Dysregulation of oxidative phosphorylation is associated with increased mitochondrial reactive oxygen species production and some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Chemical 'mitochondrial uncouplers' are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. Mitochondrial uncouplers also lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing production of reactive oxygen species. Thus, mitochondrial uncouplers are valuable chemical tools that enable the measurement of maximal mitochondrial respiration and they have been used therapeutically to decrease mitochondrial reactive oxygen species production. However, the most widely used protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol have off-target activity at other membranes that lead to a range of undesired effects including plasma membrane depolarization, mitochondrial inhibition, and cytotoxicity. These unwanted properties interfere with the measurement of mitochondrial function and result in a narrow therapeutic index that limits their usefulness in the clinic. To identify new mitochondrial uncouplers that lack off-target activity at the plasma membrane we screened a small molecule chemical library. Herein we report the identification and validation of a novel mitochondrial protonophore uncoupler (2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine, named BAM15, that does not depolarize the plasma membrane. Compared to FCCP, an uncoupler of equal potency, BAM15 treatment of cultured cells stimulates a higher maximum rate of mitochondrial respiration and is less cytotoxic. Furthermore, BAM15 is bioactive in vivo and dose-dependently protects mice from acute renal ischemic-reperfusion injury. From a technical standpoint, BAM15 represents an effective new tool that allows the study of mitochondrial function in the absence of off-target effects that can confound data interpretation. From a therapeutic perspective, BAM15-mediated protection from ischemia-reperfusion injury and its reduced toxicity will hopefully reignite interest in pharmacological uncoupling for the treatment of the myriad of diseases that are associated with altered mitochondrial function.

Objectives This study sought to perform a systematic review and meta-analysis to understand the prognostic value of myocardial scarring as evidenced by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with known or suspected cardiac sarcoidosis. Background Although CMR is increasingly used for the diagnosis of cardiac sarcoidosis, the prognostic value of CMR has been less well described in this population. Methods PubMed, Cochrane CENTRAL, and meta-Register of Controlled Trials were searched for CMR studies with ≥ 1 year of prognostic data. Primary end-points were all-cause mortality and a composite outcome of arrhythmogenic events (ventricular arrhythmia, ICD shock, sudden cardiac death) plus all-cause mortality during follow-up. Summary effect estimates were generated with random-effects modeling. Results Ten studies were included, involving a total of 760 patients with a mean follow up of 3.0 ± 1.1 years. Patients had a mean age of 53 years, 41% were male, 95.3% had known extra-cardiac sarcoidosis, and 21.6% had known cardiac sarcoidosis. The average ejection fraction was 57.8 ± 9.1%. Patients with late gadolinium enhancement had higher odds for all-cause mortality (odds ratio [OR]: 3.06, p < 0.03) and higher odds of the composite outcome (OR: 10.74, p< .00001) compared to those without LGE. Patients with LGE had an increased annualized event rate of the composite outcome (11.9% v. 1.1%; p<0.0001) Conclusions In patients with known or suspected cardiac sarcoidosis, the presence of late gadolinium enhancement on cardiac MRI is associated with increased odds of both all-cause mortality and arrhythmogenic events.

Objective Physician burnout associated with EHRs is a major concern in health care. A comprehensive assessment of differences among physicians in the areas of EHR performance, efficiency, and satisfaction has not been conducted. The study sought to study relationships among physicians’ performance, efficiency, perceived workload, satisfaction, and usability in using the electronic health record (EHR) with comparisons by age, gender, professional role, and years of experience with the EHR. Materials and Methods Mixed-methods assessments of the medical intensivists' EHR use and perceptions. Using simulated cases, we employed standardized scales, performance measures, and extensive interviews. NASA Task Load Index (TLX), System Usability Scale (SUS), and Questionnaire on User Interface Satisfaction surveys were deployed. Results The study enrolled 25 intensive care unit (ICU) physicians (11 residents, 9 fellows, 5 attendings); 12 (48%) were men, with a mean age of 33 (range, 28-55) years and a mean of 4 (interquartile range, 2.0-5.5) years of Epic experience. Overall task performance scores were similar for men (90% ± 9.3%) and women (92% ± 4.4%), with no statistically significant differences (P = .374). However, female physicians demonstrated higher efficiency in completion time (difference = 7.1 minutes; P = .207) and mouse clicks (difference = 54; P = .13). Overall, men reported significantly higher perceived EHR workload stress compared with women (difference = 17.5; P < .001). Men reported significantly higher levels of frustration with the EHR compared with women (difference = 33.15; P < .001). Women reported significantly higher satisfaction with the ease of use of the EHR interface than men (difference = 0.66; P =.03). The women’s perceived overall usability of the EHR is marginally higher than that of the men (difference = 10.31; P =.06). Conclusions Among ICU physicians, we measured significant gender-based differences in perceived EHR workload stress, satisfaction, and usability—corresponding to objective patterns in EHR efficiency. Understanding the reasons for these differences may help reduce burnout and guide improvements to physician performance, efficiency, and satisfaction with EHR use. Design Mixed-methods assessments of the medical intensivists’ EHR use and perceptions. Using simulated cases, we employed standardized scales, performance measures, and extensive interviews.

IMPORTANCE The use of electronic health records (EHRs) is directly associated with physician burnout. An underlying factor associated with burnout may be EHR-related fatigue owing to insufficient user-centered interface design and suboptimal usability. OBJECTIVE To examine the association between EHR use and fatigue, as measured by pupillometry, and efficiency, as measured by mouse clicks, time, and number of EHR screens, among intensive care unit (ICU) physicians completing a simulation activity in a prominent EHR. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, simulation-based EHR usability assessment of a leading EHR system was conducted from March 20 to April 5, 2018, among 25 ICU physicians and physician trainees at a southeastern US academic medical center. Participants completed 4 simulation patient cases in the EHR that involved information retrieval and task execution while wearing eye-tracking glasses. Fatigue was quantified through continuous eye pupil data; EHR efficiency was characterized through task completion time, mouse clicks, and EHR screen visits. Data were analyzed from June 1, 2018, to August 31, 2019. MAIN OUTCOMES AND MEASURES Primary outcomes were physician fatigue, measured by pupillometry (with lower scores indicating greater fatigue), and EHR efficiency, measured by task completion times, number of mouse clicks, and number of screens visited during EHR simulation. RESULTS The 25 ICU physicians (13 women; mean [SD] age, 33.2 [6.1] years) who completed a simulation exercise involving 4 patient cases (mean [SD] completion time, 34:43 [11:41] minutes) recorded a total of 14 hours and 27 minutes of EHR activity. All physician participants experienced physiological fatigue at least once during the exercise, and 20 of 25 participants (80%) experienced physiological fatigue within the first 22 minutes of EHR use.

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