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Background: The PROMIS ® Early Childhood Physical Activity (PROMIS EC PA) scale is a recently developed PROMIS Early Childhood measure to assess PA among children aged 1-5 years. The purpose of this study was to examine test-retest reliability and convergent validity of the PROMIS EC PA scale among toddlers., Method: An ancillary study was conducted in the toddler-mother dyad sample of the Child and Mother Physical Activity Study. Mothers completed the 7-item PROMIS EC PA scale twice: during a study visit (test) and on the last day when their child's wore an ActiGraph accelerometer on the hip for 7 days (retest). The PROMIS EC PA summed score was calculated by totaling scores from items 1-5. Test-retest reliability was assessed using intraclass correlation coefficient (ICC) for test and retest PROMIS EC PA. Convergent validity was assessed using rank correlation coefficients (rho) between PROMIS EC PA scores and accelerometer-measured moderate- and vigorous-intensity PA (MVPA)., Results: Among 74 participants (56% female; 19 ± 4 months of mean age with range of 12-30 months), average accelerometer-measured MVPA was 76 ± 24 min/day. The median number of days between PROMIS EC PA test and retest was 8 days (IQR = 6 to 8), with an average PROMIS EC PA summed score of 11.0 ± 3.5 at test and 10.5 ± 3.4 at retest. ICC for the test-retest PROMIS EC PA summed scores was 0.72 (95% CI = 0.59-0.82). The rank correlation between the PROMIS EC PA summed score and accelerometer-measured MVPA was 0.13 (95% CI=-0.10 to 0.35; p = 0.28)., Conclusion: In a sample of children aged 12-30 months, test-retest reliability for the PROMIS EC PA scale was moderate and its convergent validity against accelerometer-measured MVPA was poor. Prior to a widespread use of the PROMIS EC PA scale in large-scale research and clinical practice, the tool should be further refined and validated to elucidate how young children's lived PA experience as measured in the PROMIS EC PA scale is relevant to their health and wellbeing outcomes., (© 2024. The Author(s).)

Importance: Young children's screen time increased during the COVID-19 lockdown in 2020, but it is unknown whether their screen time returned to prepandemic levels in 2021. Knowledge of the relationship between screen time and child development and health will inform prevention and intervention targets and strategies., Objective: To evaluate screen time by family income and race and ethnicity in the prepandemic (ie, 2018, 2019) and pandemic (ie, 2020, 2021) periods and to examine the relationship between screen time and psychological well-being among young children in the US., Design, Setting, and Participants: Cross-sectional population-based web or mail survey study of 2018-2021 National Survey of Children's Health participants aged 6 months to 5 years., Exposure: Daily screen time (<1, 1, 2, 3, or ≥4 h/d) reported by participants' primary caregivers., Main Outcomes and Measures: Flourishing and externalizing behaviors, as indicators of psychological well-being. All analyses were weighted, accounting for the complex survey sample design., Results: Of the 48 775 participants (50.7% female), the proportion of those with high screen time (defined as ≥1 h/d for children aged 6 months-1 year and ≥2 h/d for children aged 2-5 years) was 48.5% (95% CI, 46.3%-50.7%) in 2018, 49.2% (95% CI, 47.0%-51.5%) in 2019, 55.3% (95% CI, 53.4%-57.2%) in 2020, and 50.0% (95% CI, 48.3%-51.6%) in 2021. Among children living in poverty (federal poverty level <100%), the proportion of those with high screen time was 48.7% (95% CI, 42.8%-54.6%) in 2018, 52.0% (95% CI, 45.4%-58.6%) in 2019, 60.9% (95% CI, 55.4%-66.4%) in 2020, and 58.9% (53.7%-64.1%) in 2021. Adjusted odds ratio of flourishing was 0.66 (95% CI, 0.51-0.85), 0.81 (95% CI, 0.66-0.99), 0.68 (95% CI, 0.52-0.88), and 0.53 (95% CI, 0.42-0.69) for less than 1, 2, 3, and 4 or more hours per day vs 1 hour per day of screen time, respectively, among children aged 3 to 5 years. No association between screen time and flourishing was found among children aged 6 months to 2 years. An adjusted externalizing behavior score was higher by 0.2 points (95% CI, -0.1 to 0.5), 0.5 points (95% CI, 0.3 to 0.8), 1.3 points (95% CI, 1.0 to 1.6), and 2.1 points (95% CI, 1.7 to 2.5) for less than 1, 2, 3, and 4 or more hours per day vs 1 hour per day of screen time, respectively, among children aged 3 to 5 years., Conclusions and Relevance: In this multiyear cross-sectional study of a representative sample of young children in the US, the increased prevalence of high screen time in 2020 returned to prepandemic levels in 2021; however, it remained elevated in children living in poverty. Two hours or more of daily screen time was associated with lower psychological well-being among preschool-aged children.

Objectives: Nuclear receptor interacting protein 1 (NRIP1) suppresses energy expenditure via repression of nuclear receptors, and its depletion markedly elevates uncoupled respiration in mouse and human adipocytes. We tested whether NRIP1 deficient adipocytes implanted into obese mice would enhance whole body metabolism. Since β-adrenergic signaling through cAMP strongly promotes adipocyte thermogenesis, we tested whether the effects of NRIP1 knock-out (NRIP1KO) require the cAMP pathway., Methods: NRIP1KO adipocytes were implanted in recipient high-fat diet (HFD) fed mice and metabolic cage studies conducted. The Nrip1 gene was disrupted by CRISPR in primary preadipocytes isolated from control vs adipose selective GsαKO (cAdGsαKO) mice prior to differentiation to adipocytes. Protein kinase A inhibitor was also used., Results: Implanting NRIP1KO adipocytes into HFD fed mice enhanced whole-body glucose tolerance by increasing insulin sensitivity, reducing adiposity, and enhancing energy expenditure in the recipients. NRIP1 depletion in both control and GsαKO adipocytes was equally effective in upregulating uncoupling protein 1 (UCP1) and adipocyte beiging, while β-adrenergic signaling by CL 316,243 was abolished in GsαKO adipocytes. Combining NRIP1KO with CL 316,243 treatment synergistically increased Ucp1 gene expression and increased the adipocyte subpopulation responsive to beiging. Estrogen-related receptor α (ERRα) was dispensable for UCP1 upregulation by NRIPKO., Conclusions: The thermogenic effect of NRIP1 depletion in adipocytes causes systemic enhancement of energy expenditure when such adipocytes are implanted into obese mice. Furthermore, NRIP1KO acts independently but cooperatively with the cAMP pathway in mediating its effect on adipocyte beiging., Competing Interests: Declaration of competing interest The authors declare the following competing Interests: M.P.C. and A.G. are inventors of granted US Patent US-8519118-B2, “RIP140 regulation of glucose transport”, and of granted US Patent US-8093223-B2, “RIP140 regulation of diabetes”, related to data in this manuscript on Nrip1/RIP140-depleted mouse and human adipocytes. M.P.C., E.T., and S.M.N. are inventors of US Patent US-20220220461-A1 and PCT WO2022076812A3, “Targeting Nrip1 to Alleviate Metabolic Disease”, related to CRISPR-based depletion of NRIP1 in mouse adipocytes in this manuscript. The University of Massachusetts is the grantee or potential grantee of all the above. M.P.C. declares that he is bound by a confidentiality agreement that prevents him from disclosing a potentially competing interest in this work. S.A.W. is a consultant for Chroma Medicine. The remaining authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Disruption of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) in mice induces browning in inguinal white adipose tissue (iWAT). However, adipocyte FASN knockout (KO) increases acetyl-coenzyme A (CoA) and malonyl-CoA in addition to depletion of palmitate. We explore which of these metabolite changes triggers adipose browning by generating eight adipose-selective KO mouse models with loss of ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), ACC2, malonyl-CoA decarboxylase (MCD) or FASN, or dual KOs ACLY/FASN, ACC1/FASN, and ACC2/FASN. Preventing elevation of acetyl-CoA and malonyl-CoA by depletion of adipocyte ACLY or ACC1 in combination with FASN KO does not block the browning of iWAT. Conversely, elevating malonyl-CoA levels in MCD KO mice does not induce browning. Strikingly, adipose ACC1 KO induces a strong iWAT thermogenic response similar to FASN KO while also blocking malonyl-CoA and palmitate synthesis. Thus, ACC1 and FASN are strong suppressors of adipocyte thermogenesis through promoting lipid synthesis rather than modulating the DNL intermediates acetyl-CoA or malonyl-CoA., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes., (© 2023. The Author(s).)

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D 2 O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic steatohepatitis (NASH) is a severe liver disorder characterized by triglyceride accumulation, severe inflammation, and fibrosis. With the recent increase in prevalence, NASH is now the leading cause of liver transplant, with no approved therapeutics available. Although the exact molecular mechanism of NASH progression is not well understood, a widely held hypothesis is that fat accumulation is the primary driver of the disease. Therefore, diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme in triglyceride synthesis, has been explored as a NASH target. RNAi-based therapeutics is revolutionizing the treatment of liver diseases, with recent chemical advances supporting long-term gene silencing with single subcutaneous administration. Here, we identified a hyper-functional, fully chemically stabilized GalNAc-conjugated small interfering RNA (siRNA) targeting DGAT2 (Dgat2-1473) that, upon injection, elicits up to 3 months of DGAT2 silencing (>80%-90%, p < 0.0001) in wild-type and NSG-PiZ "humanized" mice. Using an obesity-driven mouse model of NASH (ob/ob-GAN), Dgat2-1473 administration prevents and reverses triglyceride accumulation (>85%, p < 0.0001) without increased accumulation of diglycerides, resulting in significant improvement of the fatty liver phenotype. However, surprisingly, the reduction in liver fat did not translate into a similar impact on inflammation and fibrosis. Thus, while Dgat2-1473 is a practical, long-lasting silencing agent for potential therapeutic attenuation of liver steatosis, combinatorial targeting of a second pathway may be necessary for therapeutic efficacy against NASH., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Postoperative urinary retention (POUR) is a complication of laparoscopic inguinal hernia repair (LIHR). Previous research has identified predictive factors of POUR, such as age and history of benign prostatic hyperplasia (BPH). There is currently limited work on preventative measures. We hypothesize dexamethasone, a steroid, reduces POUR rates following LIHR due to its mechanism., Methods: Consecutive patients (n = 979) undergoing LIHR from 2009 to 2017 at a single institution were selected from a prospectively managed database. All procedures were performed by four general surgeons. Only male patients were selected, as the majority of POUR occurs in males. Patients were retroactively chart reviewed and divided into two groups, dexamethasone use (n = 623) and no dexamethasone use (n = 356). Perioperative factors were compared between groups with Chi-square and independent samples t tests. Univariable and multivariable logistic regression analysis was used to assess whether dexamethasone use was associated with POUR. A subgroup analysis was performed on the dexamethasone group to determine any dose-dependent effects., Results: We found a significant difference in POUR between the dexamethasone group and no dexamethasone group (3.7% vs. 9.8%, p = 0.0001). Patients in the dexamethasone group had a shorter length of stay, and were less likely to have BPH or a Foley placed (all p < 0.05). Age and BMI were similar between groups. Multivariable analysis showed that the use of dexamethasone was associated with a reduced risk of POUR (OR 0.52, 95% CI 0.2-0.97, p = 0.0386), while controlling for factors such as age and BPH. A subgroup analysis examined the effect of dexamethasone per unit (mg) increase. There was no significant association between dexamethasone dose and POUR rates (OR 1.07, 95% CI 0.82-1.38, p = 0.6241)., Conclusions: Patients who received dexamethasone showed a lower rate of POUR regardless of dose. These results suggest dexamethasone can be administered to reduce POUR in males undergoing LIHR.