptive signaling factors altered by exercise training.

Skeletal muscle adaptations to high-intensity, low-volume concurrent resistance and interval training in recreationally active men and women.

This study compared the structural and cellular skeletal muscle factors underpinning adaptations in maximal strength, power, aerobic capacity, and lean body mass to a 12-week concurrent resistance and interval training program in men and women. Recreationally active women and men completed three training sessions per week consisting of high-intensity, low-volume resistance training followed by interval training performed using a variety upper and lower body exercises representative of military occupational tasks. Pre- and post-training vastus lateralis muscle biopsies were analyzed for changes in muscle fiber type, cross-sectional area, capillarization, and mitochondrial biogenesis marker content. Changes in maximal strength, aerobic capacity, and lean body mass (LBM) were also assessed. Training elicited hypertrophy of type I (12.9%; p = 0.016) and type IIa (12.7%; p = 0.007) muscle fibers in men only. In both sexes, training decreased type IIx fiber expression (1.9%; p = 0.046) and increased total PGC-1α (29.7%, p < 0.001) and citrate synthase (11.0%; p < 0.014) content, but had no effect on COX IV content or muscle capillarization. In both sexes, training increased maximal strength and LBM but not aerobic capacity. The concurrent training program was effective at increasing strength and LBM but not at improving aerobic capacity or skeletal muscle adaptations underpinning aerobic performance.

Acute Resistance Exercise Modifies Extracellular Vesicle miRNAs Targeting Anabolic Gene Pathways: A Prospective Cohort Study.

BACKGROUND: Resistance training confers numerous health benefits that are mediated in part by circulating factors. Toward an enhanced molecular understanding, there is growing interest in a class of signaling biomarkers called extracellular vesicles (EV). EVs support physiological adaptations to exercise by transporting their cargo (e.g., microRNA (miRNA)) to target cells. Previous studies of changes in EV cargo have focused on aerobic exercise, with limited data examining the effects of resistance exercise. We examined the effect of acute resistance exercise on circulating EV miRNAs and their predicted target pathways. METHODS: Ten participants (5 men; age, 26.9 ± 5.5 yr; height, 173.4 ± 10.5 cm; body mass, 74.0 ± 11.1 kg; body fat, 25.7% ± 11.6%) completed an acute heavy resistance exercise test (AHRET) consisting of six sets of 10 repetitions of back squats using 75% one-repetition maximum. Pre-/post-AHRET, EVs were isolated from plasma using size exclusion chromatography, and RNA sequencing was performed. Differentially expressed miRNAs between pre- and post-AHRET EVs were analyzed using Ingenuity Pathway Analysis to predict target messenger RNAs and their target biological pathways. RESULTS: Overall, 34 miRNAs were altered by AHRET ( P < 0.05), targeting 4895 mRNAs, with enrichment of 175 canonical pathways ( P < 0.01), including 12 related to growth/metabolism (p53, IGF-I, STAT3, PPAR, JAK/STAT, growth hormone, WNT/ß-catenin, ERK/MAPK, AMPK, mTOR, and PI3K/AKT) and 8 to inflammation signaling (TGF-ß, IL-8, IL-7, IL-3, IL-6, IL-2, IL-17, IL-10). CONCLUSIONS: Acute resistance exercise alters EV miRNAs targeting pathways involved in growth, metabolism, and immune function. Circulating EVs may serve as significant adaptive signaling molecules influenced by exercise training.

The 31-Gene Expression Profile Test Outperforms AJCC in Stratifying Risk of Recurrence in Patients with Stage I Cutaneous Melanoma.

BACKGROUND: Patients with stage I cutaneous melanoma (CM) are considered at low risk for metastasis or melanoma specific death; however, because the majority of patients are diagnosed with stage I disease, they represent the largest number of melanoma deaths annually. The 31-gene expression profile (31-GEP) test has been prospectively validated to provide prognostic information independent of staging, classifying patients as low (Class 1A), intermediate (Class 1B/2A), or high (Class 2B) risk of poor outcomes. METHODS: Patients enrolled in previous studies of the 31-GEP were combined and evaluated for recurrence-free (RFS) and melanoma-specific survival (MSS) (n = 1261, "combined"). A second large, unselected real-world cohort (n = 5651) comprising clinically tested patients diagnosed 2013-2018 who were linked to outcomes data from the NCI Surveillance, Epidemiology, and End Results (SEER) Program registries was evaluated for MSS. RESULTS: Combined cohort Class 1A patients had significantly higher RFS than Class 1B/2A or Class 2B patients (97.3%, 88.6%, 77.3%, p < 0.001)-better risk stratification than AJCC8 stage IA (97.5%) versus IB (89.3%). The SEER cohort showed better MSS stratification by the 31-GEP (Class 1A = 98.0%, Class 1B/2A = 97.5%, Class 2B = 92.3%; p < 0.001) than by AJCC8 staging (stage IA = 97.6%, stage IB = 97.9%; p < 0.001). CONCLUSIONS: The 31-GEP test significantly improved patient risk stratification, independent of AJCC8 staging in patients with stage I CM. The 31-GEP provided greater separation between high- (Class 2B) and low-risk (Class 1A) groups than seen between AJCC stage IA and IB. These data support integrating the 31-GEP into clinical decision making for more risk-aligned management plans.

Effect of acute resistance exercise on bone turnover in young adults before and after concurrent resistance and interval training.

Weight-bearing physical activity can stimulate bone adaptation. This investigation explored the effect of an acute bout of resistance exercise before and after resistance+interval training on circulating biomarkers of bone metabolism and muscle-bone crosstalk. Healthy young male and female participants (n = 21 male, 28 ± 4 years; n = 17 female, 27 ± 5 years) performed a 6 × 10 squat test (75% 1RM) before and after a 12-week resistance+interval training program. Before and after completion of the training program, blood samples were collected at rest, immediately postexercise, and 2 h postexercise. Blood samples were analyzed for ßCTX, P1NP, sclerostin, osteocalcin, IGF-1, and irisin. Significant effects of acute exercise (main effect of time) were observed as increases in concentrations of IGF-1, irisin, osteocalcin, and P1NP from rest to postexercise. A sex*time interaction indicated a greater decline in ßCTX concentration from rest to 2 h postexercise and a greater increase in sclerostin concentration from rest to immediately postexercise in male compared with female participants. Sex differences (main effect of sex) were also observed for irisin and P1NP concentrations. In summary, changes in concentrations of biochemical markers of bone metabolism and muscle-bone crosstalk were observed in males and females after an acute bout of resistance exercise and following 12 weeks of resistance+interval training.

The Integrated i31-GEP Test Outperforms the MSKCC Nomogram at Predicting SLN Status in Melanoma Patients.

BACKGROUND/AIM: Sentinel lymph node biopsy (SLNB) for patients with cutaneous melanoma is primarily a prognostic procedure that broadly identifies patients who may have disease progression and may warrant additional intervention. However, 88% of patients undergoing SLNB receive a negative result and of those, some will succumb to their disease. One clinical utility of the integrated 31-GEP test, which combines gene expression data with clinicopathologic factors to provide a personalized, precise risk of SLN positivity, is SLNB guidance. This study compared the i31-GEP for SLNB to a nomogram that predicts SLN positivity using only clinicopathologic factors. PATIENTS AND METHODS: Patients with T1-T2 tumors and known SLN status (N=465) were analyzed by the i31-GEP for SLNB and a nomogram developed at Memorial Sloan Kettering Cancer Center (MSKCC). A 5% risk threshold was used to conform with national guidelines. RESULTS: In patients with <5% predicted risk, SLN positivity was 2.7% (3/111) for i31-GEP versus 10.0% (11/110, p=0.026) for MSKCC. In each T-category, the i31-GEP maintained a false-negative rate below the 5% risk threshold in those predicted to have a <5% risk, while the MSKCC nomogram did not. CONCLUSION: Integrating the 31-GEP with traditional factors outperformed a nomogram that uses clinicopathologic factors alone to predict SLN status. Incorporating the i31-GEP into clinical practice could improve identification of patients for SLNB, resulting in better risk-aligned management.

Association of clinically-measured and dynamic ankle dorsiflexion assessed by markerless motion capture during the drop-jump task on landing biomechanics and risk of ankle injury in military personnel undergoing 10 weeks of physical training.

OBJECTIVES: Determine the influence of clinically-measured maximum dorsiflexion, dynamic peak dorsiflexion and percent of clinically-measured maximum dorsiflexion used during a drop-jump task on landing biomechanics and risk of ankle injury in military personnel. DESIGN: Prospective cohort study. METHODS: 672 participants (122 women) enrolled. The weightbearing lunge test assessed clinically-measured maximum dorsiflexion averaged across limbs (degrees). Markerless motion capture and force plates collected lower extremity kinematic and kinetic data during a drop-jump task. Percent of clinically-measured maximum dorsiflexion used during landing was calculated as dynamic peak dorsiflexion divided by clinically-measured value, multiplied by 100 (%). De-identified injury data was derived from military physical therapists. Simple linear regression analysis determined the association between dorsiflexion measures and landing biomechanics. Simple binary logistic regression analyses identified predictors of ankle injuries. Statistical significance was set at α = 0.05. RESULTS: Eighteen participants sustained a traumatic ankle injury from a landing. All measures of dorsiflexion were associated with movement patterns that countered the stiff-legged landing strategy with dynamic measures showing a higher predictive value. Protective factors against ankle injury included height (odds ratio: 0.818, p = 0.006) and weight (odds ratio: 0.824, p = 0.023) for women. Relative braking impulse was a risk factor for men (odds ratio: 1.890, p = 0.001). CONCLUSIONS: Greater clinically-measured and dynamic measures of dorsiflexion were associated with movement patterns that countered the stiff-legged landing strategy but neither measure of dorsiflexion predicted ankle injury risk. Resultant biomechanics and anthropometrics influenced ankle injury risk to warrant recognition for injury prevention initiatives.

31-Gene Expression Profile Testing in Cutaneous Melanoma and Survival Outcomes in a Population-Based Analysis: A SEER Collaboration.

PURPOSE: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level. METHODS: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling. RESULTS: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients. CONCLUSION: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.

Military tactical adaptive decision making during simulated military operational stress is influenced by personality, resilience, aerobic fitness, and neurocognitive function.

Laboratory-based studies designed to mimic combat or military field training have consistently demonstrated deleterious effects on warfighter's physical, cognitive, and emotional performance during simulated military operational stress (SMOS). Purpose: The present investigation sought to determine the impact of a 48-h simulated military operational stress (SMOS) on military tactical adaptive decision making, and the influence of select psychological, physical performance, cognitive, and physiological outcome measures on decision making performance. Methods: Male (n = 48, 26.2 ± 5.5 years, 177.7 ± 6.6 cm, 84.7 ± 14.1 kg.) subjects currently serving in the U.S. military were eligible to participate in this study. Eligible subjects completed a 96-h protocol that occurred over five consecutive days and four nights. Day 2 (D2) and day 3 (D3) consisted of 48-h of SMOS wherein sleep opportunity and caloric needs were reduced to 50%. Differences in SPEAR total block score from baseline to peak stress (D3 minus D1) were calculated to assess change in military tactical adaptive decision making and groups were stratified based on increase (high adaptors) or decrease (low adaptors) of the SPEAR change score. Results: Overall, military tactical decision-making declined 1.7% from D1 to D3 (p < 0.001). High adaptors reported significantly higher scores of aerobic capacity (p < 0.001), self-report resilience (p = 0.020), extroversion (p < 0.001), and conscientiousness (p < 0.001). at baseline compared to low adaptors, while low adaptors reported greater scores in Neuroticism (p < 0.001). Conclusion: The present findings suggest that service members whose adaptive decision making abilities improved throughout SMOS (i.e., high adaptors) demonstrated better baseline psychological/self-reported resilience and aerobic capacity. Further, changes in adaptive decision-making were distinct from those of lower order cognitive functions throughout SMOS exposure. With the transition of future military conflicts placing higher priority on enhancing and sustaining cognitive readiness and resiliency, data presented here demonstrates the importance of measuring and categorizing baseline measures inherent to military personnel, in order to change and train one's ability to suffer less of a decline during high stress conditions.

Predictive utility of commercial grade technologies for assessing musculoskeletal injury risk in US Marine Corps Officer candidates.

Recently, commercial grade technologies have provided black box algorithms potentially relating to musculoskeletal injury (MSKI) risk and functional movement deficits, in which may add value to a high-performance model. Thus, the purpose of this manuscript was to evaluate composite and component scores from commercial grade technologies associations to MSKI risk in Marine Officer Candidates. 689 candidates (Male candidates = 566, Female candidates = 123) performed counter movement jumps on SPARTA™ force plates and functional movements (squats, jumps, lunges) in DARI™ markerless motion capture at the start of Officer Candidates School (OCS). De-identified MSKI data was acquired from internal OCS reports for those who presented to the Physical Therapy department for MSKI treatment during the 10 weeks of training. Logistic regression analyses were conducted to validate the utility of the composite scores and supervised machine learning algorithms were deployed to create a population specific model on the normalized component variables in SPARTA™ and DARI™. Common MSKI risk factors (cMSKI) such as older age, slower run times, and females were associated with greater MSKI risk. Composite scores were significantly associated with MSKI, although the area under the curve (AUC) demonstrated poor discrimination (AUC = .55-.57). When supervised machine learning algorithms were trained on the normalized component variables and cMSKI variables, the overall training models performed well, but when the training models were tested on the testing data the models classified MSKI "by chance" (testing AUC avg = .55-.57) across all models. Composite scores and component population specific models were poor predictors of MSKI in candidates. While cMSKI, SPARTA™, and DARI™ models performed similarly, this study does not dismiss the use of commercial technologies but questions the utility of a singular screening task to predict MSKI over 10 weeks. Further investigations should evaluate occupation specific screening, serial measurements, and/or load exposure for creating MSKI risk models.

Changes in eating pathology symptoms during initial military training in men and women and associations with BMI and injury risk.

Nutritional fitness, which comprises food choices, meal timing, and dietary intake behaviors, is an important component of military service member health and performance that has garnered recent attention. This study utilized generalized linear mixed effects modeling (GLMM) to investigate changes in eating pathology symptoms in men and women during initial military training (Marine Corps Officer Candidates School (OCS)). Associations among eating pathology, musculoskeletal injury risk and BMI were also assessed. This investigation includes data from the Eating Pathology Symptoms Inventory (EPSI) and BMI at the start of OCS (n = 598: Male n = 469, Female n = 129) and end of the 10-week program (n = 413: Male n = 329, Female n = 84), and injury surveillance throughout. At baseline, female candidates presented with greater body dissatisfaction, binge eating, purging, and restricting, but lower negative attitudes toward obesity compared to male candidates (p < 0.001). Eating symptoms changed during military training indicated by decreased body dissatisfaction in women (p = 0.003), decreased excessive exercise and negative attitudes toward obesity in men (p < 0.001), decreased cognitive restraint (p < 0.001), restricting (p < 0.001), purging (p = 0.013), and muscle building (p < 0.001) and increased binge eating (p < 0.001) in both sexes. Changes in restricting were significantly related to changes in BMI during training (p < 0.05). The likelihood of future injury was 108 % higher in female candidates than males and decreased by 5 % for each unit increase in excessive exercise. Eating attitudes and behaviors change during military training environments and are associated with military health and readiness outcomes including BMI and injury risk.

Resistance exercise differentially alters extracellular vesicle size and subpopulation characteristics in healthy men and women: an observational cohort study.

Extracellular vesicles (EVs) are established mediators of adaptation to exercise. Currently, there are no published data comparing changes in EVs between men and women after resistance exercise. We tested the hypothesis that EV profiles would demonstrate a sex-specific signature following resistance exercise. Ten men and 10 women completed an acute heavy resistance exercise test for back squats using 75% of their one-repetition maximum. Blood was drawn before and immediately after exercise. EVs were isolated from plasma using size exclusion chromatography and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and a marker for skeletal muscle EVs (SGCA). CD63+ EV concentration and proportion of total EVs increased 23% (P = 0.006) and 113% (P = 0.005) in both sexes. EV mean size declined in men (P = 0.020), but not in women, suggesting a relative increase in small EVs in men. VAMP3+ EV concentration and proportion of total EVs increased by 93% (P = 0.025) and 61% (P = 0.030) in men and women, respectively. SGCA+ EV concentration was 69% higher in women compared with men independent of time (P = 0.007). Differences were also observed for CD63, VAMP3, and SGCA median fluorescence intensity, suggesting altered surface protein density according to sex and time. There were no significant effects of time or sex on THSD1+ EVs or fluorescence intensity. EV profiles, particularly among exosome-associated and muscle-derived EVs, exhibit sex-specific differences in response to resistance exercise which should be further studied to understand their relationship to training adaptations.

Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.

BACKGROUND: Many patients with low-stage cutaneous melanoma will experience tumor recurrence, metastasis, or death, and many higher staged patients will not. OBJECTIVE: To develop an algorithm by integrating the 31-gene expression profile test with clinicopathologic data for an optimized, personalized risk of recurrence (integrated 31 risk of recurrence [i31-ROR]) or death and use i31-ROR in conjunction with a previously validated algorithm for precise sentinel lymph node positivity risk estimates (i31-SLNB) for optimized treatment plan decisions. METHODS: Cox regression models for ROR were developed (n = 1581) and independently validated (n = 523) on a cohort with stage I-III melanoma. Using National Comprehensive Cancer Network cut points, i31-ROR performance was evaluated using the midpoint survival rates between patients with stage IIA and stage IIB disease as a risk threshold. RESULTS: Patients with a low-risk i31-ROR result had significantly higher 5-year recurrence-free survival (91% vs 45%, P < .001), distant metastasis-free survival (95% vs 53%, P < .001), and melanoma-specific survival (98% vs 73%, P < .001) than patients with a high-risk i31-ROR result. A combined i31-SLNB/ROR analysis identified 44% of patients who could forego sentinel lymph node biopsy while maintaining high survival rates (>98%) or were restratified as being at a higher or lower risk of recurrence or death. LIMITATIONS: Multicenter, retrospective study. CONCLUSION: Integrating clinicopathologic features with the 31-GEP optimizes patient risk stratification compared to clinicopathologic features alone.

Unsupervised Clustering Techniques Identify Movement Strategies in the Countermovement Jump Associated With Musculoskeletal Injury Risk During US Marine Corps Officer Candidates School.

Musculoskeletal injuries (MSKI) are a significant burden on the military healthcare system. Movement strategies, genetics, and fitness level have been identified as potential contributors to MSKI risk. Screening measures associated with MSKI risk are emerging, including novel technologies, such as markerless motion capture (mMoCap) and force plates (FP) and allow for field expedient measures in dynamic military settings. The aim of the current study was to evaluate movement strategies (i.e., describe variables) of the countermovement jump (CMJ) in Marine officer candidates (MOCs) via mMoCap and FP technology by clustering variables to create distinct movement strategies associated with MSKI sustained during Officer Candidates School (OCS). 728 MOCs were tested and 668 MOCs (Male MOCs = 547, Female MOCs = 121) were used for analysis. MOCs performed 3 maximal CMJs in a mMoCap space with FP embedded into the system. De-identified MSKI data was acquired from internal OCS reports for those who presented to the OCS Physical Therapy department for MSKI treatment during the 10 weeks of OCS training. Three distinct clusters were formed with variables relating to CMJ kinetics and kinematics from the mMoCap and FPs. Proportions of MOCs with a lower extremity and torso MSKI across clusters were significantly different (p < 0.001), with the high-risk cluster having the highest proportions (30.5%), followed by moderate-risk cluster (22.5%) and low-risk cluster (13.8%). Kinetics, including braking rate of force development (BRFD), braking net impulse and propulsive net impulse, were higher in low-risk cluster compared to the high-risk cluster (p < 0.001). Lesser degrees of flexion and shorter CMJ phase durations (braking phase and propulsive phase) were observed in low-risk cluster compared to both moderate-risk and high-risk clusters. Male MOCs were distributed equally across clusters while female MOCs were primarily distributed in the high-risk cluster. Movement strategies (i.e., clusters), as quantified by mMoCap and FPs, were successfully described with MOCs MSKI risk proportions between clusters. These results provide actionable thresholds of key performance indicators for practitioners to use for screening measures in classifying greater MSKI risk. These tools may add value in creating modifiable strength and conditioning training programs before or during military training.

Utility of extracellular vesicles as a potential biological indicator of physiological resilience during military operational stress.

Extracellular vesicles (EVs) transport biological content between cells to mediate physiological processes. The association between EVs and resilience, the ability to cope with stress, is unknown. Using unbiased machine learning approaches, we aimed to identify a biological profile of resilience. Twenty servicemen (27.8 ± 5.9 years) completed the Connor Davidson Resilience (CD-RISC) questionnaire and were exposed to daily physical and cognitive exertion with 48-hr sleep and caloric restriction. Blood samples from baseline and the second day of stress were analyzed for neuroendocrine biomarkers impacted by military stress. EVs were isolated from plasma and stained with antibodies associated with exosomes (CD63), microvesicles (VAMP3), and apoptotic bodies (THSD1). Individuals were separated into high (n = 10, CD-RISC > 90) and low (n = 10, CD-RISC < 79) resilience. EV features were stratified by size, then down-selected using regression trees and compared between groups. Diagnostic accuracy was assessed using receiver operating characteristic curves. Compared to low resilience, high resilience demonstrated a greater increase in variability of THSD1 local bright spot intensities among large-sized EVs in response to stress (p = 0.002, Hedges' g = 1.59). Among medium-sized EVs, high resilience exhibited a greater decrease in side scatter intensity (p = 0.014, Hedges' g = 1.17). Both features demonstrated high to moderate diagnostic accuracy for high resilience (AUC = 0.90 and 0.79). In contrast, neuroendocrine biomarker concentrations were similar between groups. The increase in variability among THSD1 + EVs in high, but not low, resilient individuals following stress may suggest high resilience is accompanied by stress-triggered apoptotic adaptations to the environment that are not detected in neuroendocrine biomarkers.

Men and women display distinct extracellular vesicle biomarker signatures in response to military operational stress.

Extracellular vesicles (EVs) are mediators of physiological changes that occur during physical exertion. This study examined the effects of physical exertion with and without sleep and caloric restriction on EV size, concentration, and surface proteins in men and women. Twenty participants (10 men) completed a 5-day simulated military operational stress protocol with daily physical exertion. Blood was drawn before and immediately after exertion at baseline (D1) and following 48-h of sleep and caloric restriction (D3). EV size and concentration were assessed using nanoparticle tracking analysis. EVs were identified with markers associated with exosomes (CD63), microvesicles (VAMP3), apoptotic bodies (THSD1), and skeletal muscle-derived EVs (SGCA) and quantified using imaging flow cytometry. Interactive and main effects of sex, day, and time on EVs were assessed using three-way ANOVAs. EV concentration declined pre to postexertion in women on D1 and D3 but was stable in men. EV size increased from pre to postexertion and from D1 to D3 in men and women. Physical exertion following sleep and caloric restriction increased CD63+ EV concentration, proportion of total EVs, and CD63 surface protein expression regardless of sex. The proportion of SGCA+ EVs increased in men and women following exertion and from D1 to D3 but was higher in women than in men. No differences were observed in VAMP3+ and THSD1+ EVs. This study identified sexually dimorphic EV profiles in response to various stressors. Further investigations are necessary to determine if dimorphic EV responses affect health and performance outcomes during stress.NEW & NOTEWORTHY Sex is understudied in EV research, and most studies limit EV analysis to single stress conditions such as exercise. Multistress conditions consisting of physical exertion and sleep and caloric restriction are common in real-world settings. We demonstrate that physical exertion results in sex-specific EV signatures and that EV profiles vary according to single versus multistress conditions. Our data highlight important biological and ecological characteristics that should be considered in EV research.