Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11.

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extraterminal protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent antitumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent antitumor activity in vivo.

Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11.

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent "direct" degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo.

A rapid systematic review of breakthrough pain definitions and descriptions.

Background: Breakthrough pain is common in life-limiting conditions and at end-of-life. Despite over 30 years of study, there is little consensus regarding the definition and characteristics of breakthrough pain. Objective: This study aims to update and expand a 2010 systematic review by Haugen and colleagues to identify (1) all definitions of breakthrough pain and (2) all descriptions and classifications of breakthrough pain reported by patients, caregivers, clinicians, and experts. Design: This rapid systematic review followed the Cochrane Rapid Review Methods Group guidelines. A protocol is published on PROSPERO (CRD42019155583). Data sources: CINAHL, MEDLINE, PsycINFO, and the Web of Science were searched for breakthrough pain terms from the inception dates of each database to 26th August 2022. Results: We identified 65 studies that included data on breakthrough pain definitions, descriptions, or classifications from patients (n = 30), clinicians (n = 6), and experts (n = 29), but none with data from caregivers. Most experts proposed that breakthrough pain was a sudden, severe, brief pain occurring in patients with adequately controlled mild-moderate background pain. However, definitions varied and there was no consensus. Pain characteristics were broadly similar across studies though temporal factors varied widely. Experts classified breakthrough pain into nociceptive, neuropathic, visceral, somatic, or mixed types. Patients with breakthrough pain commonly experienced depression, anxiety, and interference with daily life. Conclusions: Despite ongoing efforts, there is still no consensus on the definition of breakthrough pain. A compromise is needed on breakthrough pain nomenclature to collect reliable incidence and prevalence data and to inform further refinement of the construct.

Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile.

BACKGROUND: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet. METHODS: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. RESULTS: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS. CONCLUSION: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Definition and Assessment of Paediatric Breakthrough Pain: A Qualitative Interview Study.

Infants, children and young people with life-limiting or life-threatening conditions often experience acute, transient pain episodes known as breakthrough pain. There is currently no established way to assess breakthrough pain in paediatric palliative care. Anecdotal evidence suggests that it is frequently underdiagnosed and undertreated, resulting in reduced quality of life. The development of a standardised paediatric breakthrough pain assessment, based on healthcare professionals' insights, could improve patient outcomes. This study aimed to explore how healthcare professionals define and assess breakthrough pain in paediatric palliative care and their attitudes towards a validated paediatric breakthrough pain assessment. This was a descriptive qualitative interview study. Semi-structured interviews were conducted with 29 healthcare professionals working in paediatric palliative care across the UK. An inductive thematic analysis was conducted on the data. Five themes were generated: 'the elusive nature of breakthrough pain', 'breakthrough pain assessment', 'positive attitudes towards', 'reservations towards' and 'features to include in' a paediatric breakthrough pain assessment. The definition and assessment of breakthrough pain is inconsistent in paediatric palliative care. There is a clear need for a validated assessment questionnaire to improve assessment, diagnosis and management of breakthrough pain followed by increased healthcare professional education on the concept.

Correction: Bailey et al. Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial. Cancers 2022, 14, 374.

In the original publication [...].

Noise suppression of proton magnetic resonance spectroscopy improves paediatric brain tumour classification.

Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used for clinical brain tumour diagnosis, but suffers from limited spectral quality. This retrospective and comparative study aims at improving paediatric brain tumour classification by performing noise suppression on clinical 1H-MRS. Eighty-three/forty-two children with either an ependymoma (ages 4.6 ± 5.3/9.3 ± 5.4), a medulloblastoma (ages 6.9 ± 3.5/6.5 ± 4.4), or a pilocytic astrocytoma (8.0 ± 3.6/6.3 ± 5.0), recruited from four centres across England, were scanned with 1.5T/3T short-echo-time point-resolved spectroscopy. The acquired raw 1H-MRS was quantified by using Totally Automatic Robust Quantitation in NMR (TARQUIN), assessed by experienced spectroscopists, and processed with adaptive wavelet noise suppression (AWNS). Metabolite concentrations were extracted as features, selected based on multiclass receiver operating characteristics, and finally used for identifying brain tumour types with supervised machine learning. The minority class was oversampled through the synthetic minority oversampling technique for comparison purposes. Post-noise-suppression 1H-MRS showed significantly elevated signal-to-noise ratios (P < .05, Wilcoxon signed-rank test), stable full width at half-maximum (P > .05, Wilcoxon signed-rank test), and significantly higher classification accuracy (P < .05, Wilcoxon signed-rank test). Specifically, the cross-validated overall and balanced classification accuracies can be improved from 81% to 88% overall and 76% to 86% balanced for the 1.5T cohort, whilst for the 3T cohort they can be improved from 62% to 76% overall and 46% to 56%, by applying Naïve Bayes on the oversampled 1H-MRS. The study shows that fitting-based signal-to-noise ratios of clinical 1H-MRS can be significantly improved by using AWNS with insignificantly altered line width, and the post-noise-suppression 1H-MRS may have better diagnostic performance for paediatric brain tumours.

Evidence for dopamine production and distribution of dopamine D2 receptors in the equine gastrointestinal mucosa and pancreas.

Insulin dysregulation in horses is characterised by hyperinsulinaemia and/or tissue insulin resistance and is associated with increased risk of laminitis. There is growing evidence in other species that dopamine attenuates insulin release from the pancreas; however, this has yet to be examined in horses. The present study aimed to identify whether there are cells capable of producing or responding to dopamine within the equine gastrointestinal mucosa and pancreas. Tissue samples were collected from the stomach, small and large intestines, and pancreas of six mature horses following euthanasia. Samples of stomach contents and faeces were also collected. Immunohistochemistry was performed to identify tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine production, and dopamine D2 receptors in tissue sections. Additional immunostaining for glucagon, insulin and chromogranin A was performed to identify α cells, ß cells and enteroendocrine cells, respectively. Gastric parietal cells expressed both TH and D2 receptors, indicating that they are capable of both producing and responding to dopamine. Dopamine was quantified in stomach contents and faeces by high-performance liquid chromatography with electrochemical detection, with similar concentrations found at both sites. Dopamine D2 receptors were expressed in duodenal epithelial cells but not more distally. A subset of enteroendocrine cells, located sporadically along the gastrointestinal tract, were found to be immunopositive for the D2 receptor. In pancreatic islets, TH was present in α cells, while D2 receptors were strongly expressed in ß cells and variably expressed in α cells. These findings are consistent with studies of other species; however, dynamic studies are required to further elucidate the role of dopamine in the modulation of insulin and glucagon secretion in horses. This descriptive study provides preliminary evidence for a potential role of dopamine to act as a paracrine messenger in the gastrointestinal mucosa and endocrine pancreas of horses.

Brain stem tumors in children less than 3 months: Clinical and radiologic findings of a rare disease.

PURPOSE: Brain stem tumors in children < 3 months at diagnosis are extremely rare. Our aim is to study a retrospective cohort to improve the understanding of the disease course and guide patient management. METHODS: This is a multicenter retrospective analysis across the European Society for Pediatric Oncology SIOP-E HGG/DIPG Working Group linked centers, including patients with a brainstem tumor diagnosed between 2009 and 2020 and aged < 3 months at diagnosis. Clinical data were collected, and imaging characteristics were analyzed blindly and independently by two neuroradiologists. RESULTS: Five cases were identified. No patient received any therapy. The epicenter of two tumors was in the medulla oblongata alone and in the medulla oblongata and the pons in three. For patients with tumor in equal parts in the medulla oblongata and the pons (n = 3), the extension at diagnosis involved the spinal cord; for the two patients with the tumor epicenter in the medulla oblongata alone (n = 2), the extension at diagnosis included the pons (n = 2) and the spinal cord (n = 1). Biopsy was performed in one patient identifying a pilocytic astrocytoma. Two patients died. In one patient, autopsy revealed a high-grade glioma (case 3). Three survivors showed either spontaneous tumor regression (n = 2) or stable disease (n = 1). Survivors were followed up for 10, 7, and 0.6 years, respectively. One case had the typical imaging characteristics of a dorsal exophytic low-grade glioma. CONCLUSIONS: No patient fulfilled the radiologic criteria defining a high-grade glioma. Central neuroradiological review and biopsy may provide useful information regarding the patient management.

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

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's Cancer North, British Division of the International Academy of Pathology.

A paradox of problems in accessing general practice: a qualitative participatory case study.

BACKGROUND: Despite longstanding problems of access to general practice, attempts to understand and address the issues do not adequately include perspectives of the people providing or using care, nor do they use established theories of access to understand complexity. AIM: To understand problems of access to general practice from the multiple perspectives of service users and staff using an applied theory of access. DESIGN AND SETTING: A qualitative participatory case study in an area of northwest England. METHOD: A community-based participatory approach was used with qualitative interviews, focus groups, and observation to understand perspectives about accessing general practice. Data were collected between October 2015 and October 2016. Inductive and abductive analysis, informed by Levesque et al's theory of access, allowed the team to identify complexities and relationships between interrelated problems. RESULTS: This study presents a paradox of problems in accessing general practice, in which the demand on general practice both creates and hides unmet need in the population. Data show how reactive rules to control demand have undermined important aspects of care, such as continuity. The layers of rules and decreased continuity create extra work for practice staff, clinicians, and patients. Complicated rules, combined with a lack of capacity to reach out or be flexible, leave many patients, including those with complex and/or unrecognised health needs, unable to navigate the system to access care. This relationship between demand and unmet need exacerbates existing health inequities. CONCLUSION: Understanding the paradox of access problems allows for different targets for change and different solutions to free up capacity in general practice to address the unmet need in the population.

Metabolite profiles of medulloblastoma for rapid and non-invasive detection of molecular disease groups.

BACKGROUND: The malignant childhood brain tumour, medulloblastoma, is classified clinically into molecular groups which guide therapy. DNA-methylation profiling is the current classification 'gold-standard', typically delivered 3-4 weeks post-surgery. Pre-surgery non-invasive diagnostics thus offer significant potential to improve early diagnosis and clinical management. Here, we determine tumour metabolite profiles of the four medulloblastoma groups, assess their diagnostic utility using tumour tissue and potential for non-invasive diagnosis using in vivo magnetic resonance spectroscopy (MRS). METHODS: Metabolite profiles were acquired by high-resolution magic-angle spinning NMR spectroscopy (MAS) from 86 medulloblastomas (from 59 male and 27 female patients), previously classified by DNA-methylation array (WNT (n = 9), SHH (n = 22), Group3 (n = 21), Group4 (n = 34)); RNA-seq data was available for sixty. Unsupervised class-discovery was performed and a support vector machine (SVM) constructed to assess diagnostic performance. The SVM classifier was adapted to use only metabolites (n = 10) routinely quantified from in vivo MRS data, and re-tested. Glutamate was assessed as a predictor of overall survival. FINDINGS: Group-specific metabolite profiles were identified; tumours clustered with good concordance to their reference molecular group (93%). GABA was only detected in WNT, taurine was low in SHH and lipids were high in Group3. The tissue-based metabolite SVM classifier had a cross-validated accuracy of 89% (100% for WNT) and, adapted to use metabolites routinely quantified in vivo, gave a combined classification accuracy of 90% for SHH, Group3 and Group4. Glutamate predicted survival after incorporating known risk-factors (HR = 3.39, 95% CI 1.4-8.1, p = 0.025). INTERPRETATION: Tissue metabolite profiles characterise medulloblastoma molecular groups. Their combination with machine learning can aid rapid diagnosis from tissue and potentially in vivo. Specific metabolites provide important information; GABA identifying WNT and glutamate conferring poor prognosis. FUNDING: Children with Cancer UK, Cancer Research UK, Children's Cancer North and a Newcastle University PhD studentship.

Exploring whether primary care networks can contribute to the national goal of reducing health inequalities: a mixed-methods study.

BACKGROUND: Significant health inequalities exist in England. Primary care networks (PCNs), comprised of GP practices, were introduced in England in 2019 with funding linked to membership. PCNs have been tasked with tackling health inequalities. AIM: To consider how the design and introduction of PCNs might influence their ability to tackle health inequalities. DESIGN AND SETTING: A sequential mixed-methods study of PCNs in England. METHOD: Linear regression of annual PCN-allocated funding per workload-weighted patient on income deprivation score from 2019-2023 was used. Qualitative interviews and observations of PCNs and PCN staff were undertaken across seven PCN sites in England (July 2020-March 2022). RESULTS: Across 1243 networks in 2019-2020, a 10% higher level of income deprivation resulted in £0.31 (95% confidence interval [CI] = £0.25 to £0.37), 4.50%, less funding per weighted patient. In 2022-2023, the same difference in deprivation resulted in £0.16 (95% CI = £0.11 to £0.21), 0.60%, more funding. Qualitative interviews highlighted that, although there were requirements for PCNs to tackle health inequalities, the policy design, and PCN internal relationships and maturity, shaped and sometimes restricted how PCNs approached this task locally. CONCLUSION: Allocated PCN funding has become more pro-poor over time, suggesting that the need to account for deprivation within funding models is understood by policymakers. The following additional approaches have been highlighted that could support PCNs to tackle inequalities: better management support; encouragement and support to redistribute funding internally to support practices serving more deprived populations; and greater specificity in service requirements.

Implementing the Additional Roles Reimbursement Scheme in seven English Primary Care Networks: a qualitative study.

BACKGROUND: The Additional Roles Reimbursement Scheme (ARRS) provides funding to Primary Care Networks (PCNs) in England to recruit additional staff into specified roles. The intention was to support general practice by recruiting an extra 26 000 staff by 2024, increasing access and easing workload pressures. AIM: To explore the establishment of the ARRS as part of PCNs' development to understand their role in supporting general practice. DESIGN AND SETTING: A longitudinal, qualitative case study involving seven geographically dispersed PCNs across England. METHOD: Data were collected from July 2020 to March 2022, including 91 semi-structured interviews and 87 h of meeting observations. Transcripts were analysed using the framework approach. RESULTS: Implementation of the ARRS was variable across the study sites, but most shared similar experiences and concerns. The COVID-19 pandemic had a significant impact on the introduction of the new roles, and significant variability was found in modes of employment. Cross-cutting issues included: the need for additional space to accommodate new staff; the inflexibility of aspects of the scheme, including reinvestment of unspent funds; and the need for support and oversight of employed staff. Perceived benefits of the ARRS include improved patient care and the potential to save GP time. CONCLUSION: The findings suggest the ARRS has potential to fulfil its objective of supporting and improving access to general practice. However, attention to operational requirements including appropriate funding, estates, and management of staff is important if this is to be realised, as is clarity for the scheme post-contract end in 2024.

Development of a body condition index to estimate adiposity in ponies and horses from morphometric measurements.

BACKGROUND: There is a high prevalence of obesity in ponies and pleasure horses. This may be associated with equine metabolic syndrome and an increased risk of laminitis. Body condition scoring (BCS) systems are widely used but are subjective and not very sensitive. OBJECTIVES: To derive a body condition index (BCI), based on objective morphometric measurements, that correlates with % body fat. STUDY DESIGN: Retrospective cohort study. METHODS: Morphometric measurements were obtained from 21 ponies and horses in obese and moderate body condition. Percentage body fat was determined using the deuterium dilution method and the BCI was derived to give the optimal correlation with body fat, applying appropriate weightings. The index was then validated by assessing inter-observer variation and correlation with % body fat in a separate population of Welsh ponies; and finally, the correlation between BCI and BCS was evaluated in larger populations from studies undertaken in Australia, the United Kingdom and the United States. RESULTS: The BCI correlated well with adiposity in the ponies and horses, giving a Pearson r value of 0.74 (P < 0.001); however, it was found to slightly overestimate the % body fat in leaner animals and underestimate in more obese animals. In field studies, the correlation between BCI and BCS varied particularly in Shetlands and miniature ponies, presumably due to differences in body shape. MAIN LIMITATIONS: Further work may be required to adapt the BCI to a method that is more applicable for Shetlands and miniature ponies. CONCLUSIONS: This BCI was able to provide an index of adiposity which compared favourably with condition scoring in terms of accuracy of estimating adiposity; and was more consistent and repeatable when used by inexperienced assessors. Therefore, this may be a useful tool for assessing adiposity; and may be more sensitive than condition scoring for tracking weight gain or weight loss in individual animals.

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.

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 .

A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies.

High plasma concentrations of insulin can cause acute laminitis. Ponies and horses with insulin dysregulation (ID) exhibit marked hyperinsulinemia in response to dietary hydrolyzable carbohydrates. Glucagon-like peptide-1 (GLP-1), an incretin hormone released from the gastrointestinal tract, enhances insulin release, and is increased postprandially in ponies with ID. The aim of this study was to determine whether blocking the GLP-1 receptor reduces the insulin response to a high glycemic meal. Five adult ponies were adapted to a cereal meal and then given two feed challenges 24 h apart of a meal containing 3 g/kg BW micronized maize. Using a randomized cross-over design all ponies received both treatments, where one of the feeds was preceded by the IV administration of a GLP-1 receptor blocking peptide, Exendin-3 (9-39) amide (80 µg/kg), and the other feed by a sham treatment of peptide diluent only. Blood samples were taken before feeding and peptide administration, and then at 30-min intervals via a jugular catheter for 6 h for the measurement of insulin, glucose, and active GLP-1. The peptide and meal challenge caused no adverse effects, and the change in plasma glucose in response to the meal was not affected (P = 0.36) by treatment: peak concentration 9.24 ±â€…1.22 and 9.14 ±â€…1.08 mmol/L without and with the antagonist, respectively. Similarly, there was no effect (P = 0.35) on plasma active GLP-1 concentrations: peak concentration 14.3 ±â€…1.36 pM and 13.7 ±â€…1.97 pM without and with the antagonist, respectively. However, the antagonist caused a significant decrease in the area under the curve for insulin (P = 0.04), and weak evidence (P = 0.06) of a reduction in peak insulin concentration (456 ±â€…147 µIU/mL and 370 ±â€…146 µIU/mL without and with the antagonist, respectively). The lower overall insulin response to the maize meal after treatment with the antagonist demonstrates that blocking the GLP-1 receptor partially reduced insulin production in response to a high starch, high glycemic index, diet. Using a different methodological approach to published studies, this study also confirmed that GLP-1 does contribute to the excessive insulin production in ponies with ID.

Horses and ponies are prone to suffer from laminitis if they produce too much insulin after eating a high-sugar/starch meal. Laminitis associated with high insulin is very painful and can result in the affected animals having to be put down. The reason why some ponies over-produce insulin is not known. However, we do know that small molecules produced in the upper intestine contribute to the problem. In this study we blocked the action of these molecules, to see if we could reduce the insulin released after a meal that was high in soluble carbohydrate (starch and sugar) content, in ponies. Using a specially designed drug, we were able to reduce insulin responses to the meal by over 20%. None of the ponies had any clinical problems in this study. This study helped us to explain why some animals produce excessive insulin; this compound may even have potential as a future therapy. However, whilst a promising finding, this effect was not as strong as it needs to be to help prevent laminitis in all animals. The next step is to test the drug at different doses, and under varying conditions, to see whether we can improve its performance.

Successfully targeting the cancer system with metronomics for medulloblastoma.

The prognosis of the patients with medulloblastoma who relapse after initial treatment including radiotherapy remains dismal. A recent study by Peyrl et al. in JAMA Oncology suggests that the metronomic multidrug combination used in the medulloblastoma European multitarget metronomic antiangiogenic trial (MEMMAT) given at relapse can improve long-term survival.

Primary care networks as a means of supporting primary care: findings from qualitative case study-based evaluation in the English NHS.

OBJECTIVES: This study aimed to evaluate primary care networks (PCNs) in the English National Health Service. We ask: How are PCNs constituted to meet their defined goals? What factors can be discerned as affecting their ability to deliver benefits to the community, the network as a whole and individual members? What outcomes or outputs are associated with PCNs so far? We draw policy lessons for PCN design and oversight, and consider the utility of the chosen evaluative framework. DESIGN AND SETTING: Qualitative case studies in seven PCN in England, chosen for maximum variety around geography, rurality and population deprivation. Study took place between May 2019 and December 2022. PARTICIPANTS: PCN members, staff employed in additional roles and local managers. Ninety-one semistructured interviews and approximately 87 hours of observations were undertaken remotely. Interview transcripts and observational field notes were analysed together using a framework approach. Initial codes were derived from our evaluation framework, with inductive coding of new concepts during the analysis. RESULTS: PCNs have been successfully established across England, with considerable variation in structure and operation. Progress is variable, with a number of factors affecting this. Good managerial support was helpful for PCN development. The requirement to work together to meet the specific threat of the global pandemic did, in many cases, generate a virtuous cycle by which the experience of working together built trust and legitimacy. The internal dynamics of networks require attention. Pre-existing strong relationships provided a significant advantage. While policy cannot legislate to create such relationships, awareness of their presence/absence is important. CONCLUSIONS: Networked approaches to service delivery are popular in many health systems. Our use of an explicit evaluation framework supports the extrapolation of our findings to networks elsewhere. We found the framework to be useful in structuring our study but suggest some modifications for future use.