Femtosecond Visualization of hcp-Iron Strength and Plasticity under Shock Compression.

Iron is a key constituent of planets and an important technological material. Here, we combine in situ ultrafast x-ray diffraction with laser-induced shock compression experiments on Fe up to 187(10) GPa and 4070(285) K at 10^{8} s^{-1} in strain rate to study the plasticity of hexagonal-close-packed (hcp)-Fe under extreme loading states. {101[over ¯]2} deformation twinning controls the polycrystalline Fe microstructures and occurs within 1 ns, highlighting the fundamental role of twinning in hcp polycrystals deformation at high strain rates. The measured deviatoric stress initially increases to a significant elastic overshoot before the onset of flow, attributed to a slower defect nucleation and mobility. The initial yield strength of materials deformed at high strain rates is thus several times larger than their longer-term flow strength. These observations illustrate how time-resolved ultrafast studies can reveal distinctive plastic behavior in materials under extreme environments.

Outcomes among Patients Treated with Renal Replacement Therapy during Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities used in critically ill patients suffering organ failure and metabolic derangements. Although the effects of CRRT have been extensively studied, the impact of simultaneous CRRT and ECMO is less well described. The purpose of this study is to evaluate the incidence and the impact of CRRT on outcomes of patients receiving ECMO. METHODS: A single center, retrospective chart review was conducted for patients receiving ECMO therapy over a 6-year period. Patients who underwent combined ECMO and CRRT were compared to those who underwent ECMO alone. Intergroup -statistical comparisons were performed using Wilcoxon/Kruskal-Wallis and chi-square tests. Logistic regression was performed to identify independent risk factors for mortality. RESULTS: The demographic and clinical data of 92 patients who underwent ECMO at our center were reviewed including primary diagnosis, indications for and mode of ECMO support, illness severity, oxygenation index, vasopressor requirement, and presence of acute kidney injury. In those patients that required ECMO with CRRT, we reviewed urine output prior to initiation, modality used, prescribed dose, net fluid balance after 72 h, requirement of renal replacement therapy (RRT) at discharge, and use of diuretics prior to RRT initiation. Our primary endpoint was survival to hospital discharge. During the study period, 48 patients required the combination of ECMO with CRRT. Twenty-nine of these patients survived to hospital discharge. Of the 29 survivors, 6 were dialysis dependent at hospital discharge. The mortality rate was 39.5% with combined ECMO/CRRT compared to 31.4% among those receiving ECMO alone (p = 0.074). Of those receiving combined therapy, nonsurvivors were more likely to have a significantly positive net fluid balance at 72 h (p = 0.001). A multivariate linear regression analysis showed net positive fluid balance and increased age were independently associated with mortality. CONCLUSIONS: Use of CRRT is prevalent among patients undergoing ECMO, with over 50% of our patient population receiving combination therapy. Fluid balance appears to be an important variable associated with outcomes in this cohort. Rates of renal recovery and overall survival were higher compared to previously published reports among those requiring combined ECMO/CRRT.

Increasing Medical Student Interest in Nephrology.

BACKGROUND: Interest in nephrology careers is declining, possibly due to perceptions of the field and/or training aspects. Understanding practices of medical schools successfully instilling nephrology interest could inform efforts to attract leading candidates to the specialty. METHODS: The American Society of Nephrology Workforce Committee's Best Practices Project was one of several initiatives to increase nephrology career interest. Board-certified nephrologists graduating medical school between 2002 and 2009 were identified in the American Medical Association Masterfile and their medical schools ranked by production. Renal educators from the top 10 producing institutions participated in directed focus groups inquiring about key factors in creating nephrology career interest, including aspects of their renal courses, clinical rotations, research activities, and faculty interactions. Thematic content analysis of the transcripts (with inductive reasoning implementing grounded theory) was performed to identify factors contributing to their programs' success. RESULTS: The 10 schools identified were geographically representative, with similar proportions of graduates choosing internal medicine (mean 26%) as the national graduating class (26% in the 2017 residency Match). Eighteen educators from 9 of these 10 institutions participated. Four major themes were identified contributing to these schools' success: (1) nephrology faculty interaction with medical students; (2) clinical exposure to nephrology and clinical relevance of renal pathophysiology materials; (3) use of novel educational modalities; and (4) exposure, in particular early exposure, to the breadth of nephrology practice. CONCLUSION: Early and consistent exposure to a range of clinical nephrology experiences and nephrology faculty contact with medical students are important to help generate interest in the specialty.

Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War.

BACKGROUND: During the conflicts in Iraq and Afghanistan, 52,087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. METHODS AND RESULTS: Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual's second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. CONCLUSIONS: In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease.

Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes.

Drug-induced toxicity is a leading cause of drug withdrawal from clinical development and clinical use and represents a major impediment to the development of new drugs. The mechanisms underlying drug-induced toxicities are varied; however, metabolic bioactivation to form reactive metabolites has been identified as a major contributor.1,2 These electrophilic species can covalently modify important biological macromolecules and thereby increase the risk of adverse drug reactions or idiosyncratic toxicity. Consequently, screening compounds for their propensity to form reactive metabolites has become an integral part of drug discovery programs. This screening process typically involves identification of structural alerts as well as the generation of reactive metabolites in vitro in subcellular hepatic fractions, followed by trapping the reactive species with nucleophiles and characterization via LC-MS. This article presents evidence for the bioactivation of a series of aminopyrazole derivatives via LC-MS detection of glutathione ethyl ester-trapped reactive intermediates formed in human liver microsomal incubations. These results indicate that the aminopyrazole motif, within specific contexts, may be considered a new structural alert for the potential formation of reactive metabolites.

The potential utility of urinary biomarkers for risk prediction in combat casualties: a prospective observational cohort study.

INTRODUCTION: Traditional risk scoring prediction models for trauma use either anatomically based estimations of injury or presenting vital signs. Markers of organ dysfunction may provide additional prognostic capability to these models. The objective of this study was to evaluate if urinary biomarkers are associated with poor outcomes, including death and the need for renal replacement therapy. METHODS: We conducted a prospective, observational study in United States Military personnel with traumatic injury admitted to the intensive care unit at a combat support hospital in Afghanistan. RESULTS: Eighty nine patients with urine samples drawn at admission to the intensive care unit were studied. Twelve patients subsequently died or needed renal replacement therapy. Median admission levels of urinary cystatin C (CyC), interleukin 18 (IL-18), L-type fatty acid binding protein (LFABP) and neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher in patients that developed the combined outcome of death or need for renal replacement therapy. Median admission levels of kidney injury molecule-1 were not associated with the combined outcome. The area under the receiver operating characteristic curves for the combined outcome were 0.815, 0.682, 0.842 and 0.820 for CyC, IL-18, LFABP and NGAL, respectively. Multivariable regression adjusted for injury severity score, revealed CyC (OR 1.97, 95 % confidence interval 1.26-3.10, p = 0.003), LFABP (OR 1.92, 95 % confidence interval 1.24-2.99, p = 0.004) and NGAL (OR 1.80, 95 % confidence interval 1.21-2.66, p = 0.004) to be significantly associated with the composite outcome. CONCLUSIONS: Urinary biomarker levels at the time of admission are associated with death or need for renal replacement therapy. Larger multicenter studies will be required to determine how urinary biomarkers can best be used in future prediction models.

Dysnatremias and survival in adult burn patients: a retrospective analysis.

BACKGROUND/AIMS: Dysnatremias have been evaluated in many populations and have been found to be significantly associated with mortality. However, this relationship has not been well described in the burn population. METHODS: Admissions to the burn center at our institution from January 2003 to December 2008 were examined. Independent variables included gender, age, percentage total body surface area burned (%TBSA), percentage of third-degree burn, inhalation injury, injury severity score (ISS), Acute Kidney Injury Network (AKIN) stage, hypernatremia, and hyponatremia. They were examined via Cox proportional hazard regression models against death. Moderate to severe hypo- and hypernatremia were defined as serum sodium <130 and >150 mmol/l, respectively. RESULTS: In 1,969 subjects with a mean age of 36.3 ± 16.4 years, a median %TBSA of 9 (interquartile range 4-20) and a median ISS of 5 (interquartile range 1-16) hypernatremia occurred in 9.9% (n = 194), while hyponatremia occurred in 6.8% (n = 134) with mortality rates of 33.5 and 13.8%, respectively. Patients without a dysnatremia had a mortality rate of 4.3%. On Cox proportional hazard regression age, %TBSA, ISS, and AKIN stage were found to be significant predictors of mortality. Hypernatremia (HR 2.00, 95% CI 1.212-3.31; p = 0.0066), but not hyponatremia (HR 1.72, 95% CI 0.89-3.34; p = 0.1068) was associated with mortality. CONCLUSIONS: In the burn population, hypernatremia, but not hyponatremia, is an independent predictor of mortality.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.

Two-photon fluorescence microscopy imaging of cellular oxidative stress using profluorescent nitroxides.

A range of varying chromophore nitroxide free radicals and their nonradical methoxyamine analogues were synthesized and their linear photophysical properties examined. The presence of the proximate free radical masks the chromophore's usual fluorescence emission, and these species are described as profluorescent. Two nitroxides incorporating anthracene and fluorescein chromophores (compounds 7 and 19, respectively) exhibited two-photon absorption (2PA) cross sections of approximately 400 G.M. when excited at wavelengths greater than 800 nm. Both of these profluorescent nitroxides demonstrated low cytotoxicity toward Chinese hamster ovary (CHO) cells. Imaging colocalization experiments with the commercially available CellROX Deep Red oxidative stress monitor demonstrated good cellular uptake of the nitroxide probes. Sensitivity of the nitroxide probes to H(2)O(2)-induced damage was also demonstrated by both one- and two-photon fluorescence microscopy. These profluorescent nitroxide probes are potentially powerful tools for imaging oxidative stress in biological systems, and they essentially "light up" in the presence of certain species generated from oxidative stress. The high ratio of the fluorescence quantum yield between the profluorescent nitroxide species and their nonradical adducts provides the sensitivity required for measuring a range of cellular redox environments. Furthermore, their reasonable 2PA cross sections provide for the option of using two-photon fluorescence microscopy, which circumvents commonly encountered disadvantages associated with one-photon imaging such as photobleaching and poor tissue penetration.

Retrospective review of serum creatinine and creatinine-based measures of estimated glomerular filtration rate in an amputee population.

A variety of equations are used to estimate glomerular filtration rate (eGFR). These formulas have never been validated in the setting of traumatic amputation. In this retrospective study involving 255 military personnel with traumatic amputations at a single outpatient center, muscle mass lost was estimated using percentage of estimated body weight lost (% EBWL). Serum creatinine (Scr) and eGFR by the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were compared to % EBWL for each patient. The average Scr for the group studied was also compared with a cohort matched for age, sex, and race from the Third National Health and Nutrition Examination Survey (NHANES III). Percentage EBWL correlated significantly with Scr (R2 = 0.095, p < 0.0001), eGFR by MDRD (R2 = 0.077, p < 0.0001), and eGFR by CKD-EPI (R2 = 0.074, p < 0.0001). The average Scr was significantly lower than a similar population from NHANES III (0.83 +/- 0.137 mg/dL vs. 1.14 +/- 0.127 mg/dL, p < 0.0001). Percentage EBWL has a significant correlation with Scr and eGFR by both the MDRD and CKD-EPI equations. Furthermore, patients with traumatic amputation have significantly lower Scr values than the general population. Creatinine-based estimators of GFR may overestimate renal function in the setting of traumatic amputation.

Clostridioides difficile-Associated Atypical Hemolytic-Uremic Syndrome Successfully Treated With Eculizumab: A Case Report and Literature Review.

Clostridioides difficile infection is a rare precipitant for patients to develop atypical hemolytic-uremic syndrome, of which the pathogenesis remains unclear. Previous reports suggest activation of cytokine storm from binding of cyotoxins A and B to colonic wall membranes. CASE SUMMARY: We present a case of a previously healthy 21-year-old woman who developed fulminant C. difficile colitis and atypical hemolytic-uremic syndrome requiring abdominal surgery and renal replacement therapy. She was ultimately treated with eculizumab without the use of plasmapheresis and remains in remission with full renal recovery. CONCLUSIONS: Our patient's significant response to terminal complement inhibitor, without the use of plasmapheresis, suggests that the underlying pathology is significantly driven by the alternative complement pathway. We propose that C. difficile-associated atypical hemolytic-uremic syndrome be defined as primary atypical hemolytic-uremic syndrome and strongly consider eculizumab as first-line therapy.

Chronic kidney disease management in an academic internal medicine clinic.

OBJECTIVE: We sought to evaluate the current state of chronic kidney disease (CKD) management in our academic internal medicine clinic. METHODS: A retrospective review was carried out involving all patients with laboratory evidence of CKD enrolled in our clinic. We evaluated the rate of CKD recognition as well as compliance with standard guidelines. We further subdivided our results based on physician training level, presence of diabetes, recognition of CKD, age, and race. RESULTS: Factors that significantly improved recognition and treatment of CKD in our study included presence of diabetes (p < 0.001), black race (p = 0.013), younger age (p = 0.004), and treatment by a resident physician (p = 0.009). Recognition of stage 3 CKD was associated with significant increases in urine protein analysis (p < 0.001) and nephrology consultation (p < 0.001). CONCLUSION: Chronic kidney disease remains under-recognized and undertreated despite well-publicized guidelines and widespread use of routine eGFR reporting.

Management of calciphylaxis in a burn center: A case series and review of the literature.

Calciphylaxis is a rare, necrotizing skin disorder usually associated with kidney disease, but also caused by many other systemic illnesses. This disease is associated with mortality rates as high as 80% at 1year. We present the demographic and clinical data of nine patients with calciphylaxis treated at our burn center over a 10year period. We review the literature on the clinical presentation, pathophysiology, diagnosis and treatment of this rare disease. We propose that these patients be treated similar to patients with thermal burn injury; meaning intensive wound care, surgical management, critical care and physical therapy. Burn centers are uniquely capable of caring for these incredibly complex patients due to their experience in managing patients with extensive skin and soft tissue defects, wounds and diseases.

An interdisciplinary approach to inhospital stroke improves stroke detection and treatment time.

BACKGROUND: Inhospital stroke (IHS) is associated with high morbidity and mortality, likely related to multiple factors, including delayed time to recognition, associated comorbidities, and initial care from non-stroke trained providers. We hypothesized that guided revision of a formalized 'stroke code' system can improve diagnosis and time to thrombolysis and thrombectomy. METHODS: IHS activations occurring at a comprehensive stroke center between 2013 and 2016 were retrospectively analyzed to guide revisions of an established stroke code protocol to improve provider communication and time to imaging, reduce stroke mimic rate, and improve the use of parallel processing. After protocol implementation, we prospectively collected data between 2016 and 2017 for comparison with the pre-implementation group, including diagnostic accuracy and relevant time points (code call to examination, examination to imaging, and imaging to intervention). We report descriptive statistics for comparison of patient characteristics and time metrics (time to imaging and reperfusion after IHS activation). Multivariable regression analysis was performed to identify independent predictors of stroke mimics and time metrics. RESULTS: There were 136 cases in the pre-implementation group and 69 in the post-implementation group. A reduction in stroke mimics (52% vs 33%, P=0.01) occurred after protocol initiation. Mean time to imaging after stroke code call was 7.6 min shorter (P=0.026) and mean time from imaging to acute reperfusion therapy was 45.7 vs 19.8 min (P=0.05) in the pre- versus the post-implementation group. CONCLUSION: Revision of an existing IHS protocol was associated with a lower rate of stroke mimics, and a shorter time to intravenous and intra-arterial intervention.

Fragment screening for a protein-protein interaction inhibitor to WDR5.

The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k d = ∼0.06 s-1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.

Experimental and theoretical studies of the redox potentials of cyclic nitroxides.

The redox potentials of 25 cyclic nitroxides from four different structural classes (pyrrolidine, piperidine, isoindoline, and azaphenalene) were determined experimentally by cyclic voltammetry in acetonitrile, and also via high-level ab initio molecular orbital calculations. It is shown that the potentials are influenced by the type of ring system, ring substituents and/or groups surrounding the radical moiety. For the pyrrolidine, piperidine, and isoindolines there is excellent agreement (mean absolute deviation of 0.05 V) between the calculated and experimental oxidation potentials; for the azaphenalenes, however, there is an extraordinary discrepancy (mean absolute deviation of 0.60 V), implying that their one-electron oxidation might involve additional processes not considered in the theoretical calculations. This recently developed azaphenalene class of nitroxide represents a new variant of a nitroxide ring fused to an aromatic system and details of the synthesis of five derivatives involving differing aryl substitution are also presented.

Recommendations for Endovascular Care of Stroke Patients.

The field of neurointerventional radiology (NIR) therapy, including acute ischemic stroke intervention, endovascular intracranial aneurysm management, and treatment of intra- and extracranial large-vessel disease, has evolved over the past 18 years. To support this specialized advanced care requires nursing standards of care for staff to provide direct patient care in NIR suites and intensive management of this high-risk patient population. The intent of this paper is to provide a complementary document for the Stroke Interventional Laboratory Consensus (SILC) statement that will specifically address the nursing standards of care for patients in an NIR suite.

Pro-fluorescent mitochondria-targeted real-time responsive redox probes synthesised from carboxy isoindoline nitroxides: Sensitive probes of mitochondrial redox status in cells.

Here we describe new fluorescent probes based on fluorescein and rhodamine that provide reversible, real-time insight into cellular redox status. The new probes incorporate bio-imaging relevant fluorophores derived from fluorescein and rhodamine linked with stable nitroxide radicals such that they cannot be cleaved, either spontaneously or enzymatically by cellular processes. Overall fluorescence emission is determined by reversible reduction and oxidation, hence the steady state emission intensity reflects the balance between redox potentials of critical redox couples within the cell. The permanent positive charge on the rhodamine-based probes leads to their rapid localisation within mitochondria in cells. Reduction and oxidation also leads to marked changes in the fluorophore lifetime, enabling monitoring by fluorescence lifetime imaging microscopy. Finally, we demonstrate that administration of a methyl ester version of the rhodamine-based probe can be used at concentrations as low as 5 nM to generate a readily detected response to redox stress within cells as analysed by flow cytometry.

Original Research: Evaluation of pulmonary response to inhaled tungsten (IV) oxide nanoparticles in golden Syrian hamsters.

Extensive industrial and military uses of tungsten have raised the possibilities of human occupational and environmental exposure to nanoparticles of this metal, with concomitant health concerns. The goal of this study was to investigate the potential mechanism of pulmonary toxicity associated with inhaled tungsten (IV) oxide nanoparticles (WO3 NPs) in Golden Syrian Hamsters. Animals exposed to WO3 NPs via inhalation were divided into three groups - control and two treatment groups exposed to either 5 or 10 mg/m3 of aerosolized WO3 NPs for 4 h/day for four days. A long-term exposure study (4 h/day for eight days) was also carried out using an additional three groups. Pulmonary toxicity assessed by examining changes in cell numbers, lactate dehydrogenase activity, alkaline phosphatase activity, total protein content, TNF-α, and HMGB1 levels in bronchoalveolar lavage fluids showed a significant difference when compared to control (P < 0.05). The molecular mechanism was established by assessing protein expression of cathepsin B, TXNIP, NLRP3, ASC, IL-1ß and caspase-1. Western blot analysis indicated a 1.5 and 1.7 fold changes in NLRP3 in treatment groups (5 mg/m3, P < 0.05 and 10 mg/m3, P < 0.01, respectively), whereas levels of cathepsin B were 1.3 fold higher in lung tissue exposed to WO3 NPs suggesting activation of inflammasome pathway. Morphological changes studied using light and electron microscopy showed localization of nanoparticles and subsequent perturbation in airway epithelia, macrophages, and interstitial areas of alveolar structures. Results from the current study indicate that inhalation exposure to WO3 NPs may induce cytotoxicity, morphological changes, and lung injury via pyroptotic cell death pathway caused by activation of caspase-1.

Early acute kidney injury in military casualties.

BACKGROUND: While acute kidney injury (AKI) has been well studied in a variety of patient settings, there is a paucity of data in patients injured in the course of the recent wars in Iraq and Afghanistan. We sought to establish the rate of early AKI in this population and to define risk factors for its development. METHODS: We combined the results of two studies performed at combat support hospitals in Afghanistan. Only US service members who required care in the intensive care unit were included for analysis. Data on age, race, sex, Injury Severity Score (ISS), first available lactate, and requirement for massive transfusion were collected. Univariate analyses were performed to identify factors associated with the subsequent development of early AKI. Multivariable Cox regression was used to adjust for potential confounders. RESULTS: The two observational cohorts yielded 134 subjects for analysis. The studies had broadly similar populations but differed in terms of age and need for massive transfusion. The rate of early AKI in the combined cohort was 34.3%, with the majority (80.5%) occurring within the first two hospital days. Patients with AKI had higher unadjusted mortality rates than those without AKI (21.7% vs. 2.3%, p < 0.001). After adjustment, ISS (hazard ratio, 1.02; 95% confidence interval, 1.00-1.03; p = 0.046) and initial lactate (hazard ratio, 1.16; 95% confidence interval, 1.03-1.31; p = 0.015) were independently associated with the development of AKI. CONCLUSION: AKI is common in combat casualties enrolled in two prospective intensive care unit studies, occurring in 34.3%, and is associated with crude mortality. ISS and initial lactate are independently associated with the subsequent development of early AKI. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.