A New Type 2 Diabetes Microsimulation Model to Estimate Long-Term Health Outcomes, Costs, and Cost-Effectiveness.

OBJECTIVES: This study aimed to develop a microsimulation model to estimate the health effects, costs, and cost-effectiveness of public health and clinical interventions for preventing/managing type 2 diabetes. METHODS: We combined newly developed equations for complications, mortality, risk factor progression, patient utility, and cost-all based on US studies-in a microsimulation model. We performed internal and external validation of the model. To demonstrate the model's utility, we predicted remaining life-years, quality-adjusted life-years (QALYs), and lifetime medical cost for a representative cohort of 10 000 US adults with type 2 diabetes. We then estimated the cost-effectiveness of reducing hemoglobin A1c from 9% to 7% among adults with type 2 diabetes, using low-cost, generic, oral medications. RESULTS: The model performed well in internal validation; the average absolute difference between simulated and observed incidence for 17 complications was < 8%. In external validation, the model was better at predicting outcomes in clinical trials than in observational studies. The cohort of US adults with type 2 diabetes was projected to have an average of 19.95 remaining life-years (from mean age 61), incur $187 729 in discounted medical costs, and accrue 8.79 discounted QALYs. The intervention to reduce hemoglobin A1c increased medical costs by $1256 and QALYs by 0.39, yielding an incremental cost-effectiveness ratio of $9103 per QALY. CONCLUSIONS: Using equations exclusively derived from US studies, this new microsimulation model achieves good prediction accuracy in US populations. The model can be used to estimate the long-term health impact, costs, and cost-effectiveness of interventions for type 2 diabetes in the United States.

Long-Term Effects of Cognitive-Behavioral Therapy and Yoga for Worried Older Adults.

OBJECTIVES: Cognitive-behavioral therapy (CBT) and yoga decrease worry and anxiety. There are no long-term data comparing CBT and yoga for worry, anxiety, and sleep in older adults. The impact of preference and selection on these outcomes is unknown. In this secondary data analysis, we compared long-term effects of CBT by telephone and yoga on worry, anxiety, sleep, depressive symptoms, fatigue, physical function, social participation, and pain; and examined preference and selection effects. DESIGN: In this randomized preference trial, participants (N = 500) were randomized to a: 1) randomized controlled trial (RCT) of CBT or yoga (n = 250); or 2) preference trial (selected CBT or yoga; n = 250). Outcomes were measured at baseline and Week 37. SETTING: Community. PARTICIPANTS: Community-dwelling older adults (age 60+ years). INTERVENTIONS: CBT (by telephone) and yoga (in-person group classes). MEASUREMENTS: Penn State Worry Questionnaire - Abbreviated (worry);1,2 Insomnia Severity Index (sleep);3 PROMIS Anxiety Short Form v1.0 (anxiety);4,5 Generalized Anxiety Disorder Screener (generalized anxiety);6,7 and PROMIS-29 (depression, fatigue, physical function, social participation, pain).8,9 RESULTS: Six months after intervention completion, CBT and yoga RCT participants reported sustained improvements from baseline in worry, anxiety, sleep, depressive symptoms, fatigue, and social participation (no significant between-group differences). Using data combined from the randomized and preference trials, there were no significant preference or selection effects. Long-term intervention effects were observed at clinically meaningful levels for most of the study outcomes. CONCLUSIONS: CBT and yoga both demonstrated maintained improvements from baseline on multiple outcomes six months after intervention completion in a large sample of older adults. TRIAL REGISTRATION: www. CLINICALTRIALS: gov Identifier NCT02968238.

Effect of renin-angiotensin system antihypertensive medication use on cognitive function in diabetes mellitus with obesity or overweight: An ancillary study to the Action for Health in Diabetes (Look AHEAD) trial.

AIM: To determine whether antihypertensive medication (AHM) acting through the renin angiotensin system (RAS-AHM), compared with other AHM, can mitigate effects on cognitive function and risk for impairment in a population with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This secondary analysis of the randomized controlled Action for Health in Diabetes (Look AHEAD) study included 712 community-dwelling participants who were followed over 15 years. Logistic regression was used to relate RAS-AHM use to cognitive impairment, and linear regression was used to relate RAS-AHM use to domain-specific cognitive function after adjusting for potential confounders. RESULTS: A total of 563 individuals reported RAS-AHM use and 149 reported other-AHM use during the study. RAS-AHM users have college or higher education (53%), had higher baseline glycated haemoglobin (57 mmol/mol), and reported higher diabetes medication use (86%), while other-AHM users were more likely to be White (72%), obese (25%) and to have cardiovascular history (19%). RAS-AHM use was not associated with a reduced risk of dementia compared with other-AHM use. We did observe better executive function (Trail Making Test, part B, P < 0.04), processing speed (Digit Symbol Substitution Test, P < 0.004), verbal memory (Rey Auditory Verbal Learning Test-delayed recall, P < 0.005), and composite score (P < 0.008) among RAS-AHM users compared with other-AHM users. CONCLUSION: In this sample of adults with T2DM, free of dementia at baseline, we observed a slower decline in processing speed, executive function, verbal memory, and composite score among RAS-AHM users.

Comparing data-driven and hypothesis-driven MRI-based predictors of cognitive impairment in individuals from the Atherosclerosis Risk in Communities (ARIC) study.

INTRODUCTION: A data-driven index of dementia risk based on magnetic resonance imaging (MRI), the Alzheimer's Disease Pattern Similarity (AD-PS) score, was estimated for participants in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: AD-PS scores were generated for 839 cognitively non-impaired individuals with a mean follow-up of 4.86 years. The scores and a hypothesis-driven volumetric measure based on several brain regions susceptible to AD were compared as predictors of incident cognitive impairment in different settings. RESULTS: Logistic regression analyses suggest the data-driven AD-PS scores to be more predictive of incident cognitive impairment than its counterpart. Both biomarkers were more predictive of incident cognitive impairment in participants who were White, female, and apolipoprotein E gene (APOE) ε4 carriers. Random forest analyses including predictors from different domains ranked the AD-PS scores as the most relevant MRI predictor of cognitive impairment. CONCLUSIONS: Overall, the AD-PS scores were the stronger MRI-derived predictors of incident cognitive impairment in cognitively non-impaired individuals.

Depletion of adipocyte sphingosine kinase 1 leads to cell hypertrophy, impaired lipolysis, and nonalcoholic fatty liver disease.

Sphingolipids have become established participants in the pathogenesis of obesity and its associated maladies. Sphingosine kinase 1 (SPHK1), which generates S1P, has been shown to increase in liver and adipose of obese humans and mice and to regulate inflammation in hepatocytes and adipose tissue, insulin resistance, and systemic inflammation in mouse models of obesity. Previous studies by us and others have demonstrated that global sphingosine kinase 1 KO mice are protected from diet-induced obesity, insulin resistance, systemic inflammation, and NAFLD, suggesting that SPHK1 may mediate pathological outcomes of obesity. As adipose tissue dysfunction has gained recognition as a central instigator of obesity-induced metabolic disease, we hypothesized that SPHK1 intrinsic to adipocytes may contribute to HFD-induced metabolic pathology. To test this, we depleted Sphk1 from adipocytes in mice (SK1fatKO) and placed them on a HFD. In contrast to our initial hypothesis, SK1fatKO mice displayed greater weight gain on HFD and exacerbated impairment in glucose clearance. Pro-inflammatory cytokines and neutrophil content of adipose tissue were similar, as were levels of circulating leptin and adiponectin. However, SPHK1-null adipocytes were hypertrophied and had lower basal lipolytic activity. Interestingly, hepatocyte triacylglycerol accumulation and expression of pro-inflammatory cytokines and collagen 1a1 were exacerbated in SK1fatKO mice on a HFD, implicating a specific role for adipocyte SPHK1 in adipocyte function and inter-organ cross-talk that maintains overall metabolic homeostasis in obesity. Thus, SPHK1 serves a previously unidentified essential homeostatic role in adipocytes that protects from obesity-associated pathology. These findings may have implications for pharmacological targeting of the SPHK1/S1P signaling axis.

Sphingosine kinase 1 is required for myristate-induced TNFα expression in intestinal epithelial cells.

Saturated fatty acids (SFA) have been known to trigger inflammatory signaling in metabolic tissues; however, the effects of specific SFAs in the intestinal epithelium have not been well studied. Several previous studies have implicated disruptions in sphingolipid metabolism by oversupply of SFAs in inflammatory process. Also, our previous studies have implicated sphingosine kinase 1 (SK1) and its product sphingosine-1-phosphate (S1P) as having key roles in the regulation of inflammatory processes in the intestinal epithelium. Therefore, to define the role for specific SFAs in inflammatory responses in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, significantly induced the pro-inflammatory cytokine tumor necrosis factor α (TNFα), and it was SK1-dependent. Interestingly, myristate-induced TNFα expression was not suppressed by inhibition of S1P receptors (S1PRs), hinting at a potential novel intracellular target of S1P. Additionally, myristate regulated the expression of TNFα via JNK activation in an SK1-dependent manner, suggesting a novel S1PR-independent target as a mediator between SK1 and JNK in response to myristate. Lastly, a myristate-enriched milk fat-based diet (MFBD) increased expression of TNFα in colon tissues and elevated the S1P to sphingosine ratio, demonstrating the potential of myristate-involved pathobiologies in intestinal tissues. Taken together our studies suggest that myristate regulates the expression of TNFα in the intestinal epithelium via regulation of SK1 and JNK.

Comparison of cognitive-behavioral therapy and yoga for the treatment of late-life worry: A randomized preference trial.

BACKGROUND: The purpose of this study was to compare the effects of cognitive-behavioral therapy (CBT) and yoga on late-life worry, anxiety, and sleep; and examine preference and selection effects on these outcomes. METHODS: A randomized preference trial of CBT and yoga was conducted in community-dwelling adults 60 years or older, who scored 26 or above on the Penn State Worry Questionnaire-Abbreviated (PSWQ-A). CBT consisted of 10 weekly telephone sessions. Yoga consisted of 20 biweekly group yoga classes. The primary outcome was worry (PSWQ-A); the secondary outcomes were anxiety (PROMIS-Anxiety) and sleep (Insomnia Severity Index [ISI]). We examined both preference effects (average effect for those who received their preferred intervention [regardless of whether it was CBT or yoga] minus the average for those who did not receive their preferred intervention [regardless of the intervention]) and selection effect (which addresses the question of whether there is a benefit to getting to select one intervention over the other, and measures the effect on outcomes of self-selection to a specific intervention). RESULTS: Five hundred older adults were randomized to the randomized trial (125 each in CBT and yoga) or the preference trial (120 chose CBT; 130 chose yoga). In the randomized trial, the intervention effect of yoga compared with CBT adjusted for baseline psychotropic medication use, gender, and race was 1.6 (-0.2, 3.3), p = .08 for the PSWQ-A. Similar results were observed with PROMIS-Anxiety (adjusted intervention effect: 0.3 [-1.5, 2.2], p = .71). Participants randomized to CBT experienced a greater reduction in the ISI compared with yoga (adjusted intervention effect: 2.4 [1.2, 3.7], p < .01]). Estimated in the combined data set (N = 500), the preference and selection effects were not significant for the PSWQ-A, PROMIS-Anxiety, and ISI. Of the 52 adverse events, only two were possibly related to the intervention. None of the 26 serious adverse events were related to the study interventions. CONCLUSIONS: CBT and yoga were both effective at reducing late-life worry and anxiety. However, a greater impact was seen for CBT compared with yoga for improving sleep. Neither preference nor selection effects was found.

Congenital Bronchial Stenosis Presenting as Neonatal Respiratory Distress: A Case Report.

BACKGROUND: Neonatal respiratory distress has a broad differential that includes cardiac, pulmonary, anatomic, and infectious etiologies. Congenital stenotic lesions of the trachea and bronchus are rare and can occur anywhere along the tracheobronchial tree. Patients with tracheobronchial stenosis typically present in the neonatal period with respiratory distress. CASE REPORT: We present a case of a 10-day-old term female who presented to the emergency department (ED) with tachypnea and increased work of breathing. She was found to have congenital bronchial stenosis of her right mainstem bronchus. She was stabilized in the ED and remained in the neonatal intensive care unit until successful slide tracheoplasty was performed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Congenital bronchial stenosis is a rare etiology of respiratory distress in a neonate. Anatomic lower airway abnormalities are an important cause of neonatal tachypnea and must remain on the differential. In addition to respiratory stabilization with noninvasive or invasive support, evaluation should be directed at determining the location and anatomic characteristics of the area of stenosis.

Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.

Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling. Myristate significantly increased C14-ceramide levels, whereas palmitate increased several long-chain ceramides. To define the role of ceramide synthases (CerSs) in myristate-induced ER stress, we used the pharmacologic inhibitor, fumonisin B1 (FB1), and small interfering RNA (siRNA) for CerS5 and 6, the primary isoforms that are involved in C14-ceramide generation. FB1 and siRNA for CerS5 or 6 suppressed myristate-induced C14-ceramide generation and XBP1 splicing (XBP1s). Moreover, increased XBP1s induced the downstream expression of IL-6 in a CerS5/6-dependent manner. In addition, a myristate-enriched milk fat-based diet, but not a lard-based diet, increased C14-ceramide, XBP1s, and IL-6 expression in vivo. Taken together, our data suggest that myristate modulates ER stress and cytokine production in the intestinal epithelium via CerS5/6 and C14-ceramide generation.-Choi, S., Snider, J. M., Olakkengil, N., Lambert, J. M., Anderson, A. K., Ross-Evans, J. S., Cowart, L. A., Snider, A. J. Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells.

Long-Term Effects of Telephone-Delivered Psychotherapy for Late-Life GAD.

OBJECTIVE: To examine the long-term effects of telephone-delivered cognitive-behavioral therapy (CBT-T) compared with nondirective supportive therapy (NST-T) in rural older adults with generalized anxiety disorder (GAD). METHODS: 141 adults aged 60 years and older with a principal/co-principal diagnosis of GAD were randomized to either CBT-T or NST-T. CBT-T consisted of up to 11 sessions (9 were required) focused on recognition of anxiety symptoms, relaxation, cognitive restructuring and use of coping statements, problem-solving, worry control, behavioral activation, exposure therapy, and relapse prevention, with optional chapters on sleep and pain. NST-T consisted of 10 sessions focused on providing a supportive atmosphere in which participants could share and discuss their feelings and did not provide any direct suggestions. Primary outcomes included interviewer-rated anxiety severity and self-report worry severity measured at 9 months and 15 months after randomization. Mood-specific secondary outcomes included self-report GAD symptoms and depressive symptoms. RESULTS: At 15 months, after adjustment for multiple testing, there was a significantly greater decline in general anxiety symptoms (difference in improvement: 3.31; 95% CI: 0.45-6.17; t = 2.29; df = 136; p = 0.024) and worry (difference in improvement: 3.13; 95% CI: 0.59-5.68; t = 2.43; df = 136; p = 0.016) among participants in CBT-T compared with those in the NST-T group. There were no significant differences between the conditions in terms of depressive symptoms (difference in improvement: 2.88; 95% CI: 0.17-5.60; t = 2.10; df = 136; p = 0.0376) and GAD symptoms (difference in improvement: 1.65; 95% CI: -0.20 to 3.50; t = 1.76; df = 136; p = 0.080). CONCLUSIONS: CBT-T is superior to NST-T in reducing worry and anxiety symptoms 1 year after completing treatment.

Effects of Telephone-Delivered Cognitive-Behavioral Therapy and Nondirective Supportive Therapy on Sleep, Health-Related Quality of Life, and Disability.

OBJECTIVES: The purpose of this study was to compare the effects of cognitive-behavioral therapy delivered by telephone (CBT-T) and telephone-delivered nondirective supportive therapy (NST-T) on sleep, health-related quality of life, and physical disability in rural older adults with generalized anxiety disorder. METHODS: This was a secondary analysis of a randomized clinical trial on 141 rural-dwelling adults 60 years and older diagnosed with generalized anxiety disorder. Sleep was assessed with the Insomnia Severity Index. Health-related quality of life was assessed with the 36-item Short-Form Health Survey (SF-36). Physical disability was assessed with the Pepper Center Tool for Disability. Assessments occurred at baseline, 4 months, 9 months, and 15 months. RESULTS: Insomnia declined in both groups from baseline to 4 months, with a significantly greater improvement among participants who received CBT-T. Similarly, Mental and Physical Component Summaries of the SF-36 declined in both groups, with a differential effect favoring CBT-T. Participants in both interventions reported declines in physical disability, although there were no significant differences between the two interventions. Improvements in insomnia were maintained at the 15-month assessment, whereas between-group differences shrank on the Mental and Physical Component Summaries of the SF-36 by the 15-month assessment. CONCLUSION: CBT-T was superior to NST-T in reducing insomnia and improving health-related quality of life. The effects of CBT-T on sleep were maintained 1 year after completing the treatment.

Prenatally diagnosed single umbilical artery: The role and relationship of additional risk factors in the fetus for congenital heart disease.

PURPOSE: Single umbilical artery (SUA) has been associated with an increased risk of congenital heart disease (CHD). Women carrying fetuses with an SUA are often referred for fetal echocardiography, but data to support the need for this testing remain controversial. METHODS: A retrospective review of the records for all women carrying fetuses with an SUA who had undergone fetal echocardiography between 2009 and 2012 at our center was performed. Data on the maternal and fetal risk factors for CHD were collected, and the fetuses were categorized into three groups: low risk (LR; an SUA with no additional risk factors for CHD), moderate risk (MR; an SUA with one additional risk factor for CHD), and high risk (HR; an SUA with two or more additional risk factors for CHD). RESULTS: In total, 101 such patients were identified: 69 LR, 26 MR, and 6 HR. No fetuses in the LR group, three in the MR group, and two in the HR group had CHD (p = 0.0005). CONCLUSIONS: An SUA in an LR fetus did not increase the risk of CHD in our cohort, whereas an SUA in the presence of additional risk factors was associated with significantly increased risk for CHD. Our results suggest that referral for a fetal echocardiogram is indicated for women carrying fetuses with an SUA when additional risk factors for CHD are present. In an LR fetus with an SUA, however, echocardiography may not provide additional benefit unless CHD is suggested on screening obstetric sonography.

Genetic Predictors of Depressive Symptoms in the Look AHEAD Trial.

OBJECTIVES: Numerous studies have found elevated depressive symptoms among individuals with Type 2 diabetes, yet the mechanisms remain unclear. We examined whether genetic loci previously associated with depressive symptoms predict depressive symptoms among overweight/obese individuals with Type 2 diabetes or change in depressive symptoms during behavioral weight loss. METHODS: The Illumina CARe iSelect (IBC) chip and Cardiometabochip were characterized in 2118 overweight or obese participants with Type 2 diabetes from Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive life-style intervention and diabetes support and education on cardiovascular morbidity and mortality. Primary analyses focused on baseline Beck Depression Inventory (BDI) scores and depressive symptom change at 1 year. RESULTS: Of eight single nucleotide polymorphisms (SNPs) in six loci, three a priori SNPs in two loci (chromosome 5: rs60271; LBR: rs2230419, rs1011319) were associated with baseline BDI scores, but in the opposite direction of prior research. In joint analysis of 90,003 IBC and Cardiometabochip SNPs, rs1543654 in the region of KCNE1 predicted change in BDI scores at Year 1 in diabetes support and education (ß = -1.05, standard error [SE] = 0.21, p = 6.9 × 10(-7)) at the level of chip-wide significance, while also showing a nominal association with baseline BDI (ß = 0.35, SE = 0.16, p = .026). Adjustment for antidepressant medication and/or limiting analyses to non-Hispanic white individuals did not meaningfully alter results. CONCLUSIONS: Previously reported genetic associations with depressive symptoms did not replicate in this cohort of overweight/obese individuals with Type 2 diabetes. We identified KCNE1 as a potential novel locus associated with depressive symptoms.

Prevalence of and disparities in barriers to care experienced by youth with type 1 diabetes.

OBJECTIVE: To describe the prevalence of access and process barriers to health care and to examine their relationship to sociodemographic and disease factors in a large and diverse cohort of US youth with type 1 diabetes. STUDY DESIGN: A cross-sectional analysis of 780 youth who participated in the SEARCH for Diabetes in Youth Study and were diagnosed with type 1 diabetes in 2002-2005. Experience of barriers to care was collected from parent report on questionnaires. Analyses included multivariate regression models to predict the presence of specific barriers to care. RESULTS: Overall, 81.7% of participants reported at least one barrier; the 3 most common were costs (47.5%), communication (43.0%), and getting needed information (48.4%). Problems with access to care, not having a regular provider, and receiving contextual care (care that takes into account personal and family context) were associated with poorer glycated hemoglobin levels. Adjusted multivariate models indicated that barriers related to access (regular provider, cost) were most likely for youth with low family income and those without public health insurance. Barriers associated with the processes of quality care (contextual care, communication) were more likely for Hispanic youth and those whose parents had less education. CONCLUSIONS: This study indicates that a large proportion of youth with type 1 diabetes experience substantial barriers to care. Barriers to access and those associated with processes of quality care differed by sociodemographic characteristics. Future investigators should expand knowledge of the systemic processes that lead to disparate outcomes for some youth with diabetes and assess potential solutions.

In-phase signal intensity loss in solid renal masses on dual-echo gradient-echo MRI: association with malignancy and pathologic classification.

OBJECTIVE: The purposes of this study were to determine the prevalence of in-phase signal intensity loss on dual-echo gradient-echo MRI in solid renal masses using visual and quantitative techniques and to test for any association between in-phase signal intensity loss and pathologic classification. MATERIALS AND METHODS: The renal MRI studies of 177 patients (192 solid masses consisting of 166 renal cell carcinomas [RCCs], four malignant non-RCCs, and 22 benign tumors) were qualitatively reviewed by two blinded readers for visual evidence of relative in-phase signal intensity loss. For lesions without visual evidence, whole-lesion ROIs were used to attempt quantification of subtle signal intensity loss between opposed- and in-phase images (signal intensity loss index). RESULTS: Visual in-phase signal intensity loss was noted in 18% of clear cell RCC, 42% of papillary RCC, and no benign lesions. There was significant correlation between malignancy and visual signal intensity loss (Fisher exact test, p = 0.0092). Visual signal intensity loss was predictive of papillary RCC over clear cell RCC (odds ratio, 5.79; p = 0.0002) in logistic regression analysis of all RCCs, controlling for size. Quantitative assessment of remaining lesions provided no additional diagnostic benefit. CONCLUSION: Visible in-phase signal intensity loss is relatively common within solid renal masses and was associated with RCC and particularly papillary RCC (among all RCCs) in our population. Quantitative analysis in lesions without visible signal intensity loss was not predictive of RCC. Further work should be performed to validate the usefulness of this additional imaging parameter to help characterize renal masses and to determine the impact of this finding on imaging techniques potentially sensitive to susceptibility effects.

Setting the Target: Comparing Family Medicine Among US Allopathic Target Schools.

BACKGROUND AND OBJECTIVES: Despite the persistent primary care physician shortage over 2 decades of allopathic medical school expansion, some medical schools are absent a department of family medicine; these schools are designated as "target" schools. These absences are important because evidence has demonstrated the association between structured exposure to family medicine during medical school and the proportion of students who ultimately select a career in family medicine. In this study, we aimed to address part of this gap by defining and characterizing the current landscape of US allopathic target schools. METHODS: We identified allopathic target schools by reviewing all Liaison Committee of Medical Education (LCME) accredited institutions for the presence of a family medicine department. To compare these schools in terms of family medicine representation and outcomes, we curated descriptive data from publicly available websites, previously published family medicine match results, and school rankings for primary care. RESULTS: We identified 12 target schools (8.7% of all US allopathic accredited medical schools) with considerable heterogeneity in opportunities for family medicine engagement, leadership, and training. Target schools with greater family medicine representation had increased outcomes for family medicine workforce and primary care opportunities. CONCLUSION: With growing primary care workforce gaps, target schools have a responsibility to enhance family medicine presence and representation at their institutions. We provide recommendations at the institutional, specialty, and national level to increase family medicine representation at target schools, with the goal that all schools eventually establish a department of family medicine.

Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function.

Circadian rhythms align biological functions with the 24-hour day-night cycle, but modern artificial light disrupts these patterns, contributing to health issues like obesity and cardiovascular disease. The circadian clock operates through a transcriptional-translational feedback loop involving core components such as BMAL1 and CLOCK. Recent research has shown circadian variations in sphingolipid metabolism, specifically sphingosine-1-phosphate (S1P), which plays crucial signaling roles. This study investigates the sphingolipid enzyme, sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, as a circadian-regulated gene in adipocytes. We find that SphK1 expression and activity follow a circadian rhythm, regulated by BMAL1 and CLOCK binding to its promoter. Adipocyte-specific SphK1 knockout mice exhibit disrupted circadian rhythms, and impaired adipocyte function. Additionally, SphK1 deficiency leads to reduced histone acetylation and altered histone deacetylase (HDAC) localization, affecting gene regulation. These results highlight the critical role of SphK1 in linking lipid metabolism with circadian biology.

Sphingosine kinase 1 is induced by glucocorticoids in adipose derived stem cells and enhances glucocorticoid mediated signaling in adipose expansion.

Sphingosine kinase 1 (SphK1) plays a crucial role in regulating metabolic pathways within adipocytes and is elevated in the adipose tissue of obese mice. While previous studies have reported both pro- and inhibitory effects of SphK1 and its product, sphingosine-1-phosphate (S1P), on adipogenesis, the precise mechanisms remain unclear. This study explores the timing and downstream effects of SphK1/S1P expression and activation during in vitro adipogenesis. We demonstrate that the synthetic glucocorticoid dexamethasone robustly induces SphK1 expression, suggesting its involvement in glucocorticoid-dependent signaling during adipogenesis. Notably, the activation of C/EBPδ, a key gene in early adipogenesis and a target of glucocorticoids, is diminished in SphK1-/- adipose-derived stem cells (ADSCs). Furthermore, glucocorticoid administration promotes adipose tissue expansion via SphK1 in a depot-specific manner. Although adipose expansion still occurs in SphK1-/- mice, it is significantly reduced. These findings indicate that while SphK1 is not essential for adipogenesis, it enhances early gene activation, thereby facilitating adipose tissue expansion.

Transition to Residency Courses: Recommendations for Creation and Implementation.

Transition to Residency (TTR) courses help ease the critical transition from medical school to residency, yet there is little guidance for developing and running these courses. In this perspective, the authors use their expertise as well as a review of the literature to provide guidance and review possible solutions to challenges unique to these courses. TTR courses should be specialty-specific, allow for flexibility, and utilize active learning techniques. A needs assessment can help guide course content, which should focus on what is necessary to be ready for day one of residency. The use of residents in course planning and delivery can help create a sense of community and ensure that content is practical. While course assessments are largely formative, instructors should anticipate the need for remediation, especially for skills likely to be performed with limited supervision during residency. Additionally, TTR courses should incorporate learner self-assessment and goal setting; this may be valuable information to share with learners' future residency programs. Lastly, TTR courses should undergo continuous quality improvement based on course evaluations and surveys. These recommendations are essential for effective TTR course implementation and improvement.