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Background Melatonin is commonly used to treat sleep disturbance in children and adolescents, although uncertainties about its optimal use remain.Objective To determine to what extent prescribing of melatonin complies with evidence-based clinical practice standards.Methods As part of a quality improvement programme, the Prescribing Observatory for Mental Health conducted a retrospective clinical audit in UK services for children and adolescents.Findings Data were submitted for 4151 children and adolescents up to 18 years of age, treated with melatonin: 3053 (74%) had a diagnosis of neurodevelopmental disorder. In 2655 (73%) of the 3651 patients prescribed melatonin to be taken regularly, the main reason was to reduce sleep latency (time taken to fall asleep). In 409 patients recently starting melatonin, a non-pharmacological intervention had already been tried in 279 (68%). The therapeutic response of patients early in treatment (n=899) and on long-term treatment (n=2353) had been assessed and quantified in 36% and 31%, respectively, while for review of side effects, the respective proportions were 46% and 43%. Planned treatment breaks were documented in 317 (13%) of those on long-term treatment.Conclusions Melatonin was predominantly prescribed for evidence-based clinical indications, but the clinical review and monitoring of this treatment fell short of best practice.Clinical implications With limited methodical review of melatonin use in their patients, clinicians will fail to garner reliable information on its risks and benefits for individual patients. The lack of such practice-based evidence may increase the risk of melatonin being inappropriately targeted or continued despite being ineffective or no longer indicated.

Introduction Neonatal mortality remains significant in low-income and middle-income countries (LMICs) with in-hospital mortality rates similar to those following discharge from healthcare facilities. Care continuity interventions have been suggested as a way of reducing postdischarge mortality by better linking care between facilities and communities. This scoping review aims to map and describe interventions used in LMICs to improve care continuity for newborns after discharge and examine assumptions underpinning the design and delivery of continuity.Methods We searched seven databases (MEDLINE, CINAHL, Scopus, Web of Science, EMBASE, Cochrane library and (Ovid) Global health). Publications with primary data on interventions focused on continuity of care for newborns in LMICs were included. Extracted data included year of publication, study location, study design and type of intervention. Drawing on relevant theoretical frameworks and classifications, we assessed the extent to which interventions adopted participatory methods and how they attempted to establish continuity.Results A total of 65 papers were included in this review; 28 core articles with rich descriptions were prioritised for more in-depth analysis. Most articles adopted quantitative designs. Interventions focused on improving continuity and flow of information via education sessions led by community health workers during home visits. Extending previous frameworks, our findings highlight the importance of interpersonal continuity in LMICs where communication and relationships between family members, healthcare workers and members of the wider community play a vital role in creating support systems for postdischarge care. Only a small proportion of studies focused on high-risk babies. Some studies used participatory methods, although often without meaningful engagement in problem definition and intervention implementation.Conclusion Efforts to reduce neonatal mortality and morbidity should draw across multiple continuity logics (informational, relational, interpersonal and managerial) to strengthen care after hospital discharge in LMIC settings and further focus on high-risk neonates, as they often have the worst outcomes.

Acquired factor X (FX) deficiency is a rare but well-documented clinical feature of AL amyloidosis. Patients with FX deficiency can present with clinically significant bleeding diathesis due to the adsorption of circulating FX to amyloid fibrils. Here, we report an unusual case of a man in his 60s who presented with 6months of intermittent bruising, labs demonstrating new FX deficiency, elevated free lambda light chains for underlying AL amyloidosis and concurrent new peroneal vein thrombosis. This is the first report of concurrent thrombotic complications in the setting of AL-amyloid-induced FX deficiency. We discuss the diagnostic and therapeutic conundrum of diagnosing AL amyloidosis with bruising as the leading clinical symptom and the management of acute deep vein thrombosis in the setting of FX deficiency. [ABSTRACT FROM AUTHOR]

Introduction Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysis The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and dissemination Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration number NCT01782755; Pre-results.

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.Methods Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.Conclusions Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration number NCT02407990.

BackgroundTarget 3.2 of the United Nations Sustainable Development Goals (SDGs) is to reduce neonatal mortality. In low-income and middle-income countries (LMICs), the District Health Information Software, V.2 (DHIS2) is widely used to help improve indicator data reporting. There are few reports on its use for collecting neonatal hospital data that are of increasing importance as births within facilities increase. To address this gap, we investigated implementation experiences of DHIS2 in LMICs and mapped the information flow relevant for neonatal data reporting in Kenyan hospitals.MethodsA narrative review of published literature and policy documents from LMICs was conducted. Information gathered was used to identify the challenges around DHIS2 and to map information flows from healthcare facilities to the national level. Two use cases explore how newborn data collection and reporting happens in hospitals. The results were validated, adjusted and system challenges identified.ResultsLiterature and policy documents report that DHIS2 is a useful tool with strong technical capabilities, but significant challenges can emerge with the implementation. Visualisations of information flows highlight how a complex, people-based and paper-based subsystem for inpatient information capture precedes digitisation. Use cases point to major challenges in these subsystems in accurately identifying newborn deaths and appropriate data for the calculation of mortality even in hospitals.ConclusionsDHIS2 is a tool with potential to improve availability of health information that is key to health systems, but it critically depends on people-based and paper-based subsystems. In hospitals, the subsystems are subject to multiple micro level challenges. Work is needed to design and implement better standardised information processes, recording and reporting tools, and to strengthen the information system workforce. If the challenges are addressed and data quality improved, DHIS2 can support countries to track progress towards the SDG target of improving neonatal mortality.

IntroductionThere is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue.Methods and analysisThirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning.Ethics and disseminationThis study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC-2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients.Trial registration numberACTRN12619000952145; Pre-results.

BackgroundThe risk of reinjury and other sequelae following anterior cruciate ligament reconstruction (ACLR) remains high. Lack of knowledge regarding factors contributing to these risks limits our ability to develop sensitive return to play (RTP) tests. Using a running task, we evaluate whether fatigue induces alterations in foot progression angle (FPA), a proposed biomechanical risk factor and could be used to enhance RTP test sensitivity.MethodTransverse plane foot kinematics (FPA) were assessed for 18 post-ACLR subjects during a treadmill running task, before and after a generalised lower limb fatigue protocol. Subject’s contralateral limbs were used as a control group.ResultsA small but significant difference between FPA for ACLR and contralateral limbs was observed before but not after fatigue. When confounding variables were considered, there was a significant difference in FPA change between ACLR and contralateral limbs from the prefatigue to postfatigue state.ConclusionsFollowing ACLR athletes may develop a knee-protective movement strategy that delays the progression of osteoarthritis in the ACL-injured knee. This may, however, increase the risk of ACL reinjury. Following the onset of fatigue this proposed movement strategy, and thus osteoarthritis protection, is lost.

Objective: Estimating survival can aid care planning, but the use of absolute survival projections can be challenging for patients and clinicians to contextualise. We aimed to define how heart failure and its major comorbidities contribute to loss of actuarially predicted life expectancy.Methods: We conducted an observational cohort study of 1794 adults with stable chronic heart failure and reduced left ventricular ejection fraction, recruited from cardiology outpatient departments of four UK hospitals. Data from an 11-year maximum (5-year median) follow-up period (999 deaths) were used to define how heart failure and its major comorbidities impact on survival, relative to an age-sex matched control UK population, using a relative survival framework.Results: After 10 years, mortality in the reference control population was 29%. In people with heart failure, this increased by an additional 37% (95% CI 34% to 40%), equating to an additional 2.2 years of lost life or a 2.4-fold (2.2-2.5) excess loss of life. This excess was greater in men than women (2.4 years (2.2-2.7) vs 1.6 years (1.2-2.0); p<0.001). In patients without major comorbidity, men still experienced excess loss of life, while women experienced less and were non-significantly different from the reference population (1 year (0.6-1.5) vs 0.4 years (-0.3 to 1); p<0.001). Accrual of comorbidity was associated with substantial increases in excess lost life, particularly for diabetes, chronic kidney and lung disease.Conclusions: Comorbidity accounts for the majority of lost life expectancy in people with heart failure. Women, but not men, without comorbidity experience survival close to reference controls. [ABSTRACT FROM AUTHOR]

Background Reducing avoidable harm in maternity services is a priority globally. As well as learning from mistakes, it is important to produce rigorous descriptions of 'what good looks like'. Objective We aimed to characterise features of safety in maternity units and to generate a plain language framework that could be used to guide learning and improvement. Methods We conducted a multisite ethnography involving 401 hours of non- participant observations 33 semistructured interviews with staff across six maternity units, and a stakeholder consultation involving 65 semistructured telephone interviews and one focus group. Results We identified seven features of safety in maternity units and summarised them into a framework, named For Us (For Unit Safety). The features include: (1) commitment to safety and improvement at all levels, with everyone involved; (2) technical competence, supported by formal training and informal learning; (3) teamwork, cooperation and positive working relationships; (4) constant reinforcing of safe, ethical and respectful behaviours; (5) multiple problem- sensing systems, used as basis of action; (6) systems and processes designed for safety, and regularly reviewed and optimised; (7) effective coordination and ability to mobilise quickly. These features appear to have a synergistic character, such that each feature is necessary but not sufficient on its own: the features operate in concert through multiple forms of feedback and amplification. Conclusions This large qualitative study has enabled the generation of a new plain language framework--For Us--that identifies the behaviours and practices that appear to be features of safe care in hospital- based maternity units. [ABSTRACT FROM AUTHOR]

Introduction There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue. Methods and analysis Thirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning. Ethics and dissemination This study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC- 2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients. [ABSTRACT FROM AUTHOR]

Objectives The UK Clinical Aptitude Test (UKCAT) previously piloted an assessment of ‘online confidence’, where candidates were asked to indicate how confident they were with their answers. This study examines the relationship between these ratings, the odds of receiving an offer to study medicine and subsequent undergraduate academic performance. Design National cohort study. Setting UK undergraduate medical selection. Participants 56 785 UKCAT candidates who sat the test between 2013 and 2016 and provided valid responses to the online confidence pilot study. Primary outcome measures Two measures of ‘online confidence’ were derived: the well-established ‘confidence bias’, and; a novel ‘confidence judgement’ measure, developed using Item Response Theory in order to derive a more sophisticated metric of the ability to evaluate one’s own performance on a task. Regression models investigated the relationships between these confidence measures, application success and academic performance. Results Online confidence was inversely related to cognitive performance. Relative underconfidence was associated with increased odds of receiving an offer to study medicine. For ‘confidence bias’ this effect was independent of potential confounders (OR 1.48, 1.15 to 1.91, p=0.002). While ‘confidence judgement’ was also a univariable predictor of application success (OR 1.22, 1.01 to 1.47, p=0.04), it was not an independent predictor. ‘Confidence bias’, but not ‘confidence judgement’, predicted the odds of passing the first year of university at the first attempt, independently of cognitive performance, with relative underconfidence positively related to academic success (OR 3.24, 1.08 to 9.72, p=0.04). No non-linear effects were observed, suggesting no ‘sweet spot’ exists in relation to online confidence and the outcomes studied. Conclusions Applicants who either appear underconfident, or are better at judging their own performance on a task, are more likely to receive an offer to study medicine. However, online confidence estimates had limited ability to predict subsequent academic achievement. Moreover, there are practical challenges to evaluating online confidence in high-stakes selection. [ABSTRACT FROM AUTHOR]

Introduction Permanent artificial pacemaker implantation is a safe and effective treatment for bradycardia and is associated with extended longevity and improved quality of life. However, the most common long-term complication of standard pacemaker therapy is pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to screen for heart failure to assess and optimise patient devices and medical therapy. Methods and analysis The study is a multicentre, phase-3 randomised trial. The 1200 participants will be people who have a permanent pacemaker for bradycardia for at least 12 months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker check, thereby tailoring their management directed by left ventricular function or the pacemaker check alone, continuing with routine follow-up. The primary outcome measure is time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include external validation of our risk stratification model to predict onset of heart failure and quality of life assessment. Ethics and Dissemination The trial design and protocol have received national ethical approval (12/YH/0487). The results of this randomised trial will be published in international peer-reviewed journals, communicated to healthcare professionals and patient involvement groups and highlighted using social media campaigns. [ABSTRACT FROM AUTHOR]

Introduction Foot ulceration is a multifactorial complication of diabetes. Therapeutic insoles and footwear are frequently used to reduce elevated tissue pressures associated with risk of foot ulceration. A novel protocol using in-shoe pressure measurement technology to provide an instant optimised insole and house shoe solution has been developed, with the aim of reducing foot ulceration. Aim This study aims to assess the feasibility of conducting a multicentre randomised controlled trial to compare the effectiveness of a novel instant optimised insole with a standard insole for people with diabetic neuropathy. Methods and analysis This study is a participant and assessor blinded, randomised, multicentre parallel group feasibility trial with embedded qualitative study. Seventy-six participants will be recruited from three podiatry clinics and randomised to an optimised insole plus usual care (intervention group) or standard insole plus usual care (control group) using a minimisation by randomisation procedure by study centre and previous ulcer status. Assessment visits and data collection will be at baseline, 3 months, 6 months and 12 months. Feasibility and acceptability of the trial procedures will be determined in terms of recruitment and retention rates, data completion rates, intervention adherence and effectiveness of the blinding. Assessment of the appropriateness and performance of outcome measures will inform selection of the primary and secondary outcomes and sample size estimate for the anticipated definitive randomised controlled trial. Clinical outcomes include incidence of plantar foot ulceration and change in peak plantar pressure. Twelve participants (four from each centre) and three treating podiatrists (one from each centre) will be interviewed to explore their experiences of receiving and delivering the intervention. Ethics and dissemination The study was approved by the South-West Exeter Research Ethics Committee. Findings will be disseminated through conference presentations, public platforms and academic publications. Trials registration number ISRCTN16011830; Pre-results. [ABSTRACT FROM AUTHOR]

Peritoneal melanosis is an uncommon benign condition, the pathophysiology of which is unclear. Macroscopically, it appears as diffuse dark brown or black pigmentation within the peritoneum, mimicking more sinister conditions such as metastatic melanoma. It has been described in a variety of contexts, but only exceedingly rarely in association with metastatic melanoma, with only two previous published case reports. We present a case of peritoneal melanosis associated with metastatic melanoma involving the spleen, previously treated with targeted and immune checkpoint inhibitor therapy. With increasing reports of melanoma regression manifesting as cutaneous tumorous melanosis in patients treated with immune checkpoint inhibitors, we postulate that, similarly, immunotherapy and tumour regression might have a role to play in the pathogenesis of the peritoneal pigmentation in this case. [ABSTRACT FROM AUTHOR]