The clinical significance of sub-total surgical resection in childhood medulloblastoma: a multi-cohort analysis of 1100 patients

\ua9 2024 The Author(s)Background: Medulloblastoma patients with a sub-total surgical resection (STR; >1.5 cm2 primary tumour residuum post-surgery) typically receive intensified treatment. However, the association of STR with poor outcomes has not been observed consistently, questioning the validity of STR as a high-risk disease feature. Methods: We collected extent of resection (EOR) data from 1110 patients (from UK CCLG centres (n = 416, collected between September 1990 and July 2014) and published (n = 694) cohorts), the largest cohort of molecularly and clinically annotated tumours assembled to specifically assess the significance of EOR. We performed association and univariable/multivariable survival analyses, assessing overall survival (OS) cohort-wide and with reference to the four consensus medulloblastoma molecular groups and clinical features. Findings: STR was reported in 20% (226/1110) of patients. Non-WNT (p = 0.047), children <5 years at diagnosis (p = 0.021) and metastatic patients (p < 0.0001) were significantly more likely to have a STR. In cohort-wide analysis, STR was associated with worse survival in univariable analysis (p < 0.0001). Examination of specific disease contexts showed that STR was prognostic in univariate analysis for patients receiving cranio-spinal irradiation (CSI) and chemotherapy (p = 0.016) and for patients with Group 3 tumours receiving CSI (p = 0.039). STR was not independently prognostic in multivariable analyses; outcomes for patients who have STR as their only risk-feature are as per standard-risk disease. Specifically, STR was not prognostic in non-metastatic patients that received upfront CSI. Interpretation: In a cohort of 1100 molecularly characterised medulloblastoma patients, STR (n = 226) predicted significantly lower OS in univariable analysis, but was not an independent prognostic factor. Our data suggest that maximal safe resection can continue to be carried out for patients with medulloblastoma and suggest STR should not inform patient management when observed as a sole, isolated risk-feature. Funding: Cancer Research UK, Newcastle Hospitals Charity, Children\u27s Cancer North, British Division of the International Academy of Pathology

Seismic slip on an upper-plate normal fault during a large subduction megathrust rupture

Quantification of stress accumulation and release during subduction zone seismic cycles requires an understanding of the distribution of fault slip during earthquakes. Reconstructions of slip are typically constrained to a single, known fault plane. Yet, slip has been shown to occur on multiple faults within the subducting plate1 owing to stress triggering2, resulting in phenomena such as earthquake doublets3. However, rapid stress triggering from the plate interface to faults in the overriding plate has not been documented. Here we analyse seismic data from the magnitude 7.1 Araucania earthquake that occurred in the Chilean subduction zone in 2011. We find that the earthquake, which was reported as a single event in global moment tensor solutions4, 5, was instead composed of two ruptures on two separate faults. Within 12?s a thrust earthquake on the plate interface triggered a second large rupture on a normal fault 30?km away in the overriding plate. This configuration of partitioned rupture is consistent with normal-faulting mechanisms in the ensuing aftershock sequence. We conclude that plate interface rupture can trigger almost instantaneous slip in the overriding plate of a subduction zone. This shallow upper-plate rupture may be masked from teleseismic data, posing a challenge for real-time tsunami warning systems

Implementation of a psychosocial support package for people receiving treatment for multidrug-resistant tuberculosis in Nepal: A feasibility and acceptability study

Background and objectives People receiving treatment for multidrug-resistant tuberculosis (MDR-TB) have high rates of depression. Psychosocial support in general, and treatments for depression in particular, form an important but neglected area of patient-centred care, and a key pillar in the global End TB strategy. We assessed the feasibility and acceptability of a psychosocial support package for people receiving treatment for MDR-TB in Nepal. Methods This feasibility study used a mixed quantitative and qualitative approach. We implemented the intervention package in two National Tuberculosis Programme (NTP) MDR-TB treatment centres and 8 sub-centres. We screened patients monthly for depression and anxiety (cut-off ≥24 and ≥17 respectively on the Hopkins Symptom Checklist) and also for low social support (cut-off ≤3 on the Multidimensional Scale of Perceived Social Support). Those who screened positive on either screening tool received the Healthy Activity Program (HAP), which uses brief counselling based on behavioural activation theory. Other aspects of the psychosocial package were information/education materials and group interactions with other patients. Results We screened 135 patients, of whom 12 (9%) received HAP counselling, 115 (85%) received information materials, 80 (59%) received an education session and 49 (36%) received at least one group session. Eight group sessions were conducted in total. All aspects of the intervention package were acceptable to patients, including the screening, information, group work and counselling. Patients particularly valued having someone to talk to about their concerns and worries. We were able to successfully train individuals with no experience of psychological counselling to deliver HAP. Conclusion This psychosocial support package is acceptable to patients. The information materials we developed are feasible to deliver in the current NTP. However, the structured psychological counselling (HAP), is not feasible in the current NTP due to time constraints. This requires additional investment of counsellors in TB clinics

Bottom mixed layer oxygen dynamics in the Celtic Sea

The seasonally stratified continental shelf seas are highly productive, economically important environments which are under considerable pressure from human activity. Global dissolved oxygen concentrations have shown rapid reductions in response to anthropogenic forcing since at least the middle of the twentieth century. Oxygen consumption is at the same time linked to the cycling of atmospheric carbon, with oxygen being a proxy for carbon remineralisation and the release of CO2. In the seasonally stratified seas the bottom mixed layer (BML) is partially isolated from the atmosphere and is thus controlled by interplay between oxygen consumption processes, vertical and horizontal advection. Oxygen consumption rates can be both spatially and temporally dynamic, but these dynamics are often missed with incubation based techniques. Here we adopt a Bayesian approach to determining total BML oxygen consumption rates from a high resolution oxygen time-series. This incorporates both our knowledge and our uncertainty of the various processes which control the oxygen inventory. Total BML rates integrate both processes in the water column and at the sediment interface. These observations span the stratified period of the Celtic Sea and across both sandy and muddy sediment types. We show how horizontal advection, tidal forcing and vertical mixing together control the bottom mixed layer oxygen concentrations at various times over the stratified period. Our muddy-sand site shows cyclic spring-neap mediated changes in oxygen consumption driven by the frequent resuspension or ventilation of the seabed. We see evidence for prolonged periods of increased vertical mixing which provide the ventilation necessary to support the high rates of consumption observed

Self-Supervised Discovery of Anatomical Shape Landmarks

Statistical shape analysis is a very useful tool in a wide range of medical and biological applications. However, it typically relies on the ability to produce a relatively small number of features that can capture the relevant variability in a population. State-of-the-art methods for obtaining such anatomical features rely on either extensive preprocessing or segmentation and/or significant tuning and post-processing. These shortcomings limit the widespread use of shape statistics. We propose that effective shape representations should provide sufficient information to align/register images. Using this assumption we propose a self-supervised, neural network approach for automatically positioning and detecting landmarks in images that can be used for subsequent analysis. The network discovers the landmarks corresponding to anatomical shape features that promote good image registration in the context of a particular class of transformations. In addition, we also propose a regularization for the proposed network which allows for a uniform distribution of these discovered landmarks. In this paper, we present a complete framework, which only takes a set of input images and produces landmarks that are immediately usable for statistical shape analysis. We evaluate the performance on a phantom dataset as well as 2D and 3D images.Comment: Early accept at MICCAI 202

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes

Aims: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. Methods: We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies; randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH‐I/II). Within the discriminated favourable‐risk iMBSHH DN/MBEN patient group, iMBSHH‐II had significantly better progression‐free survival than iMBSHH‐I, offering opportunities for risk‐adapted stratification of upfront therapies. Both iMBSHH‐I and iMBSHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies

Sex-biased parental care and sexual size dimorphism in a provisioning arthropod

The diverse selection pressures driving the evolution of sexual size dimorphism (SSD) have long been debated. While the balance between fecundity selection and sexual selection has received much attention, explanations based on sex-specific ecology have proven harder to test. In ectotherms, females are typically larger than males, and this is frequently thought to be because size constrains female fecundity more than it constrains male mating success. However, SSD could additionally reflect maternal care strategies. Under this hypothesis, females are relatively larger where reproduction requires greater maximum maternal effort – for example where mothers transport heavy provisions to nests. To test this hypothesis we focussed on digger wasps (Hymenoptera: Ammophilini), a relatively homogeneous group in which only females provision offspring. In some species, a single large prey item, up to 10 times the mother’s weight, must be carried to each burrow on foot; other species provide many small prey, each flown individually to the nest. We found more pronounced female-biased SSD in species where females carry single, heavy prey. More generally, SSD was negatively correlated with numbers of prey provided per offspring. Females provisioning multiple small items had longer wings and thoraxes, probably because smaller prey are carried in flight. Despite much theorising, few empirical studies have tested how sex-biased parental care can affect SSD. Our study reveals that such costs can be associated with the evolution of dimorphism, and this should be investigated in other clades where parental care costs differ between sexes and species

Caspase cleavage of the Golgi stacking factor GRASP65 is required for Fas/CD95-mediated apoptosis

GRASP65 (Golgi reassembly and stacking protein of 65 KDa) is a cis-Golgi protein with roles in Golgi structure, membrane trafficking and cell signalling. It is cleaved by caspase-3 early in apoptosis, promoting Golgi fragmentation. We now show that cleavage is needed for Fas-mediated apoptosis: expression of caspase-resistant GRASP65 protects cells, whereas expression of membrane proximal caspase-cleaved GRASP65 fragments dramatically sensitises cells. GRASP65 coordinates passage through the Golgi apparatus of proteins containing C-terminal hydrophobic motifs, via its tandem PDZ type ‘GRASP' domains. Fas/CD95 contains a C-terminal leucine–valine pairing so its trafficking might be coordinated by GRASP65. Mutagenesis of the Fas/CD95 LV motif reduces the number of cells with Golgi-associated Fas/CD95, and generates a receptor that is more effective at inducing apoptosis; however, siRNA-mediated silencing or expression of mutant GRASP65 constructs do not alter the steady state distribution of Fas/CD95. We also find no evidence for a GRASP65–Fas/CD95 interaction at the molecular level. Instead, we find that the C-terminal fragments of GRASP65 produced following caspase cleavage are targeted to mitochondria, and ectopic expression of these sensitises HeLa cells to Fas ligand. Our data suggest that GRASP65 cleavage promotes Fas/CD95-mediated apoptosis via release of C-terminal fragments that act at the mitochondria, and we identify Bcl-XL as a candidate apoptotic binding partner for GRASP65