The nonindustrialised microbiome in a modern world.

The microbiome contributes to human development and maturation, and is essential for maintenance of health and prevention of disease. While the human genome encodes one's identity, the microbiome - also individually unique - provides a window on one's lifestyle and exposure to environmental variables. The microbiome thus serves as a biomarker of host health and a driver of certain diseases. However, current understanding of the gut microbiome is largely based on studies of industrialised peoples of North America and Europe. Gaps in knowledge of the microbiomes of other groups, particularly those in developing or nonindustrialised societies, are important, particularly in view of contrasting epidemiological risks of acquiring chronic inflammatory and metabolic disorders. Here, we explore underlying mechanisms of microbiome differences and whether the potential benefits of nonindustrialised microbiome can be realised in a modern world.

Spontaneous prevertebral emphysema following weight training in a 21-year-old female.

Subcutaneous emphysema (SCE) of the head, neck and mediastinum most commonly arises due to penetrating trauma and iatrogenic events facilitating air entry into these spaces [1]. Spontaneous SCE can emerge due to a pressure gradient between the intra-alveolar air and surrounding structures, causing alveolar rupture and dissection of the peribronchovascular sheath. This is known as the Macklin effect. Potential consequences include pneumomediastinum, pneumothorax, facial emphysema and pneumoracchis [1]. We aim to describe a case of SCE in a 21-year-old female presenting to the emergency department (ED) after weight training. A 21-year-old female presented to the ED with a sore throat and dysphagia after weight lifting in the gym 6 h earlier. Training involved repeat Valsalva manoeuvres. She experienced sharp pain with onset over an hour, worse with swallowing. She had a history of gastro-oesophageal reflux disease. Vital signs, local examination and systemic examination were unremarkable. The diagnosis was made with soft tissue neck X-ray, demonstrating emphysema within the prevertebral space extending from the skull base to the first thoracic vertebra (Fig. 1). Her chest X-ray showed no pneumothorax or pneumomediastinum. No intervention was required beyond analgesia, and she was discharged from the ED. She was advised to avoid heavy lifting and diving. A follow-up radiograph showed resolution of the SCE. This case is an important rare entity and highlights for clinicians that pain after physical exercise may involve injuries extending beyond the area directly trained.

The importance of pre-training gap analyses and the identification of competencies and skill requirements of medical personnel for mass casualty incidents and disaster training.

BACKGROUND: Effective preparedness to respond to mass casualty incidents and disasters requires a well-planned and integrated effort by all involved professionals, particularly those who are working in healthcare, who are equipped with unique knowledge and skills for emergencies. This study aims to investigate and evaluate the level of knowledge and skills related to mass casualty and disaster management in a cohort of healthcare professionals. METHODS: A cross-sectional brief study was conducted using a validated and anonymous questionnaire, with a sample of 134 employees at a clinical hospital in Lublin, Poland. RESULTS: The findings of this study may indicate a need for standardization of training for hospitals employees. It also suggests a knowledge gap between different professional groups, which calls for adjusting such general training, to at least, the weakest group, while special tasks and mission can be given to other groups within the training occasion. CONCLUSION: Pre-Training gap analyses and identification of participants' competencies and skills should be conducted prior to training in mass casualty incidents and disasters. Such analyses provides an opportunity to develop training curriculum at various skill and knowledge levels from basic to advance. All training in mass casualty incidents and disasters should be subject to ongoing, not just periodic, evaluation, in order to assess continued competency.

Gut microbiota alterations associated with reduced bone mineral density in older adults.

OBJECTIVE: To investigate compositional differences in the gut microbiota associated with bone homeostasis and fractures in a cohort of older adults. METHODS: Faecal microbiota profiles were determined from 181 individuals with osteopenia (n = 61) or osteoporosis (n = 60), and an age- and gender-matched group with normal BMD (n = 60). Analysis of the 16S (V3-V4 region) amplicon dataset classified to the genus level was used to identify significantly differentially abundant taxa. Adjustments were made for potential confounding variables identified from the literature using several statistical models. RESULTS: We identified six genera that were significantly altered in abundance in the osteoporosis or osteopenic groups compared with age- and gender-matched controls. A detailed study of microbiota associations with meta-data variables that included BMI, health status, diet and medication revealed that these meta-data explained 15-17% of the variance within the microbiota dataset. BMD measurements were significantly associated with alterations in the microbiota. After controlling for known biological confounders, five of the six taxa remained significant. Overall microbiota alpha diversity did not correlate to BMD in this study. CONCLUSION: Reduced BMD in osteopenia and osteoporosis is associated with an altered microbiota. These alterations may be useful as biomarkers or therapeutic targets in individuals at high risk of reductions in BMD. These observations will lead to a better understanding of the relationship between the microbiota and bone homeostasis.

Moderate-intensity aerobic and resistance exercise is safe and favorably influences body composition in patients with quiescent Inflammatory Bowel Disease: a randomized controlled cross-over trial.

BACKGROUND: Overweight and metabolic problems now add to the burden of illness in patients with Inflammatory Bowel Disease. We aimed to determine if a program of aerobic and resistance exercise could safely achieve body composition changes in patients with Inflammatory Bowel Disease. METHODS: A randomized, cross-over trial of eight weeks combined aerobic and resistance training on body composition assessed by Dual Energy X-ray Absorptiometry was performed. Patients in clinical remission and physically inactive with a mean age of 25 ± 6.5 years and Body Mass Index of 28.9 ± 3.8 were recruited from a dedicated Inflammatory Bowel Disease clinic. Serum cytokines were quantified, and microbiota assessed using metagenomic sequencing. RESULTS: Improved physical fitness was demonstrated in the exercise group by increases in median estimated VO2max (Baseline: 43.41mls/kg/min; post-intervention: 46.01mls/kg/min; p = 0.03). Improvement in body composition was achieved by the intervention group (n = 13) with a median decrease of 2.1% body fat compared with a non-exercising group (n = 7) (0.1% increase; p = 0.022). Lean tissue mass increased by a median of 1.59 kg and fat mass decreased by a median of 1.52 kg in the exercising group. No patients experienced a deterioration in disease activity scores during the exercise intervention. No clinically significant alterations in the α- and ß-diversity of gut microbiota and associated metabolic pathways were evident. CONCLUSIONS: Moderate-intensity combined aerobic and resistance training is safe in physically unfit patients with quiescent Inflammatory Bowel Disease and can quickly achieve favourable body compositional changes without adverse effects. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov; Trial number: NCT02463916 .

A Repeated-measures Case Series of Physiological Responses to a Transoceanic Rowing Race.

This repeated-measures case series describes the changes in cardiorespiratory fitness, body composition and systemic inflammation in 4 well-trained athletes pre- and post-completion of an unsupported transatlantic rowing race. The acute effects of endurance exercise have been well described previously, but the enduring consequences of ultra-endurance on the cardiorespiratory, metabolic and immune systems are largely unknown. This study explores these physiological adaptations following 2 weeks of recovery. Cardiorespiratory fitness testing, body composition analysis, and blood sampling for inflammatory cytokines were recorded immediately before race departure and repeated 14 days following race completion. Mean VO2max (ml/kg/min) was similar pre- (48.2±2.8) and post-race (46.7±1.5). Heart rate responses were equivalent at incremental workloads. Mean blood lactate (mmol/L) was higher at low to moderate power outputs and lower at maximal effort (14.6±1.85 vs. 13.1±2.5). Percentage body fat (17.7 ± 7.9 vs. 16.2±7.4) was analogous to pre-race analysis. Low-grade inflammation persisted, indicated by an increase in IL-1ß (69%), IL-8 (10%), TNF-α (8%), IL-6 (5.4%), and C-reactive protein (22.4%). VO2max and heart rate responses were similar pre- and post-race, but sub-maximal efficiency measures of cardiorespiratory fitness were consistent with persistent fatigue. Body composition had returned to baseline but low-grade systemic inflammation persisted. Persistent pro-inflammatory cytokinaemia is known to exert deleterious consequences on immune, metabolic, and psychological function. Adequate recovery is necessary to re-establish inflammatory homeostasis, and the results of this study may inform these decisions.

The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level.

OBJECTIVE: It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state. DESIGN: Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively). RESULTS: Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups. CONCLUSIONS: Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet-exercise-gut microbiota paradigm.

GREB1 genetic variants are associated with bone mineral density in Caucasians.

Gaining an understanding of factors contributing to bone quality is key to the development of effective preventative treatments for osteoporosis and reduction in osteoporotic fractures. Oestrogen is a strong regulator of bone remodelling which maintains skeletal structural integrity. The growth regulation by oestrogen in breast cancer 1 (GREB1) gene, with an as yet undefined function, is an early response gene in the oestrogen-regulated pathway. Suggestive evidence of linkage with bone mineral density (BMD) variation has been reported with D2S168, located telomeric of GREB1. The aim of this study was to determine if genetic variation within GREB1 was associated with BMD variation at two sites with high fracture rates-the lumbar spine (LS) and the femoral neck (FN). Informative GREB1 single-nucleotide polymorphisms (SNPs) (n = 12) were selected for genotyping and tested for association in a family-based dataset (n = 508 individuals from 229 families). Significantly associated SNPs were tested further in a postmenopausal dataset from the same geographic region (n = 477 individuals). One intronic SNP, rs5020877, was significantly associated with LS and FN BMD in the family-based dataset (P ≤ 0.005). The association was not observed in the postmenopausal dataset (P > 0.017); however, rs10929757 was significantly associated with FN BMD (P = 0.006). Markers, rs5020877 and rs10929757, were constituent SNPs in one GREB1 linkage disequilibrium block, although not historically correlated (r 2 = 0.07). Our findings suggest that GREB1 is a novel gene target for osteoporosis genetics and needs to be investigated further.

Exercise, fitness, and the gut.

PURPOSE OF REVIEW: Exercise and gut symptomatology have long been connected. The possibility that regular exercise fosters intestinal health and function has been somewhat overlooked in the scientific literature. In this review, we summarize current knowledge and discuss a selection of recent, relevant, and innovative studies, hypotheses and reviews that elucidate a complex topic. RECENT FINDINGS: The multiorgan benefits of regular exercise are extensive. When taken in moderation, these benefits transcend improved cardio-respiratory fitness and likely reach the gut in a metabolic, immunological, neural, and microbial manner. This is applicable in both health and disease. However, further work is required to provide safe, effective recommendations on physical activity in specific gastrointestinal conditions. SUMMARY: Challenging methodology investigating the relationship between exercise and gut health should not deter from exploring exercise in the promotion of gastrointestinal health.

Intestinal microbiota: shaping local and systemic immune responses.

Recent studies have highlighted the fundamental role of commensal microbes in the maintenance of host homeostasis. For instance, commensals can play a major role in the control of host defense, metabolism and tissue development. Over the past few years, abundant experimental data also support their central role in the induction and control of both innate and adaptive responses. It is now clearly established that commensals are not equal in their capacity to trigger control regulatory or effector responses, however, the molecular basis of these differences has only recently begun to be explored. This review will discuss recent findings evaluating how commensals shape both effector and regulatory responses at steady state and during infections and the consequence of this effect on local and systemic protective and inflammatory responses.

Comparison of single CT scan assessment of bone mineral density, vascular calcification and fat mass with standard clinical measurements in renal transplant subjects: the ABC HeART study.

BACKGROUND: Despite limitations of routine methods, Clinical Practice Guidelines support the assessment of bone mineral density (BMD) and vascular calcification in renal transplant recipients. Changes in fat mass also occur post-transplantation, although they are traditionally difficult to measure accurately. We report the feasibility, convenience and accuracy of measuring the above 3 parameters using a novel CT protocol. METHODS: We conducted a cross-sectional study of 64 first renal allograft recipients (eGFR > 30 ml/min/1.73 m(2)). Quantitative CT (QCT) BMD analysis was conducted using CT lumbar spine (GE Medical Systems Lightspeed VCT & Mindways QCT Pro Bone Mineral Densitometry System Version 4.2.3) to calculate spinal volumetric BMD and compared with standard DXA calculated areal BMD at the spine, hip and distal forearm. Abdominal aortic calcification was assessed by semi-quantitative Aortic Calcification Index (ACI) method and compared with lateral lumbar x-ray Kappuila score and pulse wave velocity (PWV). Visceral and subcutaneous adipose tissue volume (Osirix 16 Ver 3.7.1) was compared with BMI. RESULTS: Participants were 61 % male, had a mean age of 47 years, median ESKD duration of 5.4 years and a mean eGFR of 54 ml/min. iDXA median T-score at proximal femur was -1.2 and at lumbar spine was -0.2. Median QCT Trabecular T-score at lumbar spine was -1.2. The percent of subjects with a T-score of < 2.5 by site and method was DXA Proximal Femur: 7 %, DXA distal radius: 17 %, DXA spine: 9 %, QCT (American College of Radiology cutoffs): 9 %. CT derived ACI correlated with PWV (r = 0.29, p = 0.02), pulse wave pressure (r = 0.51, p < 0.001), QCT Trabecular (-0.31, p = 0.01) and cortical volumetric BMD and history of cardiovascular events (Mann-Whitney U, p = 0.02). Both visceral and subcutaneous adipose tissue correlated with BMI (r = 0.63 & 0.64, p < 0.001). CONCLUSIONS: Single CT scan triple assessment of BMD, vascular calcification and body composition is an efficient, accurate and convenient method of risk factor monitoring post renal transplantation.

Sustainable Effectiveness of Applying Trauma Team Activation in Managing Trauma Patients in the Emergency Department.

OBJECTIVE: To determine long term effectiveness of trauma team activation criteria by measuring emergency department length of stay (EDLOS) and 28-day mortality. MATERIAL AND METHOD: A 3-year retrospective cohort study conducted in adult trauma patients who met one of the trauma team activation criteria (shock, penetrating torso injury, post traumatic arrest, respiratory rate of less than 12 or more than 30, and pulse rate of more than 120). Specific demographic data, physiologic parameters, EDLOS, injury severity score (ISS), and 28-day mortality were prospectively recorded into the Trauma Registry database. Multiple logistic regression analysis was used to determine factors affecting mortality. The Institutional Review Board approval was obtained prior to undertaking the project. RESULTS: Two hundred eighty two patients with a mean age of35.1 years old were eligible. The median ISS was 25 (range, 13-30). The median EDLOS was 85 minutes (range, 50-135) and the 28-day mortality rate was 46.5%. The mean age was 31.7 years in the survival group and 38.7 years in the fatal group (p = 0.001). The median ISS was 17 in the survival group and 26 in the fatal group (p = 0.000) and the median EDLOS was 110 minutes in the survival group and 82 minutes in the fatal group (p = 0.034). When compared to data prior to the TTA application, the median time of EDLOS improvedsustainably from 184 to 85 minutes (p = 0.000) and the mortality rate decreased from 66.7% to 46.5% (p = 0.057). The parameters affecting patient mortality were older age, high ISS, and shorter EDLOS. CONCLUSION: Trauma team activation criteria significantly improved acute trauma care in the emergency department and decreased mortality.

Exercise and associated dietary extremes impact on gut microbial diversity.

OBJECTIVE: The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota. DESIGN: Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire. RESULTS: As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro-organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase. CONCLUSIONS: The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes.

Health care system hazard vulnerability analysis: an assessment of all public hospitals in Abu Dhabi.

Hazard vulnerability analysis (HVA) is used to risk-stratify potential threats, measure the probability of those threats, and guide disaster preparedness. The primary objective of this project was to analyse the level of disaster preparedness in public hospitals in the Emirate of Abu Dhabi, utilising the HVA tool in collaboration with the Disaster Medicine Section at Harvard Medical School. The secondary objective was to review each facility's disaster plan and make recommendations based on the HVA findings. Based on the review, this article makes eight observations, including on the need for more accurate data; better hazard assessment capabilities; enhanced decontamination capacities; and the development of hospital-specific emergency management programmes, a hospital incident command system, and a centralised, dedicated regional disaster coordination centre. With this project, HVAs were conducted successfully for the first time in health care facilities in Abu Dhabi. This study thus serves as another successful example of multidisciplinary emergency preparedness processes.

A Narrative Review of Contact Sports Participation in Children and Young Athletes With a Solitary (Functioning) Kidney.

BACKGROUND: Evidence is sparse regarding the incidence or prevalence of renal or genitourinary injuries arising from contact sports. There are currently no World Health Organization or European consensus guidelines relating to the participation in sport for children and young athletes with a solitary (functioning) kidney. PURPOSE: To review the international literature and to make sport-specific recommendations for children and young athletes with a solitary (functioning) kidney participating in sports, based on the overall likelihood of potential renal or genitourinary injury. STUDY DESIGN: Narrative review; Level of evidence, 4. METHODS: A descriptive epidemiological study was conducted of current literature according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Embase, Google Scholar, Cochrane, and PubMed databases were queried from 1975 to 2023, to assess available evidence regarding the prevalence and risk of renal injury through sports participation and guidelines surrounding the participation in sports for children and young athletes with a solitary (functioning) kidney. Methodological quality and certainty of evidence were assessed according to the International Classification of Urological Disease guidelines. RESULTS: A total of 28 publications were identified after database searches and exclusions, comprising 40,889 patients. The majority of papers providing recommendations arose from the United States. Of the recommendations, 79% permitted an unrestricted return to noncontact sports. A return to contact sports is permitted in most instances after physician consultation. CONCLUSION: There is a dearth of good-quality published evidence in the literature relating to sports participation with a solitary (functioning) kidney. Overall, the risk of genitourinary injury in sports is low, and after physician assessment, there is currently no strong evidence to exclude children and young athletes with a solitary (functioning) kidney from full participation in contact and collision sports.

Suppressive CD8+ T cells arise in the absence of CD4 help and compromise control of persistent virus.

There is an urgent need to develop novel therapies for controlling chronic virus infections in immunocompromised patients. Disease associated with persistent γ-herpesvirus infection (EBV, human herpesvirus 8) is a significant problem in AIDS patients and transplant recipients, and clinical management of these conditions is difficult. Immune surveillance failure followed by γ-herpesvirus recrudescence can be modeled using murine γ-herpesvirus (MHV)-68 in mice lacking CD4(+) T cells. In contrast with other chronic infections, no obvious defect in the functional capacity of the viral-specific CD8(+) T cell response was detected. We show in this article that adoptive transfer of MHV-68-specific CD8(+) T cells was ineffective at reducing the viral burden. Together, these indicate the potential presence of T cell extrinsic suppressive factors. Indeed, CD4-depleted mice infected with MHV-68 express increased levels of IL-10, a cytokine capable of suppressing the function of both APCs and T cells. CD4-depleted mice developed a population of CD8(+) T cells capable of producing IL-10 that suppressed viral control. Although exhibiting cell surface markers indicative of activation, the IL-10-producing cells expressed increased levels of programmed death-1 but were not enriched in the MHV-68-specific compartment, nor were they uniformly CD44(hi). Therapeutic administration of an IL-10R blocking Ab enhanced control of the recrudescent virus. These data implicate IL-10 as a promising target for the restoration of immune surveillance against chronic γ-herpesvirus infection in immunosuppressed individuals.

CD4+ T cell regulation of CD25 expression controls development of short-lived effector CD8+ T cells in primary and secondary responses.

Both CD4(+) T cell help and IL-2 have been postulated to "program" activated CD8(+) T cells for memory cell development. However, the linkage between these two signals has not been well elucidated. Here we have studied effector and memory CD8(+) T cell differentiation following infection with three pathogens (Listeria monocytogenes, vesicular stomatitis virus, and vaccinia virus) in the absence of both CD4(+) T cells and IL-2 signaling. We found that expression of CD25 on antigen-specific CD8(+) T cells peaked 3-4 days after initial priming and was dependent on CD4(+) T cell help, likely through a CD28:CD80/86 mediated pathway. CD4(+) T cell or CD25-deficiency led to normal early effector CD8(+) T cell differentiation, but a subsequent lack of accumulation of CD8(+) T cells resulting in overall decreased memory cell generation. Interestingly, in both primary and recall responses KLRG1(high) CD127(low) short-lived effector cells were drastically diminished in the absence of IL-2 signaling, although memory precursors remained intact. In contrast to previous reports, upon secondary antigen encounter CD25-deficient CD8(+) T cells were capable of undergoing robust expansion, but short-lived effector development was again impaired. Thus, these results demonstrated that CD4(+) T cell help and IL-2 signaling were linked via CD25 up-regulation, which controls the expansion and differentiation of antigen-specific effector CD8(+) T cells, rather than "programming" memory cell traits.

Prepared for sudden cardiac arrest? A cross-sectional study of automated external defibrillators in amateur sport.

INTRODUCTION: Sudden cardiac arrest (SCA) is a rare but tragic part of professional and amateur sport. Following multiple high profile deaths in professional sport over the past two decades, there has been a significant trend towards the widespread availability of automated external defibrillators (AEDs) at amateur sports grounds. OBJECTIVES: To examine the availability of AEDs in amateur sports clubs in Cork, Ireland, and to investigate club practices with respect to the purchase, accessibility, maintenance and use of AEDs. DESIGN: A cross-sectional survey of 218 amateur Gaelic Athletic Association (GAA), soccer and rugby clubs was conducted between July and September 2012. Club committee representatives answered a 22-point questionnaire. RESULTS: 126 GAA clubs and 28 soccer and 17 rugby (n=171) clubs were enrolled in this study. A total of 81.3% of amateur clubs own an AED. We estimate an AED-use rate of one AED use for every 54.5 years an AED is available. Almost 50% of club representatives thought the location of their club AED could be improved while 12.9% of clubs admitted to not maintaining their club AED on a regular basis. CONCLUSIONS: A large proportion of amateur clubs in Cork City and County own an AED. Many clubs engage in regular maintenance and storage of AEDs. However, this study identifies several areas for improvement in facilitating a secure chain of survival for players in the event of an SCA.

VISTA expression and patient selection for immune-based anticancer therapy.

V-domain Ig suppressor of T-cell activation (VISTA) is a B7 family member that plays key roles in maintaining T cell quiescence and regulation of myeloid cell populations, which together establish it as a novel immunotherapy target for solid tumors. Here we review the growing literature on VISTA expression in relation to various malignancies to better understand the role of VISTA and its interactions with both tumor cells and immune cells expressing other checkpoint molecules within the tumor microenvironment (TME). The biology of VISTA creates several mechanisms to maintain the TME, including supporting the function of myeloid-derived suppressor cells, regulating natural killer cell activation, supporting the survival of regulatory T cells, limiting antigen presentation on antigen-presenting cells and maintaining T cells in a quiescent state. Understanding these mechanisms is an important foundation of rational patient selection for anti-VISTA therapy. We provide a general framework to describe distinct patterns of VISTA expression in correlation with other known predictive immunotherapy biomarkers (programmed cell death ligand 1 and tumor-infiltrating lymphocytes) across solid tumors to facilitate investigation of the most efficacious TMEs for VISTA-targeted treatment as a single agent and/or in combination with anti-programmed death 1/anti-cytotoxic T lymphocyte antigen-4 therapies.