A concerted effort to tackle the global health problem posed by traumatic brain injury (TBI) is long overdue. TBI is a public health challenge of vast, but insufficiently recognised, proportions. Worldwide, more than 50 million people have a TBI each year, and it is estimated that about half the world's population will have one or more TBIs over their lifetime. TBI is the leading cause of mortality in young adults and a major cause of death and disability across all ages in all countries, with a disproportionate burden of disability and death occurring in low-income and middle-income countries (LMICs). It has been estimated that TBI costs the global economy approximately $US400 billion annually. Deficiencies in prevention, care, and research urgently need to be addressed to reduce the huge burden and societal costs of TBI. This Commission highlights priorities and provides expert recommendations for all stakeholders—policy makers, funders, health-care professionals, researchers, and patient representatives—on clinical and research strategies to reduce this growing public health problem and improve the lives of people with TBI.Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Söderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbüchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigator

BACKGROUNDVasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODSWe randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTSA total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (−1.75 vs. −1.28, P = 0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P = 0.12). CONCLUSIONS 420T h e ne w e ngl a nd jou r na l o f m e dicine S hock is a life-threatening syndrome characterized by decreased organ perfusion that can progress to irreversible organ failure. 1 Vasodilatory shock is the most common type of shock and is characterized by peripheral vasodilation and reduced blood pressure despite preserved cardiac output. 2 Vasodilatory shock requires immediate treatment to ensure organ perfusion through the reestablishment of adequate blood pressure while the underlying cause of shock is identified and treated. 3 Vasopressors are used when intravenous fluid resuscitation alone fails to restore blood pressure. Patients with severe vasodilation who have hypotension despite the use of high doses of vasopressors have a poor prognosis, with 30-day all-cause mortality exceeding 50%. 4,5 Currently, only two classes of vasopressors are available: catecholamines (and other sympathomimetic amines) and vasopressin. 3 Both classes have narrow therapeutic windows owing to substantial toxic effects at high doses. 6 However, when hypotension occurs, human physiology engages a third system, which is represented by hormones in the renin-angiotensin-aldosterone system (RAAS). 7 Previously, modified bovine angiotensin II was shown to elicit consis...

Background: Characterization of the mesenchymal stromal cell (MSC) safety profile is important as this novel therapy continues to be evaluated in clinical trials for various inflammatory conditions. Due to an increase in published randomized controlled trials (RCTs) from 2012À2019, we performed an updated systematic review to further characterize the MSC safety profile. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science (to May 2018) were searched. RCTs that compared intravascular delivery of MSCs to controls in adult populations were included. Pre-specified adverse events were grouped according to: (1) immediate, (2) infection, (3) thrombotic/embolic, and (4) longer-term events (mortality, malignancy). Adverse events were pooled and meta-analyzed by fitting inverse-variance binary random effects models. Primary and secondary clinical efficacy endpoints were summarized descriptively. Findings: 7473 citations were reviewed and 55 studies met inclusion criteria (n = 2696 patients). MSCs as compared to controls were associated with an increased risk of fever (Relative Risk (RR) = 2¢48, 95% Confidence Interval (CI) = 1¢27À4¢86; I 2 = 0%), but not non-fever acute infusional toxicity, infection, thrombotic/ embolic events, death, or malignancy (RR = 1¢16,

ed blood cell (RBC) transfusion is the most common medical procedure in contemporary medicine. 1 In the United States, 7.6% of all hospitalized patients will receive at least 1 blood transfusion during their hospitalization, and its use has increased between 1997 and 2011 by 134%. 1 With the main objective to improve oxygen delivery to tissues, 2 RBC transfusion is used in a variety of medical situations, ranging from correction of chronic low-grade anemia to resuscitation of the massively bleeding patient. 2-5 When a decision to transfuse has been made, usual practice is to order 1 or more compatible RBC units from the blood bank. Limited characteristics of the RBC unit can be requested, such as cytomegalovirus (CMV) status, leukoreduction, or irradiation; however, evidence of clinical benefit with these specific characteristics is limited. 6 There is growing preclinical and clinical evidence that blood donor characteristics may affect recipient outcomes. Erythropoiesis is altered by aging, 7 as are other characteristics related to blood, including immune tolerance, inflammation, oncogenicity, and premature cellular turnover. 8,9 Humans who live longer may also have different genetic factors affecting RBC characteristics. 10 Immunological phenomena related to donors, such as the antileukocyte antibodies (anti-HLA or antineutrophil antibodies) that occur after pregnancies (eg, sex effect on transfusion-related acute lung injury [TRALI]), have been shown to affect clinical outcomes. 11,12 Transfusion of a blood component is analogous to solid organ transplantation because it involves the retrieval of an organ (blood) from a donor, postdonation processing and IMPORTANCE While red blood cells (RBCs) are administered to improve oxygen delivery and patient outcomes, they also have been associated with potential harm. Unlike solid organ transplantation, the clinical consequences of donor characteristics on recipients have not been evaluated in transfusion medicine. OBJECTIVE To analyze the association of RBC donor age and sex with the survival of transfusion recipients. DESIGN, SETTING, AND PARTICIPANTS We established a longitudinal cohort by linking data from a blood collection agency with clinical and administrative data at 4 academic hospitals. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression models were fitted to evaluate the risk of donor age and sex on transfusion recipient survival.