Graduate medical education well-being directors in the United States: who are they, and what does the role entail?

BACKGROUND: Institutional Graduate Medical Education (GME) Well-being Director (WBD) roles have recently emerged in the United States to support resident and fellow well-being. However, with a standard position description lacking, the current scope and responsibilities of such roles is unknown. This study describes the scope of work, salary support, and opportunities for role definition for those holding institutional leadership positions for GME well-being. METHODS: In November 2021, 43 members of a national network of GME WBDs in the United States were invited to complete a cross-sectional survey that included questions about job responsibilities, percent effort, and dedicated budget, and a free text response question about unique leadership challenges for GME WBDs. The survey was analyzed using descriptive statistics for quantitative data and thematic analysis for qualitative data. RESULTS: 26 members (60%) responded. Most were physicians, and the majority identified as female and White. Median percent effort salary support was 40%. A small minority reported overseeing an allocated budget. Most respondents worked to improve access to mental health services, oversaw institution-wide well-being programs, designed or delivered well-being content, provided consultations to individual programs, met with trainees, and partnered with diversity, equity, and inclusion (DEI) efforts. GME WBDs described unique challenges that had implications for perceived effectiveness related to resources, culture, institutional structure, and regulatory requirements in GME. DISCUSSION: There was high concordance for several key responsibilities, which may represent a set of core priorities for this role. Other reported responsibilities may reflect institution-specific needs or opportunities for role definition. A wide scope of responsibilities, coupled with limited defined budgetary support described by many GME Well-being Directors, could limit effective role execution. Future efforts to better define the role, optimize organizational reporting structures and provide funding commensurate with the scope of work may allow the GME Well-being Director to more effectively develop and execute strategic interventions.

Temporal Associations Between EHR-Derived Workload, Burnout, and Errors: a Prospective Cohort Study.

BACKGROUND: The temporal progression and workload-related causal contributors to physician burnout are not well-understood. OBJECTIVE: To characterize burnout's time course and evaluate the effect of time-varying workload on burnout and medical errors. DESIGN: Six-month longitudinal cohort study with measurements of burnout, workload, and wrong-patient orders every 4 weeks. PARTICIPANTS: Seventy-five intern physicians in internal medicine, pediatrics, and anesthesiology at a large academic medical center. MAIN MEASURES: Burnout was measured using the Professional Fulfillment Index survey. Workload was collected from electronic health record (EHR) audit logs and summarized as follows: total time spent on the EHR, after-hours EHR time, patient load, inbox time, chart review time, note-writing time, and number of orders. Wrong-patient orders were assessed using retract-and-reorder events. KEY RESULTS: Seventy-five of 104 interns enrolled (72.1%) in the study. A total of 337 surveys and 8,863,318 EHR-based actions were analyzed. Median burnout score across the cohort across all time points was 1.2 (IQR 0.7-1.7). Individual-level burnout was variable (median monthly change 0.3, IQR 0.1-0.6). In multivariable analysis, increased total EHR time (ß=0.121 for an increase from 54.5 h per month (25th percentile) to 123.0 h per month (75th percentile), 95%CI=0.016-0.226), increased patient load (ß=0.130 for an increase from 4.9 (25th percentile) to 7.1 (75th percentile) patients per day, 95%CI=0.053-0.207), and increased chart review time (ß=0.096 for an increase from 0.39 (25th percentile) to 0.59 (75th percentile) hours per patient per day, 95%CI=0.015-0.177) were associated with an increased burnout score. After adjusting for the total number of ordering sessions, burnout was not statistically associated with an increased rate of wrong-patient orders (rate ratio=1.20, 95%CI=0.76-1.89). CONCLUSIONS: Burnout and recovery were associated with recent clinical workload for a cohort of physician trainees, highlighting the elastic nature of burnout. Wellness interventions should focus on strategies to mitigate sustained elevations of work responsibilities.

Effects of Persistent Exposure to COVID-19 on Mental Health Outcomes Among Trainees: a Longitudinal Survey Study.

BACKGROUND: The rapid spread of the coronavirus disease 2019 (COVID-19) has created considerable strain on the physical and mental health of healthcare workers around the world. The effects have been acute for physician trainees-a unique group functioning simultaneously as learners and care providers with limited autonomy. OBJECTIVE: To investigate the longitudinal effects of physician trainee exposure to patients being tested for COVID-19 on stress, anxiety, depression, and burnout using three surveys conducted during the early phase of the pandemic. DESIGN: Longitudinal survey study. PARTICIPANTS: All physician trainees (N = 1375) at an academic medical center. MAIN MEASURE: Assess the relationship between repeated exposure to patients being tested for COVID-19 and stress, anxiety, depression, and burnout. KEY RESULTS: Three hundred eighty-nine trainees completed the baseline survey (28.3%). Of these, 191 and 136 completed the ensuing surveys. Mean stress, anxiety, and burnout decreased by 21% (95% confidence interval (CI): - 28 to - 12%; P < 0.001), 25% (95% CI: - 36 to - 11%; P < 0.001), and 13% (95% CI: - 18 to - 7%; P < 0.001), respectively, per survey. However, for each survey time point, there was mean increase in stress, anxiety, and burnout per additional exposure: stress [24% (95% CI: + 12 to + 38%; P < 0.001)], anxiety [22% (95% CI: + 2 to + 46%; P = 0.026)], and burnout [18% (95% CI: + 10 to + 28%; P < 0.001)]. For depression, the association between exposure was strongest for the third survey, where mean depression scores increased by 33% per additional exposure (95% CI: + 18 to + 50%; P < 0.001). CONCLUSIONS: Training programs should adapt to address the detrimental effects of the "pileup" of distress associated with persistent exposure through adaptive programs that allow flexibility for time off and recovery.

Scholarly activity training in pediatric pulmonology fellowship programs.

BACKGROUND: Scholarly activity training is a required component of pediatric pulmonology fellowship programs. However, there are no data on resources and barriers to training and factors associated with fellow productivity. METHODS: We surveyed US pediatric pulmonology fellowship program directors (FPDs) between March and October 2019. Our primary outcome was fellow productivity (>75% of fellows in the past 5 years had a manuscript accepted in a peer-reviewed journal). Analyses included descriptive statistics, χ2 and Fisher's exact tests for categorical values, and t-test or Wilcoxon rank-sum test for numerical values. RESULTS: Sixty-one percent (33/54) of FPDs completed the survey. Seventy-nine percent reported that most fellows completed clinical, basic science, or translational research. However, only 21% reported that most fellows pursued research positions after graduation; academic clinical positions were more common. For 21%, lack of funding and competing clinical responsibilities were barriers to completing the scholarly activity. Only 39% had highly productive programs; those FPDs were more likely to be highly satisfied with fellow scholarly activity products (p = 0.049) and have >6 publications in the previous 3 years (p = 0.03). Fifty-two percent of FPDs believed that pediatric pulmonary training should be shortened to 2 years for those pursuing clinical or clinician-educator careers. CONCLUSIONS: Barriers to scholarly activity training in pediatric pulmonology programs threaten the pipeline of academic pediatric pulmonologists and physician-investigators. Aligning fellow scholarly activity and clinical training with the skills required in their postgraduate positions could optimize the utilization of limited resources and better support career development.

Impact of Changes in EHR Use during COVID-19 on Physician Trainee Mental Health.

OBJECTIVES: This article investigates the association between changes in electronic health record (EHR) use during the coronavirus disease 2019 (COVID-19) pandemic on the rate of burnout, stress, posttraumatic stress disorder (PTSD), depression, and anxiety among physician trainees (residents and fellows). METHODS: A total of 222 (of 1,375, 16.2%) physician trainees from an academic medical center responded to a Web-based survey. We compared the physician trainees who reported that their EHR use increased versus those whose EHR use stayed the same or decreased on outcomes related to depression, anxiety, stress, PTSD, and burnout using univariable and multivariable models. We examined whether self-reported exposure to COVID-19 patients moderated these relationships. RESULTS: Physician trainees who reported increased use of EHR had higher burnout (adjusted mean, 1.48 [95% confidence interval [CI] 1.24, 1.71] vs. 1.05 [95% CI 0.93, 1.17]; p = 0.001) and were more likely to exhibit symptoms of PTSD (adjusted mean = 15.09 [95% CI 9.12, 21.05] vs. 9.36 [95% CI 7.38, 11.28]; p = 0.035). Physician trainees reporting increased EHR use outside of work were more likely to experience depression (adjusted mean, 8.37 [95% CI 5.68, 11.05] vs. 5.50 [95% CI 4.28, 6.72]; p = 0.035). Among physician trainees with increased EHR use, those exposed to COVID-19 patients had significantly higher burnout (2.04, p < 0.001) and depression scores (14.13, p = 0.003). CONCLUSION: Increased EHR use was associated with higher burnout, depression, and PTSD outcomes among physician trainees. Although preliminary, these findings have implications for creating systemic changes to manage the wellness and well-being of trainees.

Risk factors associated with physician trainee concern over missed educational opportunities during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic resulted in a transformation of clinical care practices to protect both patients and providers. These changes led to a decrease in patient volume, impacting physician trainee education due to lost clinical and didactic opportunities. We measured the prevalence of trainee concern over missed educational opportunities and investigated the risk factors leading to such concerns. METHODS: All residents and fellows at a large academic medical center were invited to participate in a web-based survey in May of 2020. Participants responded to questions regarding demographic characteristics, specialty, primary assigned responsibility during the previous 2 weeks (clinical, education, or research), perceived concern over missed educational opportunities, and burnout. Multivariable logistic regression was used to assess the relationship between missed educational opportunities and the measured variables. RESULTS: 22% (301 of 1375) of the trainees completed the survey. 47% of the participants were concerned about missed educational opportunities. Trainees assigned to education at home had 2.85 [95%CI 1.33-6.45] greater odds of being concerned over missed educational opportunities as compared with trainees performing clinical work. Trainees performing research were not similarly affected [aOR = 0.96, 95%CI (0.47-1.93)]. Trainees in pathology or radiology had 2.51 [95%CI 1.16-5.68] greater odds of concern for missed educational opportunities as compared with medicine. Trainees with greater concern over missed opportunities were more likely to be experiencing burnout (p = 0.038). CONCLUSIONS: Trainees in radiology or pathology and those assigned to education at home were more likely to be concerned about their missed educational opportunities. Residency programs should consider providing trainees with research or at home clinical opportunities as an alternative to self-study should future need for reduced clinical hours arise.

Correction: Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

[This corrects the article DOI: 10.2196/21366.].

Scholarly Activity During Pediatric Fellowship.

BACKGROUND AND OBJECTIVES: The educational requirements for pediatric fellows include at least 12 months of scholarly activity and generation of a work product. Yet there lacks detailed guidance on how programs can best integrate scholarly activity training into fellowships. Our objectives were to understand the resources and barriers to training and identify factors associated with productivity. METHODS: We surveyed pediatric fellowship program directors (FPDs) nationally in 2019. Data analysis included descriptive statistics, χ2 and Fisher's exact tests, and multivariable modeling to identify factors associated with high productivity (>75% of fellows in the past 5 years had an article from their fellowship accepted). RESULTS: A total of 499 of 770 FPDs responded (65%). A total of 174 programs (35%) were highly productive. The most frequent major barriers were a lack of funding for fellows to conduct scholarship (21%, n = 105) and lack of sufficient divisional faculty mentorship (16%, n = 79). The median number of months for scholarship with reduced clinical obligations scholarship was 17. A total of 40% (n = 202) of FPDs believed training should be shortened to 2 years for clinically oriented fellows. Programs with a T32 and a FPD with >5 publications in the past 3 years were twice as likely to be productive. Not endorsing lack of adequate Scholarship Oversight Committee expertise and a research curriculum as barriers was associated with increased productivity (odds ratio = 1.83-1.65). CONCLUSIONS: Despite significant protected fellow research time, most fellows do not publish. Ensuring a program culture of research may provide the support needed to take projects to publication. The fellowship community may consider reevaluating the fellowship duration, particularly for those pursing nonresearch focused careers.

Work-Related and Personal Factors Associated With Mental Well-Being During the COVID-19 Response: Survey of Health Care and Other Workers.

BACKGROUND: The response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created an unprecedented disruption in work conditions. This study describes the mental health and well-being of workers both with and without clinical exposure to patients with coronavirus disease (COVID-19). OBJECTIVE: The aim of this study is to measure the prevalence of stress, anxiety, depression, work exhaustion, burnout, and decreased well-being among faculty and staff at a university and academic medical center during the SARS-CoV-2 pandemic and describe work-related and personal factors associated with their mental health and well-being. METHODS: All faculty, staff, and postdoctoral fellows of a university, including its medical school, were invited in April 2020 to complete an online questionnaire measuring stress, anxiety, depression, work exhaustion, burnout, and decreased well-being. We examined associations between these outcomes and factors including work in high-risk clinical settings and family/home stressors. RESULTS: There were 5550 respondents (overall response rate of 34.3%). Overall, 34% of faculty and 14% of staff (n=915) were providing clinical care, while 61% of faculty and 77% of staff were working from home. Among all workers, anxiety (prevalence ratio 1.37, 95% CI 1.09-1.73), depression (prevalence ratio 1.28, 95% CI 1.03-1.59), and high work exhaustion (prevalence ratio 1.24, 95% CI 1.13-1.36) were independently associated with community or clinical exposure to COVID-19. Poor family-supportive behaviors by supervisors were also associated with these outcomes (prevalence ratio 1.40, 95% CI 1.21-1.62; prevalence ratio 1.69, 95% CI 1.48-1.92; and prevalence ratio 1.54, 95% CI 1.44-1.64, respectively). Age <40 years and a greater number of family/home stressors were also associated with these poorer outcomes. Among the subset of clinicians, caring for patients with COVID-19 and working in high-risk clinical settings were additional risk factors. CONCLUSIONS: Our findings suggest that the pandemic has had negative effects on the mental health and well-being of both clinical and nonclinical employees. Mitigating exposure to COVID-19 and increasing supervisor support are modifiable risk factors that may protect mental health and well-being for all workers.

Mitochondrial inefficiency in infants born to overweight African-American mothers.

BACKGROUND: Currently 20-35% of pregnant women are obese, posing a major health risk for mother and fetus. It is postulated that an abnormal maternal-fetal nutritional environment leads to adverse metabolic programming, resulting in altered substrate metabolism in the offspring and predisposing to risks of obesity and diabetes later in life. Data indicate that oocytes from overweight animals have abnormal mitochondria. We hypothesized that maternal obesity is associated with altered mitochondrial function in healthy neonatal offspring. METHODS: Overweight and obese (body mass index, (BMI) ≥ 25 kg/m2, n = 14) and lean (BMI < 25 kg/m2, n = 8), African-American pregnant women carrying male fetuses were recruited from the Barnes Jewish Hospital obstetric clinic. Maternal and infant data were extracted from medical records. Infants underwent body composition testing in the first days of life. Circumcision skin was collected for isolation of fibroblasts. Fibroblast cells were evaluated for mitochondrial function, metabolic gene expression, nutrient uptake, and oxidative stress. RESULTS: Skin fibroblasts of infants born to overweight mothers had significantly higher mitochondrial respiration without a concurrent increase in ATP production, indicating mitochondrial inefficiency. These fibroblasts had higher levels of reactive oxygen species and evidence of oxidative stress. Evaluation of gene expression in offspring fibroblasts revealed altered expression of multiple genes involved in fatty acid and glucose metabolism and mitochondrial respiration in infants of overweight mothers. CONCLUSIONS: This study demonstrates altered mitochondrial function and oxidative stress in skin fibroblasts of infants born to overweight mothers. Future studies are needed to determine the long-term impact of this finding on the metabolic health of these children.

High-sucrose-induced maternal obesity disrupts ovarian function and decreases fertility in Drosophila melanogaster.

As the obesity epidemic worsens, the prevalence of maternal obesity is expected to rise. Both high-fat and high-sucrose diets are known to promote maternal obesity and several studies have elucidated the molecular influence of high-fat feeding on female reproduction. However, to date, the molecular impact of a high-sucrose diet on maternal obesity remains to be investigated. Using our previously reported Drosophila high-sucrose maternal obesity model, we sought to determine how excess dietary sucrose impacted the ovary. High-sucrose diet (HSD) fed adult females developed systemic insulin resistance and exhibited an ovarian phenotype characterized by excess accumulation of lipids and cholesterol in the ovary, decreased ovary size, and impaired egg maturation. We also observed decreased expression of antioxidant genes and increased protein carbonylation in the ovaries of HSD females. HSD females laid fewer eggs; however, the overall survival of offspring was unchanged relative to lean control females. Ovaries of HSD females had increased mitochondrial DNA copy number and decreased expression of key mitochondrial regulators, suggestive of an ineffective compensatory response to mitochondrial dysfunction. Mitochondrial alterations were also observed in male offspring of obese females. This study demonstrates that high-sucrose-induced maternal obesity promotes insulin resistance, while disrupting ovarian metabolism and function.

Modeling dietary influences on offspring metabolic programming in Drosophila melanogaster.

The influence of nutrition on offspring metabolism has become a hot topic in recent years owing to the growing prevalence of maternal and childhood obesity. Studies in mammals have identified several factors correlating with parental and early offspring dietary influences on progeny health; however, the molecular mechanisms that underlie these factors remain undiscovered. Mammalian metabolic tissues and pathways are heavily conserved in Drosophila melanogaster, making the fly an invaluable genetic model organism for studying metabolism. In this review, we discuss the metabolic similarities between mammals and Drosophila and present evidence supporting its use as an emerging model of metabolic programming.

Drosophila melanogaster: An emerging model of transgenerational effects of maternal obesity.

The prevalence of obesity in the world is endemic with one rapidly growing health concern being maternal obesity. Obesity during pregnancy increases the risk of gestational diabetes, miscarriage, and preeclampsia, while rendering offspring susceptible to developmental anomalies and long-term metabolic complications including type 2 diabetes and cardiovascular disease. Several studies in humans and rodents demonstrate a correlation between the risks of maternal overnutrition and factors such as epigenetics, mitochondrial dysfunction, insulin resistance, ER stress, and immune system disruption. At present, the molecular mechanisms connecting these factors to maternal obesity are unknown. This review focuses on the use of Drosophila melanogaster to study human metabolic diseases, including obesity, and its emerging use to elucidate the mechanisms of maternal overnutrition and the impact on offspring.

Left main coronary artery dissection in pediatric sport-related chest trauma.

BACKGROUND: Traumatic coronary artery dissection (CAD) after blunt chest trauma (BCT) is extremely rare, particularly in children. Among coronary dissections, left main coronary artery (LMCA) dissection is the least common, with only two pediatric cases reported previously. Manifestations of coronary dissections can range from ST segment changes to sudden death. However, these manifestations are not specific and can be present with other cardiac injuries. To our knowledge we present the first pediatric case of traumatic LMCA dissection after sport-related BCT that was treated successfully with coronary stenting. CASE REPORT: A 14-year-old child sustained BCT during a baseball game. Early in the clinical course, he had episodes of ventricular dysrhythmias, diffuse ST changes, rising troponin I, and hemodynamic instability. Emergent cardiac catheterization revealed an LMCA dissection with extension into the proximal left anterior descending artery (LADA). A bare metal stent was placed from the LMCA to the LADA, which improved blood flow through the area of dissection. He has had almost full recovery of myocardial function and has been managed as an outpatient with oral heart failure and antiplatelet medications. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our case highlights that CAD, although rare, can occur after pediatric BCT. Pediatric emergency responders must have a heightened awareness that evidence of ongoing myocardial ischemia, such as evolving and focal myocardial infarction on electrocardiogram, persistent elevation or rising troponin I, and worsening cardiogenic shock, can represent a coronary event and warrant further evaluation. Cardiac catheterization can be both a diagnostic and therapeutic modality in such cases. Early recognition and management is vital for myocardial recovery.

Evidence for transgenerational metabolic programming in Drosophila.

Worldwide epidemiologic studies have repeatedly demonstrated an association between prenatal nutritional environment, birth weight and susceptibility to adult diseases including obesity, cardiovascular disease and type 2 diabetes. Despite advances in mammalian model systems, the molecular mechanisms underlying this phenomenon are unclear, but might involve programming mechanisms such as epigenetics. Here we describe a new system for evaluating metabolic programming mechanisms using a simple, genetically tractable Drosophila model. We examined the effect of maternal caloric excess on offspring and found that a high-sugar maternal diet alters body composition of larval offspring for at least two generations, augments an obese-like phenotype under suboptimal (high-calorie) feeding conditions in adult offspring, and modifies expression of metabolic genes. Our data indicate that nutritional programming mechanisms could be highly conserved and support the use of Drosophila as a model for evaluating the underlying genetic and epigenetic contributions to this phenomenon.

The transcriptional coactivators, PGC-1α and ß, cooperate to maintain cardiac mitochondrial function during the early stages of insulin resistance.

We previously demonstrated a cardiac mitochondrial biogenic response in insulin resistant mice that requires the nuclear receptor transcription factor PPARα. We hypothesized that the PPARα coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is necessary for mitochondrial biogenesis in insulin resistant hearts and that this response was adaptive. Mitochondrial phenotype was assessed in insulin resistant mouse models in wild-type (WT) versus PGC-1α deficient (PGC-1α(-/-)) backgrounds. Both high fat-fed (HFD) WT and 6 week-old Ob/Ob animals exhibited a significant increase in myocardial mitochondrial volume density compared to standard chow fed or WT controls. In contrast, HFD PGC-1α(-/-) and Ob/Ob-PGC-1α(-/-) hearts lacked a mitochondrial biogenic response. PGC-1α gene expression was increased in 6 week-old Ob/Ob animals, followed by a decline in 8 week-old Ob/Ob animals with more severe glucose intolerance. Mitochondrial respiratory function was increased in 6 week-old Ob/Ob animals, but not in Ob/Ob-PGC-1α(-/-) mice and not in 8 week-old Ob/Ob animals, suggesting a loss of the early adaptive response, consistent with the loss of PGC-1α upregulation. Animals that were deficient for PGC-1α and heterozygous for the related coactivator PGC-1ß (PGC-1α(-/-)ß(+/-)) were bred to the Ob/Ob mice. Ob/Ob-PGC-1α(-/-)ß(+/-) hearts exhibited dramatically reduced mitochondrial respiratory capacity. Finally, the mitochondrial biogenic response was triggered in H9C2 myotubes by exposure to oleate, an effect that was blunted with shRNA-mediated PGC-1 "knockdown". We conclude that PGC-1 signaling is important for the adaptive cardiac mitochondrial biogenic response that occurs during the early stages of insulin resistance. This response occurs in a cell autonomous manner and likely involves exposure to high levels of free fatty acids.

Peroxisome proliferator activated receptor-alpha (PPARα) and PPAR gamma coactivator-1alpha (PGC-1α) regulation of cardiac metabolism in diabetes.

Cardiovascular disease is a leading cause of mortality among patients with diabetes, and heart failure exists even in the absence of coronary disease. Myocardial metabolism is altered in the diabetic heart as a result of changes in substrate availability secondary to insulin resistance. The nuclear receptor peroxisome proliferator activated receptor-alpha (PPARα) and PPAR-gamma coactivator-1alpha (PGC-1α) play important roles in transcriptional regulation of myocardial metabolism and contribute significantly to the changes that occur in the diabetic heart. This review summarizes the role of PPARα and PGC-1α in myocardial metabolism in the normal heart and in the diabetic heart.

Mitochondrial dysfunction in diabetic cardiomyopathy.

Cardiovascular disease is common in patients with diabetes and is a significant contributor to the high mortality rates associated with diabetes. Heart failure is common in diabetic patients, even in the absence of coronary artery disease or hypertension, an entity known as diabetic cardiomyopathy. Evidence indicates that myocardial metabolism is altered in diabetes, which likely contributes to contractile dysfunction and ventricular failure. The mitochondria are the center of metabolism, and recent data suggests that mitochondrial dysfunction may play a critical role in the pathogenesis of diabetic cardiomyopathy. This review summarizes many of the potential mechanisms that lead to mitochondrial dysfunction in the diabetic heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection.

Rescue of cardiomyopathy in peroxisome proliferator-activated receptor-alpha transgenic mice by deletion of lipoprotein lipase identifies sources of cardiac lipids and peroxisome proliferator-activated receptor-alpha activators.

BACKGROUND: Emerging evidence in obesity and diabetes mellitus demonstrates that excessive myocardial fatty acid uptake and oxidation contribute to cardiac dysfunction. Transgenic mice with cardiac-specific overexpression of the fatty acid-activated nuclear receptor peroxisome proliferator-activated receptor-alpha (myosin heavy chain [MHC]-PPARalpha mice) exhibit phenotypic features of the diabetic heart, which are rescued by deletion of CD36, a fatty acid transporter, despite persistent activation of PPARalpha gene targets involved in fatty acid oxidation. METHODS AND RESULTS: To further define the source of fatty acid that leads to cardiomyopathy associated with lipid excess, we crossed MHC-PPARalpha mice with mice deficient for cardiac lipoprotein lipase (hsLpLko). MHC-PPARalpha/hsLpLko mice exhibit improved cardiac function and reduced myocardial triglyceride content compared with MHC-PPARalpha mice. Surprisingly, in contrast to MHC-PPARalpha/CD36ko mice, the activity of the cardiac PPARalpha gene regulatory pathway is normalized in MHC-PPARalpha/hsLpLko mice, suggesting that PPARalpha ligand activity exists in the lipoprotein particle. Indeed, LpL mediated hydrolysis of very-low-density lipoprotein activated PPARalpha in cardiac myocytes in culture. The rescue of cardiac function in both models was associated with improved mitochondrial ultrastructure and reactivation of transcriptional regulators of mitochondrial function. CONCLUSIONS: MHC-PPARalpha mouse hearts acquire excess lipoprotein-derived lipids. LpL deficiency rescues myocyte triglyceride accumulation, mitochondrial gene regulatory derangements, and contractile function in MHC-PPARalpha mice. Finally, LpL serves as a source of activating ligand for PPARalpha in the cardiomyocyte.

Symptom occurrence and associated clinical factors in nursing home residents with cancer.

Little is known about the factors that contribute to symptoms in nursing home residents with cancer. We compared rates of symptoms in residents with (n = 1,022) and without cancer (n = 9,910) and examined physiologic, psychologic and situational factors potentially related to symptoms in residents with cancer. Pain, shortness of breath, vomiting, weight loss, and diarrhea were significantly (p < .05) more prevalent in residents with cancer. Cancer treatments, comorbid illnesses, and situational factors were not consistently correlated with symptoms. Improved symptom control was especially needed for the 30% of residents with cancer who clinically deteriorated within 3 months of admission; physical dependence and deteriorating clinical status were associated with pain, shortness of breath, and weight loss.