Competition between cross-linking and force-induced local conformational changes determines the structure and mechanics of labile protein networks.

Folded protein hydrogels are emerging as promising new materials for medicine and healthcare applications. Folded globular proteins can be modelled as colloids which exhibit site specific cross-linking for controlled network formation. However, folded proteins have inherent mechanical stability and unfolded in response to an applied force. It is not yet understood how colloidal network theory maps onto folded protein hydrogels and whether it models the impact of protein unfolding on network properties. To address this, we study a hybrid system which contains folded proteins (patchy colloids) and unfolded proteins (biopolymers). We use a model protein, bovine serum albumin (BSA), to explore network architecture and mechanics in folded protein hydrogels. We alter both the photo-chemical cross-linking reaction rate and the mechanical properties of the protein building block, via illumination intensity and redox removal of robust intra-protein covalent bonds, respectively. This dual approach, in conjunction with rheological and structural techniques, allows us to show that while reaction rate can 'fine-tune' the mechanical and structural properties of protein hydrogels, it is the force-lability of the protein which has the greatest impact on network architecture and rigidity. To understand these results, we consider a colloidal model which successfully describes the behaviour of the folded protein hydrogels but cannot account for the behaviour observed in force-labile hydrogels containing unfolded protein. Alternative models are needed which combine the properties of colloids (folded proteins) and biopolymers (unfolded proteins) in cross-linked networks. This work provides important insights into the accessible design space of folded protein hydrogels without the need for complex and costly protein engineering, aiding the development of protein-based biomaterials.

Achieving biocompatibility and tailoring mechanical properties of SLA 3D printed devices for microfluidic and cell culture applications.

Stereolithography (SLA) and other photopolymerization-based additive manufacturing approaches are becoming popular for the fabrication of microfluidic devices and cell-infused platforms, but many of the resins employed in these techniques are cytotoxic to cells or do not have the appropriate mechanical properties for microfluidic components. Here, using a commercially available resin, we demonstrate that biocompatibility and a range of mechanical properties can be achieved through post-print optimization involving baking, soaking, network swelling, and UV exposure. We show that UV-vis spectrophotometry can be used to detect methacrylate monomer/oligomer, and utilizing this method, we found that baking at 120 °C for 24 hours was the optimal method for removing cytotoxic chemical species and creating nontoxic cell culture platforms, though UV exposure and soaking in 100% ethanol also can substantially reduce cytotoxicity. Furthermore, we show that the mechanical properties can be modified, including up to 50% for the Young's modulus and an order of magnitude for the flexural modulus, through the post-processing approach employed. Based on the study results, users can choose post-processing approaches to achieve needed cytotoxicity and mechanical profiles, simultaneously.

The Effects of Cold Exposure, Hypoxia, and Fatigue on Pistol Marksmanship and Target Engagement Decision Making in Trained Marksmen.

ABSTRACT: Segovia, M, Salmon, OF, Ugale, C, and Smith, CM. The effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement decision making in trained marksmen. J Strength Cond Res 38(11): e686-e694, 2024-This study aimed to examine the effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement in trained marksmen. Twelve healthy subjects (mean ± SD age: 28.8 ± 4.0 years) performed 3 testing visits under normal/normoxic [Norm 21 ] (24° C; 21% FiO 2 ), cold/normoxic [Cold 21 ] (10° C; 21% FiO 2 ), and cold/hypoxic [Cold 14 ] (10° C; FiO 2 : 14.3) conditions. Pistol marksmanship and target engagement were assessed through draw time (DT) and shoot-no-shoot (SNS) courses of fire. The 2 protocols were performed before (T preF ) and immediately after (T postF ) a sandbag deadlift fatiguing protocol. Significance was set at p < 0.05. Significant condition × time interactions ( p = 0.01-0.03) were found for accuracy SNS (SNS acc ), misses SNS (SNS miss ), and total shots SNS (SNS tot ). Follow-up analyses indicated that SNS acc increased by 14.3% ( p = 0.03), SNS miss decreased by 34.7% ( p = 0.02), and SNS tot decreased by 10.6% ( p = 0.04) from T preF to T postF during the Cold 21 condition alone. No significance was found for these in the Norm 21 ( p = 0.08-0.22) or Cold 14 ( p = 0.18-0.47) conditions. Total time (SNS T ) to completion of the SNS ( p = 0.09) and DT ( p = 0.14) showed no significance across time or condition. Significant difference across time for Cold 14 ( p = 0.03-0.02) for reaction time was found. Exercise likely resulted in increased thermogenesis that improved tactically relevant motor skills including SNS acc , decreased SNS miss , and SNS tot in Cold 21 , but not Cold 14 . The additive effect of hypoxia coupled with exercise in the Cold 14 condition did not improve tactical performance, suggesting multi-stressor environments result in competing physiological responses. Tactical strength and conditioning specialists as well as operators should aim to improve thermoregulation during Cold 21 conditions, with exercise as a possible intervention.

Severity-dependent test-seeking behaviors and test-negative designs: impact on estimated vaccine effectiveness and utility of analytic and design choices.

Test-negative designs are increasingly used to evaluate vaccine effectiveness because of desirable properties like reduced confounding due to healthcare-seeking behaviors and lower cost compared to other study designs. An individual's decision to seek care often depends on their disease severity, with severe disease more likely to be captured than mild disease. As many vaccines likely attenuate disease severity, this phenomenon generally results in an upward-biased estimate of vaccine effectiveness against symptomatic disease. To address the resulting bias, analytic solutions like adjusting for or matching on severity have been suggested. In this paper, we examine the performance of the test-negative design under different vaccine effects on disease severity and the utility of adjusting or matching on severity. We further consider the implications of studies that focus only on milder disease by restricting recruitment to outpatient settings. Through an analytic framework and simulations accompanied by a real-world example, we demonstrate that, when vaccination attenuates disease severity, the magnitude of bias is influenced by the degree of under-ascertainment of mild disease relative to severe disease. When vaccination does not attenuate disease severity, bias is not present. We further show that analytic fixes negligibly impact bias and that outpatient-only studies frequently produce downward-biased estimates.

Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I/II interferons and preexisting tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC. Significance: MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and Vδ1 T cells as clinically actionable mediators of ICB response in major histocompatibility complex-high and -low MCCs, respectively.

A Retrospective Analysis of Southeastern U.S. Police Recruit Health and Fitness From 4 Points in Time Within a 16-Year Period: Implications for Physical Fitness Training.

ABSTRACT: Gonzales, SM, Orr, RM, Coburn, JW, Hoffmann, MD, Kennedy, K, Dawes, JJ, and Lockie, RG. A retrospective analysis of southeastern U.S. police recruit health and fitness from 4 points in time within a 16-year period: Implications for physical fitness training. J Strength Cond Res 38(6): 1118-1126, 2024-Drawing from the general population for its recruiting needs, police departments often employ academy curricula to improve a recruit's fitness so they can perform occupational tasks. Recently, obesity and physical inactivity have increased in the general population, potentially influencing the health and fitness of incoming recruits. This study involved a retrospective, cross-sectional analysis of health and fitness data of police recruits. Data from 1 police department in southeastern United States were analyzed at 4 specific time points, splitting the recruits into natural immerging groups; 2003 (n = 93), 2006 (n = 137), 2009 (n = 74), and 2019 (n = 242). Health and fitness data for all recruits included age, height, body mass, and body mass index (BMI); systolic and diastolic blood pressure (BP); sit-and-reach; combined grip strength; push-ups and sit-ups completed in 60 seconds; physical ability test time; and 2.4-km run time. Several univariate analyses, with sex and age as covariates (analyses of covariance), and a Bonferroni's post hoc, determined whether there were significant between-group differences. Effect sizes (d) were also calculated. Key results demonstrated that 2019 recruits were heavier than the recruits in 2006 and 2009 (p ≤ 0.032; d = 0.14-0.38); had a greater BMI (p ≤ 0.028; d = 0.24-0.75) and systolic BP (p < 0.001; d = 0.47-0.65), and lesser sit-and-reach distance (p ≤ 0.020; d = 0.26-0.46), than all recruit groups; completed fewer sit-up repetitions than the recruits in 2006 and 2009 (p ≤ 0.025; d = 0.42-0.48); and were slower in the 2.4-km run than the recruits in 2006 (p = 0.009; d = 0.36). Police training staff may need to address lesser health (BMI, BP) and fitness (hamstring flexibility, abdominal endurance, aerobic fitness) in incoming recruits.

Impact of acute hypoxic exposure on neuromuscular and hemodynamic responses during step intensity dynamic constant external resistance leg extension exercise.

OBJECTIVES: This study examined the effects of acute normoxic and hypoxic exposure on neuromuscular and hemodynamic physiological responses performed during dynamic step muscle actions. METHODS: Thirteen recreationally active men (mean ± SD age: 21.2 ± 2.9 yrs) performed dynamic leg extensions unilaterally under Normoxic (FiO2 = 21 %) and Hypoxic (FiO2 = 13 %) conditions in a randomized order at 20 %, 40 %, 60 %, 80 %, and 100 % of their maximal strength. Electromyographic (EMG) amplitude, EMG frequency, (Oxygenated and Deoxygenated hemoglobin; OxyHb, DeoxyHb), Total hemoglobin (TotalHb), and skeletal muscle tissue oxygenation status (StO2) were measured from the vastus lateralis during all contractions. RESULTS: There were no detectable differences in the neuromuscular responses between normoxia and hypoxia for EMG amplitude (p = 0.37-0.74) and frequency (p = 0.17-0.83). For EMG amplitude there were general increases with intensity (p < 0.01-0.03). EMG frequency remained similar from 20% to 80% and then increased at 100 % effort (p = 0.02). There was no significant difference in patterns of responses for OxyHb (p = 0.870) and TotalHb (p = 0.200) between normoxia and hypoxia. StO2 (p = 0.028) decreased and DeoxyHb (p = 0.006) increased under hypoxia compared to normoxia during dynamic step muscle actions performed in a randomized order. CONCLUSION: Unlike fatigue, acute hypoxemia in an unfatigued state does not impact the localized neuromuscular responses, but minimally impacts the hemodynamic responses.

Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study.

Background: The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings. Methods: We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19. Findings: 46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B. Interpretation: In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days. Funding: None.

Bypassing the Brick-and-Mortar Hospital: Increasing Direct Admissions from the Emergency Department to Inpatient Hospital-at-Home.

Home hospital programs continue to grow across the United States. There are limited studies around the process of patient selection and successful acquisition from the emergency department. The article describes how an interdisciplinary team used quality improvement methodology to significantly increase the number of admissions directly from the emergency department to the Advanced Care at Home program.

Nasolacrimal duct obstruction prevalence is 0.3% among alpacas evaluated with ophthalmic disease at a veterinary teaching hospital between 2000 and 2023.

OBJECTIVE: To examine the prevalence of nasolacrimal duct (NLD) obstruction in hospital populations and assess signalment, diagnostics, and clinical approaches for alpacas and llamas diagnosed with NLD atresia or obstruction. ANIMALS: 29 alpacas and 2 llamas. CLINICAL PRESENTATION: Medical records were reviewed to identify camelids with NLD evaluated between 2000 and 2023. Signalment, history, physical examination data, diagnosis, and treatments were recorded. Follow-up information was gathered via phone and email questionnaire. Data were evaluated to determine prevalence and describe signalment and treatments for NLD disease. RESULTS: 31 camelids met the inclusion criteria. A total of 8,027 alpacas and 1,998 llamas were seen within the study period at 1 teaching institution. The prevalence of NLD obstruction for this population of alpacas was 0.3% (26/8,027). Nineteen of 31 (61%) camelids presented at 1 year of age or younger. The most common physical exam finding was ocular discharge (68%). The most common diagnosis was NLD atresia (16/31 [51%]). Patency was established by surgical opening or lavage of the NLD. Long-term follow-up was available for 13 alpacas and 2 llamas, of which 11 (73%) had successful outcomes. CLINICAL RELEVANCE: Results indicate that NLD obstruction is a condition that most commonly affects alpacas < 1 year of age and is associated with a good prognosis for treatment success.

Confronting Health Misinformation Surrounding COVID-19 Vaccines in the State of Florida.

COVID-19 vaccination is estimated to have averted more than 2.4 million deaths globally. In the United States (U.S.) alone, more than 120,000 deaths and 700,000 hospitalizations are reportedly estimated to have been prevented during the first six months of the vaccine campaign. Despite the overwhelming evidence regarding the safety and efficacy of vaccination, COVID-19 vaccine hesitancy continues to pose a significant threat to public health. Notably, an unexpected source of vaccine misinformation has been the Surgeon General of the State of Florida, Dr. Joseph Ladapo. While both a tenured faculty member of the University of Florida, College of Medicine and the Surgeon General of Florida, Dr. Ladapo has delivered official Florida Department of Health statements regarding COVID-19 vaccines that run contrary to those of the U.S. Centers for Disease Control and Prevention (CDC). While tenure is designed to protect those with contrarian views, we believe that the University has an ethical obligation to condemn misleading statements that put public health at risk. Herein, we explore the challenges of managing misinformation disseminated by someone who is simultaneously a tenured professor at a public, state-supported university, and a politically appointed public health official.

BODIPY Chemisorbed on SnO2 and TiO2 Surfaces for Photoelectrochemical Applications.

Advancement toward dye-sensitized photoelectrochemical cells to produce solar fuels by solar-driven water splitting requires a photosensitizer that is firmly attached to the semiconducting photoelectrodes. Covalent binding enhances the efficiency of electron injection from the photoexcited dye into the metal oxide. Optimization of charge transfer, efficient electron injection, and minimal electron-hole recombination are mandatory for achieving high efficiencies. Here, a BODIPY-based dye exploiting a novel surface-anchoring mode via boron is compared to a similar dye bound by a traditional carboxylic acid anchoring group. Through terahertz and transient absorption spectroscopic studies, along with interfacial electron transfer simulations, we find that, when compared to the traditional carboxylic acid anchoring group, electron injection of boron-bound BODIPY is faster into both TiO2 and SnO2. Although the surface coverage is low compared with carboxylic acids, the binding stability is improved over a wide range of pH. Subsequent photoelectrochemical studies using a sacrificial electron donor showed that this combined dye and anchoring group maintained photocurrent with good stability over long-time irradiation. This recently discovered binding mode of BODIPY shows excellent electron injection and good stability over time, making it promising for future investigations.

Correction: Effectiveness of a monthly schedule of follow-up for the treatment of uncomplicated severe acute malnutrition in Sokoto, Nigeria: A cluster randomized crossover trial.

[This corrects the article DOI: 10.1371/journal.pmed.1003923.].

Athletes' Coping With the COVID-19 Pandemic: The Role of Self-Compassion and Cognitive Appraisal.

Coping with the COVID-19 pandemic had implications for athletes' mental well-being. This mixed-methods study examined the influence of self-compassion on athletes' coping during the pandemic through the mediator of cognitive appraisal. The prospective design involved 90 athletes completing two online surveys 1 week apart measuring self-compassion, cognitive appraisal, and coping strategies. The PROCESS macro was used for the mediation analysis. A qualitative thematic analysis was used to explore athletes' responses to the pandemic during the second survey. Self-compassion had an indirect negative effect on avoidance-focused coping by appraising the pandemic as less of a threat (95% confidence interval [-0.20, -0.001]) and had a total effect on emotion-focused coping (95% confidence interval [0.02, 0.40]). Based on the thematic analysis, athletes described many raw emotions and a variety of coping strategies during the pandemic. Self-compassion demonstrated promising benefits to athletes who dealt with the challenging situation of the pandemic.

Modeling nontuberculous mycobacterial infections in zebrafish.

The incidence of infections due to nontuberculous mycobacteria (NTM) has increased rapidly in recent years, surpassing tuberculosis in developed countries. Due to inherent antimicrobial resistance, NTM infections are particularly difficult to treat with low cure rates. There is an urgent need to understand NTM pathogenesis and to develop novel therapeutic approaches for the treatment of NTM diseases. Zebrafish have emerged as an excellent animal model due to genetic amenability and optical transparency during embryonic development, allowing spatiotemporal visualization of host-pathogen interactions. Furthermore, adult zebrafish possess fully functional innate and adaptive immunity and recapitulate important pathophysiological hallmarks of mycobacterial infection. Here, we report recent breakthroughs in understanding the hallmarks of NTM infections using the zebrafish model.

Concentration-Dependent Photocatalytic Upcycling of Poly(ethylene terephthalate) Plastic Waste.

Photocatalytic plastic waste upcycling into value-added feedstock is a promising way to mitigate the environmental issues caused by the nondegradable nature of plastic waste. Here, we developed a MoS2/g-C3N4 photocatalyst that can efficiently upcycle poly(ethylene terephthalate) (PET) into valuable organic chemicals. Interestingly, the conversion mechanism is concentration-dependent. For instance, at a low ethylene glycol (EG) concentration (7.96 mM), acetate is the main product. Unexpectedly, the conversion of PET water bottle hydrolysate with only 7.96 mM ethylene glycol (EG) can produce a 4 times higher amount of acetate (704.59 nmol) than the conversion of 300 mM EG (174.50 nmol), while at a higher EG concentration (300 mM), formate is the dominant product. Herein, a 40 times higher EG concentration (300 mM compared to 7.96 mM) would produce only ∼3 times more formate (179 nmol compared to 51.86 nmol). In addition, under natural sunlight conditions, comparable amounts of liquid and gaseous products are produced when commercial PET plastics are employed. Overall, the photocatalytic PET conversion process is quite efficient under a low concentration of EG in PET hydrolysate, indicating the enormous potential of this photocatalysis strategy for real plastics upcycling.

The Psychometric Properties of Two Brief Measures of Teamwork in Sport.

In the current study, the structural and external validity of data derived from two shorter versions of the Multidimensional Assessment of Teamwork in Sport (MATS) were examined using multilevel analyses. Evidence of model-data fit was shown for both a 5-factor model comprising 19 items (with subscales assessing teamwork preparation, execution, evaluation, adjustments, and management of team maintenance) and a single-factor model comprising five items (providing a global estimate of teamwork). In general, data from both versions were positively and significantly correlated with (and distinct from) athletes' perceptions of team cohesion, collective efficacy, performance satisfaction, enjoyment in their sport, and commitment to their team and their coaches' transformational leadership. The measures appear well suited to detect between-teams differences, as evidenced by intraclass correlation coefficients and acceptable reliability estimates of team-level scores. In summary, the 19-item Multidimensional Assessment of Teamwork in Sport-Short and five-item Multidimensional Assessment of Teamwork in Sport-Global provide conceptually and psychometrically sound questionnaires to briefly measure teamwork in sport.

Visualization of Self-Assembly and Hydration of a ß-Hairpin through Integrated Small and Wide-Angle Neutron Scattering.

Fundamental understanding of the structure and assembly of nanoscale building blocks is crucial for the development of novel biomaterials with defined architectures and function. However, accessing self-consistent structural information across multiple length scales is challenging. This limits opportunities to exploit atomic scale interactions to achieve emergent macroscale properties. In this work we present an integrative small- and wide-angle neutron scattering approach coupled with computational modeling to reveal the multiscale structure of hierarchically self-assembled ß hairpins in aqueous solution across 4 orders of magnitude in length scale from 0.1 Å to 300 nm. Our results demonstrate the power of this self-consistent cross-length scale approach and allows us to model both the large-scale self-assembly and small-scale hairpin hydration of the model ß hairpin CLN025. Using this combination of techniques, we map the hydrophobic/hydrophilic character of this model self-assembled biomolecular surface with atomic resolution. These results have important implications for the multiscale investigation of aqueous peptides and proteins, for the prediction of ligand binding and molecular associations for drug design, and for understanding the self-assembly of peptides and proteins for functional biomaterials.

The impact of cold, hypoxia, and physical exertion on pistol accuracy and tactical performance.

The purpose of this study was to examine the impact of independent cold and combined cold and hypoxic exposures on operational-specific task performance including pistol marksmanship, pistol magazine reload ability, and subjective and objective thermal indices before and after a whole-body physical exertional task. Twelve participants were exposed to Thermoneutral Normoxic (24 °C; FiO2 21%), Cold Normoxic (10 °C; FiO2 21%), and Cold Hypoxic (10 °C; FiO2 14%) conditions for 30min before performing pistol marksmanship at distances of 6.40 and 13.72m and a pistol magazine reload task before and after 3 sets of sandbag deadlifts at 50% body mass. Thermal perception and hand temperatures were collected before and after the physical exertion task. There were no significant differences in Pistol Accuracy performance at distances of 6.40 and 13.72m due to physical exertion, cold, or hypoxia. Following physical exertion, Pistol Accuracy was similar between Thermoneutral and Cold Normoxic conditions but lead to 17% and a 10% reduction in performance during the Cold Hypoxic condition, compared to Thermoneutral and Cold Normoxic conditions. There was no change in Pistol Accuracy for the Thermoneutral Normoxic condition. The pistol magazine reload task was not impacted by physical exertion, but there was a reduction in performance in Cold Normoxic 21% (4.04s) and Cold Hypoxic 16% (3.08s) conditions. Physical exertion did not impact hand temperature but did increase thermal perception scores for all conditions. These findings indicate that cold exposure reduced both tactical dexterity and pistol marksmanship, however, physical exertion may offset these deficits via an increase in thermal perception. Additionally, hypoxemia was the primary mediator of marksmanship performance in cold hypoxic environments following an acute bout of physical exertion. Thus, in cold mountainous environments, marksmen should be aware of their elevation and utilize brief episodes of physical activity to enhance their thermal state when marksmanship is a priority for operational success.