Vasopressin potentiates corticotropin-releasing hormone-induced insulin release from mouse pancreatic β-cells

Arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) have both been implicated in modulating insulin secretion from pancreatic β-cells. In the present study, we investigated the insulin-secreting activities of AVP and CRH in wild-type and AVP VIb receptor knockout mice. Both neuropeptides stimulated insulin secretion from isolated mouse pancreatic islets. The response of islets to CRH was increased fourfold by concomitant incubation with a subthreshold dose of AVP that alone did not stimulate insulin secretion. Activation of the endogenously expressed M3 receptor by the cholinergic agonist carbachol also potentiated CRH-induced insulin secretion, indicating that the phenomenon may be pathway specific (i.e. Ca2+-phospholipase C) rather than agonist specific. The protein kinase C (PKC) inhibitors Ro-31-8425 and bisindolylmaleimide I attenuated the potentiating effect of AVP on CRH-stimulated insulin secretion and blocked AVP-stimulated insulin secretion. A possible interaction between the PKC and protein kinase A pathways was also investigated. The phorbol ester phorbol myristate acetate (PMA) stimulated insulin secretion, while the addition of both PMA and CRH enhanced insulin secretion over that measured with either PMA or CRH alone. Additionally, no AVP potentiation of CRH-stimulated insulin secretion was observed upon incubation in Ca2+-free Krebs–Ringer buffer. Taken together, the present study suggests a possible synergism between AVP and CRH to release insulin from pancreatic β-cells that relies at least in part on activation of the PKC signaling pathway and is dependent on extracellular Ca2+. This is the first example of a possible interplay between the AVP and CRH systems outside of the hypothalamic–pituitary–adrenal axis

The role of feedback and follow up in ambulance services: a qualitative interview study

Background: International studies have shown that the feedback that ambulance staff receive lacks structure, relevance, credibility and routine implementation (Cash, 2017; Morrison, 2017). Research from psychology and implementation science suggests that feedback can change professional behaviour, improve clinical outcomes and positively influence staff mental health (Ivers, 2012; Michie and Williams, 2003). The aim of this study was to explore the experience of ambulance staff regarding current feedback provision and their views on how feedback impacts on patient safety, staff wellbeing and professional development. Methods: A qualitative study conducted as part of a wider study of work-related wellbeing in ambulance staff. 25 semi-structured interviews with prehospital staff in a clinical role from a UK ambulance service sampled using theoretical sampling. Theoretically-informed thematic analysis using psychological theory linked to the self-motives framework for feedback-seeking behaviour. Results: Study participants viewed current feedback provision as inadequate and consistently expressed a desire for increased feedback. Participants raised concerns that inadequate feedback could negatively impact on patient safety by preventing learning from mistakes. Enhancing feedback provision was suggested to improve patient safety by supporting professional development and clinical decision-making, through facilitating reflection, knowledge acquisition and professional behaviour change. Similarly, participants thought that enhanced feedback could improve staff wellbeing by enabling closure and encouraging intra-professional dialogue and peer-support. The self-motives framework was useful in interpreting personal and professional motivators for feedback-seeking behaviour within the data. Conclusions: In accordance with previous research in this area, this study highlights prehospital clinicians’ strong desire for feedback. Furthermore, it suggests that enhancing prehospital feedback could improve patient safety by enriching clinical decision-making and supporting professional development, as well as promote staff wellbeing. Findings from this initial study will be used to guide a PhD programme to address this evidence gap

Understanding the support experiences of families of children with autism and sensory processing difficulties: A qualitative study.

Background: Support, such as information, advice and therapies, can play a vital role in the lives of families of autistic children. However, little is known about the support experiences of UK parents and carers. Aim: To explore experiences of and access to support for families of children with autism and sensory processing difficulties, from the perspective of parents and carers. Methods: Semi‐structured, timeline‐assisted interviews were conducted with parents/carers of 30 children aged 5–11, exploring experiences of support. Framework analysis was used to identify themes in the interview data. Results: Support varied widely and was not accessed equitably. Specialist autism support, together with support from other parents and voluntary organizations, was perceived as more useful than statutory and nonspecialist provision. Unmet support needs included an ongoing point of contact for information and advice for parents, and access to direct therapy and specialist mental health provision for children

Exploring critical intervention features and trial processes in the evaluation of sensory integration therapy for autistic children

Background: We evaluated the clinical and cost-effectiveness of manualised sensory integration therapy (SIT) for autistic children with sensory processing difficulties in a two-arm randomised controlled trial. Trial processes and contextual factors which may have affected intervention outcomes were explored within a nested process evaluation. This paper details the process evaluation methods and results. We also discuss implications for evaluation of individual level, tailored interventions in similar populations. Methods: The process evaluation was conducted in line with Medical Research Council guidance. Recruitment, demographics, retention, adherence, and adverse effects are reported using descriptive statistics. Fidelity of intervention delivery is reported according to the intervention scoring manual. Qualitative interviews with therapists and carers were undertaken to explore the acceptability of the intervention and trial processes. Qualitative interviews with carers explored potential contamination. Results: Recruitment, reach and retention within the trial met expected thresholds. One hundred thirty-eight children and carers were recruited (92% of those screened and 53.5% of those who expressed an interest) with 77.5% retained at 6 months and 69.9% at 12 months post-randomisation. The intervention was delivered with structural and process fidelity with the majority (78.3%) receiving a ‘sufficient dose’ of intervention. However, there was considerable individual variability in the receipt of sessions. Carers and therapists reported that trial processes were generally acceptable though logistical challenges such as appointment times, travel and COVID restrictions were frequent barriers to receiving the intervention. No adverse effects were reported. Conclusions: The process evaluation was highly valuable in identifying contextual factors that could impact the effectiveness of this individualised intervention. Rigorous evaluations of interventions for autistic children are important, especially given the limitations such as limited sample sizes and short-term follow-up as faced by previous research. One of the challenges lies in the variability of outcomes considered important by caregivers, as each autistic child faces unique challenges. It is crucial to consider the role of parents or other caregivers in facilitating access to these interventions and how this may impact effectiveness. Trial registration: This trial is registered as ISRCTN14716440. August 11, 2016

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis

Endovascular strategy or open repair for ruptured abdominal aortic aneurysm: one-year outcomes from the IMPROVE randomized trial.

AIMS: To report the longer term outcomes following either a strategy of endovascular repair first or open repair of ruptured abdominal aortic aneurysm, which are necessary for both patient and clinical decision-making. METHODS AND RESULTS: This pragmatic multicentre (29 UK and 1 Canada) trial randomized 613 patients with a clinical diagnosis of ruptured aneurysm; 316 to an endovascular first strategy (if aortic morphology is suitable, open repair if not) and 297 to open repair. The principal 1-year outcome was mortality; secondary outcomes were re-interventions, hospital discharge, health-related quality-of-life (QoL) (EQ-5D), costs, Quality-Adjusted-Life-Years (QALYs), and cost-effectiveness [incremental net benefit (INB)]. At 1 year, all-cause mortality was 41.1% for the endovascular strategy group and 45.1% for the open repair group, odds ratio 0.85 [95% confidence interval (CI) 0.62, 1.17], P = 0.325, with similar re-intervention rates in each group. The endovascular strategy group and open repair groups had average total hospital stays of 17 and 26 days, respectively, P < 0.001. Patients surviving rupture had higher average EQ-5D utility scores in the endovascular strategy vs. open repair groups, mean differences 0.087 (95% CI 0.017, 0.158), 0.068 (95% CI -0.004, 0.140) at 3 and 12 months, respectively. There were indications that QALYs were higher and costs lower for the endovascular first strategy, combining to give an INB of £3877 (95% CI £253, £7408) or €4356 (95% CI €284, €8323). CONCLUSION: An endovascular first strategy for management of ruptured aneurysms does not offer a survival benefit over 1 year but offers patients faster discharge with better QoL and is cost-effective. CLINICAL TRIAL REGISTRATION: ISRCTN 48334791

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Background: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.Aim: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.Methods: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy.Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].Conclusion: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.Peer reviewe

ARTICLEAssociation of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk