Advancing Combat Casualty Care Statistics and Other Battlefield Care Metrics.

Aggregate statistics can provide intra-conflict and inter-conflict mortality comparisons and trends within and between U.S. combat operations. However, capturing individual-level data to evaluate medical and non-medical factors that influence combat casualty mortality has historically proven difficult. The Department of Defense (DoD) Trauma Registry, developed as an integral component of the Joint Trauma System during recent conflicts in Afghanistan and Iraq, has amassed individual-level data that have afforded greater opportunity for a variety of analyses and comparisons. Although aggregate statistics are easily calculated and commonly used across the DoD, other issues that require consideration include the impact of individual medical interventions, non-medical factors, non-battle-injured casualties, and incomplete or missing medical data, especially for prehospital care and forward surgical team care. Needed are novel methods to address these issues in order to provide a clearer interpretation of aggregate statistics and to highlight solutions that will ultimately increase survival and eliminate preventable death on the battlefield. Although many U.S. military combat fatalities sustain injuries deemed non-survivable, survival among these casualties might be improved using primary and secondary prevention strategies that prevent injury or reduce injury severity. The current commentary proposes adjustments to traditional aggregate combat casualty care statistics by integrating statistics from the DoD Military Trauma Mortality Review process as conducted by the Joint Trauma System and Armed Forces Medical Examiner System.

Classification of 2-node excitatory-inhibitory networks.

We classify connected 2-node excitatory-inhibitory networks under various conditions. We assume that, as well as for connections, there are two distinct node-types, excitatory and inhibitory. In our classification we consider four different types of excitatory-inhibitory networks: restricted, partially restricted, unrestricted and completely unrestricted. For each type we give two different classifications. Using results on ODE-equivalence and minimality, we classify the ODE-classes and present a minimal representative for each ODE-class. We also classify all the networks with valence ≤2. These classifications are up to renumbering of nodes and the interchange of 'excitatory' and 'inhibitory' on nodes and arrows. These classifications constitute a first step towards analysing dynamics and bifurcations of excitatory-inhibitory networks. The results have potential applications to biological network models, especially neuronal networks, gene regulatory networks, and synthetic gene networks.

Evidence of heat sensitivity in people with Parkinson's disease.

Examining how heat affects people with Parkinson's disease is essential for informing clinical decision-making, safety, well-being, and healthcare planning. While there is evidence that the neuropathology associated with Parkinson's disease affects thermoregulatory mechanisms, little attention has been given to the association of heat sensitivity to worsening symptoms and restricted daily activities in people with this progressive disease. Using a cross-sectional study design, we examined the experiences of people diagnosed with Parkinson's disease in the heat. Two-hundred and forty-seven people completed an online survey (age: 66.0 ± 9.2 years; sex: male = 102 (41.3%), female = 145 (58.7%)), of which 195 (78.9%) reported becoming more sensitive to heat with Parkinson's disease. Motor and nonmotor symptoms worsened with heat in 182 (73.7%) and 203 (82.2%) respondents, respectively. The most commonly reported symptoms to worsen included walking difficulties, balance impairment, stiffness, tremor, fatigue, sleep disturbances, excess sweating, difficulty concentrating, and light-headedness when standing. Concerningly, over half indicated an inability to work effectively in the heat, and nearly half reported that heat impacted their ability to perform household tasks and social activities. Overall, heat sensitivity was common in people with Parkinson's disease and had a significant impact on symptomology, day-to-day activities and quality of life.

Comparison of Racial and Ethnic Mortality Disparities among Post-9/11 Veterans with and without Traumatic Brain Injury to the Total U.S. Adult Population.

INTRODUCTION: The extent of racial/ethnic disparities and whether they are attenuated in the Veteran population compared to the total US population is not well understood. We aimed to assess racial/ethnic mortality disparities from all-cause, cardiovascular (CVD) and cancer among post-9/11 military Veterans with and without exposure to TBI, compared to the total US population. METHODS: This cohort study included 2,502,101 US military Veterans (18,932,083 person-years) who served after 09/11/2001 with 3 or more years of care in the Military Health System (MHS); or had 3 or more years of care in the MHS and 2 or more years of care in the Veterans Health Administration. Mortality follow-up occurred from 01/01/2002 to 12/31/2020. Mortality rate ratios (MRR) from negative binomial regression models were reported for racial/ethnic groups compared to White non-Hispanic Veterans for all-cause, CVD and cancer mortality. Veteran MRR were compared to the total US population. RESULTS: Mortality rates for Black Non-Hispanic Veterans were higher for all-cause (MRR = 1.21;95%CI: 1.13-1.29; p < 0.001), CVD (MRR = 1.78;95%CI: 1.62-1.96; p < 0.001) and cancer (MRR = 1.17;95%CI: 1.10-1.25; p < 0.001) than in White Non-Hispanic Veterans. Among Veterans with TBI, only Black Non-Hispanics had higher mortality than White Non-Hispanics and only for CVD (MRR = 1.32;95%CI: 1.12-1.54; p < 0.001), while CVD mortality was higher among Veterans without TBI (MRR = 1.77;95%CI: 1.63-1.93;p < 0.001). MRR for Black Non-Hispanics in the total US population, were consistently higher than those in the Veteran population for all-cause (MRR = 1.52;95%CI: 1.46-1.58; p < 0.001), CVD (MRR = 2.03;95%CI: 1.95-2.13; p < 0.001) and cancer (MRR = 1.26;95%CI: 1.22-1.30; p < 0.001). CONCLUSION: This Veteran cohort experienced less racial/ethnic disparity in mortality than the total US population, especially among Veterans with TBI.

Proteomic analyses of urinary exosomes identify novel potential biomarkers for early diagnosis of sickle cell nephropathy, a sex-based study.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2 months (without albuminuria) and 4 months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, ß-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN.

The degree of aortic occlusion in the setting of trauma alters the extent of acute kidney injury associated with mitochondrial preservation.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to control noncompressible hemorrhage not addressed with traditional tourniquets. However, REBOA is associated with acute kidney injury (AKI) and subsequent mortality in severely injured trauma patients. Here, we investigated how the degree of aortic occlusion altered the extent of AKI in a porcine model. Female Yorkshire-cross swine (n = 16, 68.1 ± 0.7 kg) were anesthetized and had carotid and bilateral femoral arteries accessed for REBOA insertion and distal and proximal blood pressure monitoring. Through a laparotomy, a 6-cm liver laceration was performed and balloon inflation was performed in zone 1 of the aorta for 90 min, during which animals were randomized to target distal mean arterial pressures of 25 or 45 mmHg via balloon volume adjustment. Blood draws were taken at baseline, end of occlusion, and time of death, at which point renal tissues were harvested 6 h after balloon deflation for histological and molecular analyses. Renal blood flow was lower in the 25-mmHg group (48.5 ± 18.3 mL/min) than in the 45-mmHg group (177.9 ± 27.2 mL/min) during the occlusion phase, which recovered and was not different after balloon deflation. AKI was more severe in the 25-mmHg group, as evidenced by circulating creatinine, blood urea nitrogen, and urinary neutrophil gelatinase-associated lipocalin. The 25-mmHg group had increased tubular necrosis, lower renal citrate synthase activity, increased tissue and circulating syndecan-1, and elevated systemic inflammatory cytokines. The extent of renal ischemia-induced AKI is associated with the magnitude of mitochondrial biomass and systemic inflammation, highlighting potential mechanistic targets to combine with partial REBOA strategies to prevent AKI.NEW & NOTEWORTHY Large animal models of ischemia-reperfusion acute kidney injury (IR-AKI) are lacking. This report establishes a titratable IR-AKI model in swine in which a balloon catheter can be used to alter distal pressures experienced by the kidney, thus controlling renal blood flow. Lower blood flow results in greater renal dysfunction and structural damage, as well as lower mitochondrial biomass, elevated systemic inflammation, and vascular dysfunction.

Meta-analysis prediction intervals are under reported in sport and exercise medicine.

AIM: Prediction intervals are a useful measure of uncertainty for meta-analyses that capture the likely effect size of a new (similar) study based on the included studies. In comparison, confidence intervals reflect the uncertainty around the point estimate but provide an incomplete summary of the underlying heterogeneity in the meta-analysis. This study aimed to estimate (i) the proportion of meta-analysis studies that report a prediction interval in sports medicine; and (ii) the proportion of studies with a discrepancy between the reported confidence interval and a calculated prediction interval. METHODS: We screened, at random, 1500 meta-analysis studies published between 2012 and 2022 in highly ranked sports medicine and medical journals. Articles that used a random effect meta-analysis model were included in the study. We randomly selected one meta-analysis from each article to extract data from, which included the number of estimates, the pooled effect, and the confidence and prediction interval. RESULTS: Of the 1500 articles screened, 866 (514 from sports medicine) used a random effect model. The probability of a prediction interval being reported in sports medicine was 1.7% (95% CI = 0.9%, 3.3%). In medicine the probability was 3.9% (95% CI = 2.4%, 6.6%). A prediction interval was able to be calculated for 220 sports medicine studies. For 60% of these studies, there was a discrepancy in study findings between the reported confidence interval and the calculated prediction interval. Prediction intervals were 3.4 times wider than confidence intervals. CONCLUSION: Very few meta-analyses report prediction intervals and hence are prone to missing the impact of between-study heterogeneity on the overall conclusions. The widespread misinterpretation of random effect meta-analyses could mean that potentially harmful treatments, or those lacking a sufficient evidence base, are being used in practice. Authors, reviewers, and editors should be aware of the importance of prediction intervals.

Passive heat therapy: a promising preventive measure for people at risk of adverse health outcomes during heat extremes.

The world is experiencing increased frequency, duration, and severity of life-threatening heat extremes. Most hospitalizations and excess deaths during extreme heat events are associated with preexisting diseases in older adults. As climate change persists, the global population ages and the number of individuals with chronic diseases expands, more people are at risk of adverse health outcomes during extreme heat events. Therefore, proactive preventive measures are urgently needed to mitigate heat-related health risks within these populations. In this context, passive heat therapy (e.g., hot baths, saunas, and water-perfused suits) emerges as a promising countermeasure to improve physiological resilience to a warming planet. Passive heating improves cardiovascular function and overall health in older adults and individuals living with chronic diseases, offering the prospect of reducing cardiovascular strain during hotter days. Moreover, some studies suggest that passive heat therapy can be an effective strategy for heat acclimation (i.e., improved thermoregulation). This review describes the existing literature on the effects of passive heat therapy on cardiovascular and thermoregulatory responses in individuals with higher heat-related health risks and explores the use of passive heating as a strategy for heat acclimation to mitigate health risks during extreme heat events.NEW & NOTEWORTHY Passive heat therapy improves cardiovascular function and health in middle-aged and older adults living with or without chronic diseases. In addition, preliminary studies indicate that passive heat interventions can induce heat acclimation, improving thermoregulatory responses. Thus, passive heat therapy could serve as a preventive measure for people at risk of adverse health outcomes during extreme heat events, improving resilience to ongoing climate change.

A Novel Peritoneal Packing Method for Management of Hyperkalemia During Acute Kidney Injury in Trauma.

INTRODUCTION: United States Military operations in resource limited areas are increasing. Furthermore, future peer or near-peer conflicts will require caring for larger numbers of casualties with limited resources. In this setting, traditional renal replacement therapy is not feasible and novel methods are required to address severe acute kidney injury in austere environments lacking definitive therapies. Here, we describe experiments designed to determine the efficacy of a novel peritoneal packing material (Potassium Binding Pack-PBP, CytoSorbents INC) for the acute management of severe hyperkalemia. MATERIALS AND METHODS: Male swine (52 ±1 kg) were nephrectomized via midline laparotomy under a plane of anesthesia and randomized into one of two experimental groups (PBP & CON). Exogenous potassium was infused to achieve a serum potassium level of 7.5 mEq/L. Novel potassium absorbing packs (PBP) or sham packs (CON) were placed in the right and left upper quadrants, and the right and left paracolic gutters of the abdomen to simulate four-quadrant packing (n = 6, n = 5, respectively). Two liters of peritoneal dialysis fluid was instilled into the abdomen and temporary closure performed. Animals were observed for 12 hours. Serum and peritoneal fluid (dialysate) potassium levels were sampled at T = 15, 30, 60 min, and Q60min thereafter. Animals were humanely euthanized at the end of the observation period. RESULTS: Baseline characteristics were similar between groups. Pairwise analysis showed that serum potassium concentrations were significantly lower in the PBP group compared to CON at T = 540 and T = 720 (P = 0.006 and P = 0.015, respectively). Potassium concentrations were significantly lower in dialysate of the PBP group compared to CON at all time points after T = 15 (T = 30, P = 0.017; T = 60 through T = 720, P < 0.001). CONCLUSIONS: This is the first demonstration of an effective technology for the management of hyperkalemia in trauma in the absence of standard of care; renal replacement therapy. We identified that PBP was able to consistently maintain a concentration gradient between dialysate in the peritoneum and system potassium concentration throughout the experiment. Furthermore, systemic potassium concentrations were reduced in a clinically relevant manner in the PBP group compared to CON. This suggests that peritoneal packing technology for the management of metabolic disturbances in trauma has potential for clinical application. These results are preliminary and should be interpreted with caution.

Traumatic Brain Injury and Subsequent Risk of Brain Cancer in US Veterans of the Iraq and Afghanistan Wars.

Importance: While brain cancer is rare, it has a very poor prognosis and few established risk factors. To date, epidemiologic work examining the potential association of traumatic brain injury (TBI) with the subsequent risk of brain cancer is conflicting. Further data may be useful. Objective: To examine whether a history of TBI exposure is associated with the subsequent development of brain cancer. Design, Setting, and Participants: A retrospective cohort study was conducted from October 1, 2004, to September 20, 2019, and data analysis was performed between January 1 and June 26, 2023. The median follow-up for the cohort was 7.2 (IQR, 4.1-10.1) years. Veterans Affairs (VA) and Department of Defense (DoD) administrative data on 1 919 740 veterans from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium were included. Exposure: The main exposure of interest was TBI severity (categorized as mild, moderate or severe [moderate/severe], and penetrating). Main Outcomes and Measures: The outcome of interest was the development of brain cancer based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes in either the DoD/VA medical records or from the National Death Index. Results: After 611 107 exclusions (predominately for no encounter during the study period), a cohort including 1 919 740 veterans was included, most of whom were male (80.25%) and non-Hispanic White (63.11%). Median age at index date was 31 (IQR, 25-42) years. The cohort included 449 880 individuals with TBI (mild, 385 848; moderate/severe, 46 859; and penetrating, 17 173). Brain cancer occurred in 318 individuals without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (≤0.06%). After adjustment, moderate/severe TBI (adjusted hazard ratio [AHR], 1.90; 95% CI, 1.16-3.12) and penetrating TBI (AHR, 3.33; 95% CI, 1.71-6.49), but not mild TBI (AHR, 1.14; 95% CI, 0.88-1.47), were associated with the subsequent development of brain cancer. Conclusions and Relevance: In this cohort study of veterans of the Iraq and Afghanistan wars, moderate/severe TBI and penetrating TBI, but not mild TBI, were associated with the subsequent development of brain cancer.

Seraph 100 Microbind Affinity Blood Filter Does Not Clear Antibiotics: An Analysis of Antibiotic Concentration Data from PURIFY-OBS.

INTRODUCTION: Novel hemoperfusion systems are emerging for the treatment of sepsis. These devices can directly remove pathogens, pathogen-associated molecular patterns, cytokines, and other inflammatory markers from circulation. However, significant safety concerns such as potential antibiotic clearance need to be addressed prior to these devices being used in large clinical studies. METHODS: Prospective, observational study of 34 participants undergoing treatment with the Seraph 100® Microbind Affinity Blood Filter (Seraph 100) device at 6 participating sites in the USA. Patients were included for analysis if they had a record of receiving an antibiotic concurrent with Seraph 100 treatment. Patients were excluded if there was missing information for blood flow rate. Blood samples were drawn pre- and post-filter at 1 h and 4 h after treatment initiation. These average pre- and post-filter time-concentration observations were then used to estimate antibiotic clearance in L/h (CLSeraph) due to the Seraph 100 device. RESULTS: Of the 34 participants in the study, 17 met inclusion and exclusion criteria for the antibiotic analysis. Data were obtained for 7 antibiotics (azithromycin, cefazolin, cefepime, ceftriaxone, linezolid, piperacillin, and vancomycin) and one beta-lactamase inhibitor. Mean CLSeraph for the antibiotics investigated ranged from -0.57 to 0.47 L/h. No antibiotic had a CLSeraph statistically significant from 0. DISCUSSION/CONCLUSION: The Seraph 100 did not significantly clear any measured antibiotic in clinical samples. These data give further evidence to suggest that these therapies may be safely administered to critically ill patients and will not impact concentrations of administered antibiotics.

Inhaled "Muco-Trapping" Monoclonal Antibody Effectively Treats Established Respiratory Syncytial Virus (RSV) Infections.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable "muco-trapping" variant of motavizumab (Mota-MT), a potent neutralizing mAb against RSV F is engineered. Mota-MT traps RSV in AM via polyvalent Fc-mucin bonds, reducing the fraction of fast-moving RSV particles in both fresh pediatric and adult AM by ≈20-30-fold in a Fc-glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota-MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota-MT to RSV-infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000-fold and 100 000-fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota-MT-treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco-trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.

Association of Traumatic Brain Injury and Glioblastoma Multiforme: A Case Series.

Glioblastoma multiforme (GBM) is an aggressive variant of central nervous system gliomas that carries a dismal prognosis. Although GBM is the most frequently occurring and malignant type of glioma accounting for more than 60% of all brain tumors in adults, its overall incidence is rare, occurring at a rate of 3.21 per 100,000 persons. Little is known about the etiology of GBM, but one proposed theory is that GBM pathogenesis may be linked to a chronic inflammatory course initiated by traumatic injury to the brain. Limited case reports have suggested an association between GBMs and traumatic brain injury (TBI), but larger case-control and epidemiologic studies have been inconclusive. We present three service members (two active duty and one retired) who developed GBM near the original site of prior head trauma. Each service member's military occupation was in the special operations community and shared a common theme of TBI following head trauma/injury. The current research on the association between TBI and GBM is limited and conflicting, predominantly due to the low incidence of the disease in the general population. Evidence has indicated that TBI should be considered a chronic disease with long-term health impacts, including long-term disability, dementia, epilepsy, mental health conditions, and cardiovascular diseases. With the addition of our patients, as well as a recently published study proposing a molecular association between trauma and GBM, further research is needed to better understand the potential relationship.

The Role of Social License in Non-Industrial Marine and Coastal Planning: a Scoping Review.

Marine and coastal environments are diverse and dynamic, supporting competing human interests and demands. As society seeks to balance contested uses of space, more holistic planning processes have emerged, which consider social, economic, and ecological factors. One approach that considers social factors, and more specifically social acceptance, is "social license to operate" (SLO). Originating in the terrestrial mining industry, SLO has been adopted by various marine industries. Except for some emerging work in the conservation field, SLO is typically applied to industrial marine and coastal contexts. To understand SLO's uses in other marine and coastal planning contexts, namely conservation, adaptation, and restoration, we conducted a scoping review using the term SLO and similar concepts, including public or social acceptance, support, and buy-in. Results indicate the concept of SLO is still emerging in non-industrial marine and coastal planning, with an emphasis on gaining public acceptance rather than maintaining it. The concept of SLO was applied broadly, including as a measurement for public support and a product of effective engagement. Most publications focused on barriers and drivers of SLO. Influential factors are identified and organized by theme, then discussed based on their relationships within a social-ecological system framework. Considering the common factors and their associated systems helps to link elements necessary to obtain SLO, highlighting their interconnectedness with each other, society, and the natural environment. The findings of this review illustrate SLO's utility for academics and practitioners alike, through its application in methods, tools, values, and concepts that characterize public inclusion for marine and coastal planning.

Hot water immersion acutely reduces peripheral glucose uptake in young healthy males: An exploratory crossover randomized controlled trial.

Whether glucose concentration increases during heat exposure because of reduced peripheral tissue uptake or enhanced appearance is currently unknown. This study aimed to report glucose concentrations in both capillary and venous blood in response to a glucose challenge during passive heating (PH) to assess whether heat exposure affects glucose uptake in healthy males. Twelve healthy male participants completed two experimental sessions, where they were asked to undertake an oral glucose tolerance test (OGTT) whilst immersed in thermoneutral (CON, 35.9 (0.6) °C) and hot water (HWI, 40.3 (0.5) °C) for 120 min. Venous and capillary blood [glucose], rectal temperature, and heart rate were recorded. [Glucose] area under the curve for HWI venous (907 (104) AU) differed from CON venous (719 (88) AU, all P < 0.001). No other differences were noted (P > 0.05). Compared with CON, HWI resulted in greater rectal temperature (37.1 (0.3) °C versus 38.6 (0.4) °C, respectively) and heart rate (69 (12) bpm versus 108 (11) bpm, respectively) on cessation (P < 0.001). An OGTT results in similar capillary [glucose] during hot and thermoneutral water immersion, whereas venous [glucose] was greater during HWI when compared with CON. This indicates that peripheral tissue glucose uptake is acutely reduced in response to HWI. Abbreviations: AUC: Area under the curve; CON: Thermoneutral immersion trial; HWI: Hot water immersion trial; OGTT: Oral glucose tolerance test; PH: Passive heating; T-msk: Mean skin temperature; Trec: Rectal temperature.

A clinically-relevant mouse model that displays hemorrhage exacerbates tourniquet-induced acute kidney injury.

Hemorrhage is a leading cause of death in trauma. Tourniquets are effective at controlling extremity hemorrhage and have saved lives. However, tourniquets can cause ischemia reperfusion injury of limbs, leading to systemic inflammation and other adverse effects, which results in secondary damage to the kidney, lung, and liver. A clinically relevant animal model is critical to understanding the pathophysiology of this process and developing therapeutic interventions. Despite the importance of animal models, tourniquet-induced lower limb ischemia/reperfusion (TILLIR) models to date lack a hemorrhage component. We sought to develop a new TILLIR model that included hemorrhage and analyze the subsequent impact on kidney, lung and liver injuries. Four groups of mice were examined: group 1) control, group 2) hemorrhage, group 3) tourniquet application, and group 4) hemorrhage and tourniquet application. The hemorrhagic injury consisted of the removal of 15% of blood volume through the submandibular vein. The tourniquet injury consisted of orthodontic rubber bands applied to the inguinal area bilaterally for 80 min. Mice were then placed in metabolic cages individually for 22 h to collect urine. Hemorrhage alone did not significantly affect transcutaneous glomerular filtration rate (tGFR), blood urea nitrogen (BUN) or urinary kidney injury molecule-1 (KIM-1) levels. Without hemorrhage, TILLIR decreased tGFR by 46%, increased BUN by 162%, and increased KIM-1 by 27% (p < 0.05 for all). With hemorrhage, TILLIR decreased the tGFR by 72%, increased BUN by 395%, and increased urinary KIM-1 by 37% (p < 0.05 for all). These differences were statistically significant (p < 0.05). While hemorrhage had no significant effect on TILLIR-induced renal tubular degeneration and necrosis, it significantly increased TILLIR-induced lung total injury scores and congestion, and fatty liver. In conclusion, hemorrhage exacerbates TILLIR-induced acute kidney injury and structural damage in the lung and liver.

Trends in Suicide Rates Among Post-9/11 US Military Veterans With and Without Traumatic Brain Injury From 2006-2020.

This cohort study examines trends in suicide rates for veterans with and without traumatic brain injury compared with the US adult population.

Disposable Dosators Intended for Dry Powder Delivery to Mice.

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus metering and dosing, and a propellant-free dispersal mechanism. To develop pharmaceutical dry powder aerosol products, robust in vivo testing is essential. Typically, initial studies involve using a murine model for preliminary evaluation before conducting formal studies in larger animal species. However, a significant limitation in this approach is the lack of suitable device technology to accurately and reproducibly deliver dry powders to small animals, hindering such models' utility. To address these challenges, disposable syringe dosators were developed specifically for intrapulmonary delivery of dry powders in doses appropriate for mice. These dosators load and deliver a predetermined amount of powder obtained from a uniform bulk density powder bed. This discrete control is achieved by inserting a blunt needle to a fixed depth (tamping) into the powder bed, removing a fixed quantity each time. Notably, this dosing pattern has proven effective for a range of spray-dried powders. In experiments involving four different model spray-dried powders, the dosators demonstrated the ability to achieve doses within the range of 30 to 1100 µg. The achieved dose was influenced by factors such as the number of tamps, the size of the dosator needle, and the specific formulation used. One of the key benefits of these dosators is their ease of manufacturing, making them accessible and cost-effective for delivering dry powders to mice during initial proof-of-concept studies. The disposable nature of the dosators facilitates use in animal procedure rooms, where cleaning and refilling reusable systems and weighing materials is inconvenient. Thus, developing disposable syringe dosators has addressed a significant hurdle in murine dry powder delivery for proof-of-concept studies, enabling researchers to conduct more accurate and reproducible preliminary studies in small animal models for pulmonary drug delivery.

Pharmacokinetic Considerations for Optimizing Inhaled Spray-Dried Pyrazinoic Acid Formulations.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a leading cause of death with 1.6 million deaths worldwide reported in 2021. Oral pyrazinamide (PZA) is an integral part of anti-TB regimens, but its prolonged use has the potential to drive the development of PZA-resistant Mtb. PZA is converted to the active moiety pyrazinoic acid (POA) by the Mtb pyrazinamidase encoded by pncA, and mutations in pncA are associated with the majority of PZA resistance. Conventional oral and parenteral therapies may result in subtherapeutic exposure in the lung; hence, direct pulmonary administration of POA may provide an approach to rescue PZA efficacy for treating pncA-mutant PZA-resistant Mtb. The objectives of the current study were to (i) develop novel dry powder POA formulations, (ii) assess their feasibility for pulmonary delivery using physicochemical characterization, (iii) evaluate their pharmacokinetics (PK) in the guinea pig model, and (iv) develop a mechanism-based pharmacokinetic model (MBM) using in vivo PK data to select a formulation providing adequate exposure in epithelial lining fluid (ELF) and lung tissue. We developed three POA formulations for pulmonary delivery and characterized their PK in plasma, ELF, and lung tissue following passive inhalation in guinea pigs. Additionally, the PK of POA following oral, intravenous, and intratracheal administration was characterized in guinea pigs. The MBM was used to simultaneously model PK data following administration of POA and its formulations via the different routes. The MBM described POA PK well in plasma, ELF, and lung tissue. Physicochemical analyses and MBM predictions suggested that POA maltodextrin was the best among the three formulations and an excellent candidate for further development as it has: (i) the highest ELF-to-plasma exposure ratio (203) and lung tissue-to-plasma exposure ratio (30.4) compared with POA maltodextrin and leucine (75.7/16.2) and POA leucine salt (64.2/19.3) and (ii) the highest concentration in ELF (CmaxELF: 171 nM) within 15.5 min, correlating with a fast transfer into ELF after pulmonary administration (KPM: 22.6 1/h). The data from the guinea pig allowed scaling, using the MBM to a human dose of POA maltodextrin powder demonstrating the potential feasibility of an inhaled product.

Associations between health-related behaviors and self-reported cognitive symptoms in U.S. military personnel injured on deployment.

Health behaviors may be core contributors to cognition and mental health following mild traumatic brain injury (TBI). The aims of the present study examined: (1) whether health behaviors including sleep duration, alcohol use, and physical activity differed in injured military personnel with and without deployment-related mild TBI history and (2) the relative contributions of health behaviors and deployment-related mild TBI history to self-reported cognitive, posttraumatic stress disorder (PTSD), and depressive symptoms. Participants included 3076 military personnel injured on deployment participating in the Wounded Warrior Recovery Project, an ongoing web-based study. Military personnel with deployment-related mild TBI history reported similar rates of physical activity and levels of alcohol problems as those without, but were less likely to report receiving the recommended duration of sleep. When adjusting for demographic and injury variables, all three health behaviors were associated with cognitive, PTSD, and depressive symptoms. Alcohol problems demonstrated significant but small effects across all outcomes measures (ηp2=.01) whereas physical activity was associated with slightly larger effects albeit still within the small range (ηp2=.02-0.04). Duration of sleep bordered a medium effect for cognitive symptoms (ηp2=.05) and was in the medium range for PTSD and depressive symptoms (ηp2=.06). Although deployment-related mild TBI history was significant in all models, effect sizes were small (ηp2=.01). Findings from the present study provide support that health behaviors have stronger effects with regard to cognitive, PTSD, and depressive symptoms compared to deployment-related mild TBI history in military personnel and, given their modifiable nature, may represent treatment targets in this population.