Patient experiences of an ankle fracture and the most important factors in their recovery : a qualitative interview study

Objective The objective of this qualitative research study is to explore patient experiences of ankle fracture and the factors most important to them in recovery. Design Semistructured interviews exploring patient experiences of ankle fracture recovery at 16–23 weeks following injury. Interviews followed a topic guide and were recorded with an encrypted audio recorder and then transcribed verbatim. Thematic content analysis was used to identify themes in the data. Setting Individuals were recruited from a sample of participants of a UK-based clinical trial of immobilisation methods for ankle fracture (ISRCTN15537280 at the pre-results stage at time of writing). Interviews were conducted at the participants’ own homes or on a university campus setting. Participants A purposive sample was used to account for key variables of age, gender and fracture management. Participants recruited from the clinical trial sample were adults aged 18 years or over with a closed ankle fracture. Results Ten participants were interviewed, five of whom were female and six of whom needed an operation to fix their ankle fracture. The age range of participants was 21–75 years with a mean of 51.6 years. Eight themes emerged from the data during analysis; mobility, loss of independence, healthcare, psychological effects, social and family life, ankle symptoms, sleep disturbance and fatigue, and activities of daily living. Factors of importance to participants included regaining their independence, sleep quality and quantity, ability to drive, ability to walk without walking aids or weight-bearing restrictions, and radiological union. Conclusions The results of this research demonstrates the extensive impact of ankle fracture on individuals’ lives, including social and family life, sleep, their sense of independence and psychological well-being. The results of this study will enable an increased understanding of the factors of relevance to individuals with ankle fracture, allowing collection of appropriate outcomes in clinical studies for this condition. Ultimately these results will help formulate appropriate patient-centred rehabilitation plans for these patients

Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

Objective: The phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH). Subjects and methods: We sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype. Results: A genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years. Conclusions: In this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded

Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives: To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 µmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations

Fidelity in complex behaviour change interventions : a standardised approach to evaluate intervention integrity

Objectives: The aim of this study was to (1) demonstrate the development and testing of tools and procedures designed to monitor and assess the integrity of a complex intervention for chronic pain (COping with persistent Pain, Effectiveness Research into Self-management (COPERS) course); and (2) make recommendations based on our experiences. Design: Fidelity assessment of a two-arm randomised controlled trial intervention, assessing the adherence and competence of the facilitators delivering the intervention. Setting: The intervention was delivered in the community in two centres in the UK: one inner city and one a mix of rural and urban locations. Participants: 403 people with chronic musculoskeletal pain were enrolled in the intervention arm and 300 attended the self-management course. Thirty lay and healthcare professionals were trained and 24 delivered the courses (2 per course). We ran 31 courses for up to 16 people per course and all were audio recorded. Interventions: The course was run over three and a half days; facilitators delivered a semistructured manualised course. Outcomes: We designed three measures to evaluate fidelity assessing adherence to the manual, competence and overall impression. Results: We evaluated a random sample of four components from each course (n=122). The evaluation forms were reliable and had good face validity. There were high levels of adherence in the delivery: overall adherence was two (maximum 2, IQR 1.67–2.00), facilitator competence exhibited more variability, and overall competence was 1.5 (maximum 2, IQR 1.25–2.00). Overall impression was three (maximum 4, IQR 2.00–3.00). Conclusions: Monitoring and assessing adherence and competence at the point of intervention delivery can be realised most efficiently by embedding the principles of fidelity measurement within the design stage of complex interventions and the training and assessment of those delivering the intervention. More work is necessary to ensure that more robust systems of fidelity evaluation accompany the growth of complex interventions

A combination of nifedipine and octreotide treatment in an hyperinsulinemic hypoglycemic infant.

PublishedResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Galenos Publishing via the DOI in this record.Hyperinsulinemic hypoglycemia (HH) is the commonest cause of persistent hypoglycemia in the neonatal and infancy periods. Mutations in the ABCC8 and KCNJ11 genes, which encode subunits of the ATP-sensitive potassium channel in the pancreatic beta cell, are identified in approximately 50% of these patients. The first-line drug in the treatment of HH is diazoxide. Octreotide and glucagon can be used in patients who show no response to diazoxide. Nifedipine, a calcium-channel blocker, has been shown to be an effective treatment in a small number of patients with diazoxide-unresponsive HH. We report a HH patient with a homozygous ABCC8 mutation (p.W1339X) who underwent a near-total pancreatectomy at 2 months of age due to a lack of response to diazoxide and octreotide treatment. Severe hypoglycemic attacks continued following surgery, while the patient was being treated with octreotide. These attacks resolved when nifedipine was introduced. Whilst our patient responded well to nifedipine, the dosage could not be increased to 0.75 mg/kg/day due to development of hypotension, a reported side effect of this drug. Currently, our patient, now aged 4 years, is receiving a combination of nifedipine and octreotide treatment. He is under good control and shows no side effects. In conclusion, nifedipine treatment can be started in patients with HH who show a poor response to diazoxide and octreotide treatment.Sian Ellard is employed by the Exeter Clinical Research Facility and is a Wellcome Trust Senior Investigator. The genetic testing was funded by a research grant from the Medical Research Council

Pancreatic endocrine and exocrine function in children following near-total pancreatectomy for diffuse congenital hyperinsulinism.

Published onlineJournal ArticleCONTEXT: Congenital hyperinsulinism (CHI), the commonest cause of persistent hypoglycaemia, has two main histological subtypes: diffuse and focal. Diffuse CHI, if medically unresponsive, is managed with near-total pancreatectomy. Post-pancreatectomy, in addition to persistent hypoglycaemia, there is a very high risk of diabetes mellitus and pancreatic exocrine insufficiency. SETTING: International referral centre for the management of CHI. PATIENTS: Medically unresponsive diffuse CHI patients managed with near-total pancreatectomy between 1994 and 2012. INTERVENTION: Near-total pancreatectomy. MAIN OUTCOME MEASURES: Persistent hypoglycaemia post near-total pancreatectomy, insulin-dependent diabetes mellitus, clinical and biochemical (faecal elastase 1) pancreatic exocrine insufficiency. RESULTS: Of more than 300 patients with CHI managed during this time period, 45 children had medically unresponsive diffuse disease and were managed with near-total pancreatectomy. After near-total pancreatectomy, 60% of children had persistent hypoglycaemia requiring medical interventions. The incidence of insulin dependent diabetes mellitus was 96% at 11 years after surgery. Thirty-two patients (72%) had biochemical evidence of severe pancreatic exocrine insufficiency (Faecal elastase 1<100 µg/g). Clinical exocrine insufficiency was observed in 22 (49%) patients. No statistically significant difference in weight and height standard deviation score (SDS) was found between untreated subclinical pancreatic exocrine insufficiency patients and treated clinical pancreatic exocrine insufficiency patients. CONCLUSIONS: The outcome of diffuse CHI patients after near-total pancreatectomy is very unsatisfactory. The incidence of persistent hypoglycaemia and insulin-dependent diabetes mellitus is very high. The presence of clinical rather than biochemical pancreatic exocrine insufficiency should inform decisions about pancreatic enzyme supplementation

Primary outcome measures used in interventional trials for ankle fractures : a systematic review

Background Ankle fractures cause considerable pain, loss of function and healthcare resource use. High quality randomised controlled trials are required to evaluate the optimal management protocols for ankle fracture. However, there is debate regarding the most appropriate outcome measure to use when assessing patients with ankle fractures. The aim of this systematic review is to identify and summarise primary outcome measure use in clinical trials of non-pharmacological interventions for adults with an ankle fracture. Methods We performed comprehensive searches of the Medline, Embase, CINAHL, AMED and Cochrane CENTRAL databases, as well as ISRCTN and ClinicalTrials.gov online clinical trial registries on 19/06/2019 with no date limits applied. The titles and abstracts were initially screened to identify randomised or quasi-randomised clinical trials of non-pharmacological interventions for ankle fracture in adults. Two authors independently screened the full text of any articles which could potentially be eligible. Descriptive statistics we used to summarise the outcome measures collected in these articles including an assessment of trends over time. Secondary analysis included a descriptive summary of the multi-item patient reported outcome measures used in this study type. Results The searches returned a total of 3380 records. Following application of the eligibility criteria, 121 records were eligible for inclusion in this review. The most frequently collected primary outcome measures in this type of publication was the Olerud Molander Ankle Score, followed by radiographic and range of movement assessments. There was a total of 28 different outcome measures collected and five different multi-item, patient reported outcome measures collected as the primary outcome measure. There was a sequential increase in the number of this type of study published per decade since the 1980’s. Conclusion This review demonstrates the wide range of measurement methods used to assess outcome in adults with an ankle fracture. Future research should focus on establishing the validity and reliability of the outcome measures used in this patient population. Formulation of a consensus based core outcome set for adults with an ankle fracture would be advantageous for ensuring homogeneity across studies in order to meta-analyse trial results

Improved genetic testing for monogenic diabetes using targeted next-generation sequencing

addresses: Institute for Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, UK. [email protected]: PMCID: PMC3737433types: Journal Article; Research Support, Non-U.S. Gov'tOpen Access ArticleCurrent genetic tests for diagnosing monogenic diabetes rely on selection of the appropriate gene for analysis according to the patient's phenotype. Next-generation sequencing enables the simultaneous analysis of multiple genes in a single test. Our aim was to develop a targeted next-generation sequencing assay to detect mutations in all known MODY and neonatal diabetes genes

The impact of training non-physician clinicians in Malawi on maternal and perinatal mortality : a cluster randomised controlled evaluation of the enhancing training and appropriate technologies for mothers and babies in Africa (ETATMBA) project

Background: Maternal mortality in much of sub-Saharan Africa is very high whereas there has been a steady decline in over the past 60 years in Europe. Perinatal mortality is 12 times higher than maternal mortality accounting for about 7 million neonatal deaths; many of these in sub-Saharan countries. Many of these deaths are preventable. Countries, like Malawi, do not have the resources nor highly trained medical specialists using complex technologies within their healthcare system. Much of the burden falls on healthcare staff other than doctors including non-physician clinicians (NPCs) such as clinical officers, midwives and community health-workers. The aim of this trial is to evaluate a project which is training NPCs as advanced leaders by providing them with skills and knowledge in advanced neonatal and obstetric care. Training that will hopefully be cascaded to their colleagues (other NPCs, midwives, nurses). Methods/design: This is a cluster randomised controlled trial with the unit of randomisation being the 14 districts of central and northern Malawi (one large district was divided into two giving an overall total of 15). Eight districts will be randomly allocated the intervention. Within these eight districts 50 NPCs will be selected and will be enrolled on the training programme (the intervention). Primary outcome will be maternal and perinatal (defined as until discharge from health facility) mortality. Data will be harvested from all facilities in both intervention and control districts for the lifetime of the project (3–4 years) and comparisons made. In addition a process evaluation using both quantitative and qualitative (e.g. interviews) will be undertaken to evaluate the intervention implementation. Discussion: Education and training of NPCs is a key to improving healthcare for mothers and babies in countries like Malawi. Some of the challenges faced are discussed as are the potential limitations. It is hoped that the findings from this trial will lead to a sustainable improvement in healthcare and workforce development and training. Trial registration: ISRCTN6329415

Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Musters, C. J. M., Ieromina, O., Barmentlo, S. H., Hunting, E. R., Schrama, M., Cieraad, E., Vijver, M. G., & van Bodegom, P. M. Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities. Ecosphere, 10(11), (2019): e02910, doi:10.1002/ecs2.2910.Temperate aquatic communities are highly diverse and seasonally variable, due to internal biotic processes and environmental drivers, including human‐induced stressors. The impact of drivers on species abundance is supposed to differ fundamentally depending on whether populations are experiencing limitations, which may shift over the season. However, an integrated understanding of how drivers structure communities seasonally is currently lacking. In order to partition the effect of drivers, we used random forests to quantify interactions between all taxa and environmental factors using macrofaunal data from 18 agricultural ditches sampled over two years. We found that, over the agricultural season, taxon abundance became increasingly better predicted by the abundances of co‐occurring taxa and nutrients compared to other abiotic factors, including pesticides. Our approach provides fundamental insights in community dynamics and highlights the need to consider changes in species interactions to understand the effects of anthropogenic stressors.The authors are grateful to B. Schaub of Water Board Rijnland for his help, E. Gertenaar for assistance in the fieldwork, M. Wouterse for DOC measurements, and B. Koese for help with taxonomic identification of macrofaunal samples. CM designed the study, did the statistical modeling and analyses, and wrote the draft paper; OI did field sampling and taxonomic identification and constructed the datasets; OI and HB structured the data; EH, MS, ES, MV, and PvB contributed to the study design and the conceptual improvement of the manuscript; all authors substantially revised the subsequent drafts