Children's physical activity and sedentary behaviour in before school care: An observational study.

OBJECTIVE: In Australia, less than one quarter of children aged 5-12 years meet national physical activity (PA) guidelines. Before school care operates as part of Out of School Hours Care (OSHC) services and provide opportunities for children to meet their daily PA recommendations. The aim of this study was to explore factors associated with children meeting 15 min of moderate-to-vigorous-intensity physical activity (MVPA) while attending before school care. METHODS: A cross-sectional study was conducted in 25 services in New South Wales, Australia. Each service was visited twice between March and June 2021. Staff behaviours and PA type and context were captured using staff interviews and the validated System for Observing Staff Promotion of Physical Activity and Nutrition (SOSPAN) time sampling tool. Child PA data were collected using Actigraph accelerometers and associations between program practices and child MVPA analysed. RESULTS: PA data were analysed for 654 children who spent an average of 39.2% (±17.6) of their time sedentary; 45.4% (±11.4) in light PA; and 14.9% (±11.7) in MVPA. Only 17% of children (n = 112) reached ≥15 min MVPA, with boys more likely to achieve this. Children were more likely to meet this recommendation in services where staff promoted and engaged in PA; PA equipment was available; children were observed in child-led free play; and a written PA policy existed. CONCLUSIONS: Before school care should be supported to improve physical activity promotion practices by offering staff professional development and guidance on PA policy development and implementation practices.

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.

Structure-activity relationship of dihydropyridines for rhabdomyosarcoma.

Childhood muscle-related cancer rhabdomyosarcoma is a rare disease with a 50-year unmet clinical need for the patients presented with advanced disease. The rarity of ∼350 cases per year in North America generally diminishes the viability of large-scale, pharmaceutical industry driven drug development efforts for rhabdomyosarcoma. In this study, we performed a large-scale screen of 640,000 compounds to identify the dihydropyridine (DHP) class of anti-hypertensives as a priority compound hit. A structure-activity relationship was uncovered with increasing cell growth inhibition as side chain length increases at the ortho and para positions of the parent DHP molecule. Growth inhibition was consistent across n = 21 rhabdomyosarcoma cell line models. Anti-tumor activity in vitro was paralleled by studies in vivo. The unexpected finding was that the action of DHPs appears to be other than on the DHP receptor (i.e., L-type voltage-gated calcium channel). These findings provide the basis of a medicinal chemistry program to develop dihydropyridine derivatives that retain anti-rhabdomyosarcoma activity without anti-hypertensive effects.

Blood pressure variability is associated with Infarct Growth in Acute Ischemic Stroke.

Introduction Evidence based blood pressure (BP) targets in acute ischemic stroke are lacking. Previous observational studies have focused on single baseline BP and clinical outcomes, without consideration for dynamic changes. We aim to determine the association between BP parameters including variability, peak, nadir, median and mean during stroke and infarct growth (primary outcome), risk of haemorrhagic transformation and functional outcome (secondary outcomes). Methods Suspected stroke patients were prospectively recruited from a single comprehensive stroke centre. Multimodal computed tomography imaging was used to define infarct core. BP was recorded as per national stroke guidelines during the initial 24-hours. Infarct growth and evidence of parenchymal haemorrhage were determined by follow-up magnetic resonance imaging at 24 hours. Functional outcome at 3-months was assessed using the modified Rankin Scale. Subgroup analysis was performed according to stroke etiology and treatment for the association between BP, infarct volume growth and risk of hemorrhagic transformation. The association between BP parameters and outcomes were determined using regression modelling. Results A total of 229 patients were included in this study. The median age was 67.4, 64.4% were male and the baseline National Institutes of Health Stroke Scale was 8. Blood pressure variability (BPV) was independently associated with increased infarct growth (multivariate coefficient 1.60, 95% CI 0.27-2.94, P=0.019) and an increased odds of parenchymal haemorrhage (adjusted OR 1.21, 95% CI 1.02-1.44, P= 0.028). The odds of a favourable outcome at 90 days were inversely associated with BPV on simple, but not adjusted logistic regression. On subgroup analysis, only in patients with large vessel occlusions undergoing endovascular clot retrieval was BPV associated with infarct growth (multivariate adjusted coefficient 2.62, 95% CI 0.53-4.70, P=0.014) and an increased odds of hemorrhagic transformation (adjusted OR 1.26, 95% CI 1.01-1.57, P=0.045). Conclusions: An increase in BPV was associated with infarct expansion, increased risk of haemorrhagic transformation, and was negatively associated with favourable functional outcomes at 3-months.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

White paper: Oncofertility in pediatric patients with Wilms tumor.

The survival of childhood Wilms tumor is currently around 90%, with many survivors reaching reproductive age. Chemotherapy and radiotherapy are established risk factors for gonadal damage and are used in both COG and SIOP Wilms tumor treatment protocols. The risk of infertility in Wilms tumor patients is low but increases with intensification of treatment including the use of alkylating agents, whole abdominal radiation or radiotherapy to the pelvis. Both COG and SIOP protocols aim to limit the use of gonadotoxic treatment, but unfortunately this cannot be avoided in all patients. Infertility is considered one of the most important late effects of childhood cancer treatment by patients and their families. Thus, timely discussion of gonadal damage risk and fertility preservation options is important. Additionally, irrespective of the choice for preservation, consultation with a fertility preservation (FP) team is associated with decreased patient and family regret and better quality of life. Current guidelines recommend early discussion of the impact of therapy on potential fertility. Since most patients with Wilms tumors are prepubertal, potential FP methods for this group are still considered experimental. There are no proven methods for FP for prepubertal males (testicular biopsy for cryopreservation is experimental), and there is just a single option for prepubertal females (ovarian tissue cryopreservation), posing both technical and ethical challenges. Identification of genetic markers of susceptibility to gonadotoxic therapy may help to stratify patient risk of gonadal damage and identify patients most likely to benefit from FP methods.

Machine learning for rhabdomyosarcoma histopathology.

Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

Gender differences in the assessment, decision-making and outcomes for ventricular assist devices and heart transplantation: An analysis from a UK transplant center.

PURPOSE: There are marked gender differences in all etiologies of advanced heart failure. We sought to determine whether there is evidence of gender-specific decision making for transplant assessments, and how gender effects outcomes. METHODS: Retrospective analysis of adult heart transplant assessments at a single UK center between April 2015 and March 2020. RESULTS: Females were 32% of referrals (N = 137 females, 285 males), with marked differences between diagnoses - 11% ischemic and 43% of adult congenital. Females were younger, shorter, weighed less, and had lower pulmonary pressures. Females were much less likely to receive a ventricular assist device (13%). Blood type "O" females were relatively more likely compared to males to receive a transplant (45%). Comparing males and females who received a ventricular assist device, both had similar levels of high pulmonary pressures, indicating consistent decision-making based on hemodynamics to implant a device. Overall survival was better for females (in noncongenital patients), and this was due to female patients who were not accepted for transplant or a ventricular assist device being more often "too well for transplant," rather than in males when they were more often "unsuitable." CONCLUSIONS: Marked gender differences exist at all stages of the heart transplant assessment pathway. Appropriate decision-making based on clinical grounds is shown with less transplants in male blood type "O"s and hemodynamic criteria for ventricular assist device implantation in both genders. Further studies are needed to determine if there is a wider community bias in advanced heart failure treatments for females.

Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor.

BACKGROUND: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. PROCEDURES: In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. RESULTS: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. CONCLUSIONS: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces tumor volume in Wilms tumor PDXs, and should be further explored for its therapeutic potential.

Does infection predispose to thrombosis during long-term ventricular assist device support?

BACKGROUND: Infections and thrombotic events remain life-threatening complications in patients with ventricular assist devices (VAD). METHODS: We describe the relationship between both events in our cohort of patients (n = 220) supported with the HeartWare VAD (HVAD). This is a retrospective analysis of patients undergoing HVAD implantation between July 2009 and March 2019 at the Freeman Hospital, Newcastle upon Tyne, United Kingdom. RESULTS: Infection was the most common adverse event in HVAD patients, with 125 patients (56.8%) experiencing ≥ one infection (n = 168, 0.33 event per person year (EPPY)), followed by pump thrombosis (PT) in 61 patients (27.7%, 0.16 EPPY). VAD-specific infections were the largest group of infections. Of the 125 patients who had an infection, 66 (53%) had a thrombotic event. Both thrombotic events and infections were related to the duration of support, though there was only limited evidence that infections predispose to thrombosis. Those with higher than median levels of C-reactive protein during the infection were more likely to have an ischaemic stroke (IS) (34.5% vs 16.7%, p = .03), though not PT or a combined thrombotic event (CTE: first PT or IS). However, in multivariate analysis, there was no significant effect of infection predisposing to CTE. CONCLUSIONS: Infection and thrombotic events are significant adverse events related to the duration of support in patients receiving HVADs. Infections do not clearly predispose to thrombotic events.

Correlates of physical activity and sedentary behaviour in children attending before and after school care: a systematic review.

BACKGROUND: Out of School Hours Care (OSHC) offers structured care to elementary/primary-aged children before and after school, and during school holidays. The promotion of physical activity in OSHC is important for childhood obesity prevention. The aim of this systematic review was to identify correlates of objectively measured physical activity and sedentary behaviour in before and after school care. METHODS: A systematic search was conducted in Scopus, ERIC, MEDLINE (EBSCO), PsycINFO and Web of Science databases up to December 2021. Study inclusion criteria were: written in English; from a peer-reviewed journal; data from a centre-based before and/or after school care service; children with a mean age < 13 years; an objective measure of physical activity or sedentary behaviour; reported correlations and significance levels; and if an intervention study design these correlates were reported at baseline. Study quality was assessed using the Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal Studies. The PRISMA guidelines informed the reporting, and data were synthesised according to shared correlations and a social ecological framework. RESULTS: Database searches identified 4559 papers, with 18 cross-sectional studies meeting the inclusion criteria.There were a total of 116 physical activity correlates and 64 sedentary behaviour correlates identified. The most frequently reported correlates of physical activity were child sex (males more active), staff engaging in physical activity, an absence of elimination games, and scheduling physical activity in daily programming (all more positively associated). The most frequently reported correlates of sedentary behaviour were child sex (females more sedentary) and age (older children more sedentary). CONCLUSIONS: Encouraging physical activity engagement of female children, promoting positive staff behaviours, removing elimination elements from games, and scheduling more time for physical activity should be priorities for service providers. Additional research is needed in before school care services.

The social construction of nurse educator professional identities: Exploring the impact of a community of practice through participatory action research.

AIMS: The aim of the study was to explore whether, and how, professional nurse educator identity is co-constructed by a community of practice. DESIGN: A critical participatory action research (PAR) methodology was used as it extends the principles of action research by seeking purposeful and sustainable social change that recognizes participants as researchers and generators of knowledge. METHODS: Twenty-two sector-based nurse educators employed as either nurse educators or clinical nurse educators participated in the critical PAR. Multiple methods of data generation were pursued in a cyclic and sequential manner consistent in an action research process. Three distinct phases of the research across 2015-2017 involved the generation of data before, during and after the establishment of a nurse educator community of practice. A social constructionist lens of analysis was used to explore the social and relational outcomes. The COREQ checklist was used to appraise the study report. RESULTS: A sustained period of community of practice engagement enhanced the participants' relationships and shifted their perceived professional identities towards being validated nurse educators with a stronger collective sense of their roles. CONCLUSION: For this group of nurse educators, participation in the research resulted in collective meaning-making, praxis, knowledge generation and the co-construction of their professional identities.

Validity of Hemodynamic Monitoring Using Inert Gas Rebreathing Method in Patients With Chronic Heart Failure and Those Implanted With a Left Ventricular Assist Device.

OBJECTIVE: The present study assessed agreement between resting cardiac output estimated by inert gas rebreathing (IGR) and thermodilution methods in patients with heart failure and those implanted with a left ventricular assist device (LVAD). METHODS AND RESULTS: Hemodynamic measurements were obtained in 42 patients, 22 with chronic heart failure and 20 with implanted continuous flow LVAD (34 males, aged 50 ± 11 years). Measurements were performed at rest using thermodilution and IGR methods. Cardiac output derived by thermodilution and IGR were not significantly different in LVAD (4.4 ± 0.9 L/min vs 4.7 ± 0.8 L/min, P = .27) or patients with heart failure (4.4 ± 1.4 L/min vs 4.5 ± 1.3 L/min, P = .75). There was a strong relationship between thermodilution and IGR cardiac index (r = 0.81, P = .001) and stroke volume index (r = 0.75, P = .001). Bland-Altman analysis showed acceptable limits of agreement for cardiac index derived by thermodilution and IGR, namely, the mean difference (lower and upper limits of agreement) for patients with heart failure -0.002 L/min/m2 (-0.65 to 0.66 L/min/m2), and -0.14 L/min/m2 (-0.78 to 0.49 L/min/m2) for patients with LVAD. CONCLUSIONS: IGR is a valid method for estimating cardiac output and should be used in clinical practice to complement the evaluation and management of chronic heart failure and patients with an LVAD.

Efficacy and safety of the pregnancy-IVI, an intravenous insulin protocol for pregnancy, following antenatal betamethasone in type 1 and type 2 diabetes.

AIMS: Hyperglycaemia following antenatal corticosteroids is common in women with diabetes in pregnancy, and validated algorithms to maintain pregnancy-specific glucose targets are lacking. The Pregnancy-IVI, an intravenous-insulin (IVI) algorithm, has been validated in gestational diabetes; however, its performance in pre-existing diabetes (Type 1 and Type 2 diabetes) is not known. We hypothesised that Pregnancy-IVI would be superior to a generic Adult-IVI protocol (prior standard of care) following betamethasone in women with pre-existing diabetes. METHODS: A retrospective cohort study enrolled all women with pre-existing diabetes at a tertiary centre receiving betamethasone and treated with IVI according to one of two protocols: Adult-IVI (n = 73, 2014-2017) or Pregnancy-IVI (n = 62, 2017-2020). The primary outcome was on-IVI glycaemic time-in-range (capillary blood glucose (BGL) 3.8-7.0 mmol/L). Secondary outcomes included time with critical hyperglycaemia (BGL > 10 mmol/L); occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l) and incidence of neonatal hypoglycaemia (BGL ≤ 2.5 mmol/L). Analysis was stratified by diabetes type. RESULTS: Overall, Pregnancy-IVI achieved a higher proportion of on-IVI time-in-range (70%, IQR 56-78%) compared to Adult-IVI (52%, IQR 41-69%, p < 0.0001). The duration of critical hyperglycaemia with Pregnancy-IVI was also reduced (2% [IQR 0-7] vs 8% [IQR 4-17], p < 0.0001), without an increase in hypoglycaemia. Glycaemic variability was significantly reduced with Pregnancy-IVI. No difference in the rate of neonatal hypoglycaemia was observed. The Pregnancy-IVI was most effective in women with Type 1 diabetes. CONCLUSION: The Pregnancy-IVI algorithm is safe and effective when used following betamethasone in type 1 diabetes in pregnancy. Further study of women with type 2 diabetes is required.

Significance of hyperglycaemia in first trimester pregnancy (SHIFT): A pilot study and literature review.

International guidelines recommend screening for overt diabetes in early pregnancy. Women in their first trimester with fasting plasma glucose (FPG) levels that would be diagnostic of gestational diabetes mellitus (GDM) in later pregnancy are being identified and treated despite uncertainty regarding the risks and benefits. The evidence for the current diagnostic criteria and management recommendations in early GDM are reviewed. The results of a prospective observational study assessing the progression to GDM and prespecified maternal-fetal outcomes in women with mild fasting hyperglycaemia in the first trimester suggest that women with FPG 5.1-5.6 mmol/L may warrant proactive management in early pregnancy.

Stokes settling and particle-laden plumes: implications for deep-sea mining and volcanic eruption plumes.

Turbulent buoyant plumes moving through density stratified environments transport large volumes of fluid vertically. Eventually, the fluid reaches its neutral buoyancy level at which it intrudes into the environment. For single-phase plume, the well-known theory of Morton, Taylor and Turner (Morton BR, Taylor GI, Turner JS. 1956 Turbulent gravitational convection from maintained and instantaneous sources. Proc. R. Soc. A 234, 1-23. (doi:10.1098/rspa.1956.0011)) describes the height of the intrusion with great accuracy. However, in multiphase plumes, such as descending particle plumes formed from the surface vessel during deep-sea mining operations, or ascending volcanic plumes, consisting of hot gas and dense ash particles, the sedimentation of particles can change the buoyancy of the fluid very significantly. Even if the plume speed far exceeds the sedimentation speed, the ultimate intrusion height of the fluid may be significantly affected by particle sedimentation. We explore this process, illustrating the phenomena with a series of analogue experiments and some simple modelling, and we discuss the applications in helping to quantify some environmental impacts of deep-sea mining and in helping to assess the eruption conditions leading to the formation of large laterally spreading ash clouds in the atmosphere. This article is part of the theme issue 'Stokes at 200 (part 2)'.

The Importance of 1,5-Oxygen⋠⋠⋠Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis.

The importance of 1,5-O⋅⋅⋅chalcogen (Ch) interactions in isochalcogenourea catalysis (Ch=O, S, Se) is investigated. Conformational analyses of N-acyl isochalcogenouronium species and comparison with kinetic data demonstrate the significance of 1,5-O⋅⋅⋅Ch interactions in enantioselective catalysis. Importantly, the selenium analogue demonstrates enhanced rate and selectivity profiles across a range of reaction processes including nitronate conjugate addition and formal [4+2] cycloadditions. A gram-scale synthesis of the most active selenium analogue was developed using a previously unreported seleno-Hugerschoff reaction, allowing the challenging kinetic resolutions of tertiary alcohols to be performed at 500 ppm catalyst loading. Density functional theory (DFT) and natural bond orbital (NBO) calculations support the role of orbital delocalization (occurring by intramolecular chalcogen bonding) in determining the conformation, equilibrium population, and reactivity of N-acylated intermediates.

Some fluid mechanical constraints on crystallization and recharge within sills.

The injection of hot magma into a sill can lead to heating and melting of the walls and roof of the reservoir while the injected magma cools and crystallizes. If the crystals are relatively dense, they will try to sediment from the injected magma to form a cumulate layer. In this cumulate layer, the crystals form a porous framework which traps the melt as it is built up. As the melt within the sill continually cools and precipitates dense crystals, there will be a gradual reduction in the density of the remaining silicate liquid. As a result, the melt which is progressively trapped in the pore space of the cumulate layer will become stably stratified in density. Using an idealized model of the fluid mechanical and thermodynamical principles, we explore some of the controls on the thickness and density stratification of cumulate layers following replenishment of a sill-like magma chamber. We show the balance between jamming of the crystal laden melt to form a homogeneous layer and the formation of a stratified cumulate zone depends on the cooling time scale compared to the sedimentation time scale. A key finding is that the composition and stratification in a packed crystal-melt suspension and the associated cumulate layer formed by cooling an intrusion of hot melt injected into the crust may have considerable variability, depending on the properties of the overlying roof melt and the size and hence fall speed of crystals which form in the melt. This article is part of the Theo Murphy meeting issue 'Magma reservoir architecture and dynamics'.