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BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 ( n  = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system–penetrant, type II RAF inhibitor tovorafenib (420 mg m − 2 once weekly; 600 mg maximum) in patients with BRAF -altered, relapsed/refractory pLGG. Arm 2 ( n  = 60) is an extension cohort, which provided treatment access for patients with RAF -altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n  = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF -altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 . In a phase 2 trial, the oral type II RAF inhibitor tovorafenib exhibited an overall response rate of 67% in patients with BRAF -altered relapsed/refractory pediatric low-grade glioma.

The large diversity of central nervous system (CNS) tumor types in children and adolescents results in disparate patient outcomes and renders accurate diagnosis challenging. In this study, we prospectively integrated DNA methylation profiling and targeted gene panel sequencing with blinded neuropathological reference diagnostics for a population-based cohort of more than 1,200 newly diagnosed pediatric patients with CNS tumors, to assess their utility in routine neuropathology. We show that the multi-omic integration increased diagnostic accuracy in a substantial proportion of patients through annotation to a refining DNA methylation class (50%), detection of diagnostic or therapeutically relevant genetic alterations (47%) or identification of cancer predisposition syndromes (10%). Discrepant results by neuropathological WHO-based and DNA methylation-based classification (30%) were enriched in histological high-grade gliomas, implicating relevance for current clinical patient management in 5% of all patients. Follow-up (median 2.5 years) suggests improved survival for patients with histological high-grade gliomas displaying lower-grade molecular profiles. These results provide preliminary evidence of the utility of integrating multi-omics in neuropathology for pediatric neuro-oncology. The integration of DNA methylation profiling and targeted sequencing with neuropathology improves the diagnostic accuracy of central nervous system tumors in a population-based cohort of more than 1,200 newly diagnosed pediatric patients.

Background Food safety is integral to food security and is increasingly becoming a significant concern in the urban areas of Africa, which are rapidly growing in population. In the case of Ghana, many urban households depend on traditional open-air markets for most of their food needs. However, these urban food markets also depend on domestic food supply chains, which are prone to risks, including poor hygiene and sanitation and weather seasonality. Food safety compliance has associated costs which increase the unit cost of food products. Thus, higher food price is a risk factor to food availability and accessibility—fundamental pillars of food security. Method We use food microbial data and food retail data from food market surveys in major cities in Ghana to assess the safety of selected fresh food commodities and how retailers handle the food products they sell. Additionally, based on a two-wave balanced panel household data, we used fixed effects Poisson and Correlated Random Effects (CRE) Probit models to estimate the effect of weather seasonality on the incidence of diarrhoea and urban household dietary diversity score (HDDS). A final sample of 609 households and 565 market respondents participated in the study. Results Our findings show that selected food samples tested positive for S taphylococcus aureus and E.coli and had aflatoxin B1 levels above 5.0 ppb. Additionally, the household incidence of diarrhoea/vomiting, a proxy for food safety status, is higher in the dry season. In the dry season, the household incidence of diarrhoea/vomiting increases on average by a probability of 38% points compared to the rainy season. Regarding HDDS, the average HDDS is 7.3; however, we did not find the effect of seasonality on HDDS to be significant. Conclusions Although urban food availability and household dietary diversity are not challenges for many urban households, food safety is a challenge in the major food markets in Ghanaian cities and is associated with weather seasonality. Foods available in traditional open-air markets are not always safe for consumption, undermining households’ food security. Weak enforcement of food safety regulations contributes to the food safety challenges in Ghanaian urban food markets.

To demonstrate the feasibility of robotic middle ear access in a clinical setting, nine adult patients with severe-to-profound hearing loss indicated for cochlear implantation were included in this clinical trial. A keyhole access tunnel to the tympanic cavity and targeting the round window was planned based on preoperatively acquired computed tomography image data and robotically drilled to the level of the facial recess. Intraoperative imaging was performed to confirm sufficient distance of the drilling trajectory to relevant anatomy. Robotic drilling continued toward the round window. The cochlear access was manually created by the surgeon. Electrode arrays were inserted through the keyhole tunnel under microscopic supervision via a tympanomeatal flap. All patients were successfully implanted with a cochlear implant. In 9 of 9 patients the robotic drilling was planned and performed to the level of the facial recess. In 3 patients, the procedure was reverted to a conventional approach for safety reasons. No change in facial nerve function compared to baseline measurements was observed. Robotic keyhole access for cochlear implantation is feasible. Further improvements to workflow complexity, duration of surgery, and usability including safety assessments are required to enable wider adoption of the procedure.

This paper examines whether the combined participation in workfare and food grain subsidy programmes in India impacts the nutritional and health status of women and children, using body mass index (BMI) and short-term morbidity as indicators. Based on a nationally representative panel data survey conducted in 2005 and 2012, we estimate the participants' average treatment effects by applying a semi-parametric differences-in-differences (DID) approach on the full sample and a regression-based DID approach on a matched sample. We find that simultaneous participation in these programmes lowers women's morbidity by at least 25%, but women's BMI increases only in states implementing those programmes well. For children, there is no robust evidence of impacts. Our results suggest that various social protection programmes can operate synergistically and deliver positive impacts on children and women's nutrition or health, even though this is not their main objective. However, the effects are heterogeneous and confirm that the nutrition and health benefits, reached through a combination of the two social protection programmes, are mediated by intrahousehold dynamics. Synergistic and mediating effects must be considered in future efforts to upscale social protection in the Global South in order to deliver simultaneous progress across the Sustainable Development Goals.

Background Neurons have intrinsic capability to regenerate after lesion, though not spontaneously. Spinal cord injury (SCI) causes permanent neurological impairments partly due to formation of a glial scar that is composed of astrocytes and microglia. Astrocytes play both beneficial and detrimental roles on axonal re-growth, however, their precise role after SCI is currently under debate. Methods We analyzed molecular changes in astrocytes at multiple stages after two SCI severities using cell-specific transcriptomic analyses. Results We demonstrate that astrocyte response after injury depends on both time after injury and lesion severity. We then establish that injury induces an autologous astroglial transdifferentiation where over 10 % of astrocytes express classical neuronal progenitor markers including βIII-tubulin and doublecortin with typical immature neuronal morphology. Lineage tracing confirmed that the origin of these astrocytes is resident mature, rather than newly formed astrocytes. Astrocyte-derived neuronal progenitors subsequently express GABAergic, but not glutamatergic-specific markers. Furthermore, we have identified the neural stem cell marker fibroblast growth factor receptor 4 (Fgfr4) as a potential autologous modulator of astrocytic transdifferentiation following SCI. Finally, we establish that astroglial transdifferentiation into neuronal progenitors starts as early as 72 h and continues to a lower degrees up to 6 weeks post-lesion. Conclusion We thus demonstrate for the first time autologous injury-induced astroglial conversion towards neuronal lineage that may represent a therapeutic strategy to replace neuronal loss and improve functional outcomes after central nervous system injury.

The objective was to use convolutional neural networks (CNNs) for automatic segmentation of hip cartilage and labrum based on 3D MRI. In this retrospective single-center study, CNNs with a U-Net architecture were used to develop a fully automated segmentation model for hip cartilage and labrum from MRI. Direct hip MR arthrographies (01/2020-10/2021) were selected from 100 symptomatic patients. Institutional routine protocol included a 3D T1 mapping sequence, which was used for manual segmentation of hip cartilage and labrum. 80 hips were used for training and the remaining 20 for testing. Model performance was assessed with six evaluation metrics including Dice similarity coefficient (DSC). In addition, model performance was tested on an external dataset (40 patients) with a 3D T2-weighted sequence from a different institution. Inter-rater agreement of manual segmentation served as benchmark for automatic segmentation performance. 100 patients were included (mean age 30 ± 10 years, 64% female patients). Mean DSC for cartilage was 0.92 ± 0.02 (95% confidence interval [CI] 0.92–0.93) and 0.83 ± 0.04 (0.81–0.85) for labrum and comparable ( p  = 0.232 and 0.297, respectively) to inter-rater agreement of manual segmentation: DSC cartilage 0.93 ± 0.04 (0.92–0.95); DSC labrum 0.82 ± 0.05 (0.80–0.85). When tested on the external dataset, the DSC was 0.89 ± 0.02 (0.88–0.90) and 0.71 ± 0.04 (0.69–0.73) for cartilage and labrum, respectively.The presented deep learning approach accurately segments hip cartilage and labrum from 3D MRI sequences and can potentially be used in clinical practice to provide rapid and accurate 3D MRI models.

The conversion of tropical forests in the Amazon region for agriculture and other land uses is associated with health risks linked, for example, to air and water pollution from forest fires and agrochemical use. Several conservation policies introduced in the 2000s aimed at reducing deforestation in the Brazilian Amazon. Here we exploit variations in the regional targeting of these policies to measure human health externalities of conservation policy enforcement using a double-difference approach at close distance to the Amazon biome border. We find that the change in deforestation pressure reduces forest fire incidence. As a consequence, fine particulate matter concentrations in the air—a main vector for adverse health effects of fire smoke—also decrease. This leads to a reduction in the hospitalization and death prevalence rate due to respiratory health problems and other health benefits for the local population. Forest conservation policies driving reduced deforestation of the Brazilian Amazon improves local air quality and decreases hospitalization and mortality rates due to respiratory diseases of the population, as quantified with impact evaluation methods

Molecular groups of medulloblastoma (MB) are well established. Novel risk stratification parameters include Group 3/4 (non-WNT/non-SHH) methylation subgroups I–VIII or whole-chromosomal aberration (WCA) phenotypes. This study investigates the integration of clinical and molecular parameters to improve risk stratification of non-WNT/non-SHH MB. Non-WNT/non-SHH MB from the HIT2000 study and the HIT-MED registries were selected based on availability of DNA-methylation profiling data. MYC or MYCN amplification and WCA of chromosomes 7, 8, and 11 were inferred from methylation array-based copy number profiles. In total, 403 non-WNT/non-SHH MB were identified, 346/403 (86%) had a methylation class family Group 3/4 methylation score (classifier v11b6) ≥ 0.9, and 294/346 (73%) were included in the risk stratification modeling based on Group 3 or 4 score (v11b6) ≥ 0.8 and subgroup I–VIII score (mb_g34) ≥ 0.8. Group 3 MB (5y-PFS, survival estimation ± standard deviation: 41.4 ± 4.6%; 5y-OS: 48.8 ± 5.0%) showed poorer survival compared to Group 4 (5y-PFS: 68.2 ± 3.7%; 5y-OS: 84.8 ± 2.8%). Subgroups II (5y-PFS: 27.6 ± 8.2%) and III (5y-PFS: 37.5 ± 7.9%) showed the poorest and subgroup VI (5y-PFS: 76.6 ± 7.9%), VII (5y-PFS: 75.9 ± 7.2%), and VIII (5y-PFS: 66.6 ± 5.8%) the best survival. Multivariate analysis revealed subgroup in combination with WCA phenotype to best predict risk of progression and death. The integration of clinical (age, M and R status) and molecular (MYC/N, subgroup, WCA phenotype) variables identified a low-risk stratum with a 5y-PFS of 94 ± 5.7 and a very high-risk stratum with a 5y-PFS of 29 ± 6.1%. Validation in an international MB cohort confirmed the combined stratification scheme with 82.1 ± 6.0% 5y-PFS in the low and 47.5 ± 4.1% in very high-risk groups, and outperformed the clinical model. These newly identified clinico-molecular low-risk and very high-risk strata, accounting for 6%, and 21% of non-WNT/non-SHH MB patients, respectively, may improve future treatment stratification.

Purpose The challenges of treating central nervous system (CNS) tumors in young children are many. These include age-specific tumor characteristics, limited treatment options, and susceptibility of the developing CNS to cytotoxic therapy. The aim of this study was to analyze the long-term survival, health-related, and educational/occupational outcomes of this vulnerable patient population. Methods Retrospective study of 128 children diagnosed with a CNS tumor under 5 years of age at a single center in Switzerland between 1990 and 2019. Results Median age at diagnosis was 1.81 years [IQR, 0.98–3.17]. Median follow-up time of surviving patients was 8.39 years [range, 0.74–23.65]. The main tumor subtypes were pediatric low-grade glioma (36%), pediatric high-grade glioma (11%), ependymoma (16%), medulloblastoma (11%), other embryonal tumors (7%), germ cell tumors (3%), choroid plexus tumors (6%), and others (9%). The 5-year overall survival (OS) was 78.8% (95% CI, 71.8–86.4%) for the whole cohort. Eighty-seven percent of survivors > 5 years had any tumor- or treatment-related sequelae with 61% neurological complications, 30% endocrine sequelae, 17% hearing impairment, and 56% visual impairment at last follow-up. Most patients (72%) attended regular school or worked in a skilled job at last follow-up. Conclusion Young children diagnosed with a CNS tumor experience a range of complications after treatment, many of which are long-lasting and potentially debilitating. Our findings highlight the vulnerabilities of this population, the need for long-term support and strategies for rehabilitation, specifically tailored for young children.