Now showing items 1-20 of 398

    • The relationship between general practitioner movement behaviours with burnout and fatigue

      Biddle, G J H (2024-02-16)
      Background: Physical inactivity is associated with feelings of burnout and fatigue, which in turn are associated with reduced performance among healthcare practitioners. This study explored movement behaviours of general practitioners (GPs) and the association between these behaviours with burnout and fatigue. Methods: GPs in Northern Ireland were asked to wear a thigh-worn accelerometer for seven days and complete validated questionnaires to assess the association between daily number of steps, time spent sitting and standing with feelings of burnout and fatigue. Results: Valid accelerometer data were obtained from 47 (77.0%) participants. Average workday sitting time, standing time and number of steps were 10.6 h (SD 1.5), 3.8 h (SD 1.3), and 7796 steps (SD 3116) respectively. Participants were less sedentary (8.0 h (SD 1.6)) and more active (4.7 h (SD 1.4) standing time and 12,408 steps (SD 4496)) on non-workdays. Fourteen (30.4%) participants reported burnout and sixteen (34.8%) reported severe fatigue. There were no significant associations between sitting, standing and step counts with burnout or fatigue (p > 0.05). Conclusion: GPs were less active on workdays compared to non-workdays and exhibited high levels of sitting. Feelings of burnout and fatigue were highly prevalent, however movement behaviours were not found to be associated with burnout and fatigue. Given the increased sedentariness among GPs on workdays compared to non-workdays, GPs should consider how they can improve their movement behaviours on workdays to help optimise their wellbeing.
    • Participatory translational science of neurodivergence: model for attention-deficit/hyperactivity disorder and autism research

      Balwani, Beta (2024-02-16)
      Background: There are increasing calls for neurodivergent peoples' involvement in research into neurodevelopmental conditions. So far, however, this has tended to be achieved only through membership of external patient and public involvement (PPI) panels. The Regulating Emotions - Strengthening Adolescent Resilience (RE-STAR) programme is building a new participatory model of translational research that places young people with diagnoses of attention-deficit hyperactivity disorder (ADHD) and autism at the heart of the research team so that they can contribute to shaping and delivering its research plan. Aims: To outline the principles on which the RE-STAR participatory model is based and describe its practical implementation and benefits, especially concerning the central role of members of the Youth Researcher Panel (Y-RPers). Method: The model presented is a culmination of a 24-month process during which Y-RPers moved from advisors to co-researchers integrated within RE-STAR. It is shaped by the principles of co-intentionality. The account here was agreed following multiple iterative cycles of collaborative discussion between academic researchers, Y-RPers and other stakeholders. Results: Based on our collective reflections we offer general guidance on how to effectively integrate young people with diagnoses of ADHD and/or autism into the core of the translational research process. We also describe the specific theoretical, methodological and analytical benefits of Y-RPer involvement in RE-STAR. Conclusions: Although in its infancy, RE-STAR has demonstrated the model's potential to enrich translational science in a way that can change our understanding of the relationship between autism, ADHD and mental health. When appropriately adapted we believe the model can be applied to other types of neurodivergence and/or mental health conditions.
    • Translating trial results into interpretable risk estimates: Systematic analysis of cardiorenal outcome trials of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors Authors

      Davies, Melanie J; Zaccardi, Francesco (2023-12-20)
      Background and aims: In a randomised controlled trial (RCT), the between-arm difference in the average probability of an event per unit of time (i.e., yearly incidence risk difference, YIRD) is an easy-to-interpret treatment effect metric. We aimed to quantify the YIRD in cardiorenal RCTs of GLP-1RAs or SGLT-2is. Methods and results: We digitally searched for RCTs published up to March 1st, 2023, including subjects with type 2 diabetes randomised to GLP-1RAs or SGLT-2is and investigating cardiorenal outcomes or death. We extracted information from Kaplan-Meier (KM) plots to obtain time-to-event individual data and estimate within-arm yearly incidence risk and YIRD. Data from 19 RCTs (28 kM plots) were analysed: comparing treatment to placebo, in GLP-1RA RCTs the YIRD ranged from 0.2 % (95 % CI: -0.7 %, 1.1 %) to -1.9 % (-3.1, -0.7), for primary outcome; and from -0.2 % (-0.5, 0.2) to -0.4 % (-0.7 %, -0.0 %), for mortality. With the exception of SOLOIST-WHF (YIRD 11.9 % for primary outcome), corresponding estimates in SGLT-2is RCTs were: from -0.1 % (-0.4, 0.1) to -5.0 % (-7.7, -2.6), for primary outcome; and from -0.1 % (-0.2, 0.1) to -1.9 % (-4.4 %, 0.6 %), for mortality. Conclusion: The YIRD metric complements other relative treatment effect estimates and helps quantify the absolute benefit of GLP-1RAs and SGLT-2is.
    • Point-of-care ultrasound is a useful adjunct tool to a clinician's assessment in the evaluation of severe hyponatraemia

      Al Alaisi, Salam; Coats, Timothy; Levy, Miles; Melson, Eka; Rahman, Faizanur; Rahman, Latif; Reddy, Narendra; Sardar, Muhammad; Shafiq, Shahriar (2024-01-16)
      Introduction: Hyponatraemia is the most common electrolyte disorder in inpatients resulting mainly from an imbalance in water homeostasis. Intravascular fluid status assessment is pivotal but is often challenging given multimorbidity, polypharmacy and diuretics use. We evaluated the utility of point-of-care ultrasound (POCUS) as an adjunct tool to standard practice for fluid assessment in severe hyponatraemia patients. Methods: Patients presenting with severe hyponatremia (Serum Sodium [Na] < 120 mmol/L; Normal range: 135-145 mol/L), managed by standard care were included. Hyponatraemia biochemistry work-up and POCUS examination were undertaken. Both clinician and POCUS independently assigned one of the three fluid status groups of hypovolaemia, hypervolaemia or euvolaemia. The final diagnosis of three fluid status groups at admission was made at the time of discharge by retrospective case review. Clinician's (standard of care) and POCUS fluid assessments were compared to that of the final diagnosis at the time of discharge. Results: n = 19 patients were included. Median Na on admission was 113 mmol/L (109-116), improved to 129 ± 3 mmol/L on discharge. POCUS showed the higher degree of agreement with the final diagnosis (84%; n = 16/19), followed by the clinician (63%; n = 12/19). A trend towards higher accuracy of POCUS compared to clinician assessment of fluid status was noted (84% vs. 63%, p = 0.1611). Biochemistry was unreliable in 58% (n = 11/19) likely due to renal failure, polypharmacy or diuretic use. Inappropriate emergency fluid management was undertaken in 37% (n = 7/19) of cases based on initial clinician assessment. Thirst symptom correlated to hypovolaemia in 80% (4/5) cases. Conclusion: As subjective clinical and biochemistry assessments of fluid status are often unreliable due to co-morbidities and concurrent use of medications, POCUS can be a rapid objective diagnostic tool to assess fluid status in patients with severe hyponatraemia, to guide accurate emergency fluid management.
    • Improving self-management behaviour through a digital lifestyle intervention: An internal pilot study

      Davies, Melanie; Graham-Brown, Matthew P M; Lightfoot, Courtney; Vadaszy, Noemi (2024-01-31)
      Background: Self-management is a key component of successful chronic kidney disease (CKD) management. Here, we present the findings from the internal pilot of a multicentre randomised controlled trial (RCT) aimed to test the effect of a digital self-management programme ('My Kidneys & Me' (MK&M)). Methods: Participants (aged ≥18 years and CKD stages 3-4) were recruited from hospital kidney services across England. Study processes were completed virtually. Participants were randomised 2:1 to either intervention (MK&M) or control group. The first 60 participants recruited were included in a 10-week internal pilot which assessed study feasibility and acceptability against pre-specified progression criteria: 1) eligibility and recruitment, acceptability of 2) randomisation and 3) outcomes, 4) MK&M activation, and 5) retention and attrition rates. Semi-structured interviews further explored views on trial participation. Results: Of the 60 participants recruited, 41 were randomised to MK&M and 19 to control. All participants completed baseline measures and 62% (n=37) completed post-intervention outcome measures. All progression criteria met the minimum thresholds to proceed. Nine participants were interviewed. The themes identified were satisfaction with study recruitment processes (openness to participate, reading and agreeing to "terms and conditions"), acceptability of study design (remote study participation, acceptability of randomisation, completion of online assessment(s)), and methods to improve recruitment and retention (personalised approach, follow-up communication). Conclusion: This internal pilot demonstrated the feasibility and acceptability of a virtually run RCT. Progression criteria thresholds to proceed to the definitive RCT were met. Areas for improvement were identified and protocol amendments were made to improve trial delivery.
    • Impact of weight loss and weight gain trajectories on body composition in a population at high risk of type 2 diabetes: a prospective cohort analysis

      Arsenyadis, F; Biddle, G J H; Davies, M J; Henson, J; Papamargaritis, D; Webb, David R (2024-03)
      Aim: In a primary care population at high risk of type 2 diabetes, 24-month weight change trajectories were used to investigate the impact of weight cycling on fat mass (FM) and fat-free mass (FFM). Materials and methods: Cohort data from the Walking Away from Type 2 Diabetes trial was used, which recruited adults at-risk of type 2 diabetes from primary care in 2009/10. Annual weight change trajectories based on weight loss/gain of ≥5% were assessed over two 24-month periods. Body composition was measured by bioelectrical impedance analysis. Repeated measures were analysed using generalized estimating equations with participants contributing up to two 24-month observation periods. Results: In total, 622 participants were included (average age = 63.6 years, body mass index = 32.0 kg/m2 , 35.4% women), contributing 1163 observations. Most observations (69.2%) were from those that maintained their body weight, with no change to FM or FFM. A minority (4.6% of observations) lost over 5% of body weight between baseline and 12 months, which was then regained between 12 and 24 months. These individuals regained FM to baseline levels, but lost 1.50 (0.66, 2.35) kg FFM, adjusted for confounders. In contrast, those that gained weight between baseline and 12 months but lost weight between 12 and 24 months (5.5% of observations) had a net gain in FM of 1.70 (0.27, 3.12) kg with no change to FFM. Conclusion: Weight cycling may be associated with a progressive loss in FFM and/or gain in FM in those with overweight and obesity at-risk of type 2 diabetes.
    • Accreditation of antimicrobial stewardship programmes: addressing a global need to tackle antimicrobial resistance

      Jenkins, David (2024-02-01)
      Accreditation of healthcare services provides quality assurance of hospital practice to support safe and effective care for patients. Accreditation programmes focused on antimicrobial stewardship (AMS) have been developed in high-income countries (HIC) and recently the WHO has developed a toolkit to support AMS practice in low and middle-income (LMIC) countries. BSAC has developed their Global Antimicrobial Stewardship Accreditation Scheme (GAMSAS) for hospitals based on globally applicable standards. GAMSAS aims to support healthcare organizations to build measurable AMS programmes and to support spread of best practice. GAMSAS involves a desktop assessment by BSAC experts followed by a hospital visit to gather further insight into how a hospital's AMS programme operates. A final report of compliance with the GAMSAS standards and a recommendation about accreditation at one of three levels is formally approved at a GAMSAS panel meeting involving well-established global experts in AMS. The BSAC GAMSAS team reflect on progress during the first year and ambitions for future spread.
    • What is the pipeline for future medications for obesity?

      Davies, Melanie J; Melson, Eka; Papamargaritis, Dimitris; Uzma, Ashraf (2024-02-01)
      Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.
    • Induction implications: shaping the competence and confidence of junior doctors within complex medical specialties

      Al Saoudi, Tareq; Bhardwaj, Neil; Chawla, Kanika; Dennison, Ashley; Garcia, Guiseppe; Isherwood, John; Khasawneh, Farah; Pollard, Christina A (2023-12-19)
      Introduction The newly qualified junior doctors in the United Kingdom face challenges due to their limited experience and unfamiliarity with their rotations. We aim to share the experience of establishing a hepato-pancreato-biliary (HPB) surgery-specific induction program at the University Hospitals of Leicester NHS Trust and assess its impact on doctors' knowledge and experience. Methods A booklet was distributed to new junior doctors, and a two-hour structured teaching session was also conducted, with pre- and post-session assessments using multiple-choice questions and a feedback survey. The survey measured understanding of HPB anatomy, interventions, and satisfaction with the teaching methodology. Results The pre-session questionnaire included 22 participants, while the post-session had 20 participants. Regarding HPB anatomy understanding, in the pre-session, six (28.6%) and 11 (52.4%) participants reported levels 2 and 3, respectively, while levels 4 and 5 were reported by three (13.3%) and one (4.8%) participants. In the post-session, levels 4 and 5 were reported by six (30%) and 13 (65%), with only one (5%) reporting level 3 and none at levels 1 or 2. Similar trends were observed in understanding HPB investigation. In the pre-session, levels 2 and 3 were reported by eight (36.4%) and 11 (50%), while levels 4 and 5 were reported by two (9.1%) and one (4%). In the post-session, eight (40%) and 11 (55%) reported levels 4 and 5, with only one (5%) at level 3 and none at levels 1 or 2. For HPB management methods before teaching, levels 2 and 3 were equally reported by eight (36.4%), level 4 by four (22.7%), and none at level 5. After teaching, nine (45%) and 10 (50%) reported levels 4 and 5, with only one (5%) at level 3 and none at levels 1 or 2. Factual knowledge showed a 38% increase, rising from 49% pre-session to 87% post-session. In post-session feedback, 12 (60%) strongly agreed that the session helped augment their medical practice, and six (30%) agreed, with two (10%) neutral. Feedback on the teaching session's organization was positive, with 13 (65%) strongly agreeing that it was structured coherently, and six (30%) agreeing, with only one (5%) neutral regarding the clarity of the structure and delivery method. Conclusion Specialty-specific induction programs are crucial for providing support and ensuring the development of competent doctors. Efforts should be made to create supportive working environments for junior doctors to alleviate stress and improve their well-being.
    • Ethnic differences in cardiac structure and function assessed by MRI in healthy South Asian and White European people: a UK Biobank Study

      Alfuhied, Aseel; Arnold, Jayanth; Ayton, Sarah; Bilak, Joanna; Brady, Emer M; Dattani, Abhishek; Gulsin, Gaurav; Graham-Brown, Matthew P; McCann, Gerry P; SIngh, Anvesha; et al.
      Background: Echocardiographic studies indicate South Asian people have smaller ventricular volumes, lower mass and more concentric remodelling than White European people, but there are no data using cardiac MRI (CMR). We aimed to compare CMR quantified cardiac structure and function in White European and South Asian people. Methods: Healthy White European and South Asian participants in the UK Biobank Imaging CMR sub-study were identified by excluding those with a history of cardiovascular disease, hypertension, obesity or diabetes. Ethnic groups were matched by age and sex. Cardiac volumes, mass and feature tracking strain were compared. Results: 121 matched pairs (77 male/44 female, mean age 58±8 years) of South Asian and White European participants were included. South Asian males and females had smaller absolute but not indexed left ventricular (LV) volumes, and smaller absolute and indexed right ventricular volumes, with lower absolute and indexed LV mass and lower LV mass:volume than White European participants. Although there were no differences in ventricular or atrial ejection fractions, LV global longitudinal strain was higher in South Asian females than White European females but not males, and global circumferential strain was higher in both male and South Asian females than White European females. Peak early diastolic strain rates were higher in South Asian versus White European males, but not different between South Asian and White European females. Conclusions: Contrary to echocardiographic studies, South Asian participants in the UK Biobank study had less concentric remodelling and higher global circumferential strain than White European subjects. These findings emphasise the importance of sex- and ethnic- specific normal ranges for cardiac volumes and function.
    • Real-world study of the concomitant use of biphasic insulin as part 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes

      Davies, Melanie J (2023-12-13)
      Aims: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. Methods: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). Results: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. Conclusions: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.
    • Implementation and engagement of the SMART Work & Life sitting reduction intervention: an exploratory analysis on intervention effectiveness

      Wilson, Panna (2023-12-19)
      Background: To enhance the impact of interventions, it is important to understand how intervention engagement relates to study outcomes. We report on the level of implementation and engagement with the SMART Work & Life (SWAL) programme (delivered with (SWAL plus desk) and without a height-adjustable desk (SWAL)) and explore the effects of different levels of this on change in daily sitting time in comparison to the control group. Methods: The extent of intervention delivery by workplace champions and the extent of engagement by champions and participants (staff) with each intervention activity was assessed by training attendance logs, workplace champion withdrawal dates, intervention activities logs and questionnaires. These data were used to assess whether a cluster met defined criteria for low, medium, or high implementation and engagement or none of these. Mixed effects linear regression analyses tested whether change in sitting time varied by: (i) the number of intervention activities implemented and engaged with, and (ii) the percentage of implementation and engagement with all intervention strategies. Results: Workplace champions were recruited for all clusters, with 51/52 (98%) attending training. Overall, 12/27 (44.4%) SWAL and 9/25 (36.0%) SWAL plus desk clusters implemented all main intervention strategies. Across remaining clusters, the level of intervention implementation varied. Those in the SWAL (n = 8 (29.6%) clusters, 80 (32.1%) participants) and SWAL plus desk (n = 5 (20.0%) clusters, 41 (17.1%) participants) intervention groups who implemented and engaged with the most intervention strategies and had the highest percentage of cluster implementation and engagement with all intervention strategies sat for 30.9 (95% CI -53.9 to -7.9, p = 0.01) and 75.6 (95% CI -103.6 to -47.7, p < 0.001) fewer minutes/day respectively compared to the control group at 12 month follow up. These differences were larger than the complete case analysis. The differences in sitting time observed for the medium and low levels were similar to the complete case analysis. Conclusions: Most intervention strategies were delivered to some extent across the clusters although there was large variation. Superior effects for sitting reduction were seen for those intervention groups who implemented and engaged with the most intervention components and had the highest level of cluster implementation and engagement. Trial registration: ISRCTN11618007. Registered on 24 January 2018. .
    • A qualitative study exploring healthcare workers' lived experiences of the impacts of COVID-19 policies and guidelines on maternal and reproductive healthcare services in the United Kingdom

      Pareek, Manish (2023-11-08)
      Introduction: During the COVID-19 pandemic, pregnant women were regarded as vulnerable to poor health outcomes if infected with the SARS-CoV-2 (COVID-19) virus. To protect the United Kingdom's (UK) National Health Service (NHS) and pregnant patients, strict infection control policies and regulations were implemented. This study aimed to understand the impact of the COVID-19 policies and guidelines on maternal and reproductive health services during the pandemic from the experiences of healthcare workers (HCWs) caring for these patients. Methods: This qualitative study involved HCWs from the United Kingdom Research study into Ethnicity and COVID-19 outcomes in Healthcare workers (UK-REACH) project. Semi-structured interviews and focus groups were conducted online or by telephone with 44 diverse HCWs. Transcripts were thematically analyzed following Braun and Clarke's principles of qualitative analysis. Results: Three key themes were identified during analysis. First, infection control policies impacted appointment availability, resulting in many cancellations and delays to treatment. Telemedicine was also used extensively to reduce risks from face-to-face consultations, disadvantaging patients from minoritized ethnicities. Secondly, staff shortages and redeployments reduced availability of consultations, appointments, and sonography scans. Finally, staff and patients reported challenges accessing timely, reliable and accurate information and guidance. Conclusions: COVID-19 demonstrated how a global health crisis can impact maternal and reproductive health services, leading to reduced service quality and surgical delays due to staff redeployment policies. Our findings underscore the implications of policy and future health crises preparedness. This includes tailored infection control policies, addressing elective surgery backlogs early and improved dissemination of relevant vaccine information.
    • Twenty-four-hour physical behaviour profiles across type 2 diabetes mellitus subtypes

      Davies, Melanie J; Hall, Andrew P; Henson, Joseph (2024-01-08)
      Aim: To investigate how 24-h physical behaviours differ across type 2 diabetes (T2DM) subtypes. Materials and methods: We included participants living with T2DM, enrolled as part of an ongoing observational study. Participants wore an accelerometer for 7 days to quantify physical behaviours across 24 h. We used routinely collected clinical data (age at onset of diabetes, glycated haemoglobin level, homeostatic model assessment index of beta-cell function, homeostatic model assessment index of insulin resistance, body mass index) to replicate four previously identified subtypes (insulin-deficient diabetes [INS-D], insulin-resistant diabetes [INS-R], obesity-related diabetes [OB] and age-related diabetes [AGE]), via k-means clustering. Differences in physical behaviours across the diabetes subtypes were assessed using generalized linear models, with the AGE cluster as the reference. Results: A total of 564 participants were included in this analysis (mean age 63.6 ± 8.4 years, 37.6% female, mean age at diagnosis 53.1 ± 10.0 years). The proportions in each cluster were as follows: INS-D: n = 35, 6.2%; INS-R: n = 88, 15.6%; OB: n = 166, 29.4%; and AGE: n = 275, 48.8%. Compared to the AGE cluster, the OB cluster had a shorter sleep duration (-0.3 h; 95% confidence interval [CI] -0.5, -0.1), lower sleep efficiency (-2%; 95% CI -3, -1), lower total physical activity (-2.9 mg; 95% CI -4.3, -1.6) and less time in moderate-to-vigorous physical activity (-6.6 min; 95% CI -11.4, -1.7), alongside greater sleep variability (17.9 min; 95% CI 8.2, 27.7) and longer sedentary time (31.9 min; 95% CI 10.5, 53.2). Movement intensity during the most active continuous 10 and 30 min of the day was also lower in the OB cluster. Conclusions: In individuals living with T2DM, the OB subtype had the lowest levels of physical activity and least favourable sleep profiles. Such behaviours may be suitable targets for personalized therapeutic lifestyle interventions.
    • The development and internal pilot trial of a digital physical activity and emotional well-being intervention (Kidney BEAM) for people with chronic kidney disease

      Billany, Roseanne; Burton, James O; Graham-Brown, Matthew; Young, Hannah (2024-01-06)
      This trial assessed the feasibility and acceptability of Kidney BEAM, a physical activity and emotional well-being self-management digital health intervention (DHI) for people with chronic kidney disease (CKD), which offers live and on-demand physical activity sessions, educational blogs and videos, and peer support. In this mixed-methods, multicentre randomised waitlist-controlled internal pilot, adults with established CKD were recruited from five NHS hospitals and randomised 1:1 to Kidney BEAM or waitlist control. Feasibility outcomes were based upon a priori progression criteria. Acceptability was primarily explored via individual semi-structured interviews (n = 15). Of 763 individuals screened, n = 519 (68%, 95% CI 65 to 71%) were eligible. Of those eligible, n = 303 (58%, 95% CI 54-63%) did not respond to an invitation to participate by the end of the pilot period. Of the 216 responders, 50 (23%, 95% CI 18-29%) consented. Of the 42 randomised, n = 22 (10 (45%) male; 49 ± 16 years; 14 (64%) White British) were allocated to Kidney BEAM and n = 20 (12 (55%) male; 56 ± 11 years; 15 (68%) White British) to the waitlist control group. Overall, n = 15 (30%, 95% CI 18-45%) withdrew during the pilot phase. Participants completed a median of 14 (IQR 5-21) sessions. At baseline, 90-100% of outcome data (patient reported outcome measures and a remotely conducted physical function test) were completed and 62-83% completed at 12 weeks follow-up. Interview data revealed that remote trial procedures were acceptable. Participants' reported that Kidney BEAM increased their opportunity and motivation to be physically active, however, lack of time remained an ongoing barrier to engagement with the DHI. An randomised controlled trial of Kidney BEAM is feasible and acceptable, with adaptations to increase recruitment, retention and engagement.Trial registration NCT04872933. Date of first registration 05/05/2021.
    • Cluster analysis to identify clinical subtypes of Ménière's Disease

      Rea, Peter (2024-01-06)
      Objective: To identify distinct clinical subtypes of Ménière's disease by analyzing data acquired from a UK registry of patients who have been diagnosed with Ménière's disease. Study design: Observational study. Methods: Patients with Ménière's disease were identified at secondary/tertiary care clinics. Cluster analysis was performed by grouping participants sharing similar characteristics and risk factors into groups based on a defined measure of similarity. Results: A total of 411 participants were recruited into this study. Two main clusters were identified: participants diagnosed with ear infections (OR = 0.30, p < 0.014, 95% CI: 0.11-0.78) were more likely to be allocated in Cluster 1 (C1). Participants reporting tinnitus in both ears (OR = 11.89, p < 0.001, 95% CI: 4.08-34.64), low pitched tinnitus (OR = 21.09, p < 0.001, 95% CI: 7.47-59.54), and those reporting stress as a trigger for vertigo attacks (OR = 14.94, p < 0.001, 95% CI: 4.54-49.10) were significantly more likely to be in Cluster 2 (C2). Also, participants diagnosed with Benign Paroxysmal Positional Vertigo (OR = 13.14, <0.001, 95% CI: 4.35-39.74), autoimmune disease (OR = 5.97, p < 0.007, 95% CI: 1.62-22.03), depression (OR = 4.72, p < 0.056, 95% CI: 0.96-23.24), migraines (OR = 3.13, p < 0.008, 95% CI: 1.34-7.26), drug allergy (OR = 3.25, p < 0.029, 95% CI: 1.13-9.34), and hay fever (OR = 3.12, p < 0.009, 95% CI: 1.33-7.34) were significantly more likely to be clustered in C2. Conclusions: This study supports the hypothesis that Ménière's disease is a heterogeneous condition with subgroups that may be identifiable by clinical features. Two main clusters were identified with differing putative etiological factors. Level of evidence: 3 Laryngoscope, 2024.
    • A syndromic neurodevelopmental disorder caused by rare variants in PPFIA3

      Vasudevan, Pradeep (2024-01-04)
      PPFIA3 encodes the protein-tyrosine phosphatase, receptor-type, F-polypeptide-interacting-protein-alpha-3 (PPFIA3), which is a member of the LAR-protein-tyrosine phosphatase-interacting-protein (liprin) family involved in synapse formation and function, synaptic vesicle transport, and presynaptic active zone assembly. The protein structure and function are evolutionarily well conserved, but human diseases related to PPFIA3 dysfunction are not yet reported in OMIM. Here, we report 20 individuals with rare PPFIA3 variants (19 heterozygous and 1 compound heterozygous) presenting with developmental delay, intellectual disability, hypotonia, dysmorphisms, microcephaly or macrocephaly, autistic features, and epilepsy with reduced penetrance. Seventeen unique PPFIA3 variants were detected in 18 families. To determine the pathogenicity of PPFIA3 variants in vivo, we generated transgenic fruit flies producing either human wild-type (WT) PPFIA3 or five missense variants using GAL4-UAS targeted gene expression systems. In the fly overexpression assays, we found that the PPFIA3 variants in the region encoding the N-terminal coiled-coil domain exhibited stronger phenotypes compared to those affecting the C-terminal region. In the loss-of-function fly assay, we show that the homozygous loss of fly Liprin-α leads to embryonic lethality. This lethality is partially rescued by the expression of human PPFIA3 WT, suggesting human PPFIA3 function is partially conserved in the fly. However, two of the tested variants failed to rescue the lethality at the larval stage and one variant failed to rescue lethality at the adult stage. Altogether, the human and fruit fly data reveal that the rare PPFIA3 variants are dominant-negative loss-of-function alleles that perturb multiple developmental processes and synapse formation.
    • Circulating sphingolipids and relationship to cardiac remodelling before and following a low-energy diet in asymptomatic Type 2 Diabetes

      Athithan, Lavanya; Ayton, Sarah; Brady, Emer; Davies, Melanie J; Graham-Brown, Matthew; Gulsin, Gaurav; McCann, Gerry; Moss, Esther; Redman, Emma (2024-01-03)
      Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous multi-system syndrome with limited efficacious treatment options. The prevalence of Type 2 diabetes (T2D) continues to rise and predisposes patients to HFpEF, and HFpEF remains one of the biggest challenges in cardiovascular medicine today. Novel therapeutic targets are required to meet this important clinical need. Deep phenotyping studies including -OMIC analyses can provide important pathogenic information to aid the identification of such targets. The aims of this study were to determine; 1) the impact of a low-energy diet on plasma sphingolipid/ceramide profiles in people with T2D compared to healthy controls and, 2) if the change in sphingolipid/ceramide profile is associated with reverse cardiovascular remodelling. Methods: Post-hoc analysis of a randomised controlled trial (NCT02590822) including adults with T2D with no cardiovascular disease who completed a 12-week low-energy (∼810 kcal/day) meal-replacement plan (MRP) and matched healthy controls (HC). Echocardiography, cardiac MRI and a fasting blood for lipidomics were undertaken pre/post-intervention. Candidate biomarkers were identified from case-control comparison (fold change > 1.5 and statistical significance p < 0.05) and their response to the MRP reported. Association between change in biomarkers and change indices of cardiac remodelling were explored. Results: Twenty-four people with T2D (15 males, age 51.1 ± 5.7 years), and 25 HC (15 male, 48.3 ± 6.6 years) were included. Subjects with T2D had increased left ventricular (LV) mass:volume ratio (0.84 ± 0.13 vs. 0.70 ± 0.08, p < 0.001), increased systolic function but impaired diastolic function compared to HC. Twelve long-chain polyunsaturated sphingolipids, including four ceramides, were downregulated in subjects with T2D at baseline. Three sphingomyelin species and all ceramides were inversely associated with LV mass:volume. There was a significant increase in all species and shift towards HC following the MRP, however, none of these changes were associated with reverse cardiac remodelling. Conclusion: The lack of association between change in sphingolipids/ceramides and reverse cardiac remodelling following the MRP casts doubt on a causative role of sphingolipids/ceramides in the progression of heart failure in T2D.