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Abstract Background Cardiac rehabilitation has been identified as having the most homogenous clinical exercise service structure in the United Kingdom (UK), but inconsistencies are evident in staff roles and qualifications within and across services. The recognition of Clinical Exercise Physiologists (CEPs) as a registered health professional in 2021 in the UK, provides a potential solution to standardise the cardiac rehabilitation workforce. This case study examined, in a purposefully selected cardiac exercise service that employed registered CEPs, (i) how staff knowledge, skills and competencies contribute to the provision of the service, (ii) how these components assist in creating effective service teams, and (iii) the existing challenges from staff and patient perspectives. Methods A multi-method qualitative approach (inc., semi-structured interviews, observations, field notes and researcher reflections) was employed with the researcher immersed for 12-weeks within the service. The Consolidated Framework for Implementation Research was used as an overarching guide for data collection. Data derived from registered CEPs (n = 5), clinical nurse specialists (n = 2), dietitians (n = 1), service managers/leads (n = 2) and patients (n = 7) were thematically analysed. Results Registered CEPs delivered innovative exercise prescription based on their training, continued professional development (CPD), academic qualifications and involvement in research studies as part of the service. Exposure to a wide multidisciplinary team (MDT) allowed skill and competency transfer in areas such as clinical assessments. Developing an effective behaviour change strategy was challenging with delivery of lifestyle information more effective during less formal conversations compared to timetabled education sessions. Conclusions Registered CEPs have the specialist knowledge and skills to undertake and implement the latest evidence-based exercise prescription in a cardiac rehabilitation setting. An MDT service structure enables a more effective team upskilling through shared peer experiences, observations and collaborative working between healthcare professionals.

Background There is no consensus on optimal management of pilonidal disease. Surgical practice is varied, and existing literature is mainly single-centre cohort studies of varied disease severity, interventions and outcome assessments. Objectives A prospective cohort study to determine: disease severity and intervention relationship most valued outcomes and treatment preference by patients recommendations for policy and future research. Design Observational cohort study with nested mixed-methods case study. Discrete choice experiment. Clinician survey. Three-stage Delphi survey for patients and clinicians. Inter-rater reliability of classification system. Setting Thirty-one National Health Service trusts. Participants Patients aged > 16 years referred for elective surgical treatment of pilonidal disease. Interventions Surgery. Main outcome measures Pain postoperative days 1 and 7, time to healing and return to normal activities, complications, recurrence. Outcomes compared between major and minor procedures using regression modelling, propensity score-based approaches and augmented inverse probability weighting to account for measured potential confounding features. Results Clinician survey: There was significant heterogeneity in surgeon practice preference. Limited training opportunities may impede efforts to improve practice. Cohort study: Over half of patients (60%; N = 667) had a major procedure. For these procedures, pain was greater on day 1 and day 7 (mean difference day 1 pain 1.58 points, 95% confidence interval 1.14 to 2.01 points, n = 536; mean difference day 7 pain 1.53 points, 95% confidence interval 1.12 to 1.95 points, n = 512). There were higher complication rates (adjusted risk difference 17.5%, 95% confidence interval 9.1 to 25.9%, n = 579), lower recurrence (adjusted risk difference −10.1%, 95% confidence interval −18.1 to −2.1%, n = 575), and longer time to healing (>34 days estimated difference) and time to return to normal activities (difference 25.9 days, 95% confidence interval 18.4 to 33.4 days). Mixed-methods analysis: Patient decision-making was influenced by prior experience of disease and anticipated recovery time. The burden involved in wound care and the gap between expected and actual time for recovery were the principal reasons given for decision regret. Discrete choice experiment: The strongest predictors of patient treatment choice were risk of infection/persistence (attribute importance 70%), and shorter recovery time (attribute importance 30%). Patients were willing to trade off these attributes. Those aged over 30 years had a higher risk tolerance (22.35–34.67%) for treatment failure if they could experience rapid recovery. There was no strong evidence that younger patients were willing to accept higher risk of treatment failure in exchange for a faster recovery. Patients were uniform in rejecting excision-and-leave-open because of the protracted nursing care it entailed. Wysocki classification analysis: There was acceptable inter-rater agreement (κ = 0.52, 95% confidence interval 0.42 to 0.61). Consensus exercise: Five research and practice priorities were identified. The top research priority was that a comparative trial should broadly group interventions. The top practice priority was that any interventions should be less disruptive than the disease itself. Limitations Incomplete recruitment and follow-up data were an issue, particularly given the multiple interventions. Assumptions were made regarding risk adjustment. Conclusions and future work Results suggest the burden of pilonidal surgery is greater than reported previously. This can be mitigated with better selection of intervention according to disease type and patient desired goals. Results indicate a framework for future higher-quality trials that stratify disease and utilise broad groupings of common interventions with development of a patient-centred core outcome set. Trial registration This trial is registered as ISRCTN95551898. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/17/02) and is published in full in Health Technology Assessment; Vol. 28, No. 33. See the NIHR Funding and Awards website for further award information. Plain language summary Background Pilonidal disease is caused by ingrowing hairs between the buttocks. It can cause pain and infection and may need surgery. We do not know which operation gives the best results, or who operations help. Objectives PITSTOP aimed to find out which operation is the best and what is important to patients when deciding on surgery, and to suggest ideas for better treatment and future research. Methods We looked at what operations were done and their outcomes. We interviewed patients about their experiences. Some completed a survey to help us understand what operations they might prefer based on risks and outcomes. Surgeons completed a survey about their experiences, and we explored whether a new tool could help us tell the difference between ‘mild’ and ‘bad’ disease. We used findings from these studies to help patients and surgeons give priorities for future practice and research. Results Six hundred and sixty-seven patients joined PITSTOP. People who had a major operation had more pain and took longer to return to normal activities. Some were still affected 6 months after surgery. However, disease recurrence was lower than after a minor procedure. Patients based decisions about treatment on the likelihood of success and the time to recover. The study and the surgeons’ survey both showed marked differences in practice. Surgeons tended to offer one or two operations learned during training. A classification tool put cases in similar groups, but this did not influence treatment choices. The consensus exercise identified five research priorities, the top one being to put types of surgery into two groups. Of the five practice priorities, the top one was that surgery should not make the patient worse than the disease. Conclusions There is variation in the treatment of pilonidal disease. Wound issues and impact on daily living should be avoided. The highlighted research questions should be addressed to improve care. Scientific summary Background Despite being a common condition, there is no clear consensus as to how pilonidal disease should be managed. Throughout the UK, surgical practice is varied, and existing literature largely consists of single-centre cohort studies using a range of disease classification systems, interventions and outcome assessments. There is a need to improve clinical management of this condition and define future research processes and priorities. Objectives PITSTOP aimed to investigate surgical options for the treatment of pilonidal sinus disease (PSD). The objectives were to: Follow patients with symptomatic pilonidal sinus referred to each collaborating site, prospectively recording details of their pit/track anatomy, surgical management, medical events and health-related quality of life (QoL) until 6 months after their operation. Describe the combination of interventions currently in use and quantify clinical and patient-reported outcomes (PROs) associated with each. Identify patient-specific disease features that might predict poor outcome in each treatment group by risk-modelling methods. Derive a case mix-adjusted estimate of the risks associated with common treatment options, using causal inference methods to provisionally rank the optimal management strategies among patients for whom more than one treatment is considered appropriate. Provide an overview of patient views and experiences. Collect the views of patients on which interventions they would rather avoid and which outcomes they most value. Reach a surgeon-based consensus on which subtypes of pilonidal disease may benefit from which treatment options. Reach a surgeon and patient-based consensus on research priorities. Design and setting PITSTOP was an observational cohort with nested mixed-methods and qualitative design which took place across 33 NHS Trust sites in the UK. The study had an additional clinician survey component and validation of a classification system and culminated in a three-stage Delphi exercise to identify research and practice priorities. Participants Eligible patients undergoing surgical management for PSD and interested in participating were consented to the study. Participants referred to a collaborating centre for definitive elective surgical treatment of PSD were required to meet the following criteria: Consenting patients over 16 years of age with PSD. Participants were ineligible if any of the following conditions were met: Asymptomatic Pregnant Unable to give consent Acute abscess Hypersensitivity to the sealants. Intervention This was a non-intervention study with the choice of treatment being a shared decision made between the surgeon and patient. Treatment of PSD typically comprises two essential components (with the exception of phenol injection, seton and fistuloscope/diathermy – which aim to induce fibrosis with or without obliteration of the tracks): Excision of the affected skin and fat (the amount of which varies among patients, and surgeons differ with respect to how the resultant wound is managed). Closure of the wound, which is either left open and heals slowly by secondary intention or closed using sutures, also known as primary wound closure. There are 18 excision–closure combinations that are theoretically possible. Therefore, the operative intervention was recorded by the following excision and closure techniques: Excision procedure Local excision. Curettage. Phenol injection. Pit picking. Seton. Laser-assisted excision. EPSiT (endoscopic pilonidal sinus treatment). Closure procedure Primary midline closure. Fibrin glue (FG). Marsupialisation. Lateral closure (Karydakis; Bascom’s cleft). Flap (Limberg; rhomboid). Follow-up Participants were followed up 1 day and 7 days after surgery (with day 0 the day of elective surgical treatment), at the routine clinic visit appointment, at 6 months, and at the end of study. Main outcome measures As PITSTOP is a cohort study examining current practice, there are no primary outcome measures. The following data were collected: pain (numeric rating scale) on day 1 and day 7 postoperatively and at each follow-up EuroQol five dimensions five levels questionnaire (EQ-5D-5L) QoL at each follow-up interactions with primary and secondary care length of time to healing return to normal activities complications recurrence infection. Statistical methods The study aimed to recruit 800 patients, with at least 100 within each of the front-running management strategies. Two treatment comparisons were undertaken: any major excisional procedure versus any minor procedure, and asymmetric closure versus any minor procedure (minimal excision). Regression modelling, propensity score-based approaches [inverse probability weighting (IPW) and nearest neighbour matching] and augmented IPW were used to account for measured potential confounding. Continuous outcomes (pain at day 1 and day 7) were modelled using linear regression; binary outcomes (recurrence, complication) were modelled using logistic regression, with marginal probabilities used to estimate absolute risk difference. Time to wound healing and time to return to normal activity were modelled using parametric accelerated survival time. The following features were considered as potential risk factors for outcome and treatment choice: sex, body mass index, depth of natal cleft, presence and type of gluteal hair, smoking status, pit density, presence of unilateral or bilateral disease, distance from furthest lateral opening to the nearest pit, presence of pus and Wysocki disease classification. Features affecting treatment choice were assessed using logistic regression with treatment choice as the outcome, and the same propensity score adjustments were used for each outcome. For each outcome, three regression models were fitted: one that adjusted for all listed features, one that adjusted for features associated with the outcome (based on Akaike’s information criteria, model c-statistic and clinical review) and one that adjusted for disease classification alone. The difference in predicted outcome and corresponding 95% confidence interval (CI) were estimated for each modelling strategy on each outcome. Mixed-methods case studies Mixed-methods case studies were undertaken to understand why people make and regret decisions on their treatment. Longitudinal semistructured interviews (20 cohort participants from 13 sites) were conducted at baseline and 6 months later with framework analysis mapped findings to Witt’s coping in deliberation framework and Sekhon’s acceptability framework. We triangulated findings with baseline scores CollaboRATE shared decision-making (SDM) survey scores and 6-month decision regret (DR) scores. Discrete choice experiment An online survey using the discrete choice experiment (DCE) method was used to ask patients to choose their favoured treatment when presented with competing hypothetical treatment profiles. Regression analyses were conducted on DCE responses. Clinician survey A survey was developed following the CHERRIES statement checklist of recommendations to identify the most frequently used interventions for specific clinical scenarios in current PSD practice. It was disseminated via the surgical trainee research collaboratives to practising consultants throughout the UK. Data were captured and stored in the REDCap software. Consensus exercise and validation of a classification system Two separate surveys were undertaken. The first comprised a Delphi consensus exercise in which surgeons and patients were asked to recommend best practice and further research. In the second, 15 surgeons were each asked to retrospectively assess photographs to quantify agreement in the Wysocki classification tool, with 90 patients each assessed by 6 surgeons. Results Cohort study Participants Thirty-one UK sites recruited participants over a 46-month period from May 2019 to March 2022. Seven hundred and twenty-nine participants consented to the study; after exclusions due to no procedure (n = 45), incorrect diagnosis (n = 7) and insufficient treatment information (n = 10), there were 667 participants included in the analysis cohort. Six-month follow-up data were available for 71% of participants; recurrence and complication data were available for 94% and 96% of participants, respectively. Main results Sixty per cent of patients (n = 397) received a major procedure; this comprised 272 (41%) asymmetric closure, 49 (7%) leave open and 76 (11%) midline closure. The remaining participants received minimal excision (n = 270, 40%), most commonly glue (n = 106, 16%) or pit picking (n = 60, 9%). Pain on day 1 and day 7 was higher for patients that received major procedures compared to minor procedures (augmented IPW-adjusted mean difference in day 1 pain 1.58 points, 95% CI 1.14 to 2.01 points, n = 536; mean difference in day 7 pain 1.53 points, 95% CI 1.12 to 1.95 points, n = 512). The difference was broadly consistent regardless of adjustment method. Complications were reported by 207/385 (54%) participants that had major procedures, and 94/258 (36%) participants that had minor procedures (augmented IPW-adjusted risk difference 17.5%, 95% CI 9.1 to 25.9%, n = 579). Recurrence was reported for 86/373 (23%) of major and 87/256 (34%) of minor procedures; the augmented IPW-adjusted risk difference was −10.1% (95% CI −18.1 to −2.1%, n = 575). The estimated difference between groups was smaller for treatment failure (a composite of recurrence, failure to heal, and failure to return to normal activities), where 45% of major procedure participants versus 47% of minor procedure participants experienced treatment failure (augmented IPW-adjusted risk difference −2.3%, 95% CI −10.9 to 6.2%). The estimates for treatment difference in recurrence and complication were consistent across the various adjustment methods. Treatment differences for time to healing and time to return to normal activities were less consistent between adjustment methods. Participants receiving major procedures took an estimated minimum of 20 days longer to return to normal activities (augmented IPW difference 25.9 days, 95% CI 18.4 to 33.4 days). Difference in time to healing was estimated to be at least 34 days more in the major group, but the estimates and corresponding CIs were inconsistent across models. At 6 months, around 25% of participants in both groups had wounds that had not healed; 12% of major procedure participants and 4% of minor procedure participants were yet to return to normal activity. Comparisons of asymmetric closure with minimal excision produced results similar to the major versus minor comparisons. Clinician survey The survey was completed by 109 participants (54.5% response) who routinely cared for patients with PSD. Respondents reported a median caseload of 15 patients per year [interquartile range (IQR) 10–20]. Of those estimating their recurrence rates, 28.8% predicted they were in the 16–30% range. A wide range of treatment strategies were employed, with 65.1% practising an excision-and-leave-open technique despite this being considered obsolete as a treatment option. Surgical training in this obsolete technique was experienced by 83.1%. Many recommended non-surgical treatments despite the lack of evidence. Mixed-methods case studies No choice of treatment was offered to 9/20 participants, although this was not always seen negatively on the CollaboRATE instrument. Decision-making was influenced by prior experience of pilonidal sinus and anticipated recovery time. Participants scoring highest on DR also had among the highest SDM scores. The burden involved in wound care and the gap between expected and actual time for recovery were the principal reasons given for DR. Discrete choice experiment The survey was completed by 111 participants. The strongest predictor of treatment choice was risk of infection/persistence (attribute importance 70%), followed by shorter recovery time (attribute importance 30%). Patients were willing to trade off recovery time against risk of infection/persistence. Patients aged over 30 years had a higher risk tolerance (22.35–34.67%) for treatment failure if they could experience rapid recovery. Younger patients were willing to accept smaller risks (maximum acceptable risk 1.51–2.15) in exchange for a faster recovery. Patients were uniform in rejecting excision-and-leave-open because of the protracted nursing care it entailed. Wysocki tool classification The Wysocki tool demonstrated acceptable agreement. Overall, the kappa statistic for agreement was 0.52 (95% CI 0.42 to 0.61), with five of the six surgeons reaching consensus in 53 (59%) patients. Agreement did not differ with regard to the surgeon’s experience. This, along with the prognostic value of the tool, suggests this could be used in practice to classify PSD. Consensus exercise The top five practice statements included: any treatment should not be worse than the disease itself; minimally invasive procedures should be preferred when feasible; surgeons should have opportunities to learn new techniques; a classification tool will help inform treatment options; and delayed return to activities is an important outcome. The top five research statements included: future trials should compare broad groups of operations – minimally invasive procedures versus major excisional techniques, with stratification by severity of disease; a core outcome set and PROs should be used; there should be an attempt to develop an algorithm or decision tree to aid surgeon decision-making. Conclusions The burden of surgery for PSD is significantly greater than that reported in the literature. Many surgeons perceive this but continue to practise outdated procedures. While minimally invasive procedures may reduce this burden in many patients, they are not always offered when they could be. This practice may be driven by the desire to achieve cure at the expense of protracted recovery, but this is not always what patients want. Many would trade reduced chance of cure for more rapid recovery. Future practice priorities should follow the ethos of not making the surgery worse than the disease itself and appreciate that patients need to be properly informed about the burden associated with wound care and the likelihood of recurrence associated with different procedures, to minimise DR. Future trials should compare broad groups of interventions (minimally invasive vs. major excisions) stratified by disease severity and utilising a reliable and validated Wysocki classification system. Such trials should incorporate a core set of PROs. Trial registration This trial is registered as ISRCTN95551898. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/17/02) and is published in full in Health Technology Assessment; Vol. 28, No. 33. See the NIHR Funding and Awards website for further award information. Study protocol The original protocol for the PITSTOP study can be found here. https://figshare.shef.ac.uk/articles/journal_contribution/The_PITSTOP_Study_PIlonidal_sinus_Treatment_STudying_the_OPtions_-_Protocol/7578242. A list of the protocol amendments since the initial Research Ethics Committee (REC) approval can be found below. Version number Changes made Date of REC/HRA approval Amendment number 1.2 Errors in the flow diagramErrors that were overlooked such as age where it stated 18 years instead of 16 yearsTypological errors in the textChanges to the call at day one post surgery – this is now a phone call by a research nurse 03 May 2019/03 April 2019 SA01 1.2 Changes of collaborator Christine Moffatt University affiliation – previously University of Nottingham, now Nottingham Trent University (p7) 1.2 Addition of optional consent item described which is the taking of photos pre-surgery to assist with the development of the classification system for PSD (p19) 1.2 A follow-up call on day 1 post surgery as opposed to a text message (p19, p34, table 1) 1.2 Removal for the 4–6 week time frame from routine clinic visit follow-up as this varies from clinic to clinic (p34) 1.2 Addition of infection as outcome measure (p33) 1.3 Clarification: Patients must have a minimum of 24 hours between receiving the Patient Information Sheet and consenting to the study (p16) N/A/19 November 2019 MA07 1.3 Clarification: The postoperative routine clinic visit may also be conducted by the telephone if considered routine at site (p19) 1.3 Clarification: The recruitment end date is July 2020 (p29) 1.4 An additional telephone follow-up can be made if the participant does not attend the pre-arranged face-to-face clinic visit (p19) N/A/03 December 2019 MA08 1.4 Clarification: Data can be collected by trained research personnel or a delegated member of the research team (p19) 1.4 Addition of the REC reference on the front page (p1) 1.5 Clarification: The photographs will be used to aid the validation of the classification system for PSD (p19) 02 March 2020/07 April 2020 SA03 1.5 Clarification: Preoperative photographs of the surgical site will be uploaded on the REDCap data capture system (p20) 1.5 Clarification: A copy of the consent form will be uploaded on to the REDCap data capture system for monitoring purposes (p20) 2.0 Clarification: Sponsor and CI e-mail addresses have been updated (p6) 03 August 2020/05 August 2020 SA04 2.0 Clarification: Study coordinating staff list has been updated (p8) 2.0 Response to COVID-19: Addition of postal consent if preoperative consultations are conducted remotely OR social distancing measures inhibit research personnel to gain consent in person (p15) 2.0 Surgeon survey is also accessible via an online link hosted on REDCap (p18) 2.0 Research personnel may text a participant to arrange a follow-up call (p18) 2.0 Response to COVID-19: Baseline measures can be taken over the phone (p19) 2.0 Response to COVID-19: Follow-up data can be collected by study coordinating team if research personnel at NHS trust do not have capacity (p19) 2.0 Response to COVID-19: missed 6-month follow-up data can be collected at the end of study (p19) 2.0 The DCE questionnaire can be completed by non-PITSTOP patients. The questionnaire can be advertised using a leaflet and/or social media (p24) 2.1 Research personnel may e-mail a participant to arrange a follow-up call (p18) N/A/27 October 2020 MA11 2.2 Update to study coordinating team (p7) N/A/29 September 2022 NSA13 2.2 Clarification of study procedures for the PSD seton surgical procedure (p19) 2.2 Clarification of follow-up procedures (p20) 2.2 Update to recruitment end date (p30) 3.0 Amendment to consensus technique (p25) 18 November 2021 SA05

Abstract Background A reduction in right ventricular (RV) function during recovery from prolonged endurance exercise has been documented alongside RV dilatation. A relative elevation in pulmonary artery pressure and therefore RV afterload during exercise has been implicated in this post-exercise dysfunction but has not yet been demonstrated. The current study aimed to assess RV structure and function and pulmonary artery pressure before, during and after a 6-h cycling exercise bout. Methods Eight ultra-endurance athletes were recruited for this study. Participants were assessed prior to exercise supine and seated, during exercise at 2, 4 and 6 h whilst cycling seated at 75% maximum heart rate, and post-exercise in the supine position. Standard 2D, Doppler and speckle tracking echocardiography were used to determine indices of RV size, systolic and diastolic function. Results Heart rate and RV functional parameters increased from baseline during exercise, however RV structural parameters and indices of RV systolic and diastolic function were unchanged between in-exercise assessment points. Neither pulmonary artery pressures (26 ± 9 mmHg vs 17 ± 10 mmHg, P > 0.05) nor RV wall stress (7.1 ± 3.0 vs 6.2 ± 2.4, P > 0.05) were significantly elevated during exercise. Despite this, post-exercise measurements revealed RV dilation (increased RVD1 and 3), and reduced RV global strain (− 21.2 ± 3.5 vs − 23.8 ± 2.3, P = 0.0168) and diastolic tissue velocity (13.8 ± 2.5 vs 17.1 ± 3.4, P = 0.019) vs pre-exercise values. Conclusion A 6 h cycling exercise bout at 75% maximum heart rate did not alter RV structure, systolic or diastolic function assessments during exercise. Pulmonary artery pressures are not elevated beyond normal limits and therefore RV afterload is unchanged throughout exercise. Despite this, there is some evidence of RV dilation and altered function in post-exercise measurements.

In 2021, a ‘call to action’ was published to highlight the need for professional regulation of clinical exercise physiologists to be established within UK healthcare systems to ensure patient safety and align training and regulation with other health professions. This manuscript provides a progress report on the actions that Clinical Exercise Physiology UK (CEP-UK) has undertaken over the past 4 years, during which time clinical exercise physiologists have implemented regulation and gained formal recognition as healthcare professionals in the UK. An overview of the consultation process involved in creating a regulated health profession, notably the development of policies and procedures for both individual registration and institutional master’s degree (MSc) accreditation is outlined. Additionally, the process for developing an industry-recognised scope of practice, a university MSc-level curriculum framework, the Academy for Healthcare Science Practitioner standards of proficiency and Continuing Professional Development opportunities is included. We outline the significant activities and milestones undertaken by CEP-UK and provide insight and clarity for other health professionals to understand the training and registration process for a clinical exercise physiologist in the UK. Finally, we include short, medium and long-term objectives for the future advocacy development of this workforce in the UK.

OBJECTIVES/GOALS: Neonatal hypoglycemia is seen in 65% of maternally diabetic pregnancies, and can lead to severe neurological damage. Neonatal glycemia may also be an indicator of placental function in these pregnancies. The purpose of this study is to identify patterns of neonatal glycemia, and associated endothelial dysfunction, by maternal diabetes subtype. METHODS/STUDY POPULATION: Pregnancies with maternal Type 1 (T1DM), Type 2 (T2DM), and gestational diabetes mellitus (GDM) are being enrolled. Maternal hemoglobin A1c (HbA1c) and umbilical cord insulin/glucose are being collected from 20 pregnancies in each group, 10 of which also undergo placental/umbilical cord tissue collection. Following delivery, neonatal blood glucose levels are also collected every 3-4 hours (4+ measurements) to determine rate of glycemic change. Linear regression modeling will be used to determine associations with placental and umbilical endothelial RNA expression, umbilical cord insulin levels, and maternal HbA1c within each diabetic subtype and between normoglycemic and hypoglycemic neonates. Endothelial gene expression will be compared using paired t-tests with Benjamini-Hochberg correction. RESULTS/ANTICIPATED RESULTS: Thus far, 5 T1DM, 10 T2DM, and 13 GDM samples have been collected. Gestational age at delivery and birth weight were similar between groups (38.1 ± 1.05 weeks; 3.6 ± 0.59 kilograms) and delivery method is evenly distributed (Cesarean section or vaginal delivery). Currently, with limited cohort size, no association is evident between maternal HbA1c and umbilical cord glucose/insulin (p=0.114) or neonatal hypoglycemia diagnosis (p=0.674) when controlled for gestational age and infant birthweight. We hypothesize that, with pending analyses, maternal HbA1c and umbilical cord insulin levels will correlate negatively with the rate of neonatal glycemic change, and positively with the level of inflammatory and angiogenic transcription identified in placental and umbilical endothelium. DISCUSSION/SIGNIFICANCE: Characterization of postnatal glucose control is key to prognosis and risk stratification of infants of diabetic mothers. Understanding placental response to glucose, as well as sequela in the fetal endothelium, is also critical to understanding the pathogenesis of neonatal hypoglycemia and other adverse outcomes of diabetic pregnancy.

Introduction Cardiac rehabilitation (CR) can reduce cardiovascular mortality and improve health-related quality of life. In the United Kingdom, patient uptake of CR remains low (52%), falling well short of the target in the 2019 National Health Service long-term plan (85%). Mobile health (mHealth) technologies, offering biometric data to patients and healthcare professionals, may bridge the gap between supervised exercise and physical activity advice, enabling patients to engage in regular long-term physically active lifestyles. This randomised controlled trial (RCT) will evaluate the feasibility of mHealth technology when incorporated into a structured home-based walking intervention, in people with recent myocardial infarction.Methods and analysis This is a feasibility, assessor blinded, parallel group RCT. Participants will be allocated to either CR standard care (control group) or CR standard care+mHealth supported exercise counselling (mHealth intervention group). Feasibility outcomes will include the number of patients approached, screened and eligible; the percentage of patients who decline CR (including reasons for declining), agree to CR and consent to being part of the study; the percentage of patients who enrol in standard CR and reasons for drop out; and the percentage of participants who complete clinical, physical and psychosocial outcomes to identify a suitable primary outcome for a future definitive trial.Ethics and dissemination The trial was approved in the UK by the Northwest—Greater Manchester East Research Ethics Committee (22/NW/0301) and is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration numbers NCT05774587

Background Participation in clinical research is associated with better patient outcomes and higher staff retention and satisfaction rates. Nevertheless, patient recruitment to mental health studies is challenging due to a reliance on clinician or patient referrals (standard approach). To empower patients and make healthcare research more equitable, we explored a novel researcher-led approach, called ‘Count Me In’ (CMI).Objective To evaluate a 12-month implementation of CMI in a routine clinical setting.Methods CMI was launched in August 2021 in a mental health National Health Service (NHS) Trust in England. Patients (aged 18+) learnt about CMI at their initial clinical appointment. Unless they opted out, they became contactable for research (via research informatics searches).Findings After 12 months, 368 patients opted out and 22 741 became contactable through CMI, including 2716 through the standard approach and 20 025 through electronic searches (637% increase). Of those identified via electronic searches, 738 were contacted about specific studies and 270 consented to participate. Five themes were identified based on patient and staff experiences of CMI: ‘level of awareness and accessibility of CMI’, ‘perceptions of research and perceived engagement with CMI’, ‘inclusive research practice’, ‘engagement and incentives for research participation’, and ‘relationships between clinical and research settings’.Conclusions CMI (vs standard) led to a larger and diverse patient cohort and was favoured by patients and staff. Yet a shift in the NHS research culture is needed to ensure that this diversity translates to actual research participation.Clinical implications Through collaboration with other NHS Trusts and services, key funders (National Institute for Health and Care Research) and new national initiatives (Office for Life Sciences Mental Health Mission), CMI has the potential to address recruitment challenges through rapid patient recruitment into time-sensitive country-wide studies.

Introduction Adherence to unsupervised exercise is poor, yet unsupervised exercise interventions are utilised in most healthcare settings. Thus, investigating novel ways to enhance adherence to unsupervised exercise is essential. This study aimed to examine the feasibility of two mobile health (mHealth) technology–supported exercise and physical activity (PA) interventions to increase adherence to unsupervised exercise. Methods Eighty-six participants were randomised to online resources ( n = 44, females n = 29) or MOTIVATE ( n = 42, females n = 28). The online resources group had access to booklets and videos to assist in performing a progressive exercise programme. MOTIVATE participants received exercise counselling sessions supported via mHealth biometrics which allowed instant participant feedback on exercise intensity, and communication with an exercise specialist. Heart rate (HR) monitoring, survey-reported exercise behaviour and accelerometer-derived PA were used to quantify adherence. Remote measurement techniques were used to assess anthropometrics, blood pressure, HbA 1c and lipid profiles. Results HR–derived adherence rates were 22 ± 34% and 113 ± 68% in the online resources and MOTIVATE groups, respectively. Self-reported exercise behaviour demonstrated moderate (Cohen's d = 0.63, CI = 0.27 to 0.99) and large effects (Cohen's d = 0.88, CI = 0.49 to 1.26) in favour of online resources and MOTIVATE groups, respectively. When dropouts were included, 84% of remotely gathered data were available, with dropouts removed data availability was 94%. Conclusion Data suggest both interventions have a positive impact on adherence to unsupervised exercise but MOTIVATE enables participants to meet recommended exercise guidelines. Nevertheless, to maximise adherence to unsupervised exercise, future appropriately powered trials should explore the effectiveness of the MOTIVATE intervention.

Background Long-term adherence to exercise is often poor for people with coronary heart disease (CHD) who have completed supervised, centre-based cardiac rehabilitation. The aim of this study is to assess the feasibility of a remotely prescribed, delivered and monitored cardiac rehabilitation intervention using a wearable device to support long-term adherence to exercise and physical activity during maintenance of cardiac rehabilitation. Methods After completing cardiac rehabilitation, 30 participants with CHD, will be randomised (1:1) to an intervention ( n = 15) or a usual care group ( n = 15) in a 12-month feasibility randomised controlled trial (RCT). The intervention will comprise of an exercise consultation, personalised exercise prescription delivered via a wearable activity monitor using biometric feedback, regular monitoring via check-ins, and feedback text-messages for 6-months. Participants will be assessed at baseline (following completion of cardiac rehabilitation) and at three-, six-, and 12-months post-randomisation. The primary outcome will be feasibility, including assessment of eligibility, recruitment, adherence, and acceptability. Secondary outcomes will include exercise capacity, physical activity behaviours, cardiovascular disease risk and quality of life. Semi-structured interviews will be conducted at three-, six-, and 12-months post-randomisation (and with those who drop-out) to explore the acceptability of the study intervention and procedures. A questionnaire will be offered to those who decline participation. Discussion The MAINTAIN study will evaluate the feasibility of conducting a future definitive multi-centre RCT testing a remotely prescribed and monitored long-term mHealth maintenance exercise programme, versus usual care, for people with CHD who have completed cardiac rehabilitation. Trial registration number ClinicalTrials.gov, NCT05292287. Registered on 22/03/2022

Abstract Congenital heart disease (CHD) affects nearly 1% of births annually, and CHD pregnancies carry increased risk of developing pathologies of abnormal placentation. We previously reported significant developmental impacts of disrupting Hand1, a gene associated with CHD, expression in placenta trophoblast and endothelial cells in multiple mouse models. In this study, we aimed to build upon this knowledge and characterize the mechanistic impacts of disrupting HAND1 on human placenta trophoblast and vascular endothelial cell gene expression. HAND1 gene expression was silenced in BeWo cells, a choriocarcinoma model of human cytotrophoblasts, (n = 3–9 passages) and isolated human placental microvascular endothelial cells (HPMVEC; n = 3 passages), with HAND1 siRNA for 96 h. Cells were harvested, mRNA isolated and RNA sequencing performed using the Illumina NextSeq 550 platform. Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR packages. Statistical significance was determined using a log2 fold change of >1.0 or

PurposeThe aim of this case report was to describe the sleep responses in a male combat sport athlete, who was engaging in both chronic (CWL) and acute (AWL) weight loss practices in order to reduce body mass for a national competition.MethodsDuring the first seven weeks of training (Phases 1 and 2), the athlete adhered to a daily energy intake (EI) equating to their resting metabolic rate (1700 kcal·day−1) followed by a reduction in EI (915–300 kcal·day−1) in the 5 days before weighing in (Phase 3). Nocturnal sleep was monitored throughout the 8-week training period using wristwatch actigraphy and frequent measurements of body mass/composition, daily exercise energy expenditure and training load (TL) were taken.ResultsThe athlete was in a state of low energy availability (LEA) during the entire training period. There was a very large decrease in LEA status during phase 3 compared with phases 1 and 2 (3 vs. 20 kcal·kgFFM·day−1) and there was a small decrease in TL during phase 3 compared with phase 2 (410 vs. 523 AU). The athlete's sleep efficiency increased throughout the training period, but total sleep time displayed a small to moderate decrease in phase 3 compared with phases 1 and 2 (386 vs. 429 and 430 min). However, correlational analysis demonstrated trivial to small, non-significant relationships between sleep characteristics and the athlete's LEA status and TL.ConclusionThese findings suggest that CWL and AWL practices that cause fluctuations in LEA and TL may be implemented without compromising the sleep of combat sport athletes.

OBJECTIVES/GOALS: Fetal glucose dynamics mediate many of the adverse outcomes seen in infants of diabetic mothers (IDM). The goals of this study are to identify: (1) rates of blood glucose change in normoglycemic and hypoglycemic IDM; (2) their relation to in-utero insulin exposure; and (3) their transcriptional impacts on placental and umbilical vasculature. METHODS/STUDY POPULATION: Using a longitudinal prospective study design, placental/umbilical cord tissue and maternal hemoglobin A1c (HbA1c) are being collected from mothers diagnosed with Type 1, Type 2, or gestational diabetes mellitus. Blood glucose levels are also collected from their infants at birth, and every 3-4 hours for up to 9 hours to determine the rate of change. Linear regression modeling will be used to determine associations between placental and umbilical endothelial RNA expression, umbilical cord insulin levels, and maternal HbA1c within each diabetic sub-type. Gene expression from endothelial specimens will be compared between diabetic sub-types and between normoglycemic and hypoglycemic infants via paired t-tests using Benjamini-Hochberg procedure for false discovery rate correction. RESULTS/ANTICIPATED RESULTS: We hypothesize the following; (1) glucose levels will have a steeper rate of change in hypoglycemic infants; (2) maternal HbA1c and in-utero insulin levels will correlate with the level of transcriptional change identified in placental and umbilical endothelial samples; (3) a negative association will exist between cord insulin levels and the rate of change in infant glucose levels; and (4) a positive association will exist between cord insulin level and transcriptional change on the placental and umbilical endothelium. DISCUSSION/SIGNIFICANCE: Identifying gene expression changes in diabetic placental/umbilical endothelium, and the role of insulin/glucose in these changes, is key to managing diabetic vasculopathy and its adverse outcomes. Understanding infant insulin response may also guide management of hypoglycemia and decrease the risk for neonatal intensive care unit admission.

Background. Genetically determined hypoparathyroidism can lead to life-threatening episodes of hypocalcemia and, more rarely, to end-stage kidney disease at a young age. Parathyroid allotransplantation is the only curative treatment, and in patients already receiving immunosuppression for kidney transplantation, there may be little additional risk involved. We report the first such case in a child. Methods. An 11-y-old girl, known to have hypoparathyroidism secondary to an activating pathogenic variant in the calcium-sensing receptor, developed end-stage kidney disease and was started on intermittent hemodialysis. Since the age of 2.5 y, she had been receiving treatment with exogenous synthetic parathyroid hormone (PTH). In June 2019, at the age of 11.8 y, she received a living-donor kidney and simultaneous parathyroid gland transplant from her father. The kidney was implanted into the right iliac fossa, followed by implantation of the parathyroid gland into the exposed rectus muscle. Results. The kidney graft showed immediate function while the intrinsic serum PTH level remained low at 3 ng/L. Exogenous PTH infusion was reduced on day 6 posttransplantation to stimulate PTH production by the new gland, which resulted in improving intrinsic PTH concentrations of 28 ng/L by day 9. Twelve months after transplantation, PTH levels remain in normal range and the kidney graft function is stable with a serum creatinine of 110 μmol/L. Conclusions. Simultaneous living donation and transplantation of a kidney and a parathyroid gland into a child is safe and feasible and has the potential to cure primary hypoparathyroidism as well as kidney failure.

Abstract Background Telehealth is growing and its application in palliative care is seen as a solution to pressures on palliative care services. A 2010 UK review reported growing awareness of telehealth in palliative care but a lack of evidence-based research to support its use. The primary aim of this review was to describe the current use of telehealth in palliative care in the UK and evaluate telehealth initiatives against a digital service standard. The secondary aim was to explore whether telehealth results in a reduction in emergency care access. Methods Systematic review of the literature with thematic synthesis. Records were screened and data extracted by two reviewers. EMBASE, MEDLINE, CINAHL, Psychinfo and Cochrane central register for controlled trials were searched using pre-defined terms. Hand searching of conference literature, thesis databases and citation tracking was also conducted. The protocol for this systematic review was registered with PROSPERO and can be found at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017080038. Results The search identified 3807 titles and 30 studies were included in the review. Telehealth was used to support patients and carers, electronic record keeping and professional education. Notably, the number of home telemonitoring initiatives for patients had increased from the 2010 review. Despite this variety, many studies were small scale, descriptive and provided little evidence of evaluation of the service. Ten papers were sufficiently detailed to allow appraisal against the digital service standard and only one of these met all of the criteria to some extent. Seven studies made reference to emergency care access. Conclusions Although there is growth of telehealth services, there remains a lack of evaluation and robust study design meaning conclusions regarding the clinical application of telehealth in palliative care cannot be drawn. There is insufficient evidence to appreciate any benefit of telehealth on access to emergency care. Future work is needed to evaluate the use of telehealth in palliative care and improve telehealth design in line with digital service standards.

Exercise referral schemes (ERS) are used to promote physical activity within primary care. Traditionally, ERS are conducted in a gym or leisure-center setting, with exercise prescriptions based on moderate-intensity continuous training (MICT). Home-based high-intensity interval training (Home-HIIT) has the potential to reduce perceived barriers to exercise, including lack of time and access to facilities, compared to traditional MICT prescription used with ERS and improve health related outcomes. We hypothesized that Home-HIIT would mediate greater improvement in cardiorespiratory fitness (CRF) by virtue of greater adherence and compliance to the exercise prescription, compared to MICT.Methods: Patients enrolled on an ERS (Liverpool, United Kingdom) were recruited for a pragmatic trial. Participants self-selected either 12 weeks of MICT (45–135 min/week at 50–70% HRmax) or Home-HIIT (4–9 min × 1 min intervals at ≥80% of HRmax, interspersed with 1 min rest). The primary outcome was the change in CRF (VO2peak) at post-intervention (12 weeks) and follow-up (3-month post intervention), using intention-to-treat analysis.Results: 154 participants (age 48 ± 10y; BMI 30.5 ± 6.1 kg/m2) were recruited between October 2017 and March 2019, 87 (56%) participants chose Home-HIIT and 67 (44%) MICT. VO2peak increased post-intervention in both groups (MICT 3.9 ± 6.0 ml.kg–1.min–1, Home-HIIT 2.8 ± 4.5 ml.kg–1.min–1, P < 0.001), and was maintained at follow-up (P < 0.001). Fat mass was only reduced post MICT (MICT −1.5 ± 6.3 kg, P < 0.05, Home-HIIT −0.2 ± 2.0 kg, P = 1.00), but the reduction was not maintained at follow-up (MICT −0.6 ± 5.1 kg, Home-HIIT 0.0 ± 2.2 kg, P > 0.05). Adherence to the prescribed programs was similar (MICT 48 ± 35%, Home-HIIT 39 ± 36%, P = 0.77).Conclusion: This is the first study to evaluate the use of Home-HIIT for individuals in a primary care setting. Contrary to our hypothesis, adherence to both exercise prescriptions was poor, and CRF improved to a similar extent in both groups with improvements maintained at 3-month follow-up. We provide evidence that, although not superior, Home-HIIT could be an effective and popular additional exercise choice for patients within primary care based ERS.Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04553614].

Introduction Exercise and physical activity (PA) are fundamental to the treatment of type 2 diabetes. Current exercise and PA strategies for newly diagnosed individuals with type 2 diabetes are either clinically effective but unsuitable in routine practice (supervised exercise) or suitable in routine practice but clinically ineffective (PA advice). Mobile health (mHealth) technologies, offering biometric data to patients and healthcare professionals, may bridge the gap between supervised exercise and PA advice, enabling patients to engage in regular long-term physically active lifestyles. This feasibility randomised controlled trial (RCT) will evaluate the use of mHealth technology when incorporated into a structured home-based exercise and PA intervention, in those recently diagnosed with type 2 diabetes.Methods and analysis This feasibility multicentre, parallel group RCT will recruit 120 individuals with type 2 diabetes (diagnosis within 5–24 months, aged 40–75 years) in the UK (n=60) and Canada (n=60). Participants will undertake a 6-month structured exercise and PA intervention and be supported by an exercise specialist (active control). The intervention group will receive additional support from a smartwatch and phone app, providing real-time feedback and enabling improved communication between the exercise specialist and participant. Primary outcomes are recruitment rate, adherence to exercise and loss to follow-up. Secondary outcomes include a qualitative process evaluation and piloting of potential clinical outcome measures for a future RCT.Ethics and dissemination The trial was approved in the UK by the South East Scotland Research Ethics Committee 01 (20/SS/0101) and in Canada by the Clinical Research Ethics Board of the University of British Columbia (H20-01936), and is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration numbers ISRCTN14335124; ClinicalTrials.gov: NCT04653532.

The UK population is growing, ageing and becoming increasingly inactive and unfit. Personalised and targeted exercise interventions are beneficial for ageing and the management of chronic and complex conditions. Increasing the uptake of effective exercise and physical activity (PA) interventions is vital to support a healthier society and decrease healthcare costs. Current strategies for exercise and PA at a population level mostly involve self-directed exercise pathways, delivered largely via the fitness industry. Even for those who opt-in and manage to achieve the current recommendations regarding minimum PA, this generic ‘one-size-fits-all’ approach often fails to demonstrate meaningful physiological and health benefits. Personalised exercise prescription and appropriate exercise testing, monitoring and progression of interventions for individuals with chronic disease should be provided by appropriately trained and recognised exercise healthcare professionals, educated in the cognate disciplines of exercise science (eg, physiology, biomechanics, motor control, psychology). This workforce has operated for >20 years in the Australian public and private healthcare systems. Accredited exercise physiologists (AEPs) are recognised allied health professionals, with demonstrable health and economic benefits. AEPs have knowledge of the risks and benefits of distinct forms of exercise, skills in the personalised prescription and optimal delivery of exercise, and competencies to support sustained PA behavioural change, based on the established scientific evidence. In this charter, we propose a road map for the training, accreditation and promotion of a clinical exercise physiology profession in the UK.

Abstract Background The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour. Methods The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737. Discussion The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected. Trial registration ISRCTN, ISRCTN33631053. Retrospectively registered on 8 June 2018 (applied 17 May 2018).

Introduction: During the COVID-19 pandemic, obstetric care has adopted new precautions to ensure services can be maintained for pregnant women. The aim of this study was to describe access to and quality of obstetric care for pregnant and postpartum women during the COVID-19 pandemic and to identify factors that predict quality of care at this time.Methods: Between May 3 and June 28, 2020, we recruited women who were pregnant or within the first 6 months after delivery to participate in an online survey. This included questions on access to obstetric healthcare (type and place of health care provider, changes to obstetric appointments/services, appointment preferences) and the Quality of Prenatal Care Questionnaire (QPCQ).Results: Of the 917 eligible women, 612 (67%) were pregnant and 305 (33%) were in the first 6 months after delivery. Sixty-two percent (n = 571) reported that COVID-19 had affected their healthcare; appointments were rearranged, canceled or occurred via virtual means for 29% (n = 166), 29% (n = 167), and 31% (n = 175) of women, respectively. The majority preferred to physically attend appointments (74%; n = 676) and perceived the accompaniment of birth partners as important (77%; n = 471). Sixty-two percent (n = 380) were permitted a birth partner at delivery, 18% (n = 111) were unsure of the rules while 4% (n = 26) were not permitted accompaniment. During pregnancy, QPCQ was negatively associated with disruption to obstetric services including exclusion or uncertainty regarding birth partner permissions [F(7, 433) = 11.5, p < 0.001, R2 = 0.16] while QPCQ was negatively associated with inadequate breastfeeding support postpartum [F(1, 147) = 12.05, p = 0.001, R2 = 0.08].Conclusion: Pregnant and postpartum have experienced disruption in their access to obstetric healthcare. Perceived quality of obstetric care was negatively influenced by cancellation of appointment(s), suspension of services and exclusion of birth partners at delivery. During this time, continuity of care can be fulfilled via virtual and/or phone appointments and women should receive clear guidance on changes to services including birth partner permissions to attend delivery.

BACKGROUND The mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects. METHODS AND RESULTS A total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand‐grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (P

Background: Assessment of endothelial function using brachial artery flow-mediated dilation (FMD) predicts future cardiovascular disease (CVD) risk. However, poor adherence to protocol guidelines and lack of reference values hinders widespread FMD use. This study established age- and sex-specific reference intervals for brachial artery FMD in healthy individuals and examined the relation with CVD risk factors. Methods: Collected according to expert-consensus guidelines, we combined brachial artery FMD and subject characteristics/medical history from 5,362 individuals (4–84 years; 2,076 females). We first examined healthy individuals (n = 1,403 [582 females]) to generate age-/sex-specific percentile curves. Subsequently, we included subjects with CVD risk factors but without disease (un-medicated n = 3,167 [1,247 females], and medicated n = 792 [247 females]). Multiple linear regression tested the relation of CVD risk factors with FMD. Results: Healthy men showed a negative, curvilinear relation between FMD and age, whilst females revealed a linear relation that started higher, but declined at a faster rate. Age-/sex-related differences in FMD, at least partly, relate to baseline artery diameter. FMD was affected by CVD risk factors in un-medicated (e.g. systolic-/diastolic blood pressure, diabetes) and medicated subjects (e.g. dyslipidaemia). Importantly, sex mediated these effects (p < 0.05), with (supra) normalisation of FMD in medicated men, but not in women (except for blood pressure). Conclusion: Sex alters the age-related decline in FMD, which is partly explained through differences in artery diameter. Sex also altered the effect of some CVD risk factors and medication on FMD. This work improves interpretation and future use of the FMD technique when strictly adhering to FMD protocol guidelines.

Abstract Background Perthes’ disease is an idiopathic osteonecrosis of a developmental hip that is most frequent in Northern Europe. Currently, the absence of a common set of standardised outcomes makes comparisons between studies of different interventions challenging. This study aims to summarise the outcomes used in clinical research of interventions for Perthes’ disease and define a set of core outcomes (COS) to ensure that the variables of primary importance are measured and reported in future research studies investigating Perthes’ disease. Methods A systematic review of the current literature will be used to identify a list of outcomes reported in previous studies. Additional important outcomes will be sought by interviewing a group of children with Perthes’ disease, adults who were treated with the disease in infancy and parents of children with the disease. This list will then be evaluated by experts in Perthes’ disease using a Delphi survey divided into two rounds to ascertain the importance of each outcome. The final outcomes list obtained from the Delphi survey will be then discussed during a consensus meeting of representative key stakeholders in order to define the COS to be reported in future clinical trials related to Perthes’ disease. Discussion The absence of high-quality research and clear guidelines concerning the management of Perthes’ disease is, at least in part, due to the difficulties in the comparing the results from previous studies. The development of a COS seeks to standardise outcomes collected in future research studies to enable comparisons between studies to be made and to facilitate meta-analyses of results. Trial registration Core Outcome Measures in Effectiveness Trials Initiative (COMET), 1003. Registered on 20 July 2017. Prospero International Prospective Register of Systematic Reviews, CRD 42017069742. Registered on 10 July 2017.

Aim . To determine the social, physical, and emotional impact of living with Perthes’ disease on affected children and their family (caregivers). Patients and Methods . Through a mixed methods approach, we interviewed 18 parents and explored the perspectives of 12 children affected by Perthes’ disease (mean = 7.1 years, SD = ±4.1 years) using a survey tool. Thematic analysis of parents’ interviews provided an insight into disease-specific factors influencing patients and family’s daily life activities. Using the childhood survey tool, good and bad day scores were analyzed using MANOVA (multivariate analysis of variance). Results . Thematic analysis of the parent interviews (main themes n = 4) identified a marked effect of the disease on many facets of the child’s life, particularly pain and the impact on sleep, play, and school attendance. In addition, the interviews identified a negative effect on the family life of the parents and siblings. Children indicated that activities of daily living were affected even during “good days” ( P < .05), but pain was the key limiting factor. Conclusion . Perthes’ disease negatively affects the social, physical, and emotional well-being of children and their family. These findings provide outcome domains that are important to measure in day-to-day care and add in-depth insight into the challenges caused by this disease for health care professionals involved in clinical management.

Background Premenopausal women have a lower incidence of cardiovascular disease, which may partly be due to a protective effect of estrogen on endothelial function. Animal studies suggest that estrogen may also improve the relationship between shear rate (SR) and endothelial function. We aimed to explore the relationship between endothelial function (ie, flow‐mediated dilation [FMD]) and SR (ie, SR area under the curve [SRAUC]) in women versus men, and between pre‐ versus postmenopausal women. Methods and Results Brachial artery FMD and SRAUC were measured in accordance with expert‐consensus guidelines in 932 healthy participants who were stratified into young adults (18‐40 years, 389 men, 144 women) and older adults (>40 years, 260 men, 139 women). Second, we compared premenopausal (n=173) and postmenopausal women (n=110). There was evidence of a weak correlation between SRAUC and FMD in all groups but older men, although there was variation in strength of outcomes. Further exploration using interaction terms (age‐sex×SRAUC) in linear regression revealed differential relationships with FMD (young women versus young men [β=−5.8−4, P=0.017] and older women [β=−5.9−4, P=0.049]). The correlation between SRAUC and FMD in premenopausal women (r2=0.097) was not statistically different from that in postmenopausal women (r2=0.025; Fisher P=0.30). Subgroup analysis using stringent inclusion criteria for health markers (n=505) confirmed a stronger FMD‐SRAUC correlation in young women compared with young men and older women. Conclusions Evidence for a stronger relationship between endothelial function and the eliciting SR stimulus is present in young women compared with men. Estrogen may contribute to this finding, but larger healthy cohorts are required for conclusive outcomes.

Purpose: The mental health and well-being of employees is negatively impacted by stress, anxiety and depression. There is a need to address these issues at an organisational level to enhance workforce welfare and to decrease the number of days lost due to mental health/well-being concerns. This study aimed to evaluate a mental health and well-being toolkit designed to enhance the resilience, coping and self-talk of employees. Design/methodology/approach: The intervention was derived from counselling psychology and composed of an 8-hour programme, which was delivered over four consecutive weeks. A mixed methods approach was adopted, with the quantitative element assessing an intervention group (n = 10) and control group (n = 14) at baseline and at the end of the programme on measures of mental health and well-being. The qualitative aspect of the study involved interviews with the intervention group, which were thematically analysed.. Findings: Quantitatively, the experimental group showed statistically significant improvements in elements of resilience and well-being and a reduction in stress and anxiety. Qualitatively, participants experienced a positive effect on their well-being, benefited from the learning process, applied the taught strategies widely and found the session experience positive. Research limitations/implications: This was a small pilot study, nevertheless, the mixed methods nature of this investigation indicates that a counselling derived online training programme can enhance the well-being of employees within large organisations. Originality/value: A remotely delivered mental health and well-being toolkit could be a useful resource to enhance the well-being of employees in all organisations.

Background: In cirrhosis, a pathological gut microbiome has been linked with immune dysfunction. A pilot study of probiotic Lactobacillus casei Shirota (LcS) in alcoholic cirrhosis demonstrated significant improvement in neutrophil function. This study aimed to evaluate the efficacy of LcS on neutrophil function and significant infection rates in patients with cirrhosis. Methods: 92 cirrhotic patients (Child–Pugh score ≤10) were randomized to receive LcS or placebo, three times daily for six months. Primary end-points were incidence of significant infection and neutrophil function. Secondary end-points were cytokine profile, endotoxin, bacterial DNA positivity, intestinal permeability and quality of life. Results: Rates of infection, decompensation or neutrophil function did not differ between placebo and probiotic groups. LcS significantly reduced plasma monocyte chemotactic protein-1 and, on subgroup analysis, plasma interleukin-1β (alcoholic cirrhosis), interleukin-17a and macrophage inflammatory protein-1β (non-alcoholic cirrhosis), compared with placebo. No significant differences in intestinal permeability, bacterial translocation or metabolomic profile were observed. Conclusion: LcS supplementation in patients with early cirrhosis is safe. Although no significant infections were observed in either group, LcS improved cytokine profile towards an anti-inflammatory phenotype, an effect which appears to be independent of bacterial translocation.

Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5' insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth.

Introduction: The ability of ischemic preconditioning (IPC) to enhance exercise capacity may be mediated through altering exercise-induced blood flow and/or vascular function. This study investigated the hypothesis that (local) IPC enhances exercise-induced blood flow responses and prevents decreases in vascular function following exercise.Methods: Eighteen healthy, recreationally trained, male participants (mean ±SD: age 32 ± 8 years; BMI 24.2 ± 2.3; blood pressure 122 ± 10/72 ± 8 mmHg; resting HR 58 ± 9 beats min-1) received IPC (220 mmHg; 4 × 5-min bilateral arms), REMOTE IPC (220 mmHg; 4 × 5-min bilateral legs), or SHAM (20 mmHg; 4 × 5-min bilateral arms) in a counterbalanced order prior to 30-min of submaximal (25% maximal voluntary contraction) unilateral rhythmic handgrip exercise. Brachial artery diameter and blood flow were assessed every 5-min throughout the 30-min submaximal exercise using high resolution ultrasonography. Pre- and post-exercise vascular function was measured using flow-mediated dilation (FMD).Results: IPC resulted in enlarged brachial artery diameter during exercise [0.016 cm (0.003–0.03 cm), P = 0.015] compared to REMOTE IPC, but blood flow during exercise was similar between conditions (P > 0.05). Blood flow (l/min) increased throughout exercise (time: P < 0.005), but there was no main effect of condition (P = 0.29) or condition ∗ time interaction (P = 0.83). Post-exercise FMD was similar between conditions (P > 0.05).Conclusion: Our data show that local (but not remote) IPC, performed as a strategy prior to exercise, enhanced exercise-induced conduit artery diameter dilation, but these changes do not translate into increased blood flow during exercise nor impact post-exercise vascular function.

Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR) contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA) complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1). Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.

INTRODUCTION: Mathematical modelling of Clostridium difficile infection dynamics could contribute to the optimisation of strategies for its prevention and control. The objective of this systematic review was to summarise the available literature specifically identifying the quantitative parameters required for a compartmental mathematical model of Clostridium difficile transmission. METHODS: Six electronic healthcare databases were searched and all screening, data extraction and study quality assessments were undertaken in duplicate. Results were synthesised using a narrative approach. RESULTS: Fifty-four studies met the inclusion criteria. Reproduction numbers for hospital based epidemics were described in two studies with a range from 0.55 to 7. Two studies provided consistent data on incubation periods. For 62% of cases, symptoms occurred in less than 4 weeks (3-28 days) after infection. Evidence on contact patterns was identified in four studies but with limited data reported for populating a mathematical model. Two studies, including one without clinically apparent donor-recipient pairs, provided information on serial intervals for household or ward contacts, showing transmission intervals of

We describe the identification of, and risk factors for, the single most prevalent Mycobacterium tuberculosis strain in the West Midlands region of the UK.Prospective 15-locus MIRU-VNTR genotyping of all M. tuberculosis isolates in the West Midlands between 2004 and 2008 was undertaken. Two retrospective epidemiological investigations were also undertaken using univariable and multivariable logistic regression analysis. The first study of all TB patients in the West Midlands between 2004 and 2008 identified a single prevalent strain in each of the study years (total 155/3,056 (5%) isolates). This prevalent MIRU-VNTR profile (32333 2432515314 434443183) remained clustered after typing with an additional 9-loci MIRU-VNTR and spoligotyping. The majority of these patients (122/155, 79%) resided in three major cities located within a 40 km radius. From the apparent geographical restriction, we have named this the "Mercian" strain. A multivariate analysis of all TB patients in the West Midlands identified that infection with a Mercian strain was significantly associated with being UK-born (OR = 9.03, 95%CI = 4.56-17.87, p65 years old (OR = 0.25, 95% CI = 0.09-0.67, p < 0.01). A second more detailed investigation analyzed a cohort of 82 patients resident in Wolverhampton between 2003 and 2006. A significant association with being born in the UK remained after a multivariate analysis (OR = 9.68, 95% CI = 2.00-46.78, p < 0.01) and excess alcohol intake and cannabis use (OR = 6.26, 95%CI = 1.45-27.02, p = .01) were observed as social risk factors for infection.The continued consistent presence of the Mercian strain suggests ongoing community transmission. Whilst significant associations have been found, there may be other common risk factors yet to be identified. Future investigations should focus on targeting the relevant risk groups and elucidating the biological factors that mediate continued transmission of this strain.