Refocusing the Military Health System to Support Role 4 Definitive Care in future large-scale combat operations.

ABSTRACT: The last twenty years of sustained combat operations during the Global War on Terror generated significant advancements in combat casualty care. Improvements in point-of-injury, en route, and forward surgical care appropriately aligned with the survival, evacuation, and return to duty needs of the small-scale unconventional conflict. However, casualty numbers in large-scale combat operations have brought into focus the critical need for modernized casualty receiving and convalescence: Role 4 definitive care (R4DC). Historically, World War II was the most recent conflict in which the United States fought in multiple operational theaters, with hundreds of thousands of combat casualties returned to the continental United States. These numbers necessitated the establishment of a "Zone of the Interior" which integrated military and civilian healthcare networks for definitive treatment and rehabilitation of casualties. Current security threats demand refocusing and bolstering the Military Health System's definitive care capabilities to maximize its force regeneration capacity in a similar fashion. Medical force generation, medical force sustainment and readiness, and integrated casualty care capabilities are three pillars that must be developed for MHS readiness of Role 4 definitive care in future large-scale contingencies against near-peer/peer adversaries.

What Does the Military Health System Need to Support Future Combat Operations? Lessons from Aeromedical Evacuations from 2008 to 2020.

INTRODUCTION: Aeromedical evacuations from the past few decades have yielded massive amounts of data that may inform the Military Health System (MHS) on patient needs, specifically for understanding the inpatient and outpatient needs of evacuees. In this study, we evaluate inpatient and outpatient trends based on aeromedical evacuation data from recent conflicts. We anticipate that evacuations requiring MHS inpatient beds are primarily trauma-related and necessitate an increased need for inpatient trauma care. MATERIALS AND METHODS: We conducted a descriptive analysis of aeromedical evacuations using the U.S. Transportation Command Regulating and Command & Control Evacuation System database. We queried the database for aeromedical evacuations originating from the U.S. EUCOM and ending in the CONUS, from January 1, 2008 to June 4, 2020. With the resultant data, evacuee demographics were characterized by gender, age, active duty (AD) versus non-AD, and branch of service. Following this, the proportion of battle injury to disease and non-battle injury was categorized by both patient age ranges and year. Additionally, evacuations were stratified by their ICD codes, as well as the primary specialty responsible for care. Lastly, evacuations were categorized by inpatient and outpatient care status. RESULTS: The final dataset yielded 32,485 unique patients. The majority of evacuees were male (86.9%) with a mean age of 29.0 ± 9.6 years. Evacuees were primarily AD Military (96.7%), with the majority of those personnel being in the Army (70.2%). The total number of evacuations steadily increased from 2008 (n = 3,703) until a peak in 2010 (n = 4,929), which was also the peak year for battle injury (n = 1,472). Battle injury was also most prevalent in the 21 to 24 age group (24.7%) and declined in older age groups. Regarding diagnoses, the leading categories were injury/poisoning (33.1%), psychiatric (28.1%), and musculoskeletal (12.1%). As for specialty care of evacuees, psychiatry received the largest share of total evacuations (28.1%), followed by orthopedic surgery (22.7%) and general surgery (8.6%). Looking at proportions of inpatient and outpatient care, the majority of evacuees required outpatient care (65.6%) with a sizable minority requiring inpatient care (34.4%). Inpatient evacuations peaked in 2010 (n = 2,013), accounting for 40.8% of all evacuations that year. Orthopedic surgery had the largest share of inpatient evacuations (27.3%), followed by psychiatry (21.5%) and general surgery (18.2%). As for outpatient care, the specialties with the largest proportion of outpatient evacuations were psychiatry (33.6%), orthopedic surgery (20.3%), and neurology (9.8%). CONCLUSIONS: The results of this study reveal what the MHS can expect in future conflicts. Most evacuations are for psychiatric-/injury-/musculoskeletal-related diagnoses, typically requiring care by psychiatrists, orthopedic surgeons, or general surgeons. Outpatient care is important, though it is critical to bolster inpatient care requirements as future conflicts may bring extensive numbers of inpatient casualties. The MHS should program and plan resources accordingly, planning for the care of surgical/injured and psychiatric patients.

Geospatial Assessment to Improve Time to Treatment (GAITT).

INTRODUCTION: Geographic information systems (GIS) can optimize trauma systems by identifying ways to reduce time to treatment. Using GIS, this study analyzed a system in Maryland served by Johns Hopkins Suburban Hospital and the University of Maryland Capital Region Medical Center. It was hypothesized that including Walter Reed National Military Medical Center (WRNMMC) in the Maryland trauma system in an access simulation would provide increased timely access for a portion of the local population. MATERIALS AND METHODS: Using ArcGIS Online, catchment areas with and without WRNMMC were built. Catchment areas captured Johns Hopkins Suburban Hospital, University of Maryland Capital Region Medical Center, and WRNMMC at 5-, 10-, 15-, 20-, 25-, 30-, 45-, and 60-min. Various time conditions were simulated (12 am, 8 am, 12 pm, and 5 pm) on a weekday and weekend day. Data was enriched with 19 variables addressing population size, socioeconomic status, and diversity. RESULTS: All catchment areas benefited on at least one time-day simulation, but the largest increases in mean population coverage were in the 0-5 (10.5%), 5-10 (12.3%), and 10-15 min (5.7%) catchment areas. These areas benefited regardless of time-day simulation. The lowest increase in mean population coverage was seen in the 20-25-min catchment area (0.1%). Subgroup analysis revealed that all socioeconomic status and diversity groups gained coverage. CONCLUSIONS: This study suggests that incorporating WRNMMC into the Maryland trauma system might yield increased population coverage for timely trauma access. If incorporated, WRNMMC may provide nonstop or flexible coverage, possibly in different traffic scenarios or while civilian centers are on diversion status.

High-precision monitoring of and feedback control over drug concentrations in the brains of freely moving rats.

Knowledge of drug concentrations in the brains of behaving subjects remains constrained on a number of dimensions, including poor temporal resolution and lack of real-time data. Here, however, we demonstrate the ability of electrochemical aptamer-based sensors to support seconds-resolved, real-time measurements of drug concentrations in the brains of freely moving rats. Specifically, using such sensors, we achieve <4 µM limits of detection and 10-s resolution in the measurement of procaine in the brains of freely moving rats, permitting the determination of the pharmacokinetics and concentration-behavior relations of the drug with high precision for individual subjects. In parallel, we have used closed-loop feedback-controlled drug delivery to hold intracranial procaine levels constant (±10%) for >1.5 hours. These results demonstrate the utility of such sensors in (i) the determination of the site-specific, seconds-resolved neuropharmacokinetics, (ii) enabling the study of individual subject neuropharmacokinetics and concentration-response relations, and (iii) performing high-precision control over intracranial drug levels.

Using seconds-resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time-varying physiology.

AIM: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench-top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours-scale, time-varying physiological processes. Given the recent advent of in vivo electrochemical aptamer-based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time-dense datasets to describe time-varying pharmacokinetic models with good statistical significance. METHODS: We used seconds-resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one- and two-compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. RESULTS: We found that a modified one-compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two-compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one-compartment, time-varying model was statistically preferred over the standard one-compartment model for 80% of our datasets. CONCLUSIONS: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high-time resolution EAB sensor measurements to identify such impacts.

A natural history study of coagulopathy in a porcine 40% total body surface area burn model reveals the time-dependent significance of functional assays.

Various studies have reported discordant results on the magnitude and direction of burn-induced coagulopathy (BIC), which has recently been associated with multiple organ dysfunction syndrome (MODS) and death. The increased mechanistic understanding of BIC is due, in part, to novel assays that have expanded the armamentarium beyond traditional tests like PT and aPTT. Still, BIC is a dynamic process, and the progression is difficult to define in the thermally-injured. To this end, we aimed to enhance the understanding of burn-induced coagulation abnormalities by employing functional assessments of platelet aggregation, viscoelastic kinetics, and thrombin generation in an extensive burn model in swine. Anesthetized Yorkshire pigs sustained 40% total body surface area (TBSA) full-thickness contact burns and recovered in metabolic cages. Blood was collected at baseline (BL), as well as 6, 24, and 48 h after injury. A significant effect of burn (P < 0.0001) was seen on platelets, with mild thrombocytopenia apparent at 24 h. While slight decreases in aPTT were not significant, rotational thromboelastometry (ROTEM) analysis revealed hypercoagulation 6 and 24 h after burn by a decreased clotting time. Maximum clot firmness increased after burn, but was not statistically significant until 48 h. Hypercoagulation was not supported by platelet aggregation, as the response to ADP was greatly and persistently diminished, and the response to collagen was unchanged. Endogenous thrombin potential was significantly reduced at 6 and 24 h after burn (P < 0.0001), and also correlated with a number of ROTEM parameters and collagen-induced platelet aggregation. In contrast, PT was not correlated with other measured parameters. Taken together, novel coagulation parameters may be more sensitive than PT in characterizing coagulopathy in the setting of burns. The data presented herein makes initial strides to report the natural history of several of these variables over time in a large animal model of extensive burns, indicating early hypercoagulability followed by hypocoagulation. Future work will elucidate the effects of standard of care.

HIV-1 Matrix Protein Interactions with tRNA: Implications for Membrane Targeting.

The N-terminally myristoylated matrix (MA) domain of the HIV-1 Gag polyprotein promotes virus assembly by targeting Gag to the inner leaflet of the plasma membrane. Recent studies indicate that, prior to membrane binding, MA associates with cytoplasmic tRNAs (including tRNALys3), and in vitro studies of tRNA-dependent MA interactions with model membranes have led to proposals that competitive tRNA interactions contribute to membrane discrimination. We have characterized interactions between native, mutant, and unmyristylated (myr-) MA proteins and recombinant tRNALys3 by NMR spectroscopy and isothermal titration calorimetry. NMR experiments confirm that tRNALys3 interacts with a patch of basic residues that are also important for binding to the plasma membrane marker, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Unexpectedly, the affinity of MA for tRNALys3 (Kd = 0.63 ± 0.03 µM) is approximately 1 order of magnitude greater than its affinity for PI(4,5)P2-enriched liposomes (Kd(apparent) = 10.2 ± 2.1 µM), and NMR studies indicate that tRNALys3 binding blocks MA association with liposomes, including those enriched with PI(4,5)P2, phosphatidylserine, and cholesterol. However, the affinity of MA for tRNALys3 is diminished by mutations or sample conditions that promote myristate exposure. Since Gag-Gag interactions are known to promote myristate exposure, our findings support virus assembly models in which membrane targeting and genome binding are mechanistically coupled.

Choice of a suicide method: Trends and characteristics.

The aim of this study was to examine (1) suicide trends by most prevalent methods in Queensland, Australia, during 2000-2015, and (2) characteristics of people by choice of suicide method in 2000-2013. Data were obtained from the Queensland Suicide Register, which includes police and toxicology reports, post-mortem autopsy and Coroner's findings. Poisson and Joinpoint regression were used to study the first aim, and uni-variate and multi-variate logistic regression analyses were applied to investigate the second aim. Suicide method trends showed a significant increase in hanging for both sexes and poisoning with drugs for females, while there was a decline for poisoning by other means for both sexes, and 'other methods' decreased for males. Changes in the trends have altered the order of suicide methods, especially in males. Analyses of 8140 suicides were composed by the choice of method, distinguishable profiles by their demographic, clinical and social characteristics, such as having mental or physical illness or different recent life stressors were identified. This suggests that socio-cultural acceptability, and availability are the key drivers in the choice of suicide methods. Continuing increases in hanging is a big challenge in suicide prevention due to its lethality, easy realisation and its increasing acceptability.

An Analysis and Summary of the Recommendations Made by the U.S. DoD 2010-2014 Recovering Warrior Task Force.

In 2010, the U.S. Congress directed the Department of Defense to establish the Recovering Warrior Task Force (RWTF) to examine the effectiveness of, and recommend improvements to, military programs and policies for the care, management, and transition of wounded, ill, and injured personnel. To meet its comprehensive mandate, RWTF gathered extensive primary and secondary data that, in combination with RWTF members' relevant experience and expertise, informed and substantiated the recommendations that RWTF published each year. With the 2014 sunset of the Task Force, the authors, who provided research support to RWTF throughout its tenure, sought to systematically summarize RWTF's overall impressions regarding the shortfalls in the RW program and policy arena by analyzing the 87 recommendations that these shortfalls motivated. Our 3-part qualitative analysis included sorting by congressionally determined topics, thematic analysis, and examining topic/theme convergence. We use the results of these analyses as a framework for discussing program and policy areas that RWTF found most in need of attention over its 4 years of operation. Among these were continuing gaps in Department of Defense-wide policy governing the delivery of needed resources to RWs and family caregivers, which result in disparities across Services, Components, and locations.

CROWNWeb: the evolution of kidney data management. Part 3 of a three-part series.

The Centers for Medicare & Medicaid Services is developing a Web-based application, CROWNWeb, which is designed to facilitate the mandated entry and update of electronic data, and retrieve this data for dialysis facilities nationwide. Part III of this three-part series further explores the rationale behind CROWNWeb, discusses situations from the past where CROWNWeb could have benefited the renal community, and reviews how CROWNWeb can be used in CQI activities and to track and improve patient outcomes.

CROWNWeb: the evolution of kidney data management. 2.

The Centers for Medicare & Medicaid Services is developing a Web-based application, CROWNWeb, which is designed to update mandated electronic data entry and retrieval for dialysis facilities nationwide. Part 2 of this three-part series introduces CROWNWeb to the ESRD community. It discusses the release and impact of the recently released ESRD Conditions for Coverage, and provides an overview of the CMS CROWNWeb system, highlighting features and functionality.

CROWNWeb--the evolution of kidney data management (Part I).

The Centers for Medicare & Medicaid Services is developing a Web-based application, Consolidated Renal Operations in a Web-Enabled Network (CROWNWeb), which is designed to facilitate data entry, updating, and retrieval for dialysis facilities nationwide. Part 1 of this three-part series outlines the history of end-stage renal disease and Medicare, and covers the rapid growth of ESRD data management as well as other events that require progression to an online data collection and management system.

Selective recognition of pyrophosphate in water using a backbone modified cyclic peptide receptor.

A cyclic peptide based receptor, bearing two dipicolylamino arms complexed to zinc(II) ions, binds pyrophosphate ions with high affinity and selectivity in aqueous solution as determined using an indicator displacement assay.