East Kent Hospitals University NHS Foundation Trust

BACKGROUND Pressure-based physiological evaluation of coronary artery disease is well established, but its application is limited in left main coronary artery (LMCA) disease. Our aim was to investigate whether pressure-based indices are comparable in the left anterior descending (LAD) and left circumflex artery (LCx) branches of the LMCA, and if discordance is due to differences in microvascular function in these territories. METHODS Simultaneous measurements of coronary pressure and flow were made in patients with (1) isolated LMCA disease and (2) unobstructed coronary arteries. Fractional flow reserve, instantaneous wave-free ratio, and microvascular resistance reserve values in the LAD were compared with those of the LCx. RESULTS A total of 80 patients were enrolled (mean age 65±10 years, 56% male). In those with isolated LMCA disease, fractional flow reserve in the LAD was lower than in the LCx (0.74±0.11 versus 0.81±0.11; P <0.0001). Instantaneous wave-free ratio was also lower in the LAD (0.89 [0.76–0.92] versus 0.94 [0.88–0.97]; P <0.0001). The misclassification rates of functionally significant coronary disease, when these indices were measured in the LCx, were 21% for fractional flow reserve and 28% for instantaneous wave-free ratio. Microvascular resistance reserve was higher in the LAD than the LCx, in cohorts with diseased (3.57±1.40 versus 2.50±0.81; P <0.0001) or unobstructed LMCA (3.40±0.78 versus 2.47±0.68; P <0.0001). Microvascular resistance reserve in the LAD territory was similar regardless of whether the LMCA was obstructed or not ( P =0.56). Similarly, microvascular resistance reserve in the LCx territory was comparable between cohorts ( P =0.88). CONCLUSIONS Microvascular resistance in the LAD is lower than in the LCx territory. Consequently, fractional flow reserve and nonhyperemic pressure-derived indices are lower in the LAD than the LCx. These findings have important implications for how LMCA atheroma should be assessed in clinical practice and also suggest the need for territory-specific thresholds for defining abnormal microvascular function or epicardial conductance.

Dry eye disease (DED) is a multifactorial disorder that disturbs ocular surface equilibrium, considerably diminishing quality of life. Present therapies only offer symptomatic alleviation. Stem cell treatment, especially mesenchymal stem cells (MSCs), has surfaced as a viable approach for tissue regeneration and immunological regulation in DED. Preclinical and early clinical investigations indicate that MSCs can improve lacrimal gland functionality, diminish inflammation, and facilitate corneal regeneration. Nonetheless, obstacles persist in enhancing MSC viability, determining the optimal MSC source, and guaranteeing sustained therapeutic effectiveness. Additional extensive randomized clinical trials are required to confirm the efficacy of MSC-based therapies for severe DED.

Background & Aims Abdominal and thoracic aortic aneurysms (A/TAA) are a major cause of mortality in older adults. Most deaths post-A/TAA repair result from cardiovascular events, which may be preventable with cardiac rehabilitation (CR) – a multidisciplinary approach to cardiovascular recovery. The feasibility and acceptability of CR in A/TAA patients remain unknown. Methods This 1:1, non-blinded feasibility randomised trial compared CR to standard care (SC) after elective A/TAA repair at two UK tertiary centres. Patients <50 years, diagnosed with connective tissue disorders, or deemed too unfit for CR were excluded at screening. The CR group followed an 8-week structured programme focusing on medical risk reduction, supervised exercise, and lifestyle modification. Co-primary outcomes were enrolment (target: 60.0%) and CR compliance (target: 70.0%). Secondary outcomes included major cardiac events, cardiovascular biomarkers, echocardiography, lifestyle, and quality of life metrics. This trial was supported by a British Heart Foundation Grant (PG/13/98/30490). Results From September 2014 – September 2015, 159 patients were screened, 97 were eligible, and 68 (70.1%) were randomised (SC: 34, CR: 34). CR adherence was 61.8% (n=21), with 13 withdrawals, primarily due to travel and personal commitments (69.2%). At 36 weeks, CR participants maintained higher physical activity levels (40 min vs. 30 min, p = 0.042). Conclusion Recruiting patients after A/TAA repair to CR is feasible, with good adherence. Virtual or video-based CR may help overcome barriers related to accessing CR. Trial registration ISRCTN (65746249).

The concept of hypoglycaemic unawareness is often discussed in the literature in relation to diabetics on insulin treatment. Hypoglycaemic unawareness is a state in which patients fail to recognize neuroglycopenic symptoms and signs that could prompt the need to seek measures to reverse or treat low blood sugar readings. This can lead to serious dangers, as immediate action is vital to avert potentially life-threatening consequences. We present a finding of hypoglycaemic unawareness in a 27-year-old female with a long-term diagnosis of Von Gierke disease (a glycogen storage disorder (GSD)) who went on to be fitted with a continuous glucose monitoring (CGM) device to prevent the harmful effects of unrecognised hypoglycaemia. We have reviewed the burden and probable mechanism for the development of hypoglycaemic unawareness in this disorder and in other infrequently reported disorders for the education of health professionals and patients.

Introduction: Bronchoesophageal fistulas (BOF) have predominantly been found to result in a decreased quality of life and an increased rate of mortality, particularly due to their severe complications and difficult treatment. Case Presentation: This report discusses the case of a 71-year-old female who presented with shortness of breath and a continuous cough secondary to a fistula between the oesophagus and right bronchus on the background of squamous cell carcinoma (SCC). This patient was seen by oncologists for the treatment of her lung cancer after right middle and lower lobe lobotomies, which was then treated with radiotherapy. On admission, a computed tomography scan revealed that the patient had a BOF due to therapeutic radiotherapy for SCC. She underwent intervention from the gastrointestinal and respiratory physicians to treat the BOF. Oesophageal stent placement was performed for treatment; however, the BOF remained patent, so a bronchial stent was considered for insertion. While the patient was awaiting the bronchial stent, she died. Conclusion: This case highlights the complexities and challenges of BOFs, emphasising the need for further research and documentation to improve treatment strategies. More studies are needed to determine when oesophageal stenting is preferred over bronchial stenting and to evaluate the suitability and safety of dual stenting in both the oesophagus and bronchus.

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for ‘actionable’ genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

In this brief report, we present the findings of a survey which explores the learning curve that was achieved during the ‘Serial Lung Ultrasound in predicting the need for surfactant and Respiratory course in Preterm infants’ (SLURP) study. The aim of this survey was to evaluate the training lung ultrasound operators received in order to scan patients who were recruited into the SLURP study. The aim of the SLURP study was to validate the optimal lung ultrasound (LU) ‘cut off’ score using standard and extended LU zones that predict surfactant need in babies born ≤ 34 weeks on non-invasive respiratory support when clinicians had various levels of experience in LU. The study was a prospective observational study conducted between May 2023 to June 2024 in 3 neonatal intensive care units (NICUs) across the UK. A standardised lung ultrasound training programme was delivered across the 3 sites before starting the SLURP study which included an online module and 1 day of didactic lectures with face-to-face hands-on training. We performed a survey towards the end of the SLURP study to evaluate the learning curve of a significant number of inexperienced lung ultrasound operators participating in this study. The results of the survey showed that a structured training package alongside supervision developed clinicians’ ability to recognise common lung pathologies, perform scans independently and improve their scanning speed. Conclusion: The SLURP study was a major driving force in upskilling clinicians in LU across 3 UK NICUs. The study was unique in that it was the first prospective LU study in the UK, and it utilised a large proportion of staff with no prior LU experience. This survey demonstrates that the implementation of a structured training package and supervision led to a rapid learning curve for basic LU skills which can be replicated on a larger scale across the UK. What is Known: • Training and implementation of neonatal lung ultrasound (LU) remains inconsistent across neonatal units. • The effectiveness of neonatal LU training is infrequently evaluated and reported in the literature. What is New: • Novice neonatal LU operators can be trained within a short time frame through a structured training programme. • This training enabled the operators to perform high-quality scans, with reduced scanning time and differentiate between various neonatal lung pathologies.

Background and Importance NHS England identified a Commissioning for Quality and Innovation (CQUIN) indicator for Intravenous antibiotics to oral switch (IVTOS).After the pandemic the use of antibiotics increased in our Trust. Evidence shows benefits to IVTOS: increase bed capacity, optimise administration nurse’s time in preparing and administering antibiotics as well as reducing carbon footprint of medicines and reducing infections from the IV site. Aim and Objectives To identify the number of patients on intravenous (IVA) antimicrobials that could be eligible for oral switch, aligning with Commissioning for Quality and Innovation (CQUIN) indicators, as per national recommendations about IVTOS to be considered within 48 hours of the first dose of IV antimicrobial being administered. Material and Methods Snap tool designed to conduct audit on adult wards quarterly (aiming to include 100 patients’ each quarter).Patients had to be on IVA for a minimum of 48 hours. Collaboratively auditors were clinical nurses, pharmacist and junior doctors at each quarter, including 3–5 patients on IVA per ward. If the defined IVTOS criteria were met, the patient was considered eligible for IVTOS: AFEBRILE Temperature 36–38 for past 24 hours CLINICALLY IMPROVING Clinical signs and symptoms of infection are improving, reduction in NEWS score, WCC trending normal, CRP decreasing EATING AND DRINKING Patient is tolerating oral food or enteral feeding. No vomiting within last 24 hours. No evidence of malabsorption NO DEEP-SEATED INFECTION : Not at high-risk of deep-seated infection i.e. endocarditis, blood stream infection, empyema, meningitis, severe or necrotising soft-tissue infection, septic arthritis or undrained abscess Results A total of 443 patients were audited. The patients receiving IVA that met criteria for IVTOS were reduced. One in four patients remained on IVA past the criteria for switching in Q1. The year ended with 1 in 6 patients remaining on IVA past the criteria for switching. Conclusion and Relevance Collaborative approach auditing in a multidisciplinary way showed engagement and a reduction of patients eligible to IVTOS. References and/or Acknowledgements • National antimicrobial intravenous-to-oral switch (IVOS) criteria for early switch - GOV.UK (www.gov.uk) Improving Antimicrobial Use to Protect the Environment: What Is the Role of Infection Specialists? - PMC (nih.gov) British Journal of Nursing - Saving time when preparing intravenous antibiotics Conflict of Interest No conflict of interest

Hurthle cell carcinoma (HCC) is a rare neoplasm of the thyroid gland. There is paucity of medical literature available on this histological subtype compared to other thyroid disease and thus no consensus on optimal treatment. We conducted a single centre retrospective analysis of histologically diagnosed patients with HCC to demonstrate management of these cases and rate of recurrence. Data were collected for patients who were diagnosed with HCC between 2010 and 2022 in East Kent Hospitals University NHS Trust, UK. Our results found 8 patients diagnosed with HCC (2M:6F) with the most common presenting symptom being a neck lump. Six out of eight patients underwent radioiodine therapy post-surgery, although there is no consensus on benefits for this. None of our patients were found to have metastases or nodal involvement. Our analysis adds to the current literature on this rare topic and will be important when discussing treatment options of this disease in the future and could help to narrow the gap towards a consensus for treatment.

Purpose Swimming is one form of exercise advised to people with chronic low back pain (CLBP), there is limited research, however, supporting this recommendation and describing the experience and use of swimming in this population. The aim of this study was to explore the experience of people who use swimming to manage CLBP. Methods Semi-structure interviews were conducted with 14 swimmers who were using swimming to manage CLBP. Thematic analysis was used to analyse the interview data, and the themes were mapped onto the capability, opportunity, motivation and behaviour (COM-B) model to understand the behavioural factors. Results Five common themes were developed during the analysis: (1) My back pain journey; (2) Learning to swim with back pain; (3) How swimming looks for me; (4) What I gain from swimming; and (5) Keep calm and carry-on swimming. The themes mapped onto all three COM-B domains. Conclusions The participants found that swimming was a valuable self-management tool for CLBP. The findings from the thematic and COM-B analysis indicate that learning to swim with CLBP can be a complex journey, influenced by several interrelated behavioural factors. In the absence of multi-professional support, inclusive swimming communities and accessible swimming venues, swimming participation rates may be affected.

Background Up to 50% of kidney transplant patients are diagnosed with delayed graft function (DGF) following transplantation—the majority being linked to ischaemia reperfusion injury (IRI). DGF is traditionally defined as the requirement for dialysis during the first week after transplantation and is associated with inferior graft and patient outcomes. Local synthesis of complement components, largely by the renal tubule, plays a critical role in IRI. We have developed Mirococept, a membrane-targeted complement inhibitor, that can be administered to the donor kidney ex vivo prior to transplantation. After administration, Mirococept is retained in the donor organ, thereby minimising the risk of systemic side effects. We previously launched the EMPIRIKAL study aiming to evaluate the efficacy of Mirococept in reducing DGF in deceased-donor kidney transplantation (KT). The funding body recommended termination of the study to allow a dose-saturating study before the next stage of clinical evaluation. This was carried out in a porcine kidney model and led to a revised dosing regimen for EMPIRIKAL-2 (60–180 mg compared with 5–25 mg in the initial trial). The EMPIRIKAL-2 trial (REC 24/NE/0071) aims to identify the most safe and efficacious dose of Mirococept to reduce DGF rate in deceased-donor KT. Methods and analysis EMPIRIKAL-2 is a Phase IIa multicentre double-blind randomised controlled trial (RCT) with an initial safety run. Participants will be recruited from renal departments at National Health Service tertiary hospital sites in the UK. The purpose of the safety run is to assess the tolerance of each of the three proposed Mirococept doses (60, 120 or 180 mg), before the RCT begins. Three patients will be assigned to each treatment dose, starting from the lower dose. The safety run will be considered successful if at least one dose can be taken forward to the RCT for comparison to placebo. If safety is met, 144 participants (36 per arm excluding drop-outs) will be randomised to all doses meeting the safety criteria or placebo on a 1:1:1:1 basis. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. Enrolment in the RCT is anticipated to take approximately 12 months, and patients will be followed-up for 12 months. Ethics and dissemination The study has been approved by the Northeast - Newcastle and North Tyneside 2 Research Ethics Service Committee, REC reference 24/NE/0071. The results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals. Once published, a lay summary of the results will be made available to participants who request this information. Trial registration number ISRCTN14279222 . Registered on 4 July 2024. Protocol version 2.0 dated 9 May 2024.

89 Background: Darolutamide has authorisation for treatment of metastatic hormone sensitive prostate cancer (MHSPC) in combination with docetaxel chemotherapy and androgen deprivation therapy (triplet therapy) based on ARASENS trial results. The RECOMMEND study is a prospective real-world evaluation (RWE) of clinical outcomes in patients with MHSPC treated with this regimen in the UK. Methods: 318 patients were enrolled from 21 UK centres over 20 months from November 2022. Data cut-off was 14 August 2024. Disease characteristics were evaluated. Descriptive statistics have been used for patient demographics and PSA changes with treatment were analysed. Results: Patients on the study had a median age of 67 (range 38-84) years. Majority of the patients were de novo metastatic (91.2%). 68.2% have a Gleason score ≥8. 76 patients (23.9%) had next generation imaging (NGI) at diagnosis. Performance score was 0 (62.7%) or 1 (37.3%). The distribution of metastases (%) were: bone (84.9), nodal (60.4), lung (12.6) and liver (2.5). The median PSA level was 134 (range 1 to 5628) ng/mL at diagnosis. At the end of docetaxel chemotherapy median PSA was 0.35 ng/mL. PSA response see in the 226 patients who had completed 6 cycles of docetaxel chemotherapy at the data cut-off, PSA 50 was seen in 87.6% (198/226) and PSA 90 in 53.2%. PSA responses in those who only completed 4/5 cycles of docetaxel (n=14) did not significantly differ compared to those who completed all 6 cycles (PSA 50 p=0.445 and PSA 90 p-0.664). At 6 months from darolutamide initiation, quality of life (QoL) data is currently available for 173 patients, of these 88.4% reported either stable or improved QoL and 11.6% had a decline in QoL at the end of chemotherapy. Conclusions: The tolerability and efficacy profile of treatment with ADT+Darolutamide+Docetaxel in MHSPC in the RECOmMEnD study is similar to that reported in the ARASENS trial. The QoL data available for 173 patients to date reports either stable or improved QoL at 6 months for 88.4% cases. This provides important prospective RWE data, enabling patients and clinical teams to make informed choices in this setting.

Background The relationship between early cardiovascular dysfunction (CVD) in isolated traumatic brain injury (iTBI) and outcome has not been fully described. We aimed to (1) determine the prevalence and phenotype of CVD after iTBI in the hyper-acute phase and (2) compare treatment and outcomes in those with CVD vs non-CVD. Methods An observational cohort database study of severe iTBI patients (Head AIS 3+) at a level 1 trauma centre (2008–2019) and physician-led air ambulance service (2019–2020). CV dysfunction was defined as tachycardia or bradycardia, with hypotension. Physiology, laboratory results, 24-hour transfusion, and computer-topography (CT) findings were recorded. Outcomes were 28-day mortality and Glasgow Outcome Score (GOS). Results A total of 168 patients met inclusion criteria, average age 46 years (IQR 30–61), 77% male, median ISS 25 (IQR 17–29) with 51% Head AIS 5. Time from injury to pre-hospital assessment was 31 minutes (IQR 20–42) with 20% demonstrating CVD on initial observations. The CVD group were more shocked (lactate 6.1 (1.7–10.9) vs. 2.4 (1.4–3.3), P < 0.001) and coagulopathic (43% vs. 15%, P = 0.001). There was no difference in Head AIS or CT findings between groups, except frequency of hypoxic ischemic encephalopathy (HIE) (CVD: 21% vs. non-CVD: 1%, P < 0.001). A 24-hour transfusion was higher in CVD patients: 3 (0–8) vs. 0 (0–0) units, P < 0.001. Mortality was greater in CVD vs non-CVD iTBI (61% vs. 31%, P = 0.002), but in patients with AIS 5, there was no difference ( P = 0.262). One-third of CVD survivors (13/33) were discharged home, and 4/18 patients with recorded GOS had good neurological outcome. Conclusion One in five patients with severe iTBI develop early CVD, associated with increased mortality, coagulopathy, and HIE. However, mortality and neurological outcome is highly variable in those with CVD across the iTBI severity spectrum. Further research is needed to define the pathophysiology and optimal treatment to improve outcomes for this subgroup of iTBI.

Background There has been increased use of prehospital point-of-care ultrasound (PoCUS) by helicopter emergency medical services (HEMS) in recent years. Lack of governance structure and evidence of benefit have been described as major barriers to its implementation. This paper describes a novel approach to implementation of prehospital PoCUS and clinical governance framework in a UK HEMS. Methods A retrospective database review was undertaken at London’s Air Ambulance (LAA) from 1st September 2021 to 31st March 2023. All patients who had PoCUS examination were included. Scans were archived in a cloud-based server and reviewed weekly by expert clinicians. They were graded in adequacy, agreement between reviewer and clinician was recorded and fed back to the clinicians allowing continuous feedback learning. In-hospital diagnosis was sought for patients having the full Pump, Pleura and Pouring blood (PPPB) protocol. Cohen’s Kappa (ƙ) was calculated for inter-rater reliability. Sensitivity and specificity analysis was performed using 2 × 2 tables. Results LAA attended 3,068 missions. Our reviewers identified 701 PoCUS scanning encounters and 628 were included in the final analysis. Clinicians performed 420 scans for pneumothorax, 308 for free fluid and 305 pericardial effusions respectively. Majority of the population were male (85%) who sustained traumatic (93.5%) thoracic injuries (65%). Paramedics performed 29% of the scans. Reviewers deemed 83% of the scans of adequate quality. Inter-rater reliability between clinicians and reviewers was 0.6 for pericardial effusion, 0.67 for pneumothorax and 0.71 for free fluid respectively. A full PPPB protocol was performed in 52 patients out of which 46 were included. The sensitivity and specificity of PPPB protocol for diagnosis life-threatening injuries was 0.5 and 0.9 respectively. Conclusion Introduction of prehospital PoCUS in a HEM service utilizing high quality training, user-friendly workflow and image archiving system, robust governance framework and continuous feedback may be feasible allowing high quality ultrasound examinations. The bespoke PPPB protocol in prehospital may improve diagnosis of life-threatening injuries.

Alpelisib is a phosphatidylinositol 3-kinase inhibitor approved by the US Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α) mutation. In recent years a number of adverse effects have been observed to be associated with this therapy, the most notable of which is hyperglycemia. A literature search was conducted to include case studies, case series, systematic reviews, and meta-analyses within the last 10 years that evaluated patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. Hyperglycemia was a notable adverse effect that was found in the majority of patients without preexisting diabetes mellitus. Patients with hyperglycemia were in the high-risk groups of advanced age, prediabetes mellitus or history of insulin resistance, increased body mass index, increased blood monocyte count, and increased hemoglobin A1c (glycated hemoglobin). Hyperglycemia was manageable with antihyperglycemic agents and dose modification/discontinuation of alpelisib with no severe progression. Other notable adverse effects were rash, stomatitis, diarrhea, pneumonitis, reduced appetite, elevated liver enzymes, nausea, fatigue, and rare reports of diabetic ketoacidosis. This literature review aims to highlight the incidence and risk factors of alpelisib-induced hyperglycemia in greater depth.