Semaglutide treatment for children with obesity: an observational study.

OBJECTIVE: To assess efficacy and tolerability of semaglutide as a weight loss treatment for children living with comorbid obesity. DESIGN: Retrospective observational study of the first 50 children from a weight management service treated with semaglutide for at least 6 months. SETTING: A tertiary paediatric multidisciplinary weight management clinic in a UK hospital. PATIENTS: Aged 10-18 years old with a body mass index (BMI) SD score (SDS) >2 with a weight-related comorbidity (including insulin resistance (defined as homeostatic model assessment for insulin resistance >4), type 2 diabetes, metabolic-associated fatty liver disease, obstructive sleep apnoea or hypertension). INTERVENTIONS: Once-weekly injectable semaglutide titrated over 8 weeks to a final dose of 1 mg in addition to dietary and lifestyle advice. MAIN OUTCOME MEASURES: Primary outcome measures were change in weight, BMI SDS and percentage body weight. Secondary outcomes were side effects and cessation of treatment. RESULTS: After 6 months of treatment, statistically significant decreases in BMI SDS (0.32±0.27, p<0.001) and body weight (7.03±7.50 kg, p<0.001) were seen. Mean percentage total weight loss was 6.4±6.3% (p<0.001). For the 14 patients for whom 12-month data were available, statistically significant decreases were seen in mean BMI SDS (0.54±0.52, p<0.001). Mean body weight decreased by 9.7±10.8 kg (p<0.001). Percentage total weight loss at 12 months was 8.9±10.0% (p<0.001). Mild gastrointestinal side effects were common. One patient developed gallstones. Five patients discontinued treatment due to side effects. CONCLUSION: Semaglutide appears to be a safe and effective weight loss adjunct when used in a multidisciplinary weight management clinic.

Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress.

Oxidative stress is a known contributor to the progression of dry eye disease pathophysiology, and previous studies have shown that antioxidant intervention is a promising therapeutic approach to reduce the disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of the naturally occurring prenylated chalconoid, xanthohumol, in preclinical models for dry eye disease. Xanthohumol acts by promoting the transcription of phase II antioxidant enzymes. In this study, xanthohumol prevented tert-butyl hydroperoxide-induced loss of cell viability in human corneal epithelial (HCE-T) cells in a dose-dependent manner and resulted in a significant increase in expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of phase II endogenous antioxidant enzymes. Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro, and significantly reduced ocular surface damage and oxidative stress-associated DNA damage in corneal epithelial cells in the mouse desiccating stress/scopolamine model for dry eye disease in vivo. PLGA NP represent a safe and efficacious drug delivery vehicle for hydrophobic small molecules to the ocular surface. Optimization of NP-based antioxidant formulations with the goal to minimize instillation frequency may represent future therapeutic options for dry eye disease and related ocular surface disease.

Retinoblastoma from human stem cell-derived retinal organoids.

Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. Children with germline mutations in RB1 have a high likelihood of developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline RB1 mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following RB1 gene inactivation.

Effects of conflict and strategic processing on neural responses to errors in schizophrenia.

The error-related negativity (ERN) and error-positivity (Pe) are commonly linked to error-detection and strategic processing. Studies have documented the influence of conflict probability on ERN amplitude. However, the influence of conflict probability on ERN/Pe in schizophrenia, where such components are reduced, is unknown. A modified flanker paradigm was used to examine how the probability of conflict modulates ERN and Pe amplitudes in patients with schizophrenia (n = 33) and healthy controls (n = 25). Increased ERN was observed in response to errors on low probability, incongruent trials. No such differences were observed in Pe. While ERN and Pe showed significantly reduced amplitudes in patients relative to controls, patients showed normal condition-dependent ERN and reaction-time modulation. This suggests that while the neural mechanisms generating the ERN and Pe are compromised in schizophrenia, those modulating task performance strategy and neurophysiological responses to errors based on conflict probability are intact.

Management of obstructive sleep apnoea: an update on the role of distraction osteogenesis.

PURPOSE OF REVIEW: This article reviews the current literature on the use of distraction osteogenesis as a treatment for patients with obstructive sleep apnoea (OSA). We reviewed the indications, surgical protocols and outcomes for distraction osteogenesis in paediatric and adult OSA cases described in the literature. RECENT FINDINGS: There is evidence that distraction osteogenesis is effective in treating children with OSA as a result of underdevelopment of jaws such as those with craniofacial syndromes. Distraction osteogenesis appears to be the only available treatment that prevents tracheostomy in some of these cases, or allows decannulation after distraction. For adult OSA patients, distraction osteogenesis is reported to be reserved for challenging cases such as OSA as a consequence of temporomandibular joint ankylosis. It is used where conventional orthognathic surgery is not feasible. The studies reported high success rate/cure rate of OSA after distraction osteogenesis. Technological advances such as three-dimensional printing assist the execution of an accurate distraction process. SUMMARY: Distraction osteogenesis appears to be an effective treatment for paediatric OSA patients with craniofacial anomalies, and is used in selected cases of adult with severe OSA. With the improvement in distraction device designs and computer technology, distraction osteogenesis may play a bigger role in the treatment of OSA.

Comparison of brain activation patterns during executive function tasks in hoarding disorder and non-hoarding OCD.

We examined differences in regional brain activation during tests of executive function in individuals with Hoarding Disorder (HD), Obsessive Compulsive Disorder (OCD), and healthy controls (HC) using functional magnetic resonance imaging (fMRI). Participants completed computerized versions of the Stroop and Go/No-Go task. We found that during the conflict monitoring and response inhibition condition in the Go/No-Go task, individuals with HD had significantly greater activity than controls in the anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC). HD also exhibited significantly greater right DLPFC activity than OCD. We also observed significant differences in activity between HD and HC and between HD and OCD in regions (ACC, anterior insula, orbitofrontal cortex, and striatum) involved in evaluating stimulus-response-reward associations, or the personal and task-relevant value of stimuli and behavioral responses to stimuli. These results support the hypothesis that individuals with HD have difficulty deciding on the value or task relevance of stimuli, and may perceive an abnormally high risk of negative feedback for difficult or erroneous cognitive behavior.

Bringing Wellness to Schools: Opportunities for and Challenges to Mental Health Integration in School-Based Health Centers.

OBJECTIVE: School-based health centers (SBHCs) reduce access barriers to mental health care and improve educational outcomes for youths. This qualitative study evaluated the innovations and challenges of a unique network of SBHCs in a large, urban school district as the centers attempted to integrate health, mental health, and educational services. METHODS: The 43 participants sampled included mental health providers, primary care providers, and care coordinators at 14 SBHCs. Semistructured interviews with each participant were audio recorded and transcribed. Themes were identified and coded by using Atlas.ti 5.1 and collapsed into three domains: operations, partnership, and engagement. RESULTS: Interviews revealed provider models ranging from single agencies offering both primary care and mental health services to colocated services. Sites where the health agency provided at least some mental health services reported more mental health screenings. Many sites used SBHC wellness coordinators and coordination team meetings to facilitate relationships between schools and health agency and community mental health clinic providers. Partnership challenges included confidentiality policies and staff turnover. Participants also highlighted student and parent engagement through culturally sensitive services, peer health advocates, and "drop-in" lunches. CONCLUSIONS: Staffing and operational models are critical in the success of integrating primary care, mental health care, and education. Among the provider models observed, the combined primary care and mental health provider model offered the most integrated services. Despite barriers, providers and schools have begun to implement novel solutions to operational problems and family engagement in mental health services.

UV laser-ablated surface textures as potential regulator of cellular response.

Textured surfaces obtained by UV laser ablation of poly(ethylene terephthalate) films were used to study the effect of shape and spacing of surface features on cellular response. Two distinct patterns, cones and ripples with spacing from 2 to 25 µm, were produced. Surface features with different shapes and spacings were produced by varying pulse repetition rate, laser fluence, and exposure time. The effects of the surface texture parameters, i.e., shape and spacing, on cell attachment, proliferation, and morphology of neonatal human dermal fibroblasts and mouse fibroblasts were studied. Cell attachment was the highest in the regions with cones at ∼4 µm spacing. As feature spacing increased, cell spreading decreased, and the fibroblasts became more circular, indicating a stress-mediated cell shrinkage. This study shows that UV laser ablation is a useful alternative to lithographic techniques to produce surface patterns for controlling cell attachment and growth on biomaterial surfaces.

Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA.

PURPOSE: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. PATIENTS AND METHODS: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.

The sonic hedgehog signaling system as a bistable genetic switch.

Sonic hedgehog (Shh) controls critical cellular decisions between distinct fates in many systems, particularly in stem cells. The Shh network functions as a genetic switch, and we have theoretically and computationally analyzed how its structure can endow it with the ability to switch fate choices at a threshold Shh concentration. The network is composed of a positive transcriptional feedback loop embedded within a negative signaling feedback loop. Specifically, positive feedback by the transcription factor Gli, which upregulates its own expression, leads to a switch that can adopt two distinct states as a function of Shh. However, Gli also upregulates the signaling repressor Patched, negative feedback that reins in the strong Gli autoregulatory loop. Mutations that have been associated with cancer are predicted to yield an irreversible switch to a high Gli state. Finally, stochastic simulation reveals the negative Patched feedback loop serves a critical function of dampening Gli fluctuations to reduce spontaneous state switching and preserve the network's robust, switch-like behavior. Tightly linked positive and negative feedback loops are present in many signaling systems, and the Shh system is therefore likely representative of a large set of gene regulation networks that control stem cell fate throughout development and into adulthood.

Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo.

Neural stem cells exist in the developing and adult nervous systems of all mammals, but the basic mechanisms that control their behavior are not yet well understood. Here, we investigated the role of Sonic hedgehog (Shh), a factor vital for neural development, in regulating adult hippocampal neural stem cells. We found high expression of the Shh receptor Patched in both the adult rat hippocampus and neural progenitor cells isolated from this region. In addition, Shh elicited a strong, dose-dependent proliferative response in progenitors in vitro. Furthermore, adeno-associated viral vector delivery of shh cDNA to the hippocampus elicited a 3.3-fold increase in cell proliferation. Finally, the pharmacological inhibitor of Shh signaling cyclopamine reduced hippocampal neural progenitor proliferation in vivo. This work identifies Shh as a regulator of adult hippocampal neural stem cells.