Adipsin and adipocyte-derived C3aR1 regulate thermogenic fat in a sex-dependent fashion.

Thermogenesis in beige/brown adipose tissues can be leveraged to combat metabolic disorders such as type 2 diabetes and obesity. The complement system plays pleiotropic roles in metabolic homeostasis and organismal energy balance with canonical effects on immune cells and noncanonical effects on nonimmune cells. The adipsin/C3a/C3a receptor 1 (C3aR1) pathway stimulates insulin secretion and sustains pancreatic ß cell mass. However, its role in adipose thermogenesis has not been defined. Here, we show that male Adipsin/Cfd-knockout mice exhibited increased energy expenditure and white adipose tissue (WAT) browning. In addition, male adipocyte-specific C3aR1-knockout mice exhibited enhanced WAT thermogenesis and increased respiration. In stark contrast, female adipocyte-specific C3aR1-knockout mice displayed decreased brown fat thermogenesis and were cold intolerant. Female mice expressed lower levels of Adipsin in thermogenic adipocytes and adipose tissues than males. C3aR1 was also lower in female subcutaneous adipose tissue than in males. Collectively, these results reveal sexual dimorphism in the adipsin/C3a/C3aR1 axis in regulating adipose thermogenesis and defense against cold stress. Our findings establish a potentially new role of the alternative complement pathway in adaptive thermogenesis and highlight sex-specific considerations in potential therapeutic targets for metabolic diseases.

Changes in the Clinical Practice of Mental Health Service Providers Throughout the COVID-19 Pandemic: Longitudinal Questionnaire Study.

BACKGROUND: The COVID-19 pandemic impacted the practices of most mental health providers and resulted in a rapid transition to providing telemental health services, changes that were likely related to stay-at-home policies as well as increased need for services. OBJECTIVE: The aim of this study was to examine whether these changes to practice have been sustained over time throughout the course of the COVID-19 pandemic and whether there are differences among mental health provider type and setting. We hypothesized that there would be an increase in the number of patients seen in person after the initial surge of the pandemic in spring 2020 and subsequent discontinuation of stay-at-home policies, though with continued implementation of telemental health services across settings. METHODS: This study surveyed 235 of the 903 mental health providers who responded to a survey in spring 2020 (Time point 1) and at a 1-year follow-up in spring 2021 (Time point 2). Differences in practice adjustments, factors related to telemental health, and number of patients seen were examined across provider type (social worker, psychologist, neuropsychologist) and setting (academic medical center [AMC], community mental health, private practice, and Veterans Affairs hospital). RESULTS: From Time point 1 to Time point 2, there was a small but significant increase in the overall number of providers who were implementing telehealth (191/235, 81% to 204/235, 87%, P=.01) and there was a significant decline in canceled or rescheduled appointments (25%-50% in 2020 to 3%-7% in 2021, P<.001). Psychologists and providers working at AMCs reported decreased difficulty with telehealth implementation (P<.001), and providers working at AMCs and in private practice settings indicated they were more likely to continue telehealth services beyond spring 2021 (P<.001). The percent of time working remotely decreased overall (78% to 59%, P<.001), which was most notable among neuropsychologists and providers working at an AMC. There was an overall increase in the average number of patients seen in person per week compared with earlier in the pandemic (mean 4.3 to 8.7, P<.001), with no change in the number of patients seen via telehealth (mean 9.7 to 9.9, P=.66). CONCLUSIONS: These results show that the rapid transition to telemental health at the onset of the COVID-19 pandemic in spring 2020 was sustained over the next year, despite an overall increase in the number of patients seen in person. Although more providers reported returning to working on-site, over 50% of providers continued to use a hybrid model, and many providers reported they would be more likely to continue telemental health beyond spring 2021. This suggests the continued importance and reliance on telemental health services beyond the acute pandemic phase and has implications for future policies regulating the availability of telemental health services to patients.

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Acute hospitalizations after proton therapy versus intensity-modulated radiotherapy for locally advanced non-small cell lung cancer in the durvalumab era.

INTRODUCTION: It was hypothesized that use of proton beam therapy (PBT) in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiation and consolidative immune checkpoint inhibition is associated with fewer unplanned hospitalizations compared with intensity-modulated radiotherapy (IMRT). METHODS: Patients with locally advanced non-small cell lung cancer treated between October 2017 and December 2021 with concurrent chemoradiation with either IMRT or PBT ± consolidative immune checkpoint inhibition were retrospectively identified. Logistic regression was used to assess the association of radiation therapy technique with 90-day hospitalization and grade 3 (G3+) lymphopenia. Competing risk regression was used to compare G3+ pneumonitis, G3+ esophagitis, and G3+ cardiac events. Kaplan-Meier method was used for progression-free survival and overall survival. Inverse probability treatment weighting was applied to adjust for differences in PBT and IMRT groups. RESULTS: Of 316 patients, 117 (37%) received PBT and 199 (63%) received IMRT. The PBT group was older (p < .001) and had higher Charlson Comorbidity Index scores (p = .02). The PBT group received a lower mean heart dose (p < .0001), left anterior descending artery V15 Gy (p = .001), mean lung dose (p = .008), and effective dose to immune circulating cells (p < .001). On inverse probability treatment weighting analysis, PBT was associated with fewer unplanned hospitalizations (adjusted odds ratio, 0.55; 95% CI, 0.38-0.81; p = .002) and less G3+ lymphopenia (adjusted odds ratio, 0.55; 95% CI, 0.37-0.81; p = .003). There was no difference in other G3+ toxicities, progression-free survival, or overall survival. CONCLUSIONS: PBT is associated with fewer unplanned hospitalizations, lower effective dose to immune circulating cells and less G3+ lymphopenia compared with IMRT. Minimizing dose to lymphocytes may be warranted, but prospective data are needed.

Pneumonitis Rates Before and After Adoption of Immunotherapy Consolidation in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation.

PURPOSE: We hypothesized that after adoption of immune checkpoint inhibitor (ICI) consolidation for patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving concurrent chemoradiation therapy (cCRT), rates of symptomatic pneumonitis would increase, thereby supporting efforts to reduce lung radiation dose. METHODS AND MATERIALS: This single institution, multisite retrospective study included 783 patients with LA-NSCLC treated with definitive cCRT either before introduction of ICI consolidation (pre-ICI era cohort [January 2011-September 2017]; N = 448) or afterward (ICI era cohort [October 2017-December 2021]; N = 335). Primary endpoint was grade ≥2 pneumonitis (G2P) and secondary endpoint was grade ≥3 pneumonitis (G3P), per Common Terminology Criteria for Adverse Events v5.0. Pneumonitis was compared between pre-ICI era and ICI era cohorts using the cumulative incidence function and Gray's test. Inverse probability of treatment weighting (IPTW)-adjusted Fine-Gray models were generated. Logistic models were developed to predict the 1-year probability of G2P as a function of lung dosimetry. RESULTS: G2P was higher in the ICI era than in the pre-ICI era (1-year cumulative incidence 31.4% vs 20.1%; P < .001; IPTW-adjusted multivariable subdistribution hazard ratio, 2.03; 95% confidence interval, 1.53-2.70; P < .001). There was no significant interaction between ICI era treatment and either lung volume receiving ≥20 Gy (V20) or mean lung dose in Fine-Gray regression for G2P; however, the predicted probability of G2P was higher in the ICI era at clinically relevant values of lung V20 (≥24%) and mean lung dose (≥14 Gy). Cut-point analysis revealed a lung V20 threshold of 28% in the ICI era (1-year G2P rate 46.0% above vs 19.8% below; P < .001). Among patients receiving ICI consolidation, lung V5 was not associated with G2P. G3P was not higher in the ICI era (1-year cumulative incidence 7.5% vs 6.0%; P = .39; IPTW-adjusted multivariable subdistribution hazard ratio, 1.12; 95% confidence interval, 0.63-2.01; P = .70). CONCLUSIONS: In patients with LA-NSCLC treated with cCRT, the adoption of ICI consolidation was associated with an increase in G2P but not G3P. With ICI consolidation, stricter lung dose constraints may be warranted.

Phase 2 Trial of Consolidation Pembrolizumab After Proton Reirradiation for Thoracic Recurrences of Non-Small Cell Lung Cancer.

PURPOSE: Reirradiation (reRT) with proton beam therapy (PBT) may offer a chance of cure while minimizing toxicity for patients with isolated intrathoracic recurrences of non-small cell lung cancer (NSCLC). However, distant failure remains common, necessitating strategies to integrate more effective systemic therapy. METHODS AND MATERIALS: This was a phase 2, single-arm trial (NCT03087760) of consolidation pembrolizumab after PBT reRT for locoregional recurrences of NSCLC. Four to 12 weeks after completion of 60 to 70 Gy PBT reRT, patients without progressive disease received pembrolizumab for up to 12 months. Primary endpoint was progression-free survival (PFS), measured from the start of reRT. Secondary endpoints were overall survival (OS) and National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 toxicity. RESULTS: Between 2017 and 2021, 22 patients received PBT reRT. Median interval from prior radiation end to reRT start was 20 months. Most recurrences (91%) were centrally located. Most patients received concurrent chemotherapy (95%) and pencil beam scanning PBT (77%), and 36% had received prior durvalumab. Fifteen patients (68%) initiated consolidation pembrolizumab on trial and received a median of 3 cycles (range, 2-17). Pembrolizumab was discontinued most commonly due to toxicity (n = 5; 2 were pembrolizumab-related), disease progression (n = 4), and completion of 1 year (n = 3). Median follow-up was 38.7 months. Median PFS and OS were 8.8 months (95% CI, 4.2-23.7) and 22.8 months (95% CI, 6.9-not reached), respectively. There was only one isolated in-field failure after reRT. Grade ≥3 toxicities occurred in 10 patients (45%); 2 were pembrolizumab-related. There were 2 grade 5 toxicities, an aorto-esophageal fistula at 6.9 months and hemoptysis at 46.8 months, both probably from reRT. The trial closed early due to widespread adoption of immunotherapy off-protocol. CONCLUSIONS: In the first-ever prospective trial combining PBT reRT with consolidation immunotherapy, PFS was acceptable and OS favorable. Late grade 5 toxicity occurred in 2 of 22 patients. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC.

Factors associated with reduced sleep among spouses and caregivers of older adults with varying levels of cognitive decline.

BACKGROUND: Caregivers of persons with cognitive decline (PWCD) are at increased risk of poor sleep quantity and quality. It is unclear whether this is due to factors in the caregiver versus in the PWCD. METHODS: This secondary data analysis using Aging, Demographics, and Memory Study data from the Health Retirement Study examined factors contributing to reduced sleep/rest among spouses and caregivers of older adults with varying levels of cognitive decline (cognitively normal (CN), cognitive impairment but not dementia (CIND), or dementia). RESULTS: In our preliminary analysis, among N = 218 spouses (not necessarily caregivers) (mean age (SD) = 73.77 (7.30); 70.64% female) of older adults with varying levels of cognitive decline, regression revealed that frequency of sleep complaints was lowest among spouses with CN partners, second highest with CIND partners, and highest with dementia-partners, X2 = 26.810, P = 0.002. PRIMARY AIM: among n = 136 caregivers of PWCD (mean age (SD) = 59.27 (13.97); 74.26% female; 22.79% spouses), we analyzed whether caregiver reduced sleep/rest was predicted by PWCD factors (i.e., frequent nighttime waking, dementia severity) and/or caregiver factors (i.e., depression symptoms, caregiver role overload). Regression revealed that caregiver depression symptoms (d = 0.62) and role overload (d = 0.88), but not PWCD factors, were associated with reduced caregiver sleep/rest after adjusting for demographic factors, caregiving frequency, and shared-dwelling status (overall model: X2 = 31.876, P = 0.002). Exploratory analyses revealed that a caregiver was 7.901 times more likely (95% CI: 0.99-63.15) to endorse experiencing reduced sleep/rest if back-up care was not available (P = 0.023). CONCLUSION: Findings highlight that the frequency of reported sleep problems among spouses increases in a stepwise fashion when partners have dementia versus CIND versus CN. The results also emphasise that caregiver mental health and burden are strongly associated with caregiver sleep disturbances and thus may be targets of intervention for caregiver sleep problems.

Individualized Coordination and Empowerment for Care Partners of Persons with Dementia (ICECaP): Study rationale and protocol.

The majority of care for >10 million older adults with dementia (PWD) in the United States depends on at least on 11 million unpaid care partners (CPs). CPs are at greater risk of adverse physical, psychological, and cognitive health outcomes relative to non-caregiving peers. The goal of this paper is to establish the rationale, design, and protocol for a pilot randomized control trial to test the efficacy of the CP-focused intervention, ICECaP: Individualized Coordination and Empowerment for Care Partners of Persons with Dementia. ICECaP involves the assignment of a trained dementia care coordinator to a CP. The care coordinator maintains at least monthly contact with the CP with hybrid delivery (in-person, phone, e-mail, and video calls) and provides individualized support with care coordination for the CP navigating the PWD's care in a complex healthcare system, as well as supportive counseling, psychoeducation, and skills training for the CP. This trial will compare outcomes from baseline to 12-months among CPs who receive ICECaP versus routine care (controls). Outcomes include CP depression, burden, anxiety, and quality of life; CPs' reactions to the behavioral symptoms of dementia; and use of support services for the PWD. This trial will also assess mechanisms of intervention efficacy including changes in CP dementia knowledge, caregiving preparedness, self-efficacy, and optimism. Publication of this intervention protocol will benefit other dementia care teams seeking to support CPs and PWDs.

Obesity-dependent increase in RalA activity disrupts mitochondrial dynamics in white adipocytes.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance, and fatty liver disease. Here we report that mitochondria undergo fragmentation and reduced oxidative capacity specifically in inguinal white adipose tissue after feeding mice high fat diet (HFD) by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes from mice fed HFD. Targeted deletion of Rala in white adipocytes prevents the obesity-induced fragmentation of mitochondria and produces mice resistant to HFD-induced weight gain via increased fatty acid oxidation. As a result, these mice also exhibit improved glucose tolerance and liver function. In vitro mechanistic studies revealed that RalA suppresses mitochondrial oxidative function in adipocytes by increasing fission through reversing the protein kinase A-catalyzed inhibitory Ser637phosphorylation of the mitochondrial fission protein Drp1. Active RalA recruits protein phosphatase 2A (PP2Aa) to specifically dephosphorylate this inhibitory site on Drp1, activating the protein, thus increasing mitochondrial fission. Adipose tissue expression of the human homolog of Drp1, DNML1, is positively correlated with obesity and insulin resistance in patients. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics towards excessive fission, contributing to weight gain and related metabolic dysfunction.

Measuring the Rate of Lipolysis in Ex vivo Murine Adipose Tissue and Primary Preadipocytes Differentiated In Vitro.

Adipocytes store energy in the form of triglycerides in lipid droplets. This energy can be mobilized via lipolysis, where the fatty acid side chains are sequentially cleaved from the glycerol backbone, resulting in the release of free fatty acids and glycerol. Due to the low expression of glycerol kinase in white adipocytes, glycerol re-uptake rates are negligible, while fatty acid re-uptake is dictated by the fatty acid binding capacity of media components such as albumin. Both glycerol and fatty acid release into media can be quantified by colorimetric assays to determine the lipolytic rate. By measuring these factors at multiple time points, one can determine the linear rate of lipolysis with high confidence. Here, we provide a detailed protocol for the measurement of lipolysis in in vitro differentiated adipocytes and ex vivo adipose tissue from mice. This protocol may also be optimized for other preadipocyte cell lines or adipose tissue from other organisms; considerations and optimization parameters are discussed. This protocol is designed to be useful in determining and comparing the rate of adipocyte lipolysis between mouse models and treatments.

Culture and Differentiation of Primary Preadipocytes from Mouse Subcutaneous White Adipose Tissue.

Adipocytes are terminally differentiated cells derived from fibroblastic preadipocyte precursors. Here, we describe a method for the isolation and proliferation of preadipocytes from murine subcutaneous white adipose tissue, followed by differentiation in culture to mature adipocytes; we refer to these cells as primary preadipocytes differentiated in vitro (PPDIVs). Compared to adipogenic cell lines, PPDIV metabolism and adipokine secretion more closely resemble in vivo adipocyte biology. While primary mature adipocytes have the greatest in vivo relevance, their fragility and buoyancy make them unsuitable for many cell culture-based methods. PPDIVs can also take advantage of transgenic and knockout mouse models to produce genetically modified adipocytes. Thus, PPDIVs are a valuable resource for studying adipocyte biology in cell culture.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Adipocyte-Secreted IL-6 Sensitizes Macrophages to IL-4 Signaling.

Complex bidirectional cross talk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies have suggested that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflammation. Here, we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue immune cells. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. We report that in this context, adipocyte-secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow-derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in adipose tissue are complex and context specific. These results suggest that cAMP-driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.

Patterns of sleep disturbances across stages of cognitive decline.

OBJECTIVES: The purpose of this study was to investigate insomnia symptoms and excessive sleep/sluggishness across stages of cognitive decline (cognitively normal [CN], Cognitively Impairment, Not Demented [CIND], dementia) in a large, racially/ethnically diverse sample of older adults (70+) in the US. We also examined whether sleep disturbances at baseline predicted conversion to CIND or dementia at follow-up. METHODS: In this secondary analysis of the Aging, Demographics, and Memory Study (ADAMS) supplement of the Health Retirement Study, we analyzed patterns of informant-reported insomnia and excessive sleep symptoms among three groups of older adults (n = 846): CN, CIND, and dementia. RESULTS: CIND adults were significantly more likely to have informant-reported insomnia symptoms than those in the CN group (p = 0.013). This was driven by a significant race/ethnicity-by-insomnia interaction with diagnostic status (p = 0.029), such that CIND Black and Hispanic older adults had increased insomnia symptom rates compared to CN, whereas White adults had similar insomnia symptoms across diagnostic status. Across all racial/ethnic groups, the prevalence of excessive sleep symptoms increased stepwise from CN to CIND to dementia (p < 0.001). Overall, insomnia symptoms at baseline predicted conversion from CN to CIND (p < 0.001, OR = 0.288; 95% CI: 0.143-0.580) at 4-year (approximate) follow-up; there was no relationship between baseline insomnia or excessive sleep/sluggishness symptoms and conversion from CIND to dementia. DISCUSSION/CONCLUSION: This study provides evidence for the increased risk of insomnia symptoms among Hispanic and Black older adults with CIND, and indicates that insomnia symptoms may be associated with increased risk for development of cognitive impairment.

Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes.

OBJECTIVE: Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial. METHODS: Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria (n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes. RESULTS: Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to ß-adrenergic-agonism or TNF. CONCLUSION: Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Fetal dose from proton pencil beam scanning craniospinal irradiation during pregnancy: a Monte Carlo study.

Objective. We conducted a Monte Carlo study to comprehensively investigate the fetal dose resulting from proton pencil beam scanning (PBS) craniospinal irradiation (CSI) during pregnancy.Approach. The gestational-age dependent pregnant phantom series developed at the University of Florida (UF) were converted into DICOM-RT format (CT images and structures) and imported into a treatment planning system (TPS) (Eclipse v15.6) commissioned to a IBA PBS nozzle. A proton PBS CSI plan (prescribed dose: 36 Gy) was created on the phantoms. The TOPAS MC code was used to simulate the proton PBS CSI on the phantoms, for which MC beam properties at the nozzle exit (spot size, spot divergence, mean energy, and energy spread) were matched to IBA PBS nozzle beam measurement data. We calculated mean absorbed doses for 28 organs and tissues and whole body of the fetus at eight gestational ages (8, 10, 15, 20, 25, 30, 35, and 38 weeks). For contextual purposes, the fetal organ/tissue doses from the treatment planning CT scan of the mother's head and torso were estimated using the National Cancer Institute dosimetry system for CT (NCICT, Version 3) considering a low-dose CT protocol (CTDIvol: 8.97 mGy).Main results. The majority of the fetal organ/tissue doses from the proton PBS CSI treatment fell within a range of 3-6 mGy. The fetal organ/tissue doses for the 38 week phantom showed the largest variation with the doses ranging from 2.9 mGy (adrenals) to 8.2 mGy (eye lenses) while the smallest variation ranging from 3.2 mGy (oesophagus) to 4.4 mGy (brain) was observed for the doses for the 20 week phantom. The fetal whole-body dose ranged from 3.7 mGy (25 weeks) to 5.8 mGy (8 weeks). Most of the fetal doses from the planning CT scan fell within a range of 7-13 mGy, approximately 2-to-9 times lower than the fetal dose equivalents of the proton PBS CSI treatment (assuming a quality factor of 7).Significance. The fetal organ/tissue doses observed in the present work will be useful for one of the first clinically informative predictions on the magnitude of fetal dose during proton PBS CSI during pregnancy.

Developmental trajectories of executive functions from preschool to kindergarten.

Executive functions (EF) are key predictors of long-term success that develop rapidly in early childhood. However, EF's developmental trajectory from preschool to kindergarten is not fully understood due to conceptual ambiguity (e.g., whether it is a single construct or multiple related constructs) and methodological limitations (e.g., previous work has primarily examined linear growth). Whether and how this trajectory differs based on characteristics of children and their families also remains to be characterized. In a primarily low-income, racially and ethnically diverse, typically developing, urban sample, the present study employed confirmatory factor analyses to examine the construct of EF and latent growth curve modeling to examine nonlinear growth across five time points. Results indicated that the development of a single EF construct with partial measurement invariance across time points was best characterized as nonlinear, with disproportionately more growth during the preschool year. There was individual variability in EF trajectories, such that children with higher EF at preschool entry showed relatively steeper growth during preschool compared to low-EF peers. However, children with less EF growth in preschool had steeper growth in kindergarten, attenuating the gains of high-EF preschoolers and resulting in some convergence in EF by the end of kindergarten. Findings have implications for (1) examining EF development in early childhood with more specificity in future studies, (2) informing the timing of EF interventions in early childhood, and (3) identifying children for whom such interventions might be especially beneficial.

Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes.

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1)1,2. Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic ß-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or ß-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis.

Dual-Energy Computed Tomography Proton-Dose Calculation with Scripting and Modified Hounsfield Units.

PURPOSE: To describe an implementation of dual-energy computed tomography (DECT) for calculation of proton stopping-power ratios (SPRs) in a commercial treatment-planning system. The process for validation and the workflow for safe deployment of DECT is described, using single-energy computed tomography (SECT) as a safety check for DECT dose calculation. MATERIALS AND METHODS: The DECT images were acquired at 80 kVp and 140 kVp and were processed with computed tomography scanner software to derive the electron density and effective atomic number images. Reference SPRs of tissue-equivalent plugs from Gammex (Middleton, Wisconsin) and CIRS (Computerized Imaging Reference Systems, Norfolk, Virginia) electron density phantoms were used for validation and comparison of SECT versus DECT calculated through the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, California) application programming interface scripting tool. An in-house software was also used to create DECT SPR computed tomography images for comparison with the script output. In the workflow, using the Eclipse system application programming interface script, clinical plans were optimized with the SECT image set and then forward-calculated with the DECT SPR for the final dose distribution. In a second workflow, the plans were optimized using DECT SPR with reduced range-uncertainty margins. RESULTS: For the Gammex phantom, the root mean square error in SPR was 1.08% for DECT versus 2.29% for SECT for 10 tissue-surrogates, excluding the lung. For the CIRS Phantom, the corresponding results were 0.74% and 2.27%. When evaluating the head and neck plan, DECT optimization with 2% range-uncertainty margins achieved a small reduction in organ-at-risk doses compared with that of SECT plans with 3.5% range-uncertainty margins. For the liver case, DECT was used to identify and correct the lipiodol SPR in the SECT plan. CONCLUSION: It is feasible to use DECT for proton-dose calculation in a commercial treatment planning system in a safe manner. The range margins can be reduced to 2% in some sites, including the head and neck.

Renal 99mTc-DMSA pharmacokinetics in pediatric patients.

99mTc-DMSA is one of the most commonly used pediatric nuclear medicine imaging agents. Nevertheless, there are no pharmacokinetic (PK) models for 99mTc-DMSA in children, and currently available pediatric dose estimates for 99mTc-DMSA use pediatric S values with PK data derived from adults. Furthermore, the adult PK data were collected in the mid-70's using quantification techniques and instrumentation available at the time. Using pediatric imaging data for DMSA, we have obtained kinetic parameters for DMSA that differ from those applicable to adults. METHODS: We obtained patient data from a retrospective re-evaluation of clinically collected pediatric SPECT images of 99mTc-DMSA in 54 pediatric patients from Boston's Children Hospital (BCH), ranging in age from 1 to 16 years old. These were supplemented by prospective data from twenty-three pediatric patients (age range: 4 months to 6 years old). RESULTS: In pediatric patients, the plateau phase in fractional kidney uptake occurs at a fractional uptake value closer to 0.3 than the value of 0.5 reported by the International Commission on Radiological Protection (ICRP) for adult patients. This leads to a 27% lower time-integrated activity coefficient in pediatric patients than in adults. Over the age range examined, no age dependency in uptake fraction at the clinical imaging time was observed. Female pediatric patients had a 17% higher fractional kidney uptake at the clinical imaging time than males (P < 0.001). CONCLUSIONS: Pediatric 99mTc-DMSA kinetics differ from those reported for adults and should be considered in pediatric patient dosimetry. Alternatively, the differences obtained in this study could reflect improved quantification methods and the need to re-examine DMSA kinetics in adults.