Smoking history is associated with reduced efficacy of neoadjuvant therapy in pancreatic adenocarcinoma.

BACKGROUND: Differential responses to neoadjuvant therapy (NAT) exist in pancreatic ductal adenocarcinoma (PDAC); however, contributing factors are poorly understood. Tobacco smoke is a common risk factor for PDAC, with nicotine-induced chemoresistance observed in other cancers. This study aimed to explore the potential association between tobacco use and NAT efficacy in PDAC. METHODS: A single-center, retrospective analysis was conducted that included all consecutive patients with PDAC who underwent surgical resection after NAT with a documented smoking history (N = 208). NAT response was measured as percentage fibrosis in the surgical specimen. Multivariable models controlled for covariates and survival were modeled using the Kaplan-Meier method. RESULTS: Postoperatively, major responses to NAT (>95% fibrosis) were less frequently observed in smokers than in nonsmokers (13.7% vs 30.4%, respectively; P = .021). Pathologic complete responses were similarly less frequent in smokers than in nonsmokers (2.1% vs 9.9%, respectively; P = .023). On multivariate analysis controlling for covariates, smoking history remained independently associated with lower odds of major fibrosis (odds ratio [OR], 0.25; 95% CI, 0.10-0.59; P = .002) and pathologic complete response (OR, 0.21; 95% CI, 0.03-0.84; P = .05). The median overall survival was significantly longer in nonsmokers than in smokers (39.1 vs 26.6 months, respectively; P = .05). CONCLUSION: Tobacco use was associated with diminished pathologic responses to NAT. Future research to understand the biology underlying this observation is warranted and may inform differential NAT approaches or counseling among these populations.

Force-plate derived predictors of lateral jump performance in NCAA Division-I men's basketball players.

A lateral jump assessment may provide unique benefits in sports such as basketball that require multidirectional performance optimization. This study aimed to examine selected force-plate derived metrics as predictors of lateral jump task distance in men's basketball players. Twenty-two NCAA Division-I men's basketball players (19.4 ± 1.3 years, 95.0 ± 12.5 kg, 196.5 ± 8.1 cm) each performed six single leg lateral jumps while standing on a force plate (1200 Hz, Kistler Instrument Corp). The lateral jump task involved the subject beginning by standing on the force plate and jumping sideways off one foot and then landing on the floor with the opposite foot. Three-dimensional ground reaction force curves were used to identify the eccentric and concentric phases of the jump and variables were computed each from the lateral (y), vertical (z), and resultant (r) force traces. Peak ground reaction force (pGRF), ground reaction force angle (θr), eccentric braking rate of force development (ECC-RFD), average concentric force (CON-AVG), total jump duration, eccentric phase duration, and eccentric to total time ratio were evaluated for predictive ability. Three regression models were able to significantly (p<0.05) predict jump distance: (1) pGRFy, pGRFz, and θr (p<0.001, R2 = 0.273), (2) Relative pGRFy, Relative pGRFz, and θr ((p<0.001, R2 = 0.214), and (3) Relative CON-AVGy and Relative pGRFr (p<0.001, R2 = 0.552). While several force plate-derived metrics were identified as significant predictors, a model with Relative CON-AVGy and Relative pGRFr explained a greater variability in performance (R2 = 0.55) compared to the other variables which were low, yet also significant. These results suggest that lateral ground reaction forces can be used to evaluate lateral jump performance with the use of three-dimensional force plates. The identified predictors can be used as a starting point for performance monitoring, as basketball training interventions can be directed at specific improvements in the identified metrics.

No protective benefits of low dose acute L-glutamine supplementation on small intestinal permeability, epithelial injury and bacterial translocation biomarkers in response to subclinical exertional-heat stress: A randomized cross-over trial.

Exertional heat stress disrupts gastrointestinal permeability and, through subsequent bacterial translocation, can result in potentially fatal exertional heat stroke. Glutamine supplementation is a potential countermeasure although previously validated doses are not universally well tolerated. Ten males completed two 80-minute subclinical exertional heat stress tests (EHSTs) following either glutamine (0.3 g kg FFM-1) or placebo supplementation. Small intestinal permeability was assessed using the lactulose/rhamnose dual sugar absorption test and small intestinal epithelial injury using Intestinal Fatty-Acid Binding Protein (I-FABP). Bacterial translocation was assessed using the total 16S bacterial DNA and Bacteroides/total 16S DNA ratio. The glutamine bolus was well tolerated, with no participants reporting symptoms of gastrointestinal intolerance. Small intestinal permeability was not influenced by glutamine supplementation (p = 0.06) although a medium effect size favoring the placebo trial was observed (d = 0.73). Both small intestinal epithelial injury (p < 0.01) and Bacteroides/total 16S DNA (p = 0.04) increased following exertional heat stress, but were uninfluenced by glutamine supplementation. Low-dose acute oral glutamine supplementation does not protect gastrointestinal injury, permeability, or bacterial translocation in response to subclinical exertional heat stress.

Acute L-glutamine supplementation does not improve gastrointestinal permeability, injury or microbial translocation in response to exhaustive high intensity exertional-heat stress.

Purpose: Exertional-heat stress adversely distrupts (GI) barrier integrity and, through subsequent microbial translocation (MT), can result in potentially fatal exertional-heat stroke. Acute glutamine (GLN) supplementation is a potential nutritional countermeasure, although the practical value of current supplementation regimens is questionable.Method: Ten males completed two high-intensity exertional-heat stress tests (EHST) involving running in the heat (40°C and 40% relative humidity) at lactate threshold to volitional exhaustion. Participants ingested GLN (0.3 g kg FFM-1) or a non-calorific placebo (PLA) one hour prior to the EHST. Venous blood was drawn pre-, post- and one-hour post-EHST. GI permeability was assessed using a serum dual-sugar absorption test (DSAT) and small intestinal epithelial injury using plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using the Bacteroides/total 16S DNA ratio.Results: Volitional exhaustion occurred after 22:19 ± 2:22 (minutes: seconds) in both conditions, during which whole-body physiological responses and GI symptoms were not different (p > 0.05). GI permeability (serum DSAT) was greater following GLN (0.043 ± 0.020) than PLA (0.034 ± 0.019) (p = 0.02; d = 0.47), but small intestine epithelial injury (I-FABP) increased comparably (p = 0.22; ηp2 = 0.16) following the EHST in both trials (GLN Δ = 1.25 ± 0.63 ng ml-1; PLA Δ = 0.92 ± 0.44 ng ml-1). GI MT (Bacteroides/total 16S DNA ratio) was unchanged in either condition following the EHST (p = 0.43).Conclusion: Acute low-dose (0.3 g kg-1 fat free mass) GLN supplementation ingested one hour before high-intesity exertional-heat stress worsened GI permeability, but did not influence either small intestinal epithilial injury or microbial translocation.Abbreviations: ANOVA: Analysis of variance; CV: Coefficient of Variation; DSAT: Dual Sugar Absorption Test; EDTA: Ethylenediaminetetraacetic acid; EHST: Exertional Heat Stress Test; ELISA: Enzyme Linked Immunosorbent Assay; FFM: Fat Free Mass; GI: Gastrointestinal; GFR: Glomerular Filtration Rate; GLN: Glutamine; HPLC: High Performance Liquid Chromatography; HR: Heart Rate; I-FABP: Intestinal Fatty-Acid Binding Protein; ISAK: International Society for the Advancement of Anthropometric Kinanthropometry; L/R: Lactulose-to-Rhamnose; LT: Lactate Threshold; MT: Microbial Translocation; mVAS: Modified Visual Analogue Scale; PBS: Phosphate-Buffered Saline; PLA: Placebo; qPCR: Quantitative Polymerase Chain Reaction; RH: Relative Humidity; RPE: Rate of Perceived Exertion; SD: Standard Deviation; SEM: Sensor Electronics Module; Tcore: Core Body Temperature; Tbody: Mean Body Temperature; Tskin: Mean Skin Temperature; TS: Thermal Sensation; V̇O2max: Maximal Oxygen Uptake.Highlights The pathophysiology of exertional-heat stroke is widely hypothesised to be at least in part attributable to a systemic inflammatory response caused by the leak of gastrointestinal microbes into the circulating blood.Acute high-dose (0.9 g kg FFM-1) L-glutamine supplementation is widely promoted as a practical strategy to protect gastrointestinal barrier integrity during exertional-heat stress. However, previously validated doses are often poorly tolerated and cannot be recommended for widespread implementation.This study examined the efficacy of low-dose (0.30 g kg FFM-1; ∼20 grams) acute L-glutamine supplementation on small intestinal injury, permeability, and microbial translocation in response a high-intensity exertional-heat stress test to exhaustion (20-30 min). This type of exercise accounts for the majority of exertional-heat stroke cases in the military.Despite being universally well-tolerated across all participants, acute low-dose L-glutamine supplementation worsened gastrointestinal permeability, without influencing either small intestinal injury or microbial translocation. These findings do not support the application of low-dose L-glutamine supplementation to help prevent exertional-heat stroke.

Individual risk factors associated with exertional heat illness: A systematic review.

NEW FINDINGS: What is the topic of this review? Exertional heat illness (EHI) remains a persistent problem for athletes and individuals. This threat remains despite numerous athletic position statements and occupational guidance policies. This review explores primary evidence that demonstrates a direct association between 'known' risk factors and EHI. What advances does it highlight? Primary evidence to support 'known' risk factors associated with EHI is not comprehensive. Furthermore, it is not evident that single individual factors predispose individuals to greater risk. In fact, the evidence indicates that EHI can manifest in non-hostile compensable environments when a combination of risk factors is prevalent. ABSTRACT: Despite the widespread knowledge of exertional heat illness (EHI) and clear guidance for its prevention, the incidence of EHI remains high. We carried out a systematic review of available literature evaluating the scientific evidence underpinning the risk factors associated with EHI. Medline, PsycINFO, SportDiscus and Embase were searched from inception to January 2019 with no date limitation, with supplementary searches also being performed. Search terms included permutations of risk and heat illness, with only studies in English included. Study selection, data extraction and quality assessment, using the QUALSYST tool, were performed by two independent reviewers. Of 8898 articles identified by the searches, 42 were included in the systematic review as primary evidence demonstrating a link between a risk factor and EHI. The quality scores ranged from 57.50 to 100%, and studies were generally considered to be of strong quality. The majority of risks attributable to EHI were categorized as those associated with lifestyle factors. The findings from the systematic review suggest complex manifestation of EHI through multiple risk factors rather than any one factor in isolation. Further research is needed to explore the accumulation of risk factors to help in development of effective preventative measures.

Gastrointestinal Tolerance of Low, Medium and High Dose Acute Oral l-Glutamine Supplementation in Healthy Adults: A Pilot Study.

l-Glutamine (GLN) is a conditionally essential amino acid which supports gastrointestinal (GI) and immune function prior to catabolic stress (e.g., strenuous exercise). Despite potential dose-dependent benefits, GI tolerance of acute high dose oral GLN supplementation is poorly characterised. Fourteen healthy males (25 ± 5 years; 1.79 ± 0.07 cm; 77.7 ± 9.8 kg; 14.8 ± 4.6% body fat) ingested 0.3 (LOW), 0.6 (MED) or 0.9 (HIGH) g·kg·FFM-1 GLN beverages, in a randomised, double-blind, counter-balanced, cross-over trial. Individual and accumulated GI symptoms were recorded using a visual analogue scale at regular intervals up to 24-h post ingestion. GLN beverages were characterised by tonicity measurement and microscopic observations. 24-h accumulated upper- and lower- and total-GI symptoms were all greater in the HIGH, compared to LOW and MED trials (p < 0.05). Specific GI symptoms (discomfort, nausea, belching, upper GI pain) were all more pronounced on the HIGH versus LOW GLN trial (p < 0.05). Nevertheless, most symptoms were still rated as mild. In comparison, the remaining GI symptoms were either comparable (flatulence, urge to regurgitate, bloating, lower GI pain) or absent (heart burn, vomiting, urge to defecate, abnormal stools, stitch, dizziness) between trials (p > 0.05). All beverages were isotonic and contained a dose-dependent number of GLN crystals. Acute oral GLN ingestion in dosages up to 0.9 g·kg·FFM-1 are generally well-tolerated. However, the severity of mild GI symptoms appeared dose-dependent during the first two hours post prandial and may be due to high-concentrations of GLN crystals.

Influence of aerobic fitness on gastrointestinal barrier integrity and microbial translocation following a fixed-intensity military exertional heat stress test.

PURPOSE: Exertional-heat stress adversely disrupts gastrointestinal (GI) barrier integrity, whereby subsequent microbial translocation (MT) can result in potentially serious health consequences. To date, the influence of aerobic fitness on GI barrier integrity and MT following exertional-heat stress is poorly characterised. METHOD: Ten untrained (UT; VO2max = 45 ± 3 ml·kg-1·min-1) and ten highly trained (HT; VO2max = 64 ± 4 ml·kg-1·min-1) males completed an ecologically valid (military) 80-min fixed-intensity exertional-heat stress test (EHST). Venous blood was drawn immediately pre- and post-EHST. GI barrier integrity was assessed using the serum dual-sugar absorption test (DSAT) and plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using plasma Bacteroides/total 16S DNA. RESULTS: UT experienced greater thermoregulatory, cardiovascular and perceptual strain (p < 0.05) than HT during the EHST. Serum DSAT responses were similar between the two groups (p = 0.59), although Δ I-FABP was greater (p = 0.04) in the UT (1.14 ± 1.36 ng·ml-1) versus HT (0.20 ± 0.29 ng·ml-1) group. Bacteroides/Total 16S DNA ratio was unchanged (Δ; -0.04 ± 0.18) following the EHST in the HT group, but increased (Δ; 0.19 ± 0.25) in the UT group (p = 0.05). Weekly aerobic training hours had a weak, negative correlation with Δ I-FABP and Bacteroides/total 16S DNA responses. CONCLUSION: When exercising at the same absolute workload, UT individuals are more susceptible to small intestinal epithelial injury and MT than HT individuals. These responses appear partially attributable to greater thermoregulatory, cardiovascular, and perceptual strain.

Reliability of gastrointestinal barrier integrity and microbial translocation biomarkers at rest and following exertional heat stress.

PURPOSE: Exertional heat stress adversely distrupts (GI) barrier integrity and, through subsequent microbial translocation (MT), negativly impacts health. Despite widespread application, the temporal reliability of popular GI barrier integity and MT biomarkers is poorly characterised. METHOD: Fourteen males completed two 80-min exertional heat stress tests (EHST) separated by 7-14 days. Venous blood was drawn pre, immediately- and 1-hr post both EHSTs. GI barrier integrity was assessed using the serum Dual-Sugar Absorption Test (DSAT), Intestinal Fatty-Acid-Binding Protein (I-FABP) and Claudin-3 (CLDN-3). MT was assessed using plasma Lipopolysaccharide Binding Protein (LBP), total 16S bacterial DNA and Bacteroides DNA. RESULTS: No GI barrier integrity or MT biomarker, except absolute Bacteroides DNA, displayed systematic trial order bias (p ≥ .05). I-FABP (trial 1 = Δ 0.834 ± 0.445 ng ml-1 ; trial 2 = Δ 0.776 ± 0.489 ng ml-1 ) and CLDN-3 (trial 1 = Δ 0.317 ± 0.586 ng ml-1 ; trial 2 = Δ 0.371 ± 0.508 ng ml-1 ) were increased post-EHST (p ≤ .01). All MT biomarkers were unchanged post-EHST. Coefficient of variation and typical error of measurement post-EHST were: 11.5% and 0.004 (ratio) for the DSAT 90-min postprobe ingestion; 12.2% and 0.004 (ratio) at 150-min postprobe ingestion; 12.1% and 0.376 ng ml-1 for I-FABP; 4.9% and 0.342 ng ml-1 for CLDN-3; 9.2% and 0.420 µg ml-1 for LBP; 9.5% and 0.15 pg µl-1 for total 16S DNA; and 54.7% and 0.032 for Bacteroides/total 16S DNA ratio. CONCLUSION: Each GI barrier integrity and MT translocation biomarker, except Bacteroides/total 16S ratio, had acceptable reliability at rest and postexertional heat stress.

The Gastrointestinal Exertional Heat Stroke Paradigm: Pathophysiology, Assessment, Severity, Aetiology and Nutritional Countermeasures.

Exertional heat stroke (EHS) is a life-threatening medical condition involving thermoregulatory failure and is the most severe condition along a continuum of heat-related illnesses. Current EHS policy guidance principally advocates a thermoregulatory management approach, despite growing recognition that gastrointestinal (GI) microbial translocation contributes to disease pathophysiology. Contemporary research has focused to understand the relevance of GI barrier integrity and strategies to maintain it during periods of exertional-heat stress. GI barrier integrity can be assessed non-invasively using a variety of in vivo techniques, including active inert mixed-weight molecular probe recovery tests and passive biomarkers indicative of GI structural integrity loss or microbial translocation. Strenuous exercise is strongly characterised to disrupt GI barrier integrity, and aspects of this response correlate with the corresponding magnitude of thermal strain. The aetiology of GI barrier integrity loss following exertional-heat stress is poorly understood, though may directly relate to localised hyperthermia, splanchnic hypoperfusion-mediated ischemic injury, and neuroendocrine-immune alterations. Nutritional countermeasures to maintain GI barrier integrity following exertional-heat stress provide a promising approach to mitigate EHS. The focus of this review is to evaluate: (1) the GI paradigm of exertional heat stroke; (2) techniques to assess GI barrier integrity; (3) typical GI barrier integrity responses to exertional-heat stress; (4) the aetiology of GI barrier integrity loss following exertional-heat stress; and (5) nutritional countermeasures to maintain GI barrier integrity in response to exertional-heat stress.

Postural Stability Under Dual-Task Conditions: Development of a Post-Concussion Assessment for Lower-Extremity Injury Risk.

CONTEXT: Concussions are consequence of sports participation. Recent reports indicate there is an increased risk of lower-extremity musculoskeletal injury when returning to sport after concussion suggesting that achieving "normal" balance may not fully indicate the athlete is ready for competition. The increased risk of injury may indicate the need to refine a screening tool for clearance. OBJECTIVE: Assess the between-session reliability and the effects of adding a cognitive task to static and dynamic postural stability testing in a healthy population. SETTING: Clinical laboratory. PARTICIPANTS: Twelve healthy subjects (6 women; age 22.3 [2.9] y, height 174.4 [7.5] cm, weight 70.1 [12.7] kg) participated in this study. DESIGN: Subjects underwent static and dynamic postural stability testing with and without the addition of a cognitive task (Stroop test). Test battery was repeated 10 days later. Dynamic postural stability testing consisted of a forward jump over a hurdle with a 1-legged landing. A stability index was calculated. Static postural stability was also assessed with and without the cognitive task during single-leg balance. Variability of each ground reaction force component was averaged. MAIN OUTCOME MEASURES: Interclass correlation coefficients (ICC2,1) were computed to determine the reliability. Standard error of measure, mean standard error, mean detectable change, and 95% confidence interval were all calculated. RESULTS: Mean differences between sessions were low, with the majority of variables having moderate to excellent reliability (static .583-.877, dynamic .581-.939). The addition of the dual task did not have any significant effect on reliability of the task; however, generally, the ICC values improved (eyes open .583-.770, dual task .741-.808). CONCLUSIONS: The addition of a cognitive load to postural stability assessments had moderate to excellent reliability in a healthy population. These results provide initial evidence on the feasibility of dual-task postural stability testing when examining risk of lower-extremity musculoskeletal injury following return to sport in a concussed population.