Mitofusin-2 Regulates Platelet Mitochondria and Function.

BACKGROUND: Single-nucleotide polymorphisms linked with the rs1474868 T allele (MFN2 [mitofusin-2] T/T) in the human mitochondrial fusion protein MFN2 gene are associated with reduced platelet MFN2 RNA expression and platelet counts. This study investigates the impact of MFN2 on megakaryocyte and platelet biology. METHODS: Mice with megakaryocyte/platelet deletion of Mfn2 (Mfn2-/- [Mfn2 conditional knockout]) were generated using Pf4-Cre crossed with floxed Mfn2 mice. Human megakaryocytes were generated from cord blood and platelets isolated from healthy subjects genotyped for rs1474868. Ex vivo approaches assessed mitochondrial morphology, function, and platelet activation responses. In vivo measurements included endogenous/transfused platelet life span, tail bleed time, transient middle cerebral artery occlusion, and pulmonary vascular permeability/hemorrhage following lipopolysaccharide-induced acute lung injury. RESULTS: Mitochondria was more fragmented in megakaryocytes derived from Mfn2-/- mice and from human cord blood with MFN2 T/T genotype compared with control megakaryocytes. Human resting platelets of MFN2 T/T genotype had reduced MFN2 protein, diminished mitochondrial membrane potential, and an increased rate of phosphatidylserine exposure during ex vivo culture. Platelet counts and platelet life span were reduced in Mfn2-/- mice accompanied by an increased rate of phosphatidylserine exposure in resting platelets, especially aged platelets, during ex vivo culture. Mfn2-/- also decreased platelet mitochondrial membrane potential (basal) and activated mitochondrial oxygen consumption rate, reactive oxygen species generation, calcium flux, platelet-neutrophil aggregate formation, and phosphatidylserine exposure following dual agonist activation. Ultimately, Mfn2-/- mice showed prolonged tail bleed times, decreased ischemic stroke infarct size after cerebral ischemia-reperfusion, and exacerbated pulmonary inflammatory hemorrhage following lipopolysaccharide-induced acute lung injury. Analysis of MFN2 SNPs in the iSPAAR study (Identification of SNPs Predisposing to Altered ALI Risk) identified a significant association between MFN2 and 28-day mortality in patients with acute respiratory distress syndrome. CONCLUSIONS: Mfn2 preserves mitochondrial phenotypes in megakaryocytes and platelets and influences platelet life span, function, and outcomes of stroke and lung injury.

Facility Volume Thresholds for Optimization of Short- and Long-Term Outcomes in Patients Undergoing Hepatectomy for Primary Liver Tumors.

BACKGROUND: Volume-outcome relationships have been described for a variety of surgical procedures. We aimed to define the facility volume threshold at which postoperative mortality after hepatectomy was optimal. METHODS: We determined volume percentiles for institutions performing hepatectomy for any primary liver tumor within the National Cancer Database (2004-2017). Marginal structural logistic regression defined the volume percentile (Vmin) at which the odds of 90-day mortality were optimally reduced in patients with hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). Short-term postoperative and survival outcomes were compared between patients treated at facilities above and below Vmin. RESULTS: Thresholds for the 10th/25th/50th/75th/90th percentiles were 2/7/26/46/59 hepatectomies/year. A total of 17,833 patients underwent resection of HCC or ICC. The 90-day postoperative mortality was optimized at the 75th percentile for all hepatectomies (IP-weighted OR = 0.67, 95% CI = 0.52-0.87) and major hepatectomy (IP-weighted OR = 0.62, 95% CI = 0.49-0.80). Seven of 446 facilities met the Vmin threshold. The odds of 30-day mortality were also reduced for all hepatectomies (IP-weighted OR = 0.55, 95% CI = 0.42-0.73) and major hepatectomy (IP-weighted OR = 0.58, 95% CI = 0.41-0.75). There were no differences in length of stay or 30-day readmission rate. Patients with HCC or ICC treated at facilities ≥ 10th percentile had an associated improvement in overall survival. CONCLUSIONS: Resection of HCC and ICC is performed at a large number of facilities. Postoperative mortality is optimally reduced at facilities performing at least 46 liver operations annually. Regionalization of surgical care among patients with primary liver malignancies to high-volume centers may result in improved outcomes.

Preferences for and barriers to gender affirming surgeries in transgender and non-binary individuals.

Background: The transgender/non-binary community continues to be an underserved population in medicine, and our understanding of their interests, disinterests, and barriers to transition-related healthcare is quite limited, especially among the diverse gender identities within the transgender/non-binary umbrella. Aim: To determine the interests, disinterests and barriers to gender affirming surgeries for transgender men, transgender women and non-binary individuals of any birth-assigned sex. Methods: An anonymous, online survey using REDcap was applied across all 50 states and advertised through social media, healthcare organization websites and flyers. The responses of individuals greater than 18 years of age who identified as transgender or non-binary were analyzed. Results: Compared to the 2015 US Transgender Survey, interest in gender affirming surgeries was higher across all gender identities surveyed and for all procedures, by an average of 38%. Interest overall in gender affirming procedures varied greatly among gender identity groups as well as with age differences. Barriers were found to be a mixture of lack of resources for recovery, financial, and a fear of complications. Discussion: Our results highlight that a desire for these procedures is unique for each individual and should never be assumed for transgender/non-binary patients. In order to better aid this underserved population, the medical community must further work to mitigate the barriers to gender affirming procedures by decreasing cost, investigating ways to increase access to resources for recovery, and improving outcomes for each of the gender affirming surgeries.