RSS 1.0Women's and Child Health
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Promoting equitable genetic testing in ovarian cancer : the demonstration of improvement for molecular ovarian cancer testing (DEMO) projectParallel genetic testing (testing for both tumour and germline gene changes) after the diagnosis of ovarian cancer should be considered the standard of care and is crucial to support treatment decisions. The demonstration of improvement for molecular ovarian cancer testing (DEMO) project aimed to develop patient-focused tools to promote equitable genetic care in diverse communities with high proportions of patients with limited English proficiency and biopsy guidelines to address the variations in specimen quality in different geographical regions in the UK. Our three work packages (WP) aimed to promote awareness by addressing the information gaps in different community groups (WP1), develop infrastructure to evaluate the different tissue collection pathways in different regions (WP2) and support continuing professional development (CPD) to encourage best practices with the involvement of patients (WP3). Our output included a multimedia multilanguage information package with paired National Health Service-branded written materials to support genetic testing after ovarian cancer diagnosis (https://ovarian.org.uk/demo-uk/), a scalable database to enable a multisite audit of parallel genetic testing pathways and a collection of CPD events that had patient involvement as an essential component. In addition, we have collaborated with patient and community groups to contribute to a national consensus guidance on genetic testing in ovarian cancer. Our co-production work has been recognised by local and regional awards as an exemplar for patient and public involvement (PPI). This has supported the start of a legacy co-production group in gynaeoncology (https://www.dhlnetwork.com/gohildas) to address the critical unmet need for sustainable and equity-oriented PPI to advocate for underserved communities. The DEMO project has contributed to raising awareness of the importance of equitable genetic care in ovarian cancer. We will continue to build on this groundwork to support future quality improvement projects and research, with the ultimate goal of improving the outcomes of patients with ovarian cancer.
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Key clinical findings from the IMPROVE-UK quality improvement projects : an overviewIntroduction: Survival from ovarian cancer in the UK is poor compared with international comparators. The Ovarian Cancer Audit Feasibility Pilot demonstrated variation in 1-year and 5-year survival across the UK as well as significant variation in treatment rates. In 2020, IMPROVE-UK was established as the first major programme to address inequalities in ovarian cancer management and survival across the UK, to develop a legacy of best practice sharing across the country and to establish and evaluate quality improvement projects that could drive care at scale. Methods: Following a competitive process, seven quality improvement projects were funded to address inequalities in care and identify strategies to improve and equalise survival rates for all women with ovarian cancer in the UK, to address health inequalities from geography, age or ethnicity. Results: Projects addressed the secondary care diagnostic pathway, genomic testing, prehabilitation and improving treatment-related decision-making, particularly decisions for surgery. All seven projects at least partial achieved their aims with numerous areas across all projects identified where processes could be refined and incorporated into standard care to improve outcomes of women diagnosed with ovarian cancer. Dissemination of information regarding best practice has been undertaken. Conclusion: IMPROVE-UK was the first programme of its kind addressing significant inequalities of care in women with ovarian cancer. We demonstrate systematic quality improvement projects in ovarian cancer targeting various aspects of the treatment journey. Scaling up the results of the improve UK pilots is likely to improve survival in the UK and potentially internationally.
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The Family Concept in medical practiceNo abstract available.
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Proceedings of 20th ISPAD science school for physicians 2021.Proceedings of 20th ISPAD science school for physicians 2021
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Quality of life from cytoreductive surgery in advanced ovarian cancer: Investigating the association between disease burden and surgical complexity in the international, prospective, SOCQER-2 cohort study.Objective: To investigate quality of life (QoL) and association with surgical complexity and disease burden after surgical resection for advanced ovarian cancer in centres with variation in surgical approach. Design: Prospective multicentre observational study. Setting: Gynaecological cancer surgery centres in the UK, Kolkata, India, and Melbourne, Australia. Sample: Patients undergoing surgical resection (with low, intermediate or high surgical complexity score, SCS) for late-stage ovarian cancer. Main outcome measures: Primary: change in global score on the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30). Secondary: EORTC ovarian cancer module (OV28), progression-free survival. Results: Patients' preoperative disease burden and SCS varied between centres, confirming differences in surgical ethos. QoL response rates were 90% up to 18 months. Mean change from the pre-surgical baseline in the EORTC QLQ-C30 was 3.4 (SD 1.8, n = 88) in the low, 4.0 (SD 2.1, n = 55) in the intermediate and 4.3 (SD 2.1, n = 52) in the high-SCS group after 6 weeks (p = 0.048), and 4.3 (SD 2.1, n = 51), 5.1 (SD 2.2, n = 41) and 5.1 (SD 2.2, n = 35), respectively, after 12 months (p = 0.133). In a repeated-measures model, there were no clinically or statistically meaningful differences in EORTC QLQ-C30 global scores between the three SCS groups (p = 0.840), but there was a small statistically significant improvement in all groups over time (p < 0.001). The high-SCS group experienced small to moderate decreases in physical (p = 0.004), role (p = 0.016) and emotional (p = 0.001) function at 6 weeks post-surgery, which resolved by 6-12 months. Conclusions: The global QoL of patients undergoing low-, intermediate- and high-SCS surgery improved at 12 months after surgery and was no worse in patients undergoing extensive surgery. Tweetable abstract: Compared with surgery of lower complexity, extensive surgery does not result in poorer quality of life in patients with advanced ovarian cancer.
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Re-intervention and patient satisfaction rates following office radiofrequency endometrial ablation: a comparative retrospective study of 408 cases.This retrospective study assessed the efficacy and long-term satisfaction of radiofrequency endometrial ablation outside the context of clinical trials in 408 women, and compared the outcome between office-setting (211, 52%) and day-case procedures under general anaesthetics (197, 48%). The Kaplan Meir time-to-event analysis showed that the cumulative number of women undergoing surgical re-intervention was 32 with a probability of 9.4% (95% CI: 6.3 - 12.5%) at 2-years, and 45 with a probability of 14.5% (95% CI: 10.3 - 18.2%) at 5-years. There was no statistically significant difference in the re-intervention rate between office and day-case groups (HR = 0.7, 95% CI: 0.68 - 3.1, p = .3). The satisfaction rate, measured by Visual Analogue Scale, was not statistically different (p = .5) between office (109; 80.7%) and day-case (96; 82.8%) groups. This study showed lower surgical re-intervention rate than previously reported in observational studies, and high rates of long-term women satisfaction. The outcomes were similar in office and day-case settings.Impact statementWhat is already known on this subject? Previous studies have shown the safety and effectiveness of radiofrequency endometrial ablation for treating heavy periods. However, studies investigating it, outside clinical trials, either included a small sample size, a short-term follow-up, poor reporting so that it is impossible to judge whether some women underwent re-intervention in another centre, failed to discriminate in analysis between second-generation techniques, or assessed only short-term satisfaction.What do the results of this study add? This is the largest series reported from a single centre and the first study reporting long-term satisfaction in women, outside clinical trials. Surgical re-intervention was used as the primary outcome measure which is an objective measure rather than the change in the monthly flow which is rather subjective. More importantly, the study records the similarity, in the outcome and women's satisfaction rate, between office and day-case procedures under general anaesthetics.What are the implications of these findings for clinical practice and/or further research? Endometrial ablation service is widely implemented in office-setting in the UK. We hope the result of this study encourages implementation on a larger scale in office across centres in the world with its multiple advantages both to women and service alike.
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The evolving role of one-step nucleic acid amplification (OSNA) for the intra-operative detection of lymph node metastases: A diagnostic accuracy meta-analysisBackground: One Step Nucleic Acid Amplification (OSNA) assay has recently emerged as a rapid molecular diagnostic tool for the detection of lymph node (LN) metastases. It is a molecular technique that analyses the entire LN tissue using a reverse-transcriptase loop-mediated isothermal amplification reaction to detect tumour specific cytoceratin 19 mRNA. Aim: To ascertain the diagnostic accuracy of OSNA assay in detecting LN metastases amongst different types of malignancy. Design: We systematically searched MEDLINE, SCOPUS, ClinicalTrials.gov, and Cochrane Database, from inception up to August 2020. Quality assessment was performed using the Modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). We calculated pooled diagnostic indices using the random-effects model. Meta-regression and sub-group analyses were performed to address heterogeneity. Results: 31 studies were included in this meta-analysis, including four different types of cancer. The risk of bias and the overall quality of included studies was moderate to high. There was no evidence of publication bias. The pooled diagnostic odds ratio (DOR) for detecting LN metastases in gynaecological, head & neck/thyroid, gastrointestinal and lung cancer were 100.38, 76.17, 275.14, and 305.84, respectively. Conclusions: Our findings suggest that OSNA assay had a high diagnostic accuracy in detecting metastatic LNs in different types of malignancy. This evidence is constrained by the limited studies available for few tumour types and the rather high heterogeneity for few outcomes.
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The Major Constituent of Green Tea, Epigallocatechin-3-Gallate (EGCG), Inhibits the Growth of HPV18-Infected Keratinocytes by Stimulating Proteasomal Turnover of the E6 and E7 Oncoproteins.Epigallocatechin-3-gallate (EGCG), the primary bioactive polyphenol in green tea, has been shown to inhibit the growth of human papilloma virus (HPV)-transformed keratinocytes. Here, we set out to examine the consequences of EGCG treatment on the growth of HPV18-immortalised foreskin keratinocytes (HFK-HPV18) and an authentic HPV18-positive vulvar intraepithelial neoplasia (VIN) clone, focusing on its ability to influence cell proliferation and differentiation and to impact on viral oncogene expression and virus replication. EGCG treatment was associated with degradation of the E6 and E7 oncoproteins and an upregulation of their associated tumour suppressor genes; consequently, keratinocyte proliferation was inhibited in both monolayer and organotypic raft culture. While EGCG exerted a profound effect on cell proliferation, it had little impact on keratinocyte differentiation. Expression of the late viral protein E4 was suppressed in the presence of EGCG, suggesting that EGCG was able to block productive viral replication in differentiating keratinocytes. Although EGCG did not alter the levels of E6 and E7 mRNA, it enhanced the turnover of the E6 and E7 proteins. The addition of MG132, a proteasome inhibitor, to EGCG-treated keratinocytes led to the accumulation of the E6/E7 proteins, showing that EGCG acts as an anti-viral, targeting the E6 and E7 proteins for proteasome-mediated degradation.
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The chromatin landscape of high-grade serous ovarian cancer metastasis identifies regulatory drivers in post-chemotherapy residual tumour cellsDisease recurrence following chemotherapy is a major clinical challenge in ovarian cancer (OC), but little is known regarding how the tumour epigenome regulates transcriptional programs underpinning chemoresistance. We determine the single cell chromatin accessibility landscape of omental OC metastasis from treatment-naïve and neoadjuvant chemotherapy-treated patients and define the chromatin accessibility profiles of epithelial, fibroblast, myeloid and lymphoid cells. Epithelial tumour cells display open chromatin regions enriched with motifs for the oncogenic transcription factors MEIS and PBX. Post chemotherapy microenvironments show profound tumour heterogeneity and selection for cells with accessible chromatin enriched for TP53, TP63, TWIST1 and resistance-pathway-activating transcription factor binding motifs. An OC chemoresistant tumour subpopulation known to be present prior to treatment, and characterised by stress-associated gene expression, is enriched post chemotherapy. Nuclear receptors RORa, NR2F6 and HNF4G are uncovered as candidate transcriptional drivers of these cells whilst closure of binding sites for E2F2 and E2F4 indicate post-treated tumour having low proliferative capacity. Delineation of the gene regulatory landscape of ovarian cancer cells surviving chemotherapy treatment therefore reveals potential core transcriptional regulators of chemoresistance, suggesting novel therapeutic targets for improving clinical outcome.
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Friend or foe? The prognostic role of endometriosis in women with clear cell ovarian carcinoma. A UK population-based cohort study.Purpose: The prognostic role of endometriosis amongst women with ovarian clear cell carcinoma (OCCC) remains debatable. The aim of this study was to ascertain the effect of endometriosis on the prognosis of OCCC. Methods: A retrospective review of the medical records of 94 women diagnosed and treated for OCCC at a tertiary gynaecological cancer centre in the UK, spanning the period 2010-2019. Women were divided into two groups according to the presence of endometriosis. Clinico-pathological characteristics, progression-free survival (PFS) and overall survival (OS) were collated between the two groups. Results: Forty-six cases of endometriosis-free OCCC (Ef-OCCC) were collated with 48 cases of endometriosis-related OCCC (Er-OCCC). There was no significant difference between the two groups regarding age (p-value = 0.2), FIGO stage (p-value = 0.8), residual disease (RD) (p-value = 0.07), adjuvant chemotherapy agent (p-value = 0.4) or chemo-resistance (p-value = 0.9). The presence of endometriosis did not significantly affect either OS or PFS. The median OS in the Ef-OCCC and Er-OCCC was 55.00 (95% CI 32.00-189.00) and 71.00 (95% CI 47.00-97.00; log rank = 1.35, p-value = 0.2) months. The median PFS in the Ef-OCCC and Er-OCCC group was 39.00 (95% CI 19.00-143.00) and 39.00 (95% CI 19.00-62.00; log rank = 0.7, p-value = 0.4) months. Survival differences between the two groups were not significant after stratification analysis for independent prognosticators. Conclusion: Endometriosis was not independently associated with the prognosis of OCCC either in crude analysis or after stratification for stage and RD. Further larger, well-designed prospective studies are warranted to draw firmer conclusions on the intrinsic link between endometriosis and OCCC.
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Fluid and electrolyte therapy in childhood diabetic ketoacidosis management: A rationale for new national guideline.Fluid and electrolyte therapy in childhood diabetic ketoacidosis (DKA) management has been controversial. Previous National Institute for Health and Care Excellence (NICE) 2015 guidance advocated a restricted fluid regimen while more recent guidelines have advocated a more liberal approach to fluid replacement in DKA. At the core of the debate is the need to avoid developing cerebral oedema as a complication. Although subtle asymptomatic cerebral oedema is common in children presenting in DKA, clinically apparent cerebral oedema is rare and has been reported in approximately 0.5%-1% of DKA cases in children. Recent research evidence has shown that there was no clear evidence of a difference in rates of clinically apparent cerebral injury in children in DKA managed with a range of fluid volumes and rates of rehydration. In view of this, NICE has updated its guideline. In this paper, we review literature evidence underpinning the current understanding of the pathophysiology of cerebral oedema in children and discuss the rationale for the new NICE guidance.
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Fifteen-minute consultation: Practical use of continuous glucose monitoring.Type 1 diabetes is a self-managed condition. Regular monitoring of blood glucose (BG) levels has been the cornerstone of diabetes management. Finger prick BG testing traditionally has been the standard method employed. More recently, rapid advancements in the development of continuous glucose monitoring devices have led to increased use of technology to help children and young people with diabetes manage their condition. These devices have the potential to improve diabetes control and reduce hypoglycaemia especially if used in conjunction with a pump to automate insulin delivery. This paper aims to provide an update on main CGM devices available and practical considerations for doctors if they come across a child with diabetes who is using one of these devices.
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Effecting a national implementation project through distributed leadership in the West Midlands: rising to the spread challenge.We describe the utility and impact of a distributed leadership model to implement a National Health Service (NHS) England Academic Health Sciences national quality improvement programme, in the West Midlands. This model was adopted to address the inherent difficulties of implementing change in practice in a large geographical region with a diverse population of health service personnel. We report on the inclusion of a senior trainee as part of the implementation team, supported by a multidisciplinary clinical consultant team, with equal agency in decision making, acting as mentors and activators in the background.
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Reducing maternal infection after assisted vaginal birth in a diverse and deprived populationPostpartum maternal sepsis is a leading cause of maternal mortality and morbidity. A single dose of prophylactic antibiotics following assisted vaginal births has been shown to significantly reduce postpartum maternal infection in a landmark multicentre randomised controlled trial, which led to its national recommendation. This project aimed to improve the local implementation of prophylactic antibiotics following assisted vaginal births to reduce postnatal maternal infections.Using a prospectively collated birth register, data were collected retrospectively on prophylactic antibiotics administration and postnatal maternal infection rates after assisted vaginal births at the Sandwell and West Birmingham Hospitals National Health Service Trust in North-West Birmingham of the UK. The data were collected from routinely used electronic health records over three audit cycles (n=287) between 2020 and 2023.A mixed-method approach was used to improve the use of prophylactic antibiotics: (1) evidence-based journal clubs targeting doctors in training, (2) presentations of results after all three audit cycles at our and (3) expedited a formal change of local guidelines to support prophylactic antibiotics use.Prophylactic antibiotic administration increased from 13.2% (December 2021) to 90.7% (July 2023), associated with a reduction in maternal infection rates (18.2% when prophylaxis was given vs 22.2% when no prophylaxis was given). However, we observed a gradual increase in the overall postnatal maternal infection rates during the project period.Our repeat audit identified prophylactic antibiotics were regularly omitted after deliveries in labour ward rooms (59.3%), compared with 100% of those achieved in theatre. After further interventions, prophylactic antibiotics administration rates were comparable between these clinical areas (>90%) in 2023.Together, we have demonstrated a simple set of interventions that induced sustainable changes in practice. Further evaluation of other modifiable risk factors and infection rates following all deliveries is warranted in view of the gradual increase in the overall postnatal maternal infection rates.
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Diagnostic Accuracy of FEC-PET/CT, FDG-PET/CT, and Diffusion-Weighted MRI in Detection of Nodal Metastases in Surgically Treated Endometrial and Cervical Carcinoma.Preoperative nodal staging is important for planning treatment in cervical cancer and endometrial cancer, but remains challenging. We compare nodal staging accuracy of 18F-ethyl-choline-(FEC)-PET/CT, 18F-fluoro-deoxy-glucose-(FDG)-PET/CT, and diffusion-weighted-MRI (DW-MRI) with conventional morphologic MRI.
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Development of central precocious puberty following cannabinoid use for paediatric epilepsy: causal or coincidence?Research suggests a role for cannabidiol oil in managing certain forms of paediatric onset epilepsy. However, studies on the impact of cannabis on the hypothalamo-pituitary-gonadal (HPG) axis have conflicting results. Delta-9-tetrahydrocannabinol (Δ9-THC) acutely inhibits gonadotropin-releasing hormone in the hypothalamus, reducing testosterone levels by 65% in rhesus monkeys. Additionally, there have been reports of pubertal arrest and delayed puberty in male cannabis users. In contrast, other studies have reported higher testosterone levels following long-term cannabis use.A 2-year-old boy presented with testicular enlargement, increased penile length and growth of coarse pubic hair developing over 6 months. His mother procured cannabidiol oil online, which he started taking 7 months earlier for severe epilepsy refractory to medical management. Subsequent investigations confirmed central precocious puberty. While it is unclear whether the precocious puberty is a direct consequence of HPG axis activation by Δ9-THC, this case demonstrates a temporal association between cannabis use and development of precocious puberty.
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British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for genetic testing in epithelial ovarian cancer in the United KingdomStandard of care genetic testing has undergone significant changes in recent years. The British Gynecological Cancer Society and the British Association of Gynecological Pathologists (BGCS/BAGP) has re-assembled a multidisciplinary expert consensus group to update the previous guidance with the latest standard of care for germline and tumor testing in patients with ovarian cancer. For the first time, the BGCS/BAGP guideline group has incorporated a patient advisor at the initial consensus group meeting. We have used patient focused groups to inform discussions related to reflex tumor testing - a key change in this updated guidance. This report summarizes recommendations from our consensus group deliberations and audit standards to support continual quality improvement in routine clinical settings.
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Venous thromboembolism during neoadjuvant chemotherapy for ovarian cancerObjective: To determine the incidence of venous thromboembolism in patients with advanced epithelial ovarian cancer undergoing neoadjuvant chemotherapy in UK gynecological cancer centers. Secondary outcomes included incidence and timing of venous thromboembolism since cancer presentation, impact on cancer treatment, and mortality. Methods: All UK gynecological cancer centers were invited to participate in this multi-center retrospective audit through the British Gynecological Cancer Society. Data were captured on all patients undergoing neoadjuvant chemotherapy for International Federation of Gynecology and Obstetrics (FIGO) stage III/IV epithelial ovarian cancer within a 12-month period during 2021-2022. Patients on anticoagulation prior to cancer presentation were excluded. Patients who were diagnosed with venous thromboembolism between cancer presentation and commencing neoadjuvant chemotherapy were also excluded from our analysis of venous thromboembolism rates from neoadjuvant chemotherapy. Results: Fourteen UK gynecological cancer centers returned data on 660 eligible patients. The median age was 67 years (range 34-96). In total, 131/660 (19.8%) patients were diagnosed with venous thromboembolism from cancer presentation until discharge following cytoreductive surgery. Between commencing neoadjuvant chemotherapy and post-operative discharge, 65/594 (10.9%) patients developed venous thromboembolism (median 11.3%, IQR 5.9-11.3); 55/594 (9.3%) during neoadjuvant chemotherapy, 10/594 (1.7%) during post-operative admission. There was no significant difference across centers (p=0.47). Of these 65 patients, 44 (68%) were diagnosed with pulmonary embolism and 30 (46%) with deep-vein thrombosis (nine had both), including in major abdominal/pelvic vessels, with 36 (55%) presenting symptomatically and 29 (45%) diagnosed incidentally on imaging. Venous thromboembolism resulted in mortality (n=3/65, 5%), and delays/changes/cancelation of treatment (n=18/65, 28%). Conclusion: Across a large, representative sample of UK gynecological cancer centers, one in five patients undergoing neoadjuvant chemotherapy were diagnosed with a potentially preventable venous thromboembolism, including one in nine diagnosed after commencing chemotherapy. This led to adverse clinical consequences for one third, including delay to oncological treatment and mortality. This high venous thromboembolism rate justifies the consideration of thromboprophylaxis in this patient group.
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Coexistence of medium chain acyl-CoA dehydrogenase deficiency (MCADD) and type 1 diabetes (T1D): a management challenge.Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive fatty acid β-oxidation defect. The enzyme, medium chain acyl-CoA dehydrogenase is important in the breakdown of medium chain fats into acetyl-CoA to produce ketones. Ketones are used as an alternative energy source when glucose or hepatic glycogen stores become depleted during prolonged fasting. In MCADD during periods of fasting or acute illness, there are insufficient ketones to compensate for the glucose energy deficit, resulting in an hypoketotic hypoglycaemia alongside a build-up of fatty acids. This build-up of fatty acids can be neurotoxic and lead to altered brain function and even unexpected death. Management includes avoiding prolonged periods of starvation, consuming high carbohydrate drinks during periods of illness and in symptomatic patients, reversal of catabolism and sustained anabolism by provision of simple carbohydrates by mouth or intravenously. Coexistence of MCADD and type 1 diabetes (T1D) is rare, there is no causal association though there are some documented cases. A key goal of management in T1D is achievement of good glycaemic control to reduce risk of long-term complications. This can in some cases increase the risk of hypoglycaemia which can be catastrophic in the presence of MCAD.