Inhibition of integrin alpha v/beta 5 mitigates the protective effect induced by irisin in hemorrhage.

INTRODUCTION: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. Integrin αvß5 was recently identified as a receptor for irisin to elicit its physiologic function. It remains unknown whether integrin αvß5 is required for irisin's function in modulating the physiologic response to hemorrhage. The objective of this study is to examine if integrin αvß5 contributes to the effects of irisin during the hemorrhagic response. METHODS: Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Irisin (0.5  µg/kg) was administrated to assess its pharmacologic effects in hemorrhage. Cilengitide, a cyclic Arg-Gly-Asp peptide (cRGDyK) which is an inhibitor of integrin αvß5, or control RGDS (1 mg/kg) was administered with irisin. In another cohort of mice, the irisin-induced protective effect was examined after knocking down integrin ß5 with nanoparticle delivery of integrin ß5 sgRNA using CRSIPR/Cas-9 gene editing. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization, respectively. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium, skeletal muscles, and lung tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was carried out to assess apoptosis in tissues. RESULTS: Hemorrhage induced reduction of integrin αvß5 in skeletal muscles and repressed recovery of cardiac performance and hemodynamics. Irisin treatment led to significantly improved cardiac function, which was abrogated by treatment with Cilengitide or knockdown of integrin ß5. Furthermore, irisin resulted in a marked suppression of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), muscle edema, and inflammatory cells infiltration in myocardium and skeletal muscles, which was attenuated by Cilengitide or knockdown of integrin ß5. Irisin-induced reduction of apoptosis in the myocardium, skeletal muscles, and lung, which were attenuated by either the inhibition of integrin αvß5, or knockdown of integrin ß5. CONCLUSION: Integrin αvß5 plays an important role for irisin in modulating the protective effect during hemorrhage.

Blood Pressure Challenge Reduces Hematomas in Gender-Affirming Mastectomy: A Retrospective Chart Review of 92 Consecutive Patients.

BACKGROUND: Gender-affirming mastectomy is a common surgery for the treatment of gender incongruence and gender dysphoria and improves quality of life. Hematoma rates for gender-affirming double incision mastectomies are between 2.8% and 8.1%. This study aims to investigate the utility of a blood pressure challenge, whereby the patient's blood pressure is medically increased intraoperatively to reveal bleeding vessels that can be addressed with additional hemostasis before skin closure, to reduce postoperative hematoma. METHODS: A retrospective chart review of patients who underwent gender-affirming double incision mastectomies over a 6-year period by a single surgeon was conducted. Surgeries were separated into a blood pressure challenge experimental group and a non-blood pressure challenge control group. Demographics, surgical characteristics, and postoperative complications were compared between the 2 cohorts using Pearson χ2, Fisher exact, t tests, univariate logistic regression, and multivariable logistical regression. Significance was established at P < 0.05. RESULTS: A total of 92 patients (184 breasts) were included with 32 patients (64 breasts) in the control group and 60 (120 breasts) in the blood pressure challenge group. In the control group, there were 5 hematomas (7.81%) compared with 1 (0.83%) in the blood pressure challenge group (P = 0.02). On univariate logistical regression analysis, blood pressure challenge was the only variable significantly associated with hematoma (odds ratio, 0.1; 95% confidence interval, 0.01-0.63; P = 0.04). On multivariable logistical regression, after controlling for age, body mass index, smoking status, and mass of excised breast tissue, patients who underwent blood pressure challenge demonstrated lower hematoma rates (odds ratio, 0.08; 95% CI, 0.004-0.59; P = 0.04). CONCLUSIONS: Using an intraoperative blood pressure challenge was associated with reduced hematoma rates. Guidelines for blood pressure challenge goals should be established to standardize care and reduce complications in gender-affirming mastectomies.

Impact of medical school responses during the COVID-19 pandemic on student satisfaction: a nationwide survey of US medical students.

PURPOSE: Medical schools have faced various challenges in preparing their clinical students for the frontlines of a pandemic. This study investigated medical students' satisfaction with their institutions during the coronavirus disease 2019 (COVID-19) pandemic with the intention of guiding educators in future public health crises. METHODS: In this cross-sectional study surveying students in clinical rotations, the primary outcome was overall satisfaction regarding medical schools' responses to the pandemic, and the four secondary outcomes were school communication, exposure to COVID-19, availability of personal protective equipment, and access to COVID-19 testing. RESULTS: The survey was distributed to ten medical schools, of which 430 students responded for a response rate of 13.0%. While most students were satisfied (61.9%, n=266) with their schools' response, more than one in five (21.9%, n=94) were dissatisfied. Among the four secondary outcomes, communication with students was most predictive of overall satisfaction. CONCLUSION: In future crises, schools can best improve student satisfaction by prioritizing timely communication.

Irisin reduces inflammatory signaling pathways in inflammation-mediated metabolic syndrome.

Irisin is an exercise induced myokine first shown to induce the browning of white adipose tissue (WAT) which increases energy expenditure, improves glucose tolerance, and reduces insulin resistance. Among irisin's involvement in lipid homeostasis, osteoblast proliferation, and muscle growth, it also acts as a mediator of many inflammatory pathways throughout the body. This review aims to describe the role of irisin in inflammatory processes and understand how targeting irisin can alter the inflammatory response in metabolic syndrome (MetS). The mechanisms involved in irisin's anti-inflammatory functions include reducing production of pro-inflammatory cytokines while increasing production of anti-inflammatory cytokines, reducing macrophage proliferation, inducing alternatively activated (M2-type) macrophage polarization, inhibiting pathways of increased vascular permeability, and preventing the formation of inflammasomes. While there are some contradictory results, most studies found reduced levels of irisin in MetS and type II diabetes mellitus (T2DM). Irisin treatment of cells exposed to inflammatory stimuli ameliorates the inflammatory response and promotes cellular viability. Numerous methods have been studied to increase plasma irisin levels including dietary, behavioral, and pharmaceutical. Further investigation is necessary to understand how irisin can be targeted for disease modification.

Evaluation of blood product transfusion therapies in acute injury care in low- and middle-income countries: a systematic review.

BACKGROUND: Worldwide, injuries account for approximately five million mortalities annually, with 90% occurring in low- and middle-income countries (LMICs). Although guidelines characterizing data for blood product transfusion in injury resuscitation have been established for high-income countries (HICs), no such information on use of blood products in LMICs exists. This systematic review evaluated the available literature on the use and associated outcomes of blood product transfusion therapies in LMICs for acute care of patients with injuries. METHODS: A systematic search of PubMed, EMBASE, Global Health, CINAHL and Cochrane databases through November 2018 was performed by a health sciences medical librarian. Prospective and cross-sectional reports of injured patients from LMICs involving data on blood product transfusion therapies were included. Two reviewers identified eligible records (κ=0.92); quality was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Report elements, patient characteristics, injury information, blood transfusion therapies provided and mortality outcomes were extracted and analyzed. RESULTS: Of 3411 records, 150 full-text reports were reviewed and 17 met inclusion criteria. Identified reports came from the World Health Organization regions of Africa, the Eastern Mediterranean, and South-East Asia. A total of 6535 patients were studied, with the majority from exclusively inpatient hospital settings (52.9%). Data on transfusion therapies demonstrated that packed red blood cells were given to 27.0% of patients, fresh frozen plasma to 13.8%, and unspecified product types to 50.1%. Among patients with blunt and penetrating injuries, 5.8% and 15.7% were treated with blood product transfusions, respectively. Four reports provided data on comparative mortality outcomes, of which two found higher mortality in blood transfusion-treated patients than in untreated patients at 17.4% and 30.4%. The overall quality of evidence was either low (52.9%) or very low (41.2%), with one report of moderate quality by GRADE criteria. CONCLUSION: There is a paucity of high-quality data to inform appropriate use of blood transfusion therapies in LMIC injury care. Studies were geographically limited and did not include sufficient data on types of therapies and specific injury patterns treated. Future research in more diverse LMIC settings with improved data collection methods is needed to inform injury care globally.