Impact of Work on Personal Relationships and Physician Well-being.

OBJECTIVE: To assess the impact of work on personal relationships (IWPR) by specialty and demographic variables in a national sample of physicians, to assess the association between the IWPR and burnout, and to determine the effect of adjusting for IWPR on the risk of burnout associated with being a physician. METHODS: Analysis was conducted of data from a representative sample of US physicians surveyed between November 20, 2020, and March 23, 2021, and from a probability-based sample of other US workers. IWPR and burnout were measured with published assessments. RESULTS: Of the 7360 physicians who responded to the survey, 6271 (85.2%) completed the IWPR assessment. In multivariable analysis, moderate or higher IWPR was associated with female sex (odds ratio [OR], 1.26; 95% CI, 1.11 to 1.43), married vs single (OR, 0.59; 95% CI, 0.48 to 0.71), and emergency medicine (OR, 1.93; 95% CI, 1.43 to 2.60) or physical and rehabilitative medicine (OR, 1.67; 95% CI, 1.12 to 2.50) vs internal medicine subspecialty. Physicians were more likely than workers in other fields (OR, 2.65; 95% CI, 2.33 to 3.02) to endorse the statement "In the past year, my job contributed to me feeling more isolated or detached from the people who are important to me" as at least moderately true. After adjustment for responses to this statement, work hours, and demographic characteristics, being a physician was not associated with the risk of burnout. CONCLUSION: IWPR is associated with burnout. Adjustment for IWPR eliminated the observed difference in burnout between physicians and workers in other fields. Interventions that identify and mitigate work practices that have a negative impact on physicians' personal relationships and interventions that support affected individual physicians are warranted.

Associations Between Organizational Support, Burnout, and Professional Fulfillment Among US Physicians During the First Year of the COVID-19 Pandemic.

GOAL: This research aimed to evaluate variations in perceived organizational support among physicians during the first year of the COVID-19 pandemic and the associations between perceived organizational support, physician burnout, and professional fulfillment. METHODS: Between November 20, 2020, and March 23, 2021, 1,162 of 3,671 physicians (31.7%) responded to the study survey by mail, and 6,348 of 90,000 (7.1%) responded to an online version. Burnout was assessed using the Maslach Burnout Inventory, and perceived organizational support was assessed by questions developed and previously tested by the Stanford Medicine WellMD Center. Professional fulfillment was measured using the Stanford Professional Fulfillment Index. PRINCIPAL FINDINGS: Responses to organizational support questions were received from 5,933 physicians. The mean organizational support score (OSS) for male physicians was higher than the mean OSS for female physicians (5.99 vs. 5.41, respectively, on a 0-10 scale, higher score favorable; p < .001). On multivariable analysis controlling for demographic and professional factors, female physicians (odds ratio [OR] 0.66; 95% CI: 0.55-0.78) and physicians with children under 18 years of age (OR 0.72; 95% CI: 0.56-0.91) had lower odds of an OSS in the top quartile (i.e., a high OSS score). Specialty was also associated with perceived OSS in mean-variance analysis, with some specialties (e.g., pathology and dermatology) more likely to perceive significant organizational support relative to the reference specialty (i.e., internal medicine subspecialty) and others (e.g., anesthesiology and emergency medicine) less likely to perceive support. Physicians who worked more hours per week (OR for each additional hour/week 0.99; 95% CI: 0.99-1.00) were less likely to have an OSS in the top quartile. On multivariable analysis, adjusting for personal and professional factors, each one-point increase in OSS was associated with 21% lower odds of burnout (OR 0.79; 95% CI: 0.77-0.81) and 32% higher odds of professional fulfillment (OR 1.32; 95% CI: 1.28-1.36). PRACTICAL APPLICATIONS: Perceived organizational support of physicians during the COVID-19 pandemic was associated with a lower risk of burnout and a higher likelihood of professional fulfillment. Women physicians, physicians with children under 18 years of age, physicians in certain specialties, and physicians working more hours reported lower perceived organizational support. These gaps must be addressed in conjunction with broad efforts to improve organizational support.

Reports of Burnout Among Historically Marginalized and Female Graduating Medical Students During the COVID-19 Pandemic.

PURPOSE: To examine graduating medical student reports of burnout by sex, race and ethnicity, and sexual orientation and explore trends within intersectional demographic groups from 2019-2021 in a national sample. METHOD: The authors obtained medical student responses to the 2019-2021 Association of American Medical Colleges (AAMC) Graduation Questionnaires (GQs) linked to data from other AAMC sources. The dataset included year of GQ completion, responses to a modified Oldenburg Burnout Inventory (exhaustion subscale range: 0-24; disengagement subscale range: 0-15), and demographics previously shown to relate to the risk of burnout in medical students, residents, or physicians. Multivariable linear regression analysis was performed to evaluate independent associations between demographics and burnout. RESULTS: Overall response rate was 80.7%. After controlling for other factors, mean exhaustion scores were higher among Asian (parameter estimate [PE] 0.38, 95% confidence interval [CI] 0.21, 0.54), bisexual (PE 0.97, 95% CI 0.76, 1.17), and gay or lesbian (PE 0.55, 95% CI 0.35, 0.75) students than those who did not identify with each of those respective groups. Mean disengagement scores were lower among female (PE -0.47, 95% CI -0.52, -0.42), Hispanic (PE -0.11, 95% CI -0.22, -0.01), and White (PE -0.10, 95% CI -0.19, 0.00) students and higher among Asian (PE 0.17, 95% CI 0.07, 0.27), Black or African American (PE 0.31, 95% CI 0.18, 0.44), bisexual (PE 0.54, 95% CI 0.41, 0.66), and gay or lesbian (PE 0.23, 95% CI 0.11, 0.35) students than those who did not identify with each of those respective groups. From 2019-2021, mean exhaustion and disengagement scores were relatively stable or improved across nearly all intersectional groups. CONCLUSIONS: Male, Asian, Black or African American, and sexual minority students had a higher risk of burnout, while female, Hispanic, White, and heterosexual or straight students had a lower risk of burnout.

Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Reactive capture of CO2 via amino acid.

Reactive capture of carbon dioxide (CO2) offers an electrified pathway to produce renewable carbon monoxide (CO), which can then be upgraded into long-chain hydrocarbons and fuels. Previous reactive capture systems relied on hydroxide- or amine-based capture solutions. However, selectivity for CO remains low (<50%) for hydroxide-based systems and conventional amines are prone to oxygen (O2) degradation. Here, we develop a reactive capture strategy using potassium glycinate (K-GLY), an amino acid salt (AAS) capture solution applicable to O2-rich CO2-lean conditions. By employing a single-atom catalyst, engineering the capture solution, and elevating the operating temperature and pressure, we increase the availability of dissolved in-situ CO2 and achieve CO production with 64% Faradaic efficiency (FE) at 50 mA cm-2. We report a measured CO energy efficiency (EE) of 31% and an energy intensity of 40 GJ tCO-1, exceeding the best hydroxide- and amine-based reactive capture reports. The feasibility of the full reactive capture process is demonstrated with both simulated flue gas and direct air input.

Scaling CO2 Electrolyzer Cell Area from Bench to Pilot.

To contribute meaningfully to carbon dioxide (CO2) emissions reduction, CO2 electrolyzer technology will need to scale immensely. Bench-scale electrolyzers are the norm, with active areas <5 cm2. However, cell areas on the order of 100s or 1000s of cm2 will be required for industrial deployment. Here, we study the effects of increasing cell area, scaling over 2 orders of magnitude from a 5 cm2 lab-scale cell to an 800 cm2 pilot plant-scale cell. A direct scaling of the bench-scale cell architecture to the larger area results in a ∼20% drop in ethylene (C2H4) selectivity and an increase in the parasitic hydrogen (H2) evolution reaction (HER). We instrument an 800 cm2 electrolyzer cell to serve as a diagnostic tool and determine that nonuniformities in electrode compression and flow-influenced local CO2 availability are the key drivers of performance loss upon scaling. Machining of an initial 800 cm2 cell results in a standard deviation in MEA compression that is 7-fold that of a similarly produced 5 cm2 cell (0.009 mm). Using these findings, we redesign an 800 cm2 cell for compression tolerance and increased CO2 transport and achieve an H2 FE in the revised 800 cm2 cell similar to that of the 5 cm2 case (16% at 200 mA cm-2). These results demonstrate that by ensuring uniform compression and fluid flow, the CO2 electrolyzer area can be scaled over 100-fold and retain C2H4 selectivity (within 10% of small-scale selectivity).

Futureproofing Medical Education Through Scenario Analysis: Instrumental Case Study.

Developments in technology and climate change, as well as other "megatrends" are having lasting impacts in society and healthcare. A scenario analysis was conducted to explore the impact of megatrends on medical education. Three scenarios were developed for the year 2035, showing varying levels of technological integration and environmental focus. Implications for an updated curricula focus on health inequalities, digital health, and globalization effects.

Stenting versus medical treatment alone for symptomatic intracranial artery stenosis: a preplanned pooled individual patient data analysis.

BACKGROUND: Whether the safety and efficacy of percutaneous transluminal angioplasty and stenting (PTAS) is significantly different from that of medical treatment alone for symptomatic intracranial arterial stenosis (ICAS) is debatable. A study was undertaken to determine the safety and efficacy of both treatments for symptomatic ICAS. METHODS: This preplanned pooled individual patient data analysis included 400 participants treated with PTAS and 409 treated with medical treatment alone in two large multicenter randomized clinical trials (SAMMPRIS and CASSISS). Patients were treated with PTAS using a self-expanding stent or medical treatment alone. The primary outcome was stroke or death within 30 days, or ischemic stroke in the territory of the qualifying artery more than 30 days after enrollment. RESULTS: Individual data were obtained for 809 patients, 451 from SAMMPRIS and 358 from CASSISS. 400 participants were randomly assigned to the PTAS group and 409 to the medical group. The risk of the primary outcome was not significant between the PTAS and medical groups (17.5% vs 13.2%; HR 1.37 (95% CI 0.96 to 1.95), P=0.08). However, the risk of stroke or death within 30 days was higher in the PTAS group (10.5% vs 4.2%; HR 2.62 (95% CI 1.49 to 4.61), P<0.001). Patients of white ethnicity (HR 1.97, 95% CI 1.17 to 3.31) and those with hyperlipidemia (HR 2.04, 95% CI 1.27 to 3.26) or a transient ischemic attack (TIA) (HR 2.19, 95% CI 1.08 to 4.45) were at higher risk for PTAS. CONCLUSIONS: PTAS poses an increased risk of short-term stroke/death and therefore is not advised as primary treatment for symptomatic ICAS. A balance exists between stroke risks and revascularization benefits. For patients with asymptomatic ICAS of white ethnicity and those with hyperlipidemia or a history of TIA, a thorough assessment is warranted before considering PTAS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00576693, NCT01763320.

Carbon Dots in Photodynamic/Photothermal Antimicrobial Therapy.

Antimicrobial resistance (AMR) presents an escalating global challenge as conventional antibiotic treatments become less effective. In response, photodynamic therapy (PDT) and photothermal therapy (PTT) have emerged as promising alternatives. While rooted in ancient practices, these methods have evolved with modern innovations, particularly through the integration of lasers, refining their efficacy. PDT harnesses photosensitizers to generate reactive oxygen species (ROS), which are detrimental to microbial cells, whereas PTT relies on heat to induce cellular damage. The key to their effectiveness lies in the utilization of photosensitizers, especially when integrated into nano- or micron-scale supports, which amplify ROS production and enhance antimicrobial activity. Over the last decade, carbon dots (CDs) have emerged as a highly promising nanomaterial, attracting increasing attention owing to their distinctive properties and versatile applications, including PDT and PTT. They can not only function as photosensitizers, but also synergistically combine with other photosensitizers to enhance overall efficacy. This review explores the recent advancements in CDs, underscoring their significance and potential in reshaping advanced antimicrobial therapeutics.

Perspectives of US Medical Residency and Fellowship Applicants on No-Stakes Campus Visits.

Background Virtual interviews may limit an applicant's ability to ascertain the culture of a training program. No-stakes campus visits (NSCVs) have been offered but their value is unknown. Objective The purpose of our study was to determine factors that influence applicants' rank lists and determine barriers to and perceptions of NSCVs and their impact on applicants' final rank lists. Methods All interviewed applicants of graduate medical education (GME) programs who agreed to participate in the study were emailed a survey after the 2023 National Resident Matching Program Match. The survey contained sections on demographics, perspectives on factors affecting ranking decisions, and perceptions of NSCVs. Results Of 796 applicants, 183 (22.9%) who interviewed at 16 different Mayo Clinic GME programs responded to the survey. Of 131 respondents who answered whether they accepted an NSCV offer, 39 (29.8%) accepted. Of 35 respondents who answered whether they thought attending NSCVs impacted their rank, 19 (54.3%) were either uncertain or said yes. Of 34 respondents who answered whether the NSCV influenced their ranking of the program, 16 (47.1%) said their rank did not change, 12 (35.3%) said they ranked the program higher, and 5 (14.7%) said they ranked the program lower. For respondents who did not attend NSCVs, financial burden and lack of time were primary reasons. Conclusions NSCVs are perceived positively by most respondents. Many either believed they influenced their position on the program's rank list or were unsure. Most respondents said NSCVs either improved or did not change their ranking of the program.

A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.

The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward.

BACKGROUND: The intravesical gene therapy nadofaragene firadenovec (rAd-IFNα/Syn3) was FDA approved in 2022 for non-muscle invasive bladder cancer (NMIBC) unresponsive to frontline treatment with BCG, and the first gene therapy developed for bladder cancer. This non-replicating recombinant adenovirus vector delivers a copy of the human interferon alpha-2b gene into urothelial and tumor cells, causing them to express this pleotropic cytokine with potent antitumor effects. OBJECTIVE: To provide a historical overview describing how several decades of preclinical and clinical studies investigating the role of interferon in the treatment of bladder cancer ultimately led to the development of gene therapy with nadofaragene for NMIBC. METHODS: We conducted a review of the literature using PubMed, Google Scholar, and ClinicalTrials.gov to summarize our knowledge of the evolution of interferon-based therapy in NMIBC. RESULTS: The FDA approval of this therapy represents an important landmark in urologic oncology and several decades of research dedicated to the study of interferon's direct and indirect antitumor properties in NMIBC. The data gathered from the phase 1, 2, and 3 clinical trials continue to provide additional insights into the precise mechanisms underlying both the efficacy of and resistance to nadofaragene. CONCLUSIONS: Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.

A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle Invasive Bladder Cancer.

Background We performed a pilot study of daratumumab (monoclonal antibody directed against CD38) in muscle invasive bladder cancer (MIBC) and treatment refractory metastatic renal cell carcinoma (mRCC). Methods Patients with MIBC underwent baseline TURBT followed by 4 weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent a baseline and a sequential biopsy after 8 weekly doses. The primary endpoint was safety. The secondary endpoints: MIBC pathologic complete response rate (pCR), mRCC: objective response rate (ORR) and progression free survival (PFS). Exploratory analyses included immune monitoring. A Bayesian sequencing monitoring design for toxicity was used for excessive toxicity (TOX). Results: In both the MIBC (n=8) and mRCC (n= 8), no TOX events were encountered. In the MIBC cohort, 1 patient experienced pCR. In mRCC, no objective responses and the median PFS was 1.5 months (95%CI: 1.1, 1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts' post treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, while baseline levels in MIBC were low. Conclusions Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC and conclusions on activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC.

Measuring Documentation Burden in Healthcare.

BACKGROUND: The enactment of the Health Information Technology for Economic and Clinical Health Act and the wide adoption of electronic health record (EHR) systems have ushered in increasing documentation burden, frequently cited as a key factor affecting the work experience of healthcare professionals and a contributor to burnout. This systematic review aims to identify and characterize measures of documentation burden. METHODS: We integrated discussions with Key Informants and a comprehensive search of the literature, including MEDLINE, Embase, Scopus, and gray literature published between 2010 and 2023. Data were narratively and thematically synthesized. RESULTS: We identified 135 articles about measuring documentation burden. We classified measures into 11 categories: overall time spent in EHR, activities related to clinical documentation, inbox management, time spent in clinical review, time spent in orders, work outside work/after hours, administrative tasks (billing and insurance related), fragmentation of workflow, measures of efficiency, EHR activity rate, and usability. The most common source of data for most measures was EHR usage logs. Direct tracking such as through time-motion analysis was fairly uncommon. Measures were developed and applied across various settings and populations, with physicians and nurses in the USA being the most frequently represented healthcare professionals. Evidence of validity of these measures was limited and incomplete. Data on the appropriateness of measures in terms of scalability, feasibility, or equity across various contexts were limited. The physician perspective was the most robustly captured and prominently focused on increased stress and burnout. DISCUSSION: Numerous measures for documentation burden are available and have been tested in a variety of settings and contexts. However, most are one-dimensional, do not capture various domains of this construct, and lack robust validity evidence. This report serves as a call to action highlighting an urgent need for measure development that represents diverse clinical contexts and support future interventions.

Multi-generational benefits of genetic rescue.

Genetic rescue-an increase in population fitness following the introduction of new alleles-has been proven to ameliorate inbreeding depression in small, isolated populations, yet is rarely applied as a conservation tool. A lingering question regarding genetic rescue in wildlife conservation is how long beneficial effects persist in admixed populations. Using data collected over 40 years from 1192 endangered Florida panthers (Puma concolor coryi) across nine generations, we show that the experimental genetic rescue implemented in 1995-via the release of eight female pumas from Texas-alleviated morphological, genetic, and demographic correlates of inbreeding depression, subsequently preventing extirpation of the population. We present unequivocal evidence, for the first time in any terrestrial vertebrate, that genetic and phenotypic benefits of genetic rescue remain in this population after five generations of admixture, which helped increase panther abundance (> fivefold) and genetic effective population size (> 20-fold). Additionally, even with extensive admixture, microsatellite allele frequencies in the population continue to support the distinctness of Florida panthers from other North American puma populations, including Texas. Although threats including habitat loss, human-wildlife conflict, and infectious diseases are challenges to many imperiled populations, our results suggest genetic rescue can serve as an effective, multi-generational tool for conservation of small, isolated populations facing extinction from inbreeding.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.