MiRNA-Mediated Control of HLA-G Expression and Function

HLA-G is a non-classical HLA class-Ib molecule expressed mainly by the extravillous cytotrophoblasts (EVT) of the placenta. The expression of HLA-G on these fetal cells protects the EVT cells from immune rejection and is therefore important for a healthy pregnancy. The mechanisms controlling HLA-G expression are largely unknown. Here we demonstrate that miR-148a and miR-152 down-regulate HLA-G expression by binding its 3′UTR and that this down-regulation of HLA-G affects LILRB1 recognition and consequently, abolishes the LILRB1-mediated inhibition of NK cell killing. We further demonstrate that the C/G polymorphism at position +3142 of HLA-G 3′UTR has no effect on the miRNA targeting of HLA-G. We show that in the placenta both miR-148a and miR-152 miRNAs are expressed at relatively low levels, compared to other healthy tissues, and that the mRNA levels of HLA-G are particularly high and we therefore suggest that this might enable the tissue specific expression of HLA-G

Use of Combat Casualty Care Data to Assess the US Military Trauma System During the Afghanistan and Iraq Conflicts, 2001-2017.

IMPORTANCE: Although the Afghanistan and Iraq conflicts have the lowest US case-fatality rates in history, no comprehensive assessment of combat casualty care statistics, major interventions, or risk factors has been reported to date after 16 years of conflict. OBJECTIVES: To analyze trends in overall combat casualty statistics, to assess aggregate measures of injury and interventions, and to simulate how mortality rates would have changed had the interventions not occurred. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of all available aggregate and weighted individual administrative data compiled from Department of Defense databases on all 56 763 US military casualties injured in battle in Afghanistan and Iraq from October 1, 2001, through December 31, 2017. Casualty outcomes were compared with period-specific ratios of the use of tourniquets, blood transfusions, and transport to a surgical facility within 60 minutes. MAIN OUTCOMES AND MEASURES: Main outcomes were casualty status (alive, killed in action [KIA], or died of wounds [DOW]) and the case-fatality rate (CFR). Regression, simulation, and decomposition analyses were used to assess associations between covariates, interventions, and individual casualty status; estimate casualty transitions (KIA to DOW, KIA to alive, and DOW to alive); and estimate the contribution of interventions to changes in CFR. RESULTS: In aggregate data for 56 763 casualties, CFR decreased in Afghanistan (20.0% to 8.6%) and Iraq (20.4% to 10.1%) from early stages to later stages of the conflicts. Survival for critically injured casualties (Injury Severity Score, 25-75 [critical]) increased from 2.2% to 39.9% in Afghanistan and from 8.9% to 32.9% in Iraq. Simulations using data from 23 699 individual casualties showed that without interventions assessed, CFR would likely have been higher in Afghanistan (15.6% estimated vs 8.6% observed) and Iraq (16.3% estimated vs 10.1% observed), equating to 3672 additional deaths (95% CI, 3209-4244 deaths), of which 1623 (44.2%) were associated with the interventions studied: 474 deaths (12.9%) (95% CI, 439-510) associated with the use of tourniquets, 873 (23.8%) (95% CI, 840-910) with blood transfusion, and 275 (7.5%) (95% CI, 259-292) with prehospital transport times. CONCLUSIONS AND RELEVANCE: Our analysis suggests that increased use of tourniquets, blood transfusions, and more rapid prehospital transport were associated with 44.2% of total mortality reduction. More critically injured casualties reached surgical care, with increased survival, implying improvements in prehospital and hospital care

A descriptive study of US Special Operations Command fatalities, 2001 to 2018.

BACKGROUND: Studies of fatalities from injury and disease guide prevention and treatment efforts for populations at risk. Findings can inform leadership and direct clinical practice guidelines, research, and personnel, training, and equipment requirements. METHODS: A retrospective review and descriptive analysis was conducted of United States Special Operations Command (USSOCOM) fatalities who died while performing duties from September 11, 2001, to September 10, 2018. Characteristics analyzed included subcommand, military activity, operational posture, and manner of death. RESULTS: Of 614 USSOCOM fatalities (median age, 30 years; male, 98.5%) the leading cause of death was injury (97.7%); specifically, multiple/blunt force injury (34.5%), blast injury (30.7%), gunshot wound (GSW; 30.3%), and other (4.5%). Most died outside the United States (87.1%), during combat operations (85.3%), in the prehospital environment (91.5%), and the same day of insult (90.4%). Most fatalities were with the US Army Special Operations Command (67.6%), followed by the Naval Special Warfare Command (16.0%), Air Force Special Operations Command (9.3%), and Marine Corps Forces Special Operations Command (7.2%). Of 54.6% who died of injuries incurred during mounted operations, most were on ground vehicles (53.7%), followed by rotary-wing (37.3%) and fixed-wing (9.0%) aircrafts. The manner of death was primarily homicide (66.0%) and accident (30.5%), followed by natural (2.1%), suicide (0.8%), and undetermined (0.7%). Specific homicide causes of death were GSW (43.7%), blast injury (42.2%), multiple/blunt force injury (13.8%), and other (0.2%). Specific accident causes of death were multiple/blunt force injury (80.7%), blast injury (6.4%), GSW (0.5%), and other (12.3%). Of accident fatalities with multiple/blunt force injury, the mechanism was mostly aircraft mishaps (62.9%), particularly rotary wing (68.4%). CONCLUSION: Most USSOCOM fatalities died abroad from injury in the prehospital setting. To improve survival from military activities worldwide, leaders must continue to optimize prehospital capability and develop strategies that rapidly connect patients to advanced resuscitative and surgical care. LEVEL OF EVIDENCE: Epidemiological, level IV; Therapeutic level IV

Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes

BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo