No abstract

Weight-loss interventions, especially comprehensive lifestyle interventions, are associated with improvements in OSA severity, cardiometabolic comorbidities, and quality of life. The American Thoracic Society recommends that clinicians regularly assess weight and incorporate weight management strategies that are tailored to individual patient preferences into the routine treatment of adult patients with OSA who are overweight or obese.

-Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis. sepsis; lung injury; mitogen-activated protein kinases; mitochondria; mitophagy; biogenesis SEPSIS, A SYSTEMIC INFLAMMATORY reaction to infection, is the leading cause of death globally. The incidence of sepsis worldwide is 18 million every year with 30% mortality. The economic impact of sepsis is substantial with costs of up to $50,000/patient and $17 billion annually in United States alone (30, 43). Death from sepsis occurs due to multiorgan failure, and biological therapies do not exist. Prevailing theories attribute multiple organ failure in sepsis to an uncontrolled inflammatory response, apoptosis, or disorders in the coagulation (38). Unfortunately, therapies against these responses, such as anti-inflammatory agents and activated protein C, have been unsuccessful. Since current medical care remains purely supportive, there is an urgent need to develop targeted therapies.Mitochondria are mediators of inflammatory responses (19, 54) and become dysfunctional in sepsis and lung injury (4, 6), suggesting they are involved in the observed pathology. Mitochondria are essential hubs of innate immune signaling and inflammation in sepsis (48, 49) and are also major sites of reactive oxygen species (ROS) production in the cells. Mitochondria are constantly exposed to ROS, and hence ongoing biogenesis and turnover are needed to maintain a functional network. Dysfunctional mitochondria are removed through selective degradation via autophagy by the lysosomal mach...

Background The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been investigated specifically. The aim of this study was to identify genetic variants contributing to ARDS from pulmonary or extrapulmonary causes. Methods We conducted a multi-stage genetic association study. We first performed a large-scale genotyping (50K IBC Chip) in 1,717 Caucasian critically ill patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p ≤ 0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n = 765) and pneumonia/pulmonary sepsis (Population II; n = 838), as causes for ARDS/ALI. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n = 224, Stage III). Results In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p < 0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p < 0.007, Stage II; p < 0.05, Stage III). Meta-analysis confirmed these associations. Conclusions Different genetic variants may influence ARDS susceptibility depending on direct vs indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI, respectively.

Women in medicine have made progress since Elizabeth Blackwell: the first women to receive her medical degree in the United States in 1849. Yet although women currently represent just over one-half of medical school applicants and matriculates, they continue to face many challenges that hinder them from entering residency, achieving leadership positions that exhibit final decision-making and budgetary power, and, in academic medicine, being promoted. Challenges include gender bias in promotion, salary inequity, professional isolation, bullying, sexual harassment, and lack of recognition, all of which lead to higher rates of attrition and burnout in women physicians. These challenges are even greater for women from groups that have historically been marginalized and excluded, in all aspects of their career and especially in achieving leadership positions. It is important to note that, in several studies, it was indicated that women physicians are more likely to adhere to clinical guidelines, provide preventive care and psychosocial counseling, and spend more time with their patients than their male peers. Additionally, some studies reveal improved clinical outcomes with women physicians. Therefore, it is critical for health care systems to promote workforce diversity in medicine and support women physicians in their career development and success and their wellness from early to late career.