Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort.

Machine learning models are increasingly being used to estimate "brain age" from neuroimaging data. The gap between chronological age and the estimated brain age gap (BAG) is potentially a measure of accelerated and resilient brain aging. Brain age calculated in this fashion has been shown to be associated with mortality, measures of physical function, health, and disease. Here, we estimate the BAG using a voxel-based elastic net regression approach, and then, we investigate its associations with mortality, cognitive status, and measures of health and disease in participants from Atherosclerosis Risk in Communities (ARIC) study who had a brain MRI at visit 5 of the study. Finally, we used the SOMAscan assay containing 4877 proteins to examine the proteomic associations with the MRI-defined BAG. Among N = 1849 participants (age, 76.4 (SD 5.6)), we found that increased values of BAG were strongly associated with increased mortality and increased severity of the cognitive status. Strong associations with mortality persisted when the analyses were performed in cognitively normal participants. In addition, it was strongly associated with BMI, diabetes, measures of physical function, hypertension, prevalent heart disease, and stroke. Finally, we found 33 proteins associated with BAG after a correction for multiple comparisons. The top proteins with positive associations to brain age were growth/differentiation factor 15 (GDF-15), Sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SEVP 1), matrilysin (MMP7), ADAMTS-like protein 2 (ADAMTS), and heat shock 70 kDa protein 1B (HSPA1B) while EGF-receptor (EGFR), mast/stem-cell-growth-factor-receptor (KIT), coagulation-factor-VII, and cGMP-dependent-protein-kinase-1 (PRKG1) were negatively associated to brain age. Several of these proteins were previously associated with dementia in ARIC. These results suggest that circulating proteins implicated in biological aging, cellular senescence, angiogenesis, and coagulation are associated with a neuroimaging measure of brain aging.

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.

Consensus-derived Recommended Skills for Transition to Residency Courses.

PURPOSE: Transition to residency (TTR) courses facilitate the medical student-residency transition and are an integral part of senior medical student training. The authors established a common set of skills for TTR courses and an expected level of entrustment students should demonstrate in each skill on TTR course completion. METHOD: A modified Delphi approach was used with 3 survey iterations between 2020 and 2022 to establish skills to be included in a TTR course. Nine TTR experts suggested general candidate skills and conducted a literature search to ensure no vital skills were missed. A stakeholder panel was solicited from email lists of TTR educators, residency program directors, and residents at the panelists' institutions. Consensus was defined as more than 75% of participants selecting a positive inclusion response. An entrustment questionnaire asked panelists to assign a level of expected entrustment to each skill, with 1 indicating observation only and 6 indicating perform independently. RESULTS: The stakeholder panel initially consisted of 118 respondents with representation across educational contexts and clinical specialties. Response rates were 54% in iteration 2, 42% in iteration 3, and 33% on the entrustment questionnaire. After 3 iterations, 54 skills met consensus and were consolidated into 37 final skills categorized into 18 clinical skills (e.g., assessment and management of inpatient concerns), 14 communication skills (e.g., delivering serious news or having difficult conversations), 4 personal and professional skills (e.g., prioritization of clinical tasks), and 1 procedural skill (mask ventilation). Median entrustment levels were reported for all skills, with 19 skills having a level of expected entrustment of 4 (perform independently and have all findings double-checked). CONCLUSIONS: These consensus skills can serve as the foundation of a standardized national TTR curriculum framework. Entrustment guidance may help educational leaders optimize training and allocation of resources for TTR curriculum development and implementation.

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.

The long-term effect of intentional weight loss on changes in bone mineral density in persons with type 2 diabetes: results from the Look AHEAD randomized trial.

Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men. PURPOSE: Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known. METHODS: Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16). RESULTS: At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women. CONCLUSION: Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001.

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.

Patient Responses to the Term Pain Catastrophizing: Thematic Analysis of Cross-sectional International Data.

Pain catastrophizing is understood as a negative cognitive and emotional response to pain. Researchers, advocates and patients have reported stigmatizing effects of the term in clinical settings and the media. We conducted an international study to investigate patient perspectives on the term pain catastrophizing. Open-ended electronic patient and caregiver proxy surveys were promoted internationally by collaborator stakeholders and through social media. 3,521 surveys were received from 47 countries (77.3% from the U.S.). The sample was mainly female (82.1%), with a mean age of 41.62 (SD 12.03) years; 95% reported ongoing pain and pain duration > 10 years (68.4%). Forty-five percent (n = 1,295) had heard of the term pain catastrophizing; 12% (n = 349) reported being described as a 'pain catastrophizer' by a clinician with associated high levels of feeling blamed, judged, and dismissed. We present qualitative thematic data analytics for responses to open-ended questions, with 32% of responses highlighting the problematic nature of the term. We present the patients' perspective on the term pain catastrophizing, its material effect on clinical experiences, and associations with negative gender stereotypes. Use of patient-centered terminology may be important for favorably shaping the social context of patients' experience of pain and pain care. PERSPECTIVE: Our international patient survey found that 45% had heard of the term pain catastrophizing, about one-third spontaneously rated the term as problematic, and 12% reported the term was applied to them with most stating this was a negative experience. Clinician education on patient-centered terminology may improve care and reduce stigma.

Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging?

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

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.

Family Physician Income Disparities by Race and Gender.

A race and gender salary gap has been well-documented throughout the U.S. economy, but little described in primary care. Using self-reported data on the most widely distributed primary care physician specialty, we reveal lower incomes and hourly wages among Black/African American and female family physicians. The clear gradient in family physician compensation by race and gender demands further study and action to better understand and address the underlying sources of these differences.

Variation in Scope and Area of Practice by Family Physician Race and Ethnicity.

Family physicians who are self-identified members of Black, Hispanic, and American Indian/Alaska Native racial groups are more likely to practice in disadvantaged areas but also tend to have narrower scopes of practice when compared with White family physicians, despite holding the same certification. Considering the established benefits of comprehensive primary care, these results suggest the need for policies incentivizing and supporting broader scopes of practice in disadvantaged areas.

A Randomized Preference Trial Comparing Cognitive-Behavioral Therapy and Yoga for the Treatment of Late-Life Worry: Examination of Impact on Depression, Generalized Anxiety, Fatigue, Pain, Social Participation, and Physical Function.

Background: Depression, generalized anxiety, fatigue, diminished physical function, reduced social participation, and pain are common for many older adults and negatively impact quality of life. The purpose of the overall trial 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. Objective: The present analyses compared effects of the 2 interventions on additional outcomes (depressive symptoms, generalized anxiety symptoms, fatigue, pain interference/intensity, physical function, social participation); and examined whether there are preference and selection effects for these treatments. Methods: A randomized preference trial of CBT and yoga was conducted in adults ≥60 years who scored ≥26 on the Penn State Worry Questionnaire-Abbreviated (PSWQ-A), recruited from outpatient medical clinics, mailings, and advertisements. Cognitive-behavioral therapy consisted of 10 weekly telephone sessions. Yoga consisted of 20 bi-weekly group yoga classes. Participants were randomized to(1): a randomized controlled trial (RCT) of CBT or yoga (n = 250); or (2) a preference trial in which they selected their treatment (CBT or yoga; n = 250). Outcomes were measured at baseline and post-intervention. Results: Within the RCT, there were significant between-group differences for both pain interference and intensity. The pain interference score improved more for the CBT group compared with the yoga group [intervention effect of (mean (95% CI) = 2.5 (.5, 4.6), P = .02]. For the pain intensity score, the intervention effect also favored CBT over yoga [.7 (.2, 1.3), P < .01]. Depressive symptoms, generalized anxiety, and fatigue showed clinically meaningful within-group changes in both groups. There were no changes in or difference between physical function or social participation for either group. No preference or selection effects were found. Conclusion: Both CBT and yoga may be useful for older adults for improving psychological symptoms and fatigue. Cognitive-behavioral therapy may offer even greater benefit than yoga for decreasing pain.

Racial/ethnic and socioeconomic disparities in the use of newer diabetes medications in the Look AHEAD study.

Background: Among patients with type 2 diabetes, minority racial/ethnic groups have a higher burden of cardiovascular disease, chronic kidney disease, and hypoglycaemia. These groups may especially benefit from newer diabetes medication classes, but high cost may limit access. We examined the association of race/ethnicity with the initiation of newer diabetes medications (GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors). Methods: We conducted a secondary analysis of the Look AHEAD (Action for Health in Diabetes) trial including participants with at least one study visit after April 28, 2005. Cox proportional hazards models were used to estimate the association between race/ethnicity and socioeconomic factors with time to initiation of any newer diabetes medication from April 2005 to February 2020. Models were adjusted for demographic and clinical characteristics. Findings: Among 4,892 participants, 63.6%, 15.7%, 12.6%, 5.2%, and 2.9% were White, Black, Hispanic, American Indian or Alaskan Native (AI/AN), or other race/ethnicity, respectively. During a median follow-up of 8.3 years, 2,180 (45.2%) participants were initiated on newer diabetes medications. Race/ethnicity was associated with newer diabetes medication initiation (p=.019). Specifically, initiation was lower among Black (HR 0.81, 95% CI 0.70 -0.94) and AI/AN participants (HR 0.51, 95% CI 0.26-0.99). Yearly family income was inversely associated with initiation of newer diabetes medications (HR 0.78, 95% CI 0.62-0.98) comparing the lowest and highest income groups. Findings were mostly driven by GLP-1 receptor agonists. Interpretation: These findings provide evidence of racial/ethnic disparities in the initiation of newer diabetes medications, independent of socioeconomic factors, which may contribute to worse health outcomes.

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.

Analysis of the Sphingolipidome in NAFLD.

The relationship between sphingolipid levels and NAFLD pathology has been recognized for some time. Numerous studies using pharmacological and genetic approaches in vitro and in animal models of NAFLD have demonstrated that modifications to sphingolipid metabolism can attenuate various facets of NAFLD pathology. However, a more precise understanding of the role of sphingolipids and NAFLD pathology is essential to creating therapeutics that target this pathway. This chapter touches on the scale and variety of sphingolipid metabolites at play in NAFLD, which vary widely in their chemical structures and biological functions. With advances in liquid chromatography and tandem mass spectrometry approaches, each of thousands of individual sphingolipid species and sphingolipid metabolites can be identified and precisely quantified. These approaches are beginning to reveal specific sub-classes and species of sphingolipids that change in NAFLD, and as such, enzymes that generate them can be identified and potentially serve as therapeutic targets. Advances in lipidomics technology have been, and will continue to be, critical to these gains in our understanding of NAFLD.

Ultrasound guided peripheral IV placement: An observational study of the learning curve in pediatric patients.

BACKGROUND: Ultrasound guided peripheral intravenous catheter placement (USGPIV) has demonstrated benefits in children including higher success rates and fewer attempts compared to the traditional technique. Little is known about the experience needed to establish competence with USGPIV in children. In adult patients, nurses with four USGPIV attempts had a subsequent 70% probability of success after training. The objective of this study is to measure the competency of nurses with USGPIV in children after training. METHODS: Pediatric nurses completed 2 h of training on USGPIV, after which they used ultrasound at their discretion for children with difficult access. Data was collected prospectively via study forms and retrospectively from medical records. Mixed effects logistic regression models were used to estimate the probability of successful USGPIV placement. RESULTS: Thirty-five nurses underwent training from the pediatric emergency department and intravenous access team. The overall USGPIV success rate was 70%. Participants with less nursing experience made more USGPIV attempts than those with more experience, but had similar success rates. Forty percent of participants performed ten or more attempts during the study period. Mixed effects logistic regression estimated that it took nine USGPIV attempts after training for learners to achieve a 70% probability of success for the subsequent attempt. CONCLUSION: After training, 40% of participants adopted USGPIV into their practice. When developing training programs for USGPIV for children with difficult access, trainers can anticipate the experience needed to acquire this skill and the fact that not everyone trained will use this skill in their daily practice.

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.

Using a brief tool to assess healthy school environments: a pilot study.

OBJECTIVES: HealthPartners developed a checklist, the School Environment Index (SEI), that it uses to help elementary schools identify opportunities to improve student nutrition and increase physical activity. The objective in this pilot study was to assess whether the SEI, as administered, can be used to measure the progress of these programs. STUDY DESIGN: The authors focused their evaluation on the National Quality Forum measure evaluation components of reliability and validity; feasibility; and use and usability to assess the SEI's performance. METHODS: The authors used data from 214 SEIs completed by the 69 schools that participated in the school challenge in at least 1 of the years 2015 through 2019. Between 29 and 53 schools participated in a particular year. RESULTS: Cronbach's α was 0.79, intraclass correlation was 0.36 (95% CI, 0.22-0.53), and sensitivity to change was 0.41 (95% CI, 0.17-0.66) per 1-year change in the standardized SEI score. The median (interquartile range) time required to complete the survey was 11 (7-21) minutes. On only 8 surveys was an entire domain of the SEI skipped or only a single response to the domain recorded. CONCLUSIONS: The SEI shows adequate internal consistency and sensitivity to change in this pilot evaluation. It is also feasible and useful to identify opportunities to improve practices and policies related to student nutrition and physical activity in partnership with the participating elementary schools. However, it lacks reliability as used. Increasing the number of respondents per school might moderate the impact of individual respondents and thereby increase reliability.