Activated protein C (APC) is a signaling protease with anticoagulant activity. Here, we have used mice expressing a mutation in superoxide dismutase-1 (SOD1) that is linked to amyotrophic lateral sclerosis (ALS) to show that administration of APC or APC analogs with reduced anticoagulant activity after disease onset slows disease progression and extends survival. A proteolytically inactive form of APC with reduced anticoagulant activity provided no benefit. APC crossed the blood-spinal cord barrier in mice via endothelial protein C receptor. When administered after disease onset, APC eliminated leakage of hemoglobin-derived products across the blood-spinal cord barrier and delayed microglial activation. In microvessels, motor neurons, and microglial cells from SOD1-mutant mice and in cultured neuronal cells, APC transcriptionally downregulated SOD1. Inhibition of SOD1 synthesis in neuronal cells by APC required protease-activated receptor-1 (PAR1) and PAR3, which inhibited nuclear transport of the Sp1 transcription factor. Diminished mutant SOD1 synthesis by selective gene excision within endothelial cells did not alter disease progression, which suggests that diminished mutant SOD1 synthesis in other cells, including motor neurons and microglia, caused the APCmediated slowing of disease. The delayed disease progression in mice after APC administration suggests that this approach may be of benefit to patients with familial, and possibly sporadic, ALS.

BackgroundThe article introduces Programs for Injury Categorization, using the International Classification of Diseases (ICD) and R statistical software (ICDPIC-R). Starting with ICD-8, methods have been described to map injury diagnosis codes to severity scores, especially the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). ICDPIC was originally developed for this purpose using Stata, and ICDPIC-R is an open-access update that accepts both ICD-9 and ICD-10 codes.MethodsData were obtained from the National Trauma Data Bank (NTDB), Admission Year 2015. ICDPIC-R derives CDC injury mechanism categories and an approximate ISS (“RISS”) from either ICD-9 or ICD-10 codes. For ICD-9-coded cases, RISS is derived similar to the Stata package (with some improvements reflecting user feedback). For ICD-10-coded cases, RISS may be calculated in several ways: The “GEM” methods convert ICD-10 to ICD-9 (using General Equivalence Mapping tables from CMS) and then calculate ISS with options similar to the Stata package; a “ROCmax” method calculates RISS directly from ICD-10 codes, based on diagnosis-specific mortality in the NTDB, maximizing the C-statistic for predicting NTDB mortality while attempting to minimize the difference between RISS and ISS submitted by NTDB registrars (ISSAIS). Findings were validated using data from the National Inpatient Survey (NIS, 2015).ResultsNTDB contained 917,865 cases, of which 86,878 had valid ICD-10 injury codes. For a random 100,000 ICD-9-coded cases in NTDB, RISS using the GEM methods was nearly identical to ISS calculated by the Stata version, which has been previously validated. For ICD-10-coded cases in NTDB, categorized ISS using any version of RISS was similar to ISSAIS; for both NTDB and NIS cases, increasing ISS was associated with increasing mortality. Prediction of NTDB mortality was associated with C-statistics of 0.81 for ISSAIS, 0.75 for RISS using the GEM methods, and 0.85 for RISS using the ROCmax method; prediction of NIS mortality was associated with C-statistics of 0.75–0.76 for RISS using the GEM methods, and 0.78 for RISS using the ROCmax method. Instructions are provided for accessing ICDPIC-R at no cost.ConclusionsThe ideal methods of injury categorization and injury severity scoring involve trained personnel with access to injured persons or their medical records. ICDPIC-R may be a useful substitute when this ideal cannot be obtained.

Introduction The distribution of survival times after injury has been described as “trimodal”, but several studies have not confirmed this. The purpose of this study was to clarify the distribution of survival times after injury. Methods We defined survival time (ts) as the interval between injury time and declared death time. We constructed histograms for ts <=150 minutes from the 2004-2007 Fatality Analysis Reporting System (FARS, for traffic crashes) and National Violent Death Reporting System (NVDRS, for homicides). We estimated statistical models in which death times known only within intervals were treated as interval-censored. For confirmation, we also obtained EMS response times (tr), prehospital times (tp), and hospital times (th) for decedents in the 2008 National Trauma Data Bank (NTDB) with ts=tp+th<=150. We approximated times until circulatory arrest (tx) as tr for patients pulseless at the injury scene, tp for other patients pulseless at hospital admission, and ts for the rest; for any declared ts, we calculated mean tx / ts. We used this ratio to estimate tx for hospital deaths in FARS or NVDRS, and provide independent support for using interval-censored methods. Results FARS and NVDRS deaths were most frequent in the first few minutes. Both showed a second peak at 35-40 minutes after injury, corresponding to peaks in hospital deaths. Third peaks were not present. Estimated tx in FARS and NVDRS did not show second peaks, and were similar to estimates treating some death times as interval-censored. Conclusions Increases in frequency of survival times at 35-40 minutes are primarily artifacts created because declaration of death in hospitals is delayed until completing resuscitative attempts. By avoiding these artifacts, interval censoring methods are useful for analysis of injury survival times.

The aim of this study is to quantify the changes in incidence, severity, and mortality in burn injuries in the state of Maine over the past 50 years from both prevention and treatment perspectives. The authors analyzed the data from multiple sources, including the U.S. Census, death certificates, hospital discharge abstracts, and institutional burn registries in Maine and Boston. The average annual number of burn-related deaths decreased from 53 in 1960-1964 to 14 in 2004-2008. The Maine age-adjusted rate of burn deaths was 8.6% above the national rate in 1960 and 1.4% below it in 2006. The annual number of burn patients admitted to Maine hospitals declined by 65% from 1978 to 2009. Since 1999, 12% of hospitalized patients in Maine were treated in an American Burn Association-certified burn center in Boston. Mortality for Maine burn patients, including those treated at Boston hospitals, is directly related to age and burn severity and similar to stratified mortality in the National Burn Repository. Incidence, severity, and mortality of burn injuries in Maine have decreased dramatically over the past 5 decades. Prevention programs, legislation, and a regionalized system of burn care have all likely contributed to bringing Maine's morbidity and mortality rate below the national average.

Salts are transduced by at least 2 mechanisms: (a) antagonized by amiloride and (b) antagonized by cetylpyridinium chloride (CPC). The authors report on 4 behavioral experiments in rats that characterize the orosensory properties of CPC itself as well as its effect in suppressing the intensity of NaCl and KCl taste. Experiments 1 and 2 indicated that CPC has a quinine-like taste quality. Experiments 3 and 4 demonstrated that the recognition of KCl, but not NaCl, is modestly reduced by mixture with CPC. However, control experiments call into question the mechanism of the salt suppression of CPC, because both CPC-salt and quinine-salt mixtures had similar effects. The relevance of these studies for understanding salt and bitter taste coding is discussed.

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