Accurate fetal brain tissue segmentation and biometric measurement are essential for monitoring neurodevelopment and detecting abnormalities in utero. The Fetal Tissue Annotation (FeTA) Challenges have established robust multi-center benchmarks for evaluating state-of-the-art segmentation methods. This paper presents the results of the 2024 challenge edition, which introduced three key innovations. First, we introduced a topology-aware metric based on the Euler characteristic difference (ED) to overcome the performance plateau observed with traditional metrics like Dice or Hausdorff distance (HD), as the performance of the best models in segmentation surpassed the inter-rater variability. While the best teams reached similar scores in Dice (0.81-0.82) and HD95 (2.1-2.3 mm), ED provided greater discriminative power: the winning method achieved an ED of 20.9, representing roughly a 50% improvement over the second- and third-ranked teams despite comparable Dice scores. Second, we introduced a new 0.55T low-field MRI test set, which, when paired with high-quality super-resolution reconstruction, achieved the highest segmentation performance across all test cohorts (Dice=0.86, HD95=1.69, ED=6.26). This provides the first quantitative evidence that low-cost, low-field MRI can match or surpass high-field systems in automated fetal brain segmentation. Third, the new biometry estimation task exposed a clear performance gap: although the best model reached a mean average percentage error (MAPE) of 7.72%, most submissions failed to outperform a simple gestational-age-based linear regression model (MAPE=9.56%), and all remained above inter-rater variability with a MAPE of 5.38%. Finally, by analyzing the top-performing models from FeTA 2024 alongside those from previous challenge editions, we identify ensembles of 3D nnU-Net trained on both real and synthetic data with both image- and anatomy-level augmentations as the most effective approaches for fetal brain segmentation. Our quantitative analysis reveals that acquisition site, super-resolution strategy, and image quality are the primary sources of domain shift, informing recommendations to enhance the robustness and generalizability of automated fetal brain analysis methods.
Publications by Year: 2026
2026
While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.
OBJECTIVE: Cranial bone flap fixation is typically achieved by using titanium plates and screws (TPS), which are the standard of care. However, the use of hardware to achieve long-term bone fixation and healing across a kerf line poses challenges and potential complications, including infection, nonunion, loosening, cranial flap bone resorption, pain, cosmetic deformity, and CSF leakage. The use of a tetracalcium phosphate and phosphoserine (TTCP-PS) regenerative bone adhesive to fixate cranial flaps has been previously shown to be advantageous compared to TPS in an in vivo ovine model and a human cadaveric model. However, the potential impact of TTCP-PS on the underlying brain has not been previously studied. To investigate the local tissue effects of TTCP-PS bone adhesive compared to TPS, a clinically relevant sheep craniotomy model was developed.
METHODS: Twelve skeletally mature crossbred sheep were used in this study. All craniotomies and surgical procedures were performed by an experienced, US-trained, licensed, and practicing attending neurosurgeon. Bilateral parietal craniotomies were created using a Medtronic Midas Rex craniotome and perforator. Durotomy was performed and repaired in half of the subjects. Craniotomies were repaired with TPS or the TTCP-PS bone adhesive. CT scans were performed postoperatively and at 12 weeks. Histopathology was performed on the brain and cranial bone.
RESULTS: All sheep reached the study endpoint. Histopathological changes in underlying cerebral cortical tissue were comparable in magnitude and incidence between groups (minimal superficial cortical deformation/loss and/or malacia/loss). The magnitude of microgliosis and astrogliosis related to the cortical changes was comparable between groups (minimal/mild and minimal, respectively). Histopathological findings were procedural in nature, associated with the craniotomy model, and unrelated to the bone flap fixation method. The histological changes did not result in clinically adverse effects.
CONCLUSIONS: TTCP-PS was safe, producing no significant difference in adverse effects on local tissues compared to standard craniotomy with plate and screw fixation. This is the first study to quantify histological changes in the underlying cerebral cortex due to standard craniotomy technique.
Community Health Workers (CHWs) are vital in delivering primary health care in low- and middle-income countries (LMICs). To inform their broader rollout, this study updates a 2015 review, critically examining the costs, cost-effectiveness and affordability of reproductive, maternal, newborn and child health (RMNCH) CHW programs in LMICs. A scoping review was conducted using ten databases and grey literature, covering studies published between August 2015 and July 2024. Search terms related to "Community Health Workers" and "Economic Evaluations" were used. Studies were screened via Covidence software based on inclusion and exclusion criteria. Data on study methodology, costs, and outcomes were extracted, tabulated in Microsoft Excel, and analysed. Across 53 studies (21 about reproductive health, maternal and newborn care and 32 child health focused), covering 161 scenarios, the most common cost metrics for CHW-led interventions were cost per beneficiary (ranging from $0.02 to $1,547), cost per capita (ranging from $0.09 to $20.25), and cost per consultation (ranging from $0.26 to $52.91). Of 100 scenarios that assessed cost-effectiveness, the majority concluded CHWs were cost-effective, most frequently when compared against an alternative service or delivery modality, such as facility-based care, or the no-longer widely accepted threshold of a country's gross domestic product per capita. Few studies assessed the affordability of CHW programs for government and/or partners. Evidence suggests that CHWs are often more cost-effective than alternative service or delivery modalities, particularly for child health. The evidence is however constrained by the heterogeneity of methods and reporting standards. To best guide future implementation of CHW programs, future research should focus on whether these interventions are affordable to governments and/or partners.
BACKGROUND: Methyl Methanesulfonate-Sensitivity Protein 22-Like (MMS22L) plays a key role in homology-directed DNA repair, and experimental models have shown that its loss confers sensitivity to Poly (ADP-ribose) polymerase inhibitors (PARPi). A rare germline loss-of-function founder mutation in MMS22L, F722fs (c.2164_2168del), was recently identified as a prostate cancer risk factor among individuals of Ashkenazi Jewish ancestry. The impact of this mutation on the disease course following prostate cancer diagnosis remains unclear. Here, we report the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute at Johns Hopkins University.
METHODS: We investigated the longitudinal outcomes of seven MMS22L F722fs carriers diagnosed with different stages of prostate cancer identified at the Brady Urological Institute.
RESULTS: With a follow-up time ranging from 5 to 27 years, five of the seven patients who were initially treated with radical prostatectomy remain alive and disease-free, including two patients who had adjuvant and salvage therapies, and one patient who was cured after developing metastatic disease post-surgery. For the remaining two patients with metastatic prostate cancer at diagnosis, one patient responded to ADT for 11 years, and the other died of unknown causes 5 years after diagnosis. None of these patients received PARPi.
CONCLUSIONS: Although limited by its retrospective design and small cohort size, this series suggests the potential for exceptional outcomes in F722fs mutation carriers diagnosed with prostate cancer, despite the aggressive disease features and lack of treatment with PARPi. The findings also suggest that prostate cancer patients with this mutation may respond well to standard systemic treatments.
Randomized controlled trials (RCTs) represent the gold standard for establishing the efficacy of new interventions. Yet, RCTs are often conducted in selected populations, not representative of those at risk for or living with the disease. This lack of representativeness has raised concerns about the generalizability of RCT results to those populations not (adequately) represented in RCTs, in particular in the absence of evidence on potential differences in treatment effects across population subgroups. In the field of cardiovascular disease, women are often underrepresented in RCTs relative to disease burden. The present paper seeks to define representative participation of women in RCTs. Trial data from two cardiovascular trials, the ADVANCE trial and the LoDoCo2 trial, are used to illustrate sample size requirements for (i) achieving representative participation, (ii) achieving representative contribution to knowledge gained, and (iii) assessing whether treatment effects are the same or different in men and women (i.e. sex * treatment interactions). Achieving representative participation and representative contribution to knowledge gained requires relatively small increases in sample size and is mainly driven by sex differences in disease rates. However, sample size requirements for RCTs powered to assess sex differences in treatment effects are unfeasibly large. Hence, while efforts to enhance representative trial participation should continue, as RCTs provide the cornerstone for guideline recommendations and clinical decision-making, these should be complemented by mechanistic studies to provide insights in possible treatment interactions and inform optimal treatment for both women and men.
The mesothelium is a squamous monolayer that ensheathes internal organs and lines the body cavities. Aside from facilitating tissue sliding, its additional functions remain poorly understood. Here, we study the mesothelium through investigating myelin regulatory factor (Myrf), a transcription factor expressed in the mesothelium and a top mutated gene in congenital diaphragmatic hernia (CDH), a developmental disorder that affects the lung and diaphragm. In mice, inactivation of Myrf early in embryogenesis resulted in CDH and defective mesothelium specification, compromising its role as a signaling center for lung growth. Inactivation after mesothelium specification led to additional defects, including enhanced differentiation into various mesenchymal cell types, causing a striking accumulation of elastin-expressing smooth muscle/myofibroblasts encasing the lung, mimicking pleuroparenchymal fibroelastosis (PPFE), a rare adult lung condition. Compound mutants demonstrate that MYRF functions synergistically with YAP/TAZ in mesothelium differentiation. Together, these findings highlight the complex role of the mesothelium in development and disease.
Senescent cells (SCs) accumulate with aging and contribute to the development of age-related pathologies. These cells evade apoptosis through upregulation of senescent cell anti-apoptotic pathways (SCAPs), making their selective elimination, a strategy termed senolysis, a promising therapeutic avenue. Proteolysis-targeting chimeras (PROTACs) represent an emerging class of bifunctional molecules that exploit the ubiquitin-proteasome system to degrade specific target proteins. By concurrently binding to a protein of interest and an E3 ubiquitin ligase, PROTACs catalyze the degradation of SCAP components, offering a novel pharmacological approach to clear SCs. This review summarizes the principles and recent advances in PROTAC technology, with a focus on its application as a senolytic strategy. We highlight how PROTACs can overcome limitations of conventional inhibitors, such as targeting "undruggable" SCAP proteins, and provide a comparative analysis of major PROTAC classes targeting BCL-2 family members, p53, BRD4, SA-β-gal, and other emerging senescence regulators. Furthermore, we also discuss the aging-specific biological and translational challenges, including altered proteasomal activity, pharmacokinetics, tissue microenvironment, and immune clearance, which must be addressed to advance PROTAC senolytics toward clinical use in age-related diseases.
INTRODUCTION: Acute kidney injury (AKI) is a major health concern, disproportionately affecting children in low- and lower-middle-income countries (LLMICs). Diarrhoeal diseases, a leading cause of paediatric morbidity and mortality, are significant contributors to AKI.
METHODS: This study systematically reviewed literature published post-2000 on three groups of children: those hospitalised with diarrhoea who developed AKI (Diarrhoea/AKI), those hospitalised with AKI attributable to diarrhoea (AKI/Diarrhoea), and those with diarrhoea-associated haemolytic uraemic syndrome (D+-HUS).
RESULTS: After screening 1895 titles and abstracts, 92 studies were included. Most focused on D+-HUS (76%), with fewer addressing AKI/Diarrhoea (15%) and Diarrhoea/AKI (9%). Studies were predominantly retrospective and high-income country (HIC)-based. In children hospitalised with diarrhoea, mean AKI prevalence was higher in LLMICs than in HICs (43.2±30.5% vs 10.1±12.7%). Similarly in children hospitalized with AKI, diarrhoea was more frequent in LLMICs compared with HICs (23.8±12.3% vs . 16.1±5.9%). Among children with D+-HUS, 60% required dialysis, and mortality was substantially higher in LLMICs compared with HICs (28.5±17.43% vs . 3.7±3.6%).
CONCLUSION: Diarrhoea is a common yet underreported associated clinical finding among children with AKI, particularly in resource-limited settings. Enhanced monitoring of kidney outcomes in children with diarrhoea is essential to address the overlapping burden of these conditions and improve outcomes globally.