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Background: Behavioral weight loss interventions achieve only limited weight loss in adolescent samples and weight regain is common. This limited intervention success may be attributed, in part, to adolescents' lack of self-regulation skills essential for lifestyle modification and use of a one-size fits-all approach to produce weight loss in boys and girls. Interventions which teach self-regulation skills, such as Acceptance-Based Therapy (ABT), and are tailored to meet gender-specific concerns, are critical to help adolescents adapt to pervasive biological and environmental influences toward weight gain., Objective: This trial tests the effect of an ABT intervention on cardiometabolic health, health-related behaviors, and psychological factors among adolescent girls with overweight or obesity (OW/OB)., Methods: Girls 14-19 years (N = 148; ≥ 40% racial/ethnic minorities) with OW/OB (BMI: ≥ 85th percentile) will be enrolled in the study. Participants will be randomized to one of two 6-month interventions, consisting of either 18 sessions of ABT or 9 sessions of a health education control, an augmented version of standard care for adolescent OW/OB, both led by bachelor's level interventionists., Results: Recruitment is taking place in Philadelphia, USA, from January 2024 to January 2028. Cardiometabolic health markers (adiposity; blood pressure; blood lipids), health-related behaviors (dietary intake; physical activity; sleep), and psychological factors (quality of life; depression; disordered eating; psychological flexibility) will be measured at baseline, mid-treatment, post-treatment, 6-month follow-up, and 12-month follow-up., Conclusions: This study will provide valuable information on a novel intervention tailored to the needs of adolescent girls with OW/OB to address self-regulation and cardiometabolic health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michelle I. Cardel is an employee and shareholder at WW International, Inc., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The CYFIP1 gene, located in the neurodevelopmental risk locus 15q11.2, is highly expressed in microglia, but its role in human microglial function as it relates to neurodevelopment is not well understood., Methods: We generated multiple CRISPR (clustered regularly interspaced short palindromic repeat) knockouts of CYFIP1 in patient-derived models of microglia to characterize function and phenotype. Using microglia-like cells reprogrammed from peripheral blood mononuclear cells, we quantified phagocytosis of synaptosomes (isolated and purified synaptic vesicles) from human induced pluripotent stem cell (iPSC)-derived neuronal cultures as an in vitro model of synaptic pruning. We repeated these analyses in human iPSC-derived microglia-like cells derived from 3 isogenic wild-type/knockout line pairs derived from 2 donors and further characterized microglial development and function through morphology and motility., Results: CYFIP1 knockout using orthogonal CRISPR constructs in multiple patient-derived cell lines was associated with a statistically significant decrease in synaptic vesicle phagocytosis in microglia-like cell models derived from both peripheral blood mononuclear cells and iPSCs. Morphology was also shifted toward a more ramified profile, and motility was significantly reduced. However, iPSC-CYFIP1 knockout lines retained the ability to differentiate to functional microglia., Conclusions: The changes in microglial phenotype and function due to the loss of function of CYFIP1 observed in this study implicate a potential impact on processes such as synaptic pruning that may contribute to CYFIP1-related neurodevelopmental disorders. Investigating risk genes in a range of central nervous system cell types, not solely neurons, may be required to fully understand the way in which common and rare variants intersect to yield neuropsychiatric disorders., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Issue : Historically excluded patient populations-particularly racial, ethnic, and sexually and gender minoritized people-experience gross inequities in health, worsened by the HIV and COVID-19 pandemics. Culturally responsive communication (CRC) is a vital tool health professionals can use to address these inequities. Yet, CRC can be challenging to teach , particularly during pandemics. The authors argue that pandemics magnify the powerful intersecting oppressions of heterosexism, racism, transphobia, nationalism, and sexism, essentially targeting Othered bodies for dying, a phenomenon known as necropolitics. Evidence : Five aspects of pandemics make teaching CRC more difficult and, because of the magnification of necropolitics, more critical. First, pandemics heighten teachers' and learners' personal frailties, engendering worries about their own and their families' health and increasing cognitive load. This can make it difficult for them to embrace the discomfort required of CRC, particularly when an increased patient load is squeezing instructional time. Second, guidelines for HIV and COVID-19 testing, prevention, and treatment are ever-changing, often faster than the pace of curriculum development and instructor professional development. Third, for instructors who may already be stretched thin, it is challenging to prepare learners for the variability in how their future practice contexts may address HIV and COVID-19 and, further, how to take a social justice approach to assess and resist the distinct equity issues of each of these contexts. Fourth, pandemics cause uncertain access to patient information about testing, disease status, and vaccination or pre-exposure prophylaxis. This worsens already disparate outcomes for minoritized patients and adds to the complexity of CRC curricula. Finally, virtual care is more prevalent in pandemics and teaching CRC in online contexts can be difficult. Implications : To address these challenges, we adopt the Dimensionality and R4P Health Equity Framework as a tool for evaluating academic programs for CRC so that it remains robust amidst pandemics. This tool addresses the varied social positions and identities (i.e., "dimensions") that present different opportunities for health. We offer specific evaluation questions programs can ask and approaches they can take to (a) redress past harms through removing existing racist, heteronormative and transphobic structures and repairing the damage they have done; (b) plan for a more equitable future by restructuring via policy and organizational change and providing programs that address intersectional disadvantage; and (c) critically evaluate the present by remediating current damage immediately until restructuring efforts are fully functional. As Martin Luther King, Jr. stated, "Of all the forms of inequality, injustice in healthcare is the most shocking and inhuman because it often results in physical death." It is our imperative to teach CRC with intentionality; otherwise we will support necropolitics as we continue to condone disproportionate morbidity and mortality for racialized and queer bodies.

Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N -acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.

Introduction: Childhood obesity is a chronic disease that requires multidisciplinary and specialist intervention to address its complex pathophysiology, though access to treatment is limited globally. Evaluating the impact of evidence-based interventions implemented in real-world clinical settings is essential, in order to increase the translation of research into practice and enhance child health outcomes. In Ireland, the National Model of Care for Obesity highlighted the need to develop and improve healthcare services for children and adolescents with obesity., Aims: This study aims to evaluate the impact of a family-based, Tier 3 multi-disciplinary child and adolescent obesity outpatient service (www.w82go.ie) on standardized body mass index (BMI-SDS)., Methods: Following referral by pediatricians, patients were assessed by a pediatric multidisciplinary team (physiotherapist, dietician, and psychologist) and personalized obesity treatment plans were developed. Anthropometric and demographic information were recorded at baseline and final visit. Descriptive statistics were used to explore distribution, central tendency and variation in the demographic data, change in BMI-SDS over time was assessed using a t -test, and multiple linear regression analysis was used to investigate the association of demographic factors on the change in BMI-SDS., Results: The overall mean BMI-SDS reduction across the whole cohort ( n = 692) was -0.17 (95% CI = -0.20, -0.13; P < 0.001). Younger age at admission and longer duration of treatment were associated with greater BMI-SDS reduction but there was no significant association between change in BMI-SDS and any of the other parameters (deprivation score, treatment type, sex, obesity category at admission or presence of comorbid condition)., Conclusion: Engagement in a specialist Tier 3 pediatric obesity service was associated with reductions in BMI-SDS in children and adolescents with obesity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wyse, Case, Walsh, Shortall, Jordan, McCrea and O'Malley.)

Background: As the Accreditation Council for Graduate Medical Education (ACGME) began to ask programs to report their efforts surrounding diversity, equity, and inclusion (DEI), program directors felt ill prepared to evaluate their programs and measure change., Objective: To develop a tool that would allow graduate medical education (GME) programs to evaluate the current state of DEI within their residencies, identify areas of need, and track progress; to evaluate feasibility of using this assessment method within family medicine training programs; and to analyze and report pilot data from implementation of these milestones within family medicine residency programs., Methods: The Association of Family Medicine Residency Directors (AFMRD) Diversity and Health Equity (DHE) Task Force developed a tool for program DEI evaluation modeled after the ACGME Milestones. These milestones focus on DEI assessment in 5 key domains: Institution, Curriculum, Evaluation, Resident Personnel, and Faculty Personnel. After finalizing a draft, a pilot implementation of the milestones was conducted by a convenience sample of 10 AFMRD DHE Task Force members for their own programs., Results: Scores varied widely across surveyed programs for all milestones. Highest average scores were seen for the Curriculum milestone (2.65) and the lowest for the Faculty Personnel milestone (2.0). Milestone assessments were completed within 10 to 40 minutes using various methods., Conclusions: The AFMRD DEI Milestones were developed for program assessment, goal setting, and tracking of progress related to DEI within residency programs. The pilot implementation showed these milestones were easily used by family medicine faculty members in diverse settings., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Purpose: The purpose of this study was to describe the cellular architecture of normal human peripapillary sclera (PPS) and evaluate surface topography's role in fibroblast behavior., Methods: PPS cryosections from nonglaucomatous eyes were labelled for nuclei, fibrillar actin (FA), and alpha smooth muscle actin (αSMA) and imaged. Collagen fibrils were imaged using second harmonic generation. Nuclear density and aspect ratio of the internal PPS (iPPS), outer PPS (oPPS), and peripheral sclera were determined. FA and αSMA fibril alignment with collagen extracellular matrix (ECM) was determined. PPS fibroblasts were cultured on smooth or patterned membranes under mechanical strain and in the presence of TGFβ1 and 2., Results: The iPPS (7.1 ± 2.0 × 10-4, P < 0.0001) and oPPS (5.3 ± 1.4 × 10-4, P = 0.0013) had greater nuclei density (nuclei/µm2) than peripheral sclera (2.5 ± 0.8 × 10-4). The iPPS (2.0 ± 0.3, P = 0.002) but not oPPS (2.4 ± 0.4, P = 0.45) nuclei had smaller aspect ratios than peripheral (2.7 ± 0.5) nuclei. FA was present throughout the scleral stroma and was more aligned with oPPS collagen (9.6 ± 1.9 degrees) than in the peripheral sclera (15.9 ± 3.9 degrees, P =0.002). The αSMA fibers in the peripheral sclera were less aligned with collagen fibrils (26.4 ± 4.8 degrees) than were FA (15.9 ± 3.9 degrees, P = 0.0002). PPS fibroblasts cultured on smooth membranes shifted to an orientation perpendicular to the direction of cyclic uniaxial strain (1 Hz, 5% strain, 42.2 ± 7.1 degrees versus 62.0 ± 8.5 degrees, P < 0.0001), whereas aligned fibroblasts on patterned membranes were resistant to strain-induced reorientation (5.9 ± 1.4 degrees versus 10 ± 3.3 degrees, P = 0.21). Resistance to re-orientation was reduced by TGFβ treatment (10 ± 3.3 degrees without TGFβ1 compared to 23.1 ± 4.5 degrees with TGFβ1, P < 0.0001)., Conclusions: Regions of the posterior sclera differ in cellular density and nuclear morphology. Topography alters the cellular response to mechanical strain.

Scleral fibroblast activation occurs in glaucomatous and myopic eyes. Here we perform an unbiased screen to identify kinase inhibitors that reduce fibroblast activation to diverse stimuli in vitro and to in vivo intraocular pressure (IOP) elevation. Primary cultures of peripapillary scleral (PPS) fibroblasts from two human donors were screened using a library of 80 kinase inhibitors to identify compounds that inhibit TGFβ-induced extracellular matrix (ECM) synthesis. Inhibition of myofibroblast differentiation was verified by alpha smooth muscle actin (αSMA) immunoblot and collagen contraction assay. Inhibition of IOP-induced scleral fibroblast proliferation was assessed by ELISA assay for proliferating cell nuclear antigen (PCNA). The initial screen identified 7 inhibitors as showing>80% reduction in ECM binding. Three kinase inhibitors were verified to reduce TGFβ-induced αSMA expression and cellular contractility (rottlerin, PP2, tyrphostin 9). The effect of three Src inhibitors, bosutinib, dasatinib, and SU-6656, on myofibroblast differentiation was evaluated, with only dasatinib significantly inhibiting TGFβ-induced ECM synthesis, αSMA expression, and cellular contractility at nanomolar dosages. Subconjunctival injection of dasatinib reduced IOP-induced scleral fibroblast proliferation compared to control (4.9 ± 11.1 ng/sclera with 0.1 μM versus 88.7 ± 38.6 ng/sclera in control, P < 0.0001). Dasatinib inhibits scleral myofibroblast differentiation and there is pharmacologic evidence that this inhibition is not solely due to Src-kinase inhibition., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Lactobacilli are normal colonizers of the oropharynx, gastrointestinal tract, and vagina. Infection is rare, but has been reported in individuals with predisposing conditions. Here we describe the case of a woman with pyelonephritis and bacteremia in which Lactobacillus delbrueckii was determined to be the causative agent.