Presurgery health influences outcomes following vertical sleeve gastrectomy in adolescents.

OBJECTIVE: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG. METHODS: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG. RESULTS: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m2. Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m2 (35.3%) versus the BAWL group, who lost 8.8 kg/m2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities. CONCLUSIONS: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG.

Multifocal Insulinoma as the Unique Presenting Feature of Multiple Endocrine Neoplasia Type 1 in an Adolescent.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder defined by the presence of two of the following endocrinopathies: primary hyperparathyroidism, anterior pituitary tumors, and duodenopancreatic neuroendocrine tumors (NETs). NETs, which can secrete hormones including insulin, gastrin, and glucagon, among others, are common in patients with MEN1 and are a major cause of morbidity and premature death. NETs are more common later in life, with very few cases described in children. Here, we describe a unique case of an adolescent with multifocal pancreatic NETs as the single presenting feature of MEN1. CASE PRESENTATION: A 13-year-old healthy male presented with severe weakness, altered mental status, and syncope in the setting of a venous blood glucose (BG) of 36 mg/dL. Workup showed an elevated insulin level (14 µIU/mL) when BG was 39 mg/dL with positive response to glucagon, concerning for hyperinsulinism. Diazoxide and chlorothiazide were started but not well tolerated secondary to emesis. Three suspected NETs were identified by magnetic resonance imaging and 68-Ga DOTATATE PET-CT imaging, including the largest, a 2.1 cm mass in the pancreatic head. A fourth mass in the pancreatic tail was identified via intraoperative ultrasound. All lesions were successfully enucleated and excised, and glucose levels normalized off diazoxide by post-op day 2. While the primary lesion stained for insulin and somatostatin by immunofluorescence (IF), consistent with his clinical presentation, the additional tumors expressed glucagon, somatostatin, pancreatic polypeptide, and chromogranin A but were negative for insulin. Genetic testing confirmed a pathogenic heterozygous mutation in MEN1 (c.969C>A, p.Tyr323). He had no other signs of MEN-associated comorbidities on screening. DISCUSSION/CONCLUSION: This case demonstrates that young patients with MEN1 can present with multifocal NETs. These NETs may have polyhormonal expression patterns despite a clinical presentation consistent with one primary hormone. Our patient had clinical symptoms and laboratory evaluation consistent with an insulinoma but was found to have four NETs, each with different IF staining patterns. Advanced preoperative and intraoperative imaging is important to identify and treat all present NETs. Moreover, serum hormone levels pre- and posttreatment could help evaluate whether NETs are actively secreting hormones into the bloodstream or simply expressing them within the pancreas. Finally, this case highlights the importance of genetic testing for MEN1 in all young patients with insulinomas.

Development and Implementation of a Multidisciplinary Clinic Focused on the Care of Adolescents with Youth-Onset Type 2 Diabetes.

Introduction: Diabetes self-management education and lifestyle interventions are the cornerstones of type 2 diabetes (T2D) care; however, the higher risk of comorbidities among youth with T2D requires a comprehensive care model. Traditionally, sub-specialty care relies on a referral model placing the burden on patients/families. In response, we developed a pediatric T2D multidisciplinary clinic (MDC)-A single physical location where patients can access various sub-specialists. The goals of the MDC are to aid with lifestyle modifications and provide referral/access to sub-specialists within the MDC, as determined through screening labs and assessment tools. Methods: We conducted a retrospective chart review of youth seen in the T2D MDC clinic at Cincinnati Children's Hospital from 1/2020 to 12/2021. We evaluated the frequency that youth met with each specialist and completion rates of annual screening labs. Results: The cohort consisted of 227 youth with T2D (mean age 17.6 years, mean BMI 40.9kg/m2, 64% female, 50% Black or African American, 65% public insurance). All patients met with a diabetes provider and 81.2% met with a registered dietitian/certified diabetes education specialist. Exercise physiology met with 51.5% of patients, gastroenterology met with 34.8% of patients, social work met with 44.1% of patients, clinical psychology met with 27.3% of patients, and bariatric surgery met with 9.7% of patients. Percent completion of annual labs were: 98.2% for HbA1c, 84.6% for urine microalbumin, 83.7% for lipids, 90% for liver function, 59.5% for retinopathy, and 45.4% for the Patient Health Questionnaire-9. Conclusion: The majority of patients received diabetes and nutrition education and annual screening labs. Exercise counseling and sub-specialty care remain below 60% in part due to services not being available at every MDC. Our goals are to increase access to subspecialty care within the MDC's and consider additional care delivery methods to provide comprehensive care to youth with T2D.

Candidate biomarkers as predictors of future kidney disease and cardiovascular dysfunction in adolescents with type 2 diabetes.

AIMS: Evaluate changes in circulating biomarkers as predictors of kidney disease, and cardiac/vascular dysfunction in participants from the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Candidate biomarkers were assessed annually in 507 participants over a mean follow-up of 6.9 ± 2.4 years. Moderate albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g and hyperfiltration as eGFR ≥ 135 mL/min/1.73 m2 at two consecutive visits. Echocardiography (n = 256) and pulse wave velocity (n = 193) were evaluated twice, 5 years apart. Adjusted Cox proportional hazard models and logistic regression models were used to examine associations between biomarkers and outcomes. RESULTS: At baseline, 35.7% were male, with a mean age 13.9 years, diabetes duration 7.8 months, and HbA1c 6.0%. Higher concentrations of E-selectin and proinsulin were associated with incident moderate albuminuria and hyperfiltration. Higher concentrations of FGF-23 were associated with lower risk of hyperfiltration and negatively correlated with eGFR. No candidate biomarkers predicted a decline in cardiac or vascular function. CONCLUSIONS: Circulating biomarkers of endothelial dysfunction and markers of ß-cell dysfunction and insulin sensitivity could be used in a more personalized risk assessment of kidney disease in youth-onset type 2 diabetes. However, biomarkers studied have limited value in predicting cardiac dysfunction or vascular stiffness.

Dispelling myths: The case for women in radiology and radiation oncology.

Common misconceptions about radiology and radiation oncology exist and may dissuade women from pursuing these specialties. The American Association for Women in Radiology (AAWR) Medical Student Outreach Subcommittee began a multi-year social media campaign aimed at addressing these myths. Here, we outline several myths presented in this social media campaign and provide a combination of literature review and experts' opinions to deconstruct and dispel them.

Relationship between Arterial Stiffness and Subsequent Cardiac Structure and Function in Young Adults with Youth-Onset Type 2 Diabetes: Results from the TODAY Study.

BACKGROUND: Higher arterial stiffness may contribute to future alterations in left ventricular systolic and diastolic function. We tested this hypothesis in individuals with youth-onset type 2 diabetes from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Arterial stiffness (pulse wave velocity [carotid-femoral, femoral-foot, and carotid-radial], augmentation index, brachial distensibility) was measured in 388 participants with type 2 diabetes (mean age, 21 years; diabetes duration, 7.7 ± 1.5 years). To reflect overall (composite) vascular stiffness, the five arterial stiffness measures were aggregated. An echocardiogram was performed in the same cohort 2 years later. Linear regression models assessed whether composite arterial stiffness was associated with left ventricular mass index or systolic and diastolic function, independent of age, sex, race/ethnicity, current cigarette smoking, and long-term exposure (time-weighted mean values over 9.1 years) of hemoglobin A1c, blood pressure, and body mass index. Interactions among arterial stiffness and time-weighted mean hemoglobin A1c, blood pressure, and body mass were also examined. RESULTS: After adjustment, arterial stiffness remained significantly associated with left ventricular mass index and diastolic function measured by mitral valve E/Em, despite attenuation by time-weighted mean body mass index. A significant interaction revealed a greater adverse effect of composite arterial stiffness on mitral valve E/Em among participants with higher levels of blood pressure over time. Arterial stiffness was unrelated to left ventricular systolic function. CONCLUSIONS: The association of higher arterial stiffness with future left ventricular diastolic dysfunction suggests the path to future heart failure may begin early in life in this setting of youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328.

Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study.

AIM: The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). METHODS: Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n = 20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n = 19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. RESULTS: Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5 ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r = -0.70, p = 0.002) and in regional clusters. CONCLUSIONS: In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

Conformational flexibility of apolipoprotein A-I amino- and carboxy-termini is necessary for lipid binding but not cholesterol efflux.

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1's ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the "double super helix." Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux.

Study protocol: a prospective controlled clinical trial to assess surgical or medical treatment for paediatric type 2 diabetes (ST2OMP).

INTRODUCTION: The pathophysiology of type 2 diabetes (T2D) in youth differs from adults and conventional medical treatment approaches with lifestyle change, metformin, thiazolidinediones or insulin are inadequate. Metabolic bariatric surgery (MBS) improves multiple health outcomes in adults with T2D. Initial small, uncontrolled studies of Roux-en-Y gastric bypass have also suggested beneficial effects in adolescents. Definitive studies in youth with T2D are lacking, especially with the now more common form of MBS, vertical sleeve gastrectomy (VSG). The surgical or medical treatment for paediatric type 2 diabetes (ST2OMP) clinical trial was designed to test the hypothesis that VSG will more effectively reduce hyperglycaemic and diabetes comorbidities than the best currently available medical treatment incorporating state of the art pharmacotherapies. ST2OMP is also designed to better understand the pancreatic and enterohepatic mechanisms by which MBS improves diabetes and its associated comorbidities. METHODS AND ANALYSIS: ST2OMP is a prospective, open-label, controlled clinical trial that will recruit 90 postpubertal participants, age range 13-19.9 years, with body mass index ≥35 kg/m2 or >120% of 95th percentile and youth-onset T2D. The primary outcome is the per cent of youth achieving haemoglobin A1c <6.0% at 12 months postgroup allocation (post-VSG vs postmedical group allocation). Secondary outcomes include remission of comorbidities and measures of ß-cell and incretin responses at 12 and 24 months post VSG versus AMT. ETHICS AND DISSEMINATION: The ST2OMP protocol was approved by the Cincinnati Children's Hospital Medical Center and the University of Colorado Institutional Review Boards. Written informed consent is obtained prior to study enrolment. Study findings will be widely disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov NCT04128995.

A Quality Improvement Learning Collaborative for Human Papillomavirus Vaccination.

Many published accounts have shown that quality improvement (QI) initiatives within medical practice settings can increase vaccination rates. Project ECHO is a telementoring platform that uses video conferencing technology to educate and support healthcare professionals through case-based learning and brief lectures. This manuscript explores the results of a learning collaborative focused on combining QI and Project ECHO to increase human papillomavirus (HPV) vaccination rates within pediatric practices. METHODS: The American Academy of Pediatrics (AAP) recruited 3 AAP chapters that then recruited individual pediatricians and their practices for participation. Participants responded to surveys regarding chapter and pediatrician experience and satisfaction. Impact on HPV immunization rates (HPV initiation, series completion, and missed opportunities to vaccinate during visits) was measured using practice reports of chart reviews to AAP's data aggregator, which produced run charts. RESULTS: Thirty-four pediatricians within 8 practices completed the project; 1 practice withdrew. Physicians self-reported increased confidence in communicating with vaccine-hesitant families and implementing QI activities. We analyzed practice run charts utilizing QI run chart rules and found nonrandom change towards improvement for aggregate missed opportunities to vaccinate but not for HPV vaccine initiation or series completion. CONCLUSIONS: An HPV QI learning collaborative improved participant confidence in HPV vaccine communication and QI skills and decreased missed opportunities to vaccinate. Future projects should consider a more extended project period or more frequent data collection to reduce data variability to make it easier to spot nonrandom changes.

Integrating quality improvement into the ECHO model to improve care for children and youth with epilepsy.

OBJECTIVE: Project ECHO (Extension for Community Healthcare Outcomes), a telementoring program, utilizes lectures, case-based learning, and an "all teach-all learn" approach to increase primary care provider (PCP) knowledge/confidence in managing chronic health conditions. The American Academy of Pediatrics (AAP) Epilepsy and Comorbidities ECHO incorporated quality improvement (QI) methodology to create meaningful practice change, while increasing PCP knowledge/self-efficacy in epilepsy management using the ECHO model. METHODS: Monthly ECHO sessions (May 2018 to December 2018) included lectures, case presentations/discussion, and QI review. Pediatric practices were recruited through the AAP. Practices engaged in ECHO sessions and improvement activities including monthly Plan-Do-Study-Act cycles, team huddles, chart reviews, and QI coaching calls to facilitate practice change. They were provided resource toolkits with documentation templates, safety handouts, and medication side effects sheets. QI measures were selected from the American Academy of Neurology Measurement Set for Epilepsy. The AAP Quality Improvement Data Aggregator was used for data entry, run chart development, and tracking outcomes. Participants completed retrospective surveys to assess changes in knowledge and self-efficacy. RESULTS: Seven practices participated across five states. Average session attendance was 14 health professionals (range = 13-17). A total of 479 chart reviews demonstrated improvement in six of seven measures: health care transition (45.3%, P = .005), safety education (41.6%, P = .036), mental/behavioral health screening (32.2% P = .027), tertiary center referral (26.7%, not significant [n.s.]), antiseizure therapy side effects (23%, n.s.), and documenting seizure frequency (7.1%, n.s.); counseling for women of childbearing age decreased by 7.8%. SIGNIFICANCE: This project demonstrated that integrating QI into an ECHO model results in practice change and increases PCP knowledge/confidence/self-efficacy in managing epilepsy.

Metabolic outcomes of surgery in youth with type 2 diabetes.

Youth-onset type 2 diabetes (T2D) is a formidable threat to the health of obese adolescents because of its potential for early-onset and aggressive co-morbidities and complications. The physiology of youth-onset T2D differs from T2D in adults and is associated with a greater degree of insulin resistance, a more rapid decline in pancreatic ß-cell function, and a poorer response to medications. Medical management in youth is focused on combining lifestyle intervention and pharmacological treatment, but these therapies have yet to demonstrate improvements in disease progression. Metabolic bariatric surgery (MBS) is now recommended for the treatment of T2D in adults largely because of the beneficial effects on weight, ability to improve glycemic control, and, in a large proportion of people, induce diabetes remission. MBS is now being performed in adolescents with severe obesity and T2D, with initial results also showing high rates of T2D remission. Here, we review the state of medical management of youth-onset T2D and the outcomes of MBS studies in youth with T2D published to date.

Effect of Surgical Versus Medical Therapy on Diabetic Kidney Disease Over 5 Years in Severely Obese Adolescents With Type 2 Diabetes.

OBJECTIVE: To compare diabetic kidney disease (DKD) rates over 5 years of follow-up in two cohorts of severely obese adolescents with type 2 diabetes (T2D) undergoing medical or surgical treatment for T2D. RESEARCH DESIGN AND METHODS: A secondary analysis was performed of data collected from obese participants of similar age and racial distribution enrolled in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) and the Treatment Options of Type 2 Diabetes in Adolescents and Youth (TODAY) studies. Teen-LABS participants underwent metabolic bariatric surgery (MBS). TODAY participants were randomized to metformin alone or in combination with rosiglitazone or intensive lifestyle intervention, with insulin therapy given for glycemic progression. Glycemic control, BMI, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and prevalence of hyperfiltration (eGFR ≥135 mL/min/1.73 m2) and elevated UAE (≥30 mg/g) were assessed annually. RESULTS: Participants with T2D from Teen-LABS (n = 30, mean ± SD age, 16.9 ± 1.3 years; 70% female; 60% white; BMI 54.4 ± 9.5 kg/m2) and TODAY (n = 63, age 15.3 ± 1.3 years; 56% female; 71% white; BMI 40.5 ± 4.9 kg/m2) were compared. During 5 years of follow-up, hyperfiltration decreased from 21% to 18% in Teen-LABS and increased from 7% to 48% in TODAY. Elevated UAE decreased from 27% to 5% in Teen-LABS and increased from 21% to 43% in TODAY. Adjusting for baseline age, sex, BMI, and HbA1c, TODAY participants had a greater odds of hyperfiltration (odds ratio 15.7 [95% CI 2.6, 94.3]) and elevated UAE (27.3 [4.9, 149.9]) at 5 years of follow-up. CONCLUSIONS: Compared with MBS, medical treatment of obese youth with T2D was associated with a higher odds of DKD over 5 years.

A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL.

APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDL's cardioprotective functions, in part via its activation of the enzyme, LCAT. On nascent discoidal HDL, APOA1 comprises 10 α-helical repeats arranged in an anti-parallel stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown. Here, we placed cysteine residues at locations predicted to form disulfide bonds in each orientation and then measured APOA1's ability to adopt the two registries during HDL particle formation. We found that most APOA1 oriented with the fifth helix of one molecule across from fifth helix of the other (5/5 helical registry), but a fraction adopted a 5/2 registry. Engineered HDLs that were locked in 5/5 or 5/2 registries by disulfide bonds equally promoted cholesterol efflux from macrophages, indicating functional particles. However, unlike the 5/5 registry or the WT, the 5/2 registry impaired LCAT cholesteryl esterification activity (P < 0.001), despite LCAT binding equally to all particles. Chemical cross-linking studies suggest that full LCAT activity requires a hybrid epitope composed of helices 5-7 on one APOA1 molecule and helices 3-4 on the other. Thus, APOA1 may use a reciprocating thumbwheel-like mechanism to activate HDL-remodeling proteins.

Metabolic Imaging of Head and Neck Cancer Organoids.

Head and neck cancer patients suffer from toxicities, morbidities, and mortalities, and these ailments could be minimized through improved therapies. Drug discovery is a long, expensive, and complex process, so optimized assays can improve the success rate of drug candidates. This study applies optical imaging of cell metabolism to three-dimensional in vitro cultures of head and neck cancer grown from primary tumor tissue (organoids). This technique is advantageous because it measures cell metabolism using intrinsic fluorescence from NAD(P)H and FAD on a single cell level for a three-dimensional in vitro model. Head and neck cancer organoids are characterized alone and after treatment with standard therapies, including an antibody therapy, a chemotherapy, and combination therapy. Additionally, organoid cellular heterogeneity is analyzed quantitatively and qualitatively. Gold standard measures of treatment response, including cell proliferation, cell death, and in vivo tumor volume, validate therapeutic efficacy for each treatment group in a parallel study. Results indicate that optical metabolic imaging is sensitive to therapeutic response in organoids after 1 day of treatment (p<0.05) and resolves cell subpopulations with distinct metabolic phenotypes. Ultimately, this platform could provide a sensitive high-throughput assay to streamline the drug discovery process for head and neck cancer.

Autofluorescence flow sorting of breast cancer cell metabolism.

Clinical cancer treatment aims to target all cell subpopulations within a tumor. Autofluorescence microscopy of the metabolic cofactors NAD(P)H and FAD has shown sensitivity to anti-cancer treatment response. Alternatively, flow cytometry is attractive for high throughput analysis and flow sorting. This study measures cellular autofluorescence in three flow cytometry channels and applies cellular autofluorescence to sort a heterogeneous mixture of breast cancer cells into subpopulations enriched for each phenotype. Sorted cells were grown in culture and sorting was validated by morphology, autofluorescence microscopy, and receptor expression. Ultimately, this method could be applied to improve drug development and personalized treatment planning.

Bariatric Surgery: A Potential Treatment for Type 2 Diabetes in Youth.

Type 2 diabetes, once referred to as "adult-onset" diabetes, has now emerged as a formidable threat to the health of obese adolescents. Although there is growing evidence regarding the epidemiology of type 2 diabetes in youth and its multisystem health consequences, treatment options have lagged and progression of disease occurs even with aggressive medical therapy. Increasing interest in the application of bariatric surgery for adolescents with type 2 diabetes has evolved in part because of the evidence demonstrating improvement or remission in many adults with diabetes after surgery. Here, we review the burden of type 2 diabetes in youth including its associated complications, discuss the outcomes and complications of bariatric surgery in adolescents with diabetes, and conclude with recommendations for future research and options for refinement of the use of bariatric surgery in this patient population.

Predictors of Increased Carotid Intima-Media Thickness in Youth With Type 1 Diabetes: The SEARCH CVD Study.

OBJECTIVE: Youth with type 1 diabetes have worse cardiovascular (CV) risk factors and higher carotid intima-media thickness (IMT) than their peers without diabetes. Whether the burden of CV risk factors over time is associated with carotid IMT at follow-up in youth with type 1 diabetes is not known. RESEARCH DESIGN AND METHODS: Two hundred ninety-eight youth with type 1 diabetes (mean age 13.3 ± 2.9 years, 87.6% non-Hispanic white, 53.7% male) had two study visits 5 years apart. CV risk factors, including BMI, lipids, blood pressure, hemoglobin A(1c), and smoking status, were assessed at both visits, and carotid IMT was measured at follow-up using B-mode ultrasonography. Linear regression models with an area under the curve measurement that incorporated the baseline and follow-up CV risk factors were used to evaluate the relationship with carotid IMT at follow-up. RESULTS: All CV risk factors worsened significantly over time (except LDL cholesterol) (P < 0.05). From baseline to follow-up, the number of abnormal CV risk factors also increased (P < 0.05). Predictors of carotid IMT were older age, male sex, and higher BMI z score area under the curve (all P < 0.05). CONCLUSIONS: The CV risk factor burden increases over time in youth with type 1 diabetes. BMI z score was the only modifiable CV risk factor that predicted carotid IMT. This study highlights the critical need to better understand the risk factors that influence carotid IMT early in the course of type 1 diabetes.

In Vivo Autofluorescence Imaging of Tumor Heterogeneity in Response to Treatment.

Subpopulations of cells that escape anti-cancer treatment can cause relapse in cancer patients. Therefore, measurements of cellular-level tumor heterogeneity could enable improved anti-cancer treatment regimens. Cancer exhibits altered cellular metabolism, which affects the autofluorescence of metabolic cofactors NAD(P)H and FAD. The optical redox ratio (fluorescence intensity of NAD(P)H divided by FAD) reflects global cellular metabolism. The fluorescence lifetime (amount of time a fluorophore is in the excited state) is sensitive to microenvironment, particularly protein-binding. High-resolution imaging of the optical redox ratio and fluorescence lifetimes of NAD(P)H and FAD (optical metabolic imaging) enables single-cell analyses. In this study, mice with FaDu tumors were treated with the antibody therapy cetuximab or the chemotherapy cisplatin and imaged in vivo two days after treatment. Results indicate that fluorescence lifetimes of NAD(P)H and FAD are sensitive to early response (two days post-treatment, P<.05), compared with decreases in tumor size (nine days post-treatment, P<.05). Frequency histogram analysis of individual optical metabolic imaging parameters identifies subpopulations of cells, and a new heterogeneity index enables quantitative comparisons of cellular heterogeneity across treatment groups for individual variables. Additionally, a dimensionality reduction technique (viSNE) enables holistic visualization of multivariate optical measures of cellular heterogeneity. These analyses indicate increased heterogeneity in the cetuximab and cisplatin treatment groups compared with the control group. Overall, the combination of optical metabolic imaging and cellular-level analyses provide novel, quantitative insights into tumor heterogeneity.