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Structure-Based Discovery Targeting GSK-3α Reveals Potent Nanomolar Selective 4-Phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine Inhibitor with Promising Glioblastoma and CNS-Active Potential in Cellular Models
No full textGlycogen synthase kinase-3 (GSK-3) is linked with multiple CNS conditions, including glioblastoma (GBM). Compared to the GSK-3β isoform, structure-based inhibitor design targeting GSK-3α is limited. Virtual screening was employed to identify GSK-3α inhibitors with CNS-active potential. Using a GSK-3α homology model, an optimized protocol with three-dimensional (3D)-pharmacophore filtering and Glide-SP docking was used to screen the ZINC20 biogenic subset. From 14 compounds selected for binding assay validation, three novel hit compounds were identified, with 1 (4-phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine scaffold) exhibiting nanomolar activity against GSK-3α/β (IC50s ∼ 0.26 μM). Selectivity profiling (12 homologous kinases) revealed selectivity for GSK-3α/β and protein kinase A (PKA). Compound 1 was more potent against three GBM cell lines (cell viability IC50s = 3–6 μM at 72 h) compared to benchmark GSK-3 inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), and nontoxic to human astrocytes. It demonstrated CNS-active potential in an all-human in vitro blood–brain barrier GBM model, good in vitro metabolic stability, excellent predicted oral bioavailability and represents a promising lead compound for development
Transforming Care: The role of institutional violence
No full textIn this chapter, I explore the portrayal of people with learning disabilities in exposés of institutional violence. I argue that such representations present a key opportunity to demonstrate the link between structural violence and material violence. Yet the responses to this high-profile exposure have been the greater individualisation of binary notions of ‘vulnerable/dangerous’. Despite public outrage and change in policy in response to Winterbourne View, real change has yet to be realised. I argue that this is because of the reduced possibility to imagine alternatives, as notions of paternalism and protection remain. I explore how certain impositions are considered mundane when it comes to the containment and representation of this particular group of people who are rendered ‘not quite human’ due to implicit hierarchies not questioned within depictions of violence. Finally, I will use ethnographic and interview research to show how some types of violence are normalised and others rationalised and individualised as natural or provoked responses to ‘challenging behaviour’
Digital Competencies, Disaster Risk Reduction, and Education: An Introduction to the Digital Competency Framework to Develop Digital Pedagogical Competencies of Educators in Disaster Risk Reduction
No full textThe COVID-19 pandemic was a novel biological hazard that emerged in 2019 and significantly impacted various sectors of society. While sectors such as the economy and health were severely affected, the education sector was no stranger to the grave impact of the pandemic. While the pandemic called for regulations such as lockdowns and social distancing, the education sector was required to shift the classrooms into distance digital-based classrooms, which led to several grave impacts. In this context, the EU Erasmus + co-funded project titled INCLUsive Disaster Education (INCLUDE) was initiated to find solutions to these adverse impacts of the emergency shift towards digital education in the field of Disaster Risk Reduction (DRR) Education with partners from Lithuania, Japan, Sweden, and the United Kingdom. This chapter presents the project's final output, a digital competency framework for DRR educators. This framework is not just a tool, but a significant step in building the digital pedagogical competencies of educators, thereby enhancing the quality of DRR education. The methodology adopted to develop the framework was threefold. The process initiated with a literature review to trace the main types of digital pedagogical competencies. Next, the existing project output reports were evaluated to investigate the relevant digital competencies the DRR educators require. Finally, the framework was developed by matching the findings of the first two stages, and it was validated with the inputs of relevant experts. The literature review showed that knowledge, skills and attitudes have been recognised as critical in developing a digital competency framework. Therefore, the competency framework was developed based on those dimensions within the DRR education throughout the stages of preparation, execution and reflection. Further, the framework was based on the main virtues of responsiveness, adaptability and flexibility to consider the multidisciplinary and context-specific challenges of online DRR education. As a way forward, the research team recommends considering the role of institutions as the primary regulatory stakeholders in providing digital DRR education
Carboprost versus Oxytocin as the first-line treatment of primary postpartum haemorrhage (COPE): protocol for a phase IV, double-blind, double-dummy, randomised controlled trial and economic analysis
Get PDFIntroduction: Excessive bleeding after childbirth (postpartum haemorrhage, PPH) affects 5% of births and causes 75 000 maternal deaths worldwide annually. It is the leading cause of direct maternal deaths globally and continues to be a major cause of mortality in the UK. Oxytocin is the standard first-line treatment for atonic PPH. The PPH rate is increasing, and this may be partially related to the overuse of oxytocics in labour. Laboratory studies on myometrium suggest that repeated use of oxytocics leads to the saturation of oxytocin receptors and reduced therapeutic efficacy of oxytocin. Carboprost (a prostaglandin analogue) is usually reserved for second-line management of atonic PPH. A systematic review comparing the efficacy of carboprost and conventional uterotonics for PPH prophylaxis found that carboprost was associated with less blood loss, but around 15% of women experienced side effects. The study’s aim is to compare intramuscular carboprost with intravenous oxytocin for the initial treatment of PPH. In addition, to assess the cost-effectiveness of both treatments, participants’ views on the two treatments and the consent process. Methods and analysis: COPE is a double-blind, double-dummy, randomised controlled trial that aims to recruit 2000 women (1:1 allocation, stratified by mode of birth) across 20 hospitals in the UK. Due to the emergency nature of PPH, COPE uses a research without prior consent (RWPC) model. Randomisation and treatment will occur if eligibility criteria are met once bleeding starts. Postnatal consent will be sought for disclosure of identifiable data and continued follow-up. Clinical efficacy outcomes will be collected at 24 and 48 hours or at hospital discharge, if sooner. Questionnaires will also be collected at 24 hours and 4 weeks postrandomisation. Cost-effectiveness will be based on the incremental cost per quality-adjusted life-year, calculated from the perspective of the NHS and personal social services. Ethics and dissemination: This study has been approved by the Coventry and Warwickshire Research Ethics Committee (REC) (18/WM/0227) and the Health Research Authority. Results will be disseminated via peer-reviewed publications. Trial registration number: ISRCTN16416766
Journal update monthly top five
No full textThis month’s update is by the Royal Blackburn Hospital. We used a multimodal search strategy, drawing on free open-access medical education resources and literature searches. We identified the five most interesting and relevant papers (decided by consensus) and highlight the main findings, key limitations and clinical bottom line for each paper.
The papers are ranked as:
Worth a peek—interesting, but not yet ready for prime time.
Head turner—new concepts.
Game changer—this paper could/should change practice
ACT on Vaping: Pilot Randomized Controlled Trial of a Novel Digital Health App with Text Messaging for Young Adult Vaping Cessation
Get PDFBackground
There is no published evidence to support the efficacy of any digital vaping cessation program for young adults (YAs) at differing levels of readiness to quit. In this pilot randomized controlled trial, we evaluated the preliminary acceptability and efficacy of a program for vaping cessation based on acceptance and commitment therapy (ACT on Vaping), delivered via a smartphone app and text messaging.
Methods
YAs age 18-30 (n=61) were randomized 1:1 to ACT on Vaping (n=31) or incentivized text message control (n=30). Outcome data were collected at 3 months post-randomization. Results were compared against a priori benchmarks for acceptability (satisfaction of ≥ 3.5 on 5-point scale) and efficacy relative to control (meeting at least one of three): ≥ 1-point difference in Contemplation Ladder change scores; ≥ 5 percentage difference in 24-hour quit attempts, ≥ 5 percentage difference in cotinine-confirmed 30-day point prevalence abstinence (PPA) from all non-therapeutic nicotine/tobacco.
Results
Satisfaction with ACT on Vaping averaged 3.8, exceeding the acceptability benchmark. A higher proportion of participants in the ACT on Vaping arm reported a 24-hour quit attempt (87.5% vs. 75.9%), exceeding the efficacy benchmark. Both change in quit readiness (+0.96 in ACT on Vaping vs. +0.72 in control) and cotinine-confirmed 30-day PPA (4.2% in ACT on Vaping vs. 0% in control) were descriptively higher for ACT on Vaping but did not reach the benchmark level for efficacy.
Conclusions
ACT on Vaping had promising acceptability and preliminary efficacy. A fully-powered trial of ACT on Vaping is warranted to evaluate its efficacy.
Implications
Digital interventions are a promising yet under-researched approach for reaching and supporting young adults to quit vaping. This proof-of-concept pilot randomized controlled trial evaluated a novel mobile health application and associated text messaging program (ACT on Vaping) for young adult vaping cessation and found preliminary evidence for acceptability and efficacy relative to an incentivized text message control arm, warranting evaluation in a fully-powered trial as a next step
How can we strengthen the fragile relationship between families with mental health needs and children's social care?
No full textBackground:
Children of parents with a diagnosed mental illness are four times more likely to be removed by social services worsening parental mental health and introducing further trauma. A previous review synthesised the evidence on the views and experiences of parents with mental health problems (MHPs) and social care practitioners regarding the support provided.
Aim:
This commentary aims to critically appraise this review and expand upon its findings in the context of current evidence and practice. Methods: The quality of the review was assessed using the Joanna Briggs Institute Critical Appraisal Checklist.
Findings:
Despite potential biases in the review and some methodological issues in the included studies, the findings reveal important challenges in supporting parents with MHPs.
Conclusions:
Mutually trusting relationships between families and professionals are key in facilitating engagement. A strengths-based holistic approach would yield more positive outcomes for all. Adequate central government funding for local authorities is essential to deliver the care required
Post-traumatic stress symptoms, rumination, and posttraumatic growth in women with a traumatic childbirth experience
No full textBackground
Rumination can either prolong distress or foster growth following traumatic experiences like childbirth. This study investigates the association between post-traumatic stress symptoms and post-traumatic growth in women who underwent traumatic childbirth, examining the potential mediating role of two types of rumination – intrusive and deliberate.
Methods
A cross-sectional study in Northern Portugal from January 2020 to December 2021 surveyed 202 women with infants under 12 months, self-reporting traumatic childbirth experiences. Instruments included the City Birth Trauma Scale, Event-Related Rumination Inventory, and Post-traumatic Growth Inventory.
Results
Women experienced various childbirth-related traumatic events, with most showing post-traumatic stress symptoms for over three months. Approximately 60% met post-traumatic stress disorder criteria.
The results indicate that post-traumatic stress symptoms were positively correlated with post-traumatic growth, and both showed positive associations with intrusive rumination and deliberate rumination. Mediation analysis revealed deliberate rumination significantly mediated post-traumatic stress symptoms and post-traumatic growth, highlighting its role in trauma outcomes.
Conclusions
This study illuminated the pathway through which post-traumatic stress symptoms can lead to posttraumatic growth, highlighting the pivotal role of deliberate rumination in this association. This finding is essential for tailoring therapeutic interventions that effectively foster post-traumatic recovery and resilience, underscoring the importance of promoting deliberate rumination
ESPGHAN/NASPGHAN guidelines for treatment of irritable bowel syndrome and functional abdominal pain‐not otherwise specified in children aged 4–18 years
Get PDFObjectives: Abdominal pain related disorders of gut–brain interaction (AP‐DGBIs) such as irritable bowel syndrome (IBS) and functional abdominal pain‐not otherwise specified (FAP) are common conditions in children, significantly impacting quality of life. This treatment guideline for IBS and FAP in children of 4–18 years is a collaborative effort of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN and NASPGHAN). We aim to comprehensively review the current evidence on treatment options and offer evidence‐based recommendations with utility across all treatment settings worldwide, as well as to provide methodological directions for future research. Methods: The guideline development followed the “Grading of Recommendations Assessment, Development and Evaluation” (GRADE) approach, which is in accordance with the GRADE handbook and supported by the World Health Organization. The Guideline Development Group (GDG) comprised clinical experts, representing ESPGHAN, NASPGHAN, and Cochrane. Individual members have put forward a final consensus list of treatment options, which were then translated into “patient, intervention, comparison, outcome” (PICO) format options. Prospective agreement on decision thresholds for efficacy and safety outcomes was reached through a Delphi process among the GDG to support GRADEing of the literature. Consensus voting was used to finalize recommendations, and a treatment algorithm was developed. Results: Systematic literature searches for this output identified 86 original randomized controlled trials assessing treatment of IBS and FAP. Consensus was reached for 25 GRADEd recommendations. Ten best practice statements were formulated, and guidance for future research methodology was proposed. Conclusion: This guideline represents the first collaborative output of ESPGHAN and NASPGHAN on treatment options for AP‐DGBIs. Systematic review of the evidence has exposed major evidence gaps for the treatment of these disorders and incentivizes large pediatric trials, particularly on treatment options for which, to date, no evidence exists
Efficacy and safety of azacitidine in the treatment of elderly patients with higher-risk myelodysplastic syndromes.
No full textBackground: Hypomethylating agent Azacitidine (AZA) is standard of care for high-risk myelodysplastic syndromes (MDS). There is limited real-life data, however, characterizing the efficacy and safety profile of AZA in elderly patients. Methods: A retrospective chart review of high-risk MDS patients at our institution who received front-line AZA therapy. Patients who proceeded with stem cell transplant were excluded. Patients were stratified by age: ≥75 years (elderly) vs 80 years, 49 were younger (median age 69). ECOG 3 had 8.9% of older & 12.2% of younger patients. Median R-IPSS score was 6.5 in younger vs 5.8 in elderly groups. Median number of comorbidities was 5 vs 6 in younger and elderly groups. 98% of elderly and 90% of younger patients received the full dose of AZA (75mg/m2). Median number of AZA cycles was 8 [range 1-107] in elderly vs 6 [1-96] in younger cohorts. Treatment delays had 35.7% of elderly vs 30.6% of younger patients, most commonly due to infection complications. Neutropenia, thrombocytopenia and anemia rates were 29.3%, 29.2%, and 26.8% in younger vs 43.6%, 25.2%, and 34.5% in older patients. Overall response rate was 92.8% in younger and 96.4% of elder patients, including complete remission in 53.7% and 58.3%, respectively. Relapse disease occurred in 48.8% of younger and 40.0% of elder patients. Transformation to AML was found in 9.8% of younger and 19.2% of elderly patients. Median OS was 17.3 months in the younger subgroup vs 15.7 in the elder group and 11.9 months in patients over 80 years. Rates of death were: 53.1% in younger vs 46.4% in the elderly. Causes of death were similar, including disease progression, sepsis, febrile neutropenia, pneumonia. Conclusions: AZA monotherapy is well-tolerated and effective in higher-risk MDS, even in very elderly patients (>80 years). Compared to clinical trial, patients in the real-world setting have shorter survival, higher ECOG status, and more comorbidities, potentially contributing to inferior outcomes.
Clinical and hematological responses.
Efficacy parameter/Age cohort, years (N) <75 (49) ≥75 (56) p value Hematological Response (median [min-max]) Baseline Hemoglobin (g/L) 77 [46-100] 80 [56-140] 0.014 Best Hemoglobin achieved on AZA (g/L) 103 [74-152] 108 [70-155] NS Baseline ANC (x10 9 /L) 0.7 [0-27] 0.89 [0.02-58] NS Best ANC achieved on AZA (x10 9 /L) 1.4 [0.02-12.3] 2.2 [0.04-9.6] 0.047 Baseline platelet count (x10 9 /L) 49 [2-600] 57 [16-558] 0.029 Best achieved on AZA (x10 9 /L) 128 [21-474] 155 [10-767] NS Transformation to AML N, (%) 4 (9.8) 10 (18.2) NS Reached transfusion independence, N (%) 30 (61.0) 38 (67.2) NS Response rate, N (%) ORR 46 (92.8) 54 (96.4) NS Complete Response 26 (53.7) 33 (58.2) NS Partial Response 11 (22.0) 11 (20.0) NS Stable Disease 8 (17.1) 10 (18.2) NS Mean Leukemia Free Survival (years) 1.13 1.05 NS Mean Overall Survival (years) 1.14 1.05 N