Short-stay urgent hospital admissions of children with convulsions: A mixed methods exploratory study to inform out of hospital care pathways.

OBJECTIVE: To inform interventions focused on safely reducing urgent paediatric short stay admissions (SSAs) for convulsions. METHODS: Routinely acquired administrative data from hospital admissions in Scotland between 2015-2017 investigated characteristics of unscheduled SSAs (an urgent admission where admission and discharge occur on the same day) for a diagnosis of febrile and/or afebrile convulsions. Semi-structured interviews to explore perspectives of health professionals (n = 19) making referral or admission decisions about convulsions were undertaken. Interpretation of mixed methods findings was complemented by interviews with four parents with experience of unscheduled SSAs of children with convulsion. RESULTS: Most SSAs for convulsions present initially at hospital emergency departments (ED). In a subset of 10,588 (11%) of all cause SSAs with linked general practice data available, 72 (37%) children with a convulsion contacted both the GP and ED pre-admission. Within 30 days of discharge, 10% (n = 141) of children admitted with afebrile convulsions had been readmitted to hospital with a further convulsion. Interview data suggest that panic and anxiety, through fear that the situation is life threatening, was a primary factor driving hospital attendance and admission. Lengthy waits to speak to appropriate professionals exacerbate parental anxiety and can trigger direct attendance at ED, whereas some children with complex needs had direct access to convulsion professionals. CONCLUSIONS: SSAs for convulsions are different to SSAs for other conditions and our findings could inform new efficient convulsion-specific pre and post hospital pathways designed to improve family experiences and reduce admissions and readmissions.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Identifying and prioritising future interventions with stakeholders to improve paediatric urgent care pathways in Scotland, UK: a mixed-methods study.

OBJECTIVES: To identify and prioritise interventions, from the perspectives of parents and health professionals, which may be alternatives to current unscheduled paediatric urgent care pathways. DESIGN: FLAMINGO (FLow of AdMissions in chIldren and youNG peOple) is a sequential mixed-methods study, with public and patient involvement (PPI) throughout. Data linkage for urgent admissions and three referral sources: emergency department, out of hours service and general practice, was followed by qualitative interviews with parents and professionals. Findings were presented and discussed at a stakeholder intervention prioritisation event. SETTING: National Health Service in Scotland, UK. PARTICIPANTS: Quantitative data: children with urgent medical admission to hospital from 2015 to 2017. Qualitative interviews: parents and health professionals with experiences of urgent short stay hospital admissions of children. PPI engagement was conducted with nine parent-toddler groups and a university-based PPI advisory group. Stakeholder event: parents, health professionals and representatives from Scottish Government, academia, charities and PPI attended. RESULTS: Data for 171 039 admissions which included 92 229 short stay admissions were analysed and 48 health professionals and 21 parents were interviewed. The stakeholder event included 7 parents, 12 health professionals and 28 other stakeholders. Analysis and synthesis of all data identified seven interventions which were prioritised at the stakeholder event: (1) addressing gaps in acute paediatric skills of health professionals working in community settings; (2) assessment and observation of acutely unwell children in community settings; (3) creation of holistic children's 'hubs'; (4) adoption of 'hospital at home' models; and three specialised care pathways for subgroups of children; (5) convulsions; (6) being aged <2 years old; and (7) wheeze/bronchiolitis. Stakeholders prioritised interventions 1, 2 and 3; these could be combined into a whole population intervention. Barriers to progressing these include resources, staffing and rurality. CONCLUSIONS: Health professionals and families want future interventions that are patient-centred, community-based and aligned to outcomes that matter to them.

Regional variations in short stay urgent paediatric hospital admissions: a sequential mixed-methods approach exploring differences through data linkage and qualitative interviews.

OBJECTIVES: The aim of this sequential mixed-methods study was to describe and understand how paediatric short stay admission (SSA) rates vary across Health Board regions of Scotland. DESIGN: Exploratory sequential mixed-methods study. Routinely acquired data for the annual (per capita) SSA to hospital were compared across the 11 regions. Five diverse regions with different SSA per capita formed cases for qualitative interviews with health professionals and parents to explore how care pathways, service features and geography may influence decisions to admit. SETTING: Scotland. PARTICIPANTS: All children admitted to hospital 2015-2017. Healthcare staff (n=48) and parents (n=15) were interviewed. RESULTS: Of 171 039 urgent hospital admissions, 92 229 were SSAs, with a fivefold variation between 14 and 69/1000 children/year across regions. SSAs were higher for children in the most deprived compared with the least deprived communities. When expressed as a ratio of highest to lowest SSA/1000 children/year for diagnosed conditions between regions, the ratio was highest (10.1) for upper respiratory tract infection and lowest (2.8) for convulsions. Readmissions varied between 0.80 and 2.52/1000/year, with regions reporting higher SSA rates more likely to report higher readmission rates (r=0.70, p=0.016, n=11). Proximity and ease of access to services, local differences in service structure and configuration, national policy directives and disparities in how an SSA is defined were recognised by interviewees as explaining the observed regional variations in SSAs. Socioeconomic deprivation was seldom spontaneously raised by professionals when reflecting on reasons to refer or admit a child. Instead, greater emphasis was placed on the wider social circumstances and parents' capacity to cope with and manage their child's illness at home. CONCLUSION: SSA rates for children vary quantitatively by region, condition and area deprivation and our interviews identify reasons for this. These findings can usefully inform future care pathway interventions.

Audit, Feedback, and Education to Improve Quality and Outcomes in Transurethral Resection and Single-Instillation Intravesical Chemotherapy for Nonmuscle Invasive Bladder Cancer Treatment: Protocol for a Multicenter International Observational Study With an Embedded Cluster Randomized Trial.

BACKGROUND: Nonmuscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. It is common and costly. Cost and detriment to patient outcomes and quality of life are driven by high recurrence rates and the need for regular invasive surveillance and repeat treatments. There is evidence that the quality of the initial surgical procedure (transurethral resection of bladder tumor [TURBT]) and administration of postoperative bladder chemotherapy significantly reduce cancer recurrence rates and improve outcomes (cancer progression and mortality). There is surgeon-reported evidence that TURBT practice varies significantly across surgeons and sites. There is limited evidence from clinical trials of intravesical chemotherapy that NMIBC recurrence rate varies significantly between sites and that this cannot be accounted for by differences in patient, tumor, or adjuvant treatment factors, suggesting that how the surgery is performed may be a reason for the variation. OBJECTIVE: This study primarily aims to determine if feedback on and education about surgical quality indicators can improve performance and secondarily if this can reduce cancer recurrence rates. Planned secondary analyses aim to determine what surgeon, operative, perioperative, institutional, and patient factors are associated with better achievement of TURBT quality indicators and NMIBC recurrence rates. METHODS: This is an observational, international, multicenter study with an embedded cluster randomized trial of audit, feedback, and education. Sites will be included if they perform TURBT for NMIBC. The study has four phases: (1) site registration and usual practice survey; (2) retrospective audit; (3) randomization to audit, feedback, and education intervention or to no intervention; and (4) prospective audit. Local and national ethical and institutional approvals or exemptions will be obtained at each participating site. RESULTS: The study has 4 coprimary outcomes, which are 4 evidence-based TURBT quality indicators: a surgical performance factor (detrusor muscle resection); an adjuvant treatment factor (intravesical chemotherapy administration); and 2 documentation factors (resection completeness and tumor features). A key secondary outcome is the early cancer recurrence rate. The intervention is a web-based surgical performance feedback dashboard with educational and practical resources for TURBT quality improvement. It will include anonymous site and surgeon-level peer comparison, a performance summary, and targets. The coprimary outcomes will be analyzed at the site level while recurrence rate will be analyzed at the patient level. The study was funded in October 2020 and began data collection in April 2021. As of January 2023, there were 220 hospitals participating and over 15,000 patient records. Projected data collection end date is June 30, 2023. CONCLUSIONS: This study aims to use a distributed collaborative model to deliver a site-level web-based performance feedback intervention to improve the quality of endoscopic bladder cancer surgery. The study is funded and projects to complete data collection in June 2023. TRIAL REGISTRATION: ClinicalTrials.org NCT05154084; https://clinicaltrials.gov/ct2/show/NCT05154084. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42254.

Antenatal size, early childhood growth, and asthma within a cohort created by data linkage.

INTRODUCTION: The gestation when small for gestational age (SGA) is first associated with asthma is not well understood. Here, we use routinely acquired data from 10 weeks gestation to up to 28 years of age to test the hypothesis that SGA before birth is associated with an increased risk for asthma in a large population born between 1987 and 2015. METHODS: Databases were linked to produce a single database that held antenatal fetal ultrasound measurements; maternal characteristics; birth measurements; childhood anthropometric measurements at age 5 years; hospital admission data (1987-2015); and family doctor prescribing (2009-2015). Asthma admission and receipt of any asthma medications were the outcomes. Analyses related single and then multiple anthropometric measurements to asthma outcomes. RESULTS: Outcome data were available for 63,930 individuals. Increased length in the first-trimester size was associated with a reduced odds ratio (OR) for asthma admission of 0.991 [0.983, 0.998] per mm increase and also a shorter time to first admission, with a hazard ratio risk of 0.987 [0.980, 0.994] per mm increase. Independent of all earlier measurements, increased height at 5 years (available in a subset of 15,760) was associated with reduced OR for an asthma admission, with OR of 0.874 [0.790, 0.967] per z score. Longitudinal measurements of weight were not related to asthma outcomes. CONCLUSIONS: Longer first-trimester length is associated with more favorable asthma outcomes, and subsequently, increased height in childhood is also independently associated with more favorable asthma outcomes. Interventions that reduce SGA and encourage healthy postnatal growth might improve asthma outcomes.

Cost-effectiveness of cognitive behavioural and personalized exercise interventions for reducing fatigue in inflammatory rheumatic diseases.

OBJECTIVES: To estimate the cost-effectiveness of a cognitive behavioural approach (CBA) or a personalized exercise programme (PEP), alongside usual care (UC), in patients with inflammatory rheumatic diseases who report chronic, moderate to severe fatigue. METHODS: A within-trial cost-utility analysis was conducted using individual patient data collected within a multicentre, three-arm randomized controlled trial over a 56-week period. The primary economic analysis was conducted from the UK National Health Service (NHS) perspective. Uncertainty was explored using cost-effectiveness acceptability curves and sensitivity analysis. RESULTS: Complete-case analysis showed that, compared with UC, both PEP and CBA were more expensive [adjusted mean cost difference: PEP £569 (95% CI: £464, £665); CBA £845 (95% CI: £717, £993)] and, in the case of PEP, significantly more effective [adjusted mean quality-adjusted life year (QALY) difference: PEP 0.043 (95% CI: 0.019, 0.068); CBA 0.001 (95% CI: -0.022, 0.022)]. These led to an incremental cost-effectiveness ratio (ICER) of £13 159 for PEP vs UC, and £793 777 for CBA vs UC. Non-parametric bootstrapping showed that, at a threshold value of £20 000 per QALY gained, PEP had a probability of 88% of being cost-effective. In multiple imputation analysis, PEP was associated with significant incremental costs of £428 (95% CI: £324, £511) and a non-significant QALY gain of 0.016 (95% CI: -0.003, 0.035), leading to an ICER of £26 822 vs UC. The estimates from sensitivity analyses were consistent with these results. CONCLUSION: The addition of a PEP alongside UC is likely to provide a cost-effective use of health care resources.

Insights from and limitations of data linkage studies: analysis of short-stay urgent admission referral source from routinely collected Scottish data.

INTRODUCTION: This study identified the referral source for urgent short-stay admissions (SSAs) and compared characteristics of children with SSA stratified by different referral sources. METHODS: Routinely acquired data from urgent admissions to Scottish hospitals during 2015-2017 were linked to data held by the three referral sources: emergency department (ED), out-of-hours (OOH) service and general practice (GP). RESULTS: There were 171 039 admissions including 92 229 (54%) SSAs. Only 171 (19%) of all of Scotland's GP practices contributed data. Among the subgroup of 10 588 SSAs where GP data were available (11% all SSA), there was contact with the following referral source on the day of admission: only ED, 1853 (18%); only GP, 3384 (32%); and only OOH, 823 (8%). Additionally, 2165 (20%) had contact with more than one referral source, and 1037 (10%) had contact with referral source(s) on the day before the admission. When all 92 229 SSAs were considered, those with an ED referrer were more likely to be for older children, of white ethnicity, living in more deprived communities and diagnosed with asthma, convulsions or croup. The odds ratio for an SSA for a given condition differed by referral source and ranged from 0.07 to 1.9 (with reference to ED referrals). CONCLUSION: This study yielded insights and potential limitations regarding data linkage in a healthcare setting. Data coverage, particularly from primary care, needs to improve further. Evidence from data linkage studies can inform future intervention designed to provide safe integrated care pathways.

PROSPECT: 4- and 6-year follow-up of a randomised trial of surgery for vaginal prolapse.

INTRODUCTION AND HYPOTHESIS: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse. METHODS: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures. RESULTS: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups. CONCLUSIONS: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs.

Cost-utility analysis of shockwave lithotripsy vs ureteroscopic stone treatment in adults.

OBJECTIVES: To assess the cost-effectiveness, resource use implications, quality-adjusted life-years (QALYs) and cost per QALY of care pathways starting with either extracorporeal shockwave lithotripsy (SWL) or with ureteroscopic retrieval (ureteroscopy [URS]) for the management of ureteric stones. PATIENTS AND METHODS: Data on quality of life and resource use for 613 patients, collected prospectively in the Therapeutic Interventions for Stones of the Ureter (TISU) randomized controlled trial (ISRCTN 92289221), were used to assess the cost-effectiveness of two care pathways, SWL and URS. A health provider (UK National Health Service) perspective was adopted to estimate the costs of the interventions and subsequent resource use. Quality-of-life data were calculated using a generic instrument, the EuroQol EQ-5D-3L. Results are expressed as incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. RESULTS: The mean QALY difference (SWL vs URS) was -0.021 (95% confidence interval [CI] -0.033 to -0.010) and the mean cost difference was -£809 (95% CI -£1061 to -£551). The QALY difference translated into approximately 10 more healthy days over the 6-month period for the patients on the URS care pathway. The probabaility that SWL is cost-effective is 79% at a society's willingness to pay (WTP) threshold for 1 QALY of £30,000 and 98% at a WTP threshold of £20,000. CONCLUSION: The SWL pathway results in lower QALYs than URS but costs less. The incremental cost per QALY is £39 118 cost saving per QALY lost, with a 79% probability that SWL would be considered cost-effective at a WTP threshold for 1 QALY of £30 000 and 98% at a WTP threshold of £20 000. Decision-makers need to determine if costs saved justify the loss in QALYs.

Short stay hospital admissions for an acutely unwell child: A qualitative study of outcomes that matter to parents and professionals.

BACKGROUND: Numbers of urgent short stay admissions (SSAs) of children to UK hospitals are rising rapidly. This paper reports on experiences of SSAs from the perspective of parents accessing urgent care for their acutely unwell child and of health professionals referring, caring for, or admitting children. METHODS: A qualitative interview study was conducted by a multi-disciplinary team with patient and public involvement (PPI) to explore contextual factors relating to SSAs and better understand pre-hospital urgent care pathways. Purposive sampling of Health Board areas in Scotland, health professionals with experience of paediatric urgent care pathways and parents with experience of a SSA for their acutely unwell child was undertaken to ensure maximal variation in characteristics such as deprivation, urban-rural and hospital structure. Interviews took place between Dec 2019 and Mar 2021 and thematic framework analysis was applied. RESULTS: Twenty-one parents and forty-eight health professionals were interviewed. In the context of an urgent SSA, the themes were centred around shared outcomes of care that matter. The main outcome which was common to both parents and health professionals was the importance of preserving the child's safety. Additional shared outcomes by parents and health professionals were a desire to reduce worries and uncertainty about the illness trajectory, and provide reassurance with sufficient time, space and personnel to undertake a period of skilled observation to assess and manage the acutely unwell child. Parents wanted easy access to urgent care and, preferably, with input from paediatric-trained staff. Healthcare professionals considered that it was important to reduce the number of children admitted to hospital where safe and appropriate to do so. CONCLUSIONS: The shared outcomes of care between parents and health professionals emphasises the potential merit of adopting a partnership approach in identifying, developing and testing interventions to improve the acceptability, safety, efficiency, and cost-effectiveness of urgent care pathways between home and hospital.

Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial.

Background: Chronic fatigue is a poorly managed problem in people with inflammatory rheumatic diseases. Cognitive behavioural approaches (CBA) and personalised exercise programmes (PEP) can be effective, but they are not often implemented because their effectivenesses across the different inflammatory rheumatic diseases are unknown and regular face-to-face sessions are often undesirable, especially during a pandemic. We hypothesised that remotely delivered CBA and PEP would effectively alleviate fatigue severity and life impact across inflammatory rheumatic diseases. Methods: LIFT is a multicentre, randomised, controlled, open-label, parallel-group trial to assess usual care alongside telephone-delivered CBA or PEP against usual care alone in UK hospitals. Patients with any stable inflammatory rheumatic disease were eligible if they reported clinically significant, persistent fatigue. Treatment allocation was assigned by a web-based randomisation system. CBA and PEP sessions were delivered over 6 months by trained health professionals in rheumatology. Coprimary outcomes were fatigue severity (Chalder Fatigue Scale) and impact (Fatigue Severity Scale) at 56 weeks. The primary analysis was by full analysis set. This study was registered at ClinicalTrials.gov (NCT03248518). Findings: From Sept 4, 2017, to Sept 30, 2019, we randomly assigned and treated 367 participants to PEP (n=124; one participant withdrew after being randomly assinged), CBA (n=121), or usual care alone (n=122), of whom 274 (75%) were women and 92 (25%) were men with an overall mean age of 57·5 (SD 12·7) years. Analyses for Chalder Fatigue Scale included 101 participants in the PEP group, 107 in the CBA group, and 107 in the usual care group and for Fatigue Severity Scale included 101 in PEP, 106 in CBA, and 107 in usual care groups. PEP and CBA significantly improved fatigue severity (Chalder Fatigue Scale; PEP: adjusted mean difference -3·03 [97·5% CI -5·05 to -1·02], p=0·0007; CBA: -2·36 [-4·28 to -0·44], p=0·0058) and fatigue impact (Fatigue Severity Scale; PEP: -0·64 [-0·95 to -0·33], p<0·0001; CBA: -0·58 [-0·87 to -0·28], p<0·0001); compared with usual care alone at 56 weeks. No trial-related serious adverse events were reported. Interpretation: Telephone-delivered CBA and PEP produced and maintained statistically and clinically significant reductions in the severity and impact of fatigue in a variety of inflammatory rheumatic diseases. These interventions should be considered as a key component of inflammatory rheumatic disease management in routine clinical practice. Funding: Versus Arthritis.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

Marine-derived n-3 fatty acids therapy for stroke.

BACKGROUND: Currently, with stroke burden increasing, there is a need to explore therapeutic options that ameliorate the acute insult. There is substantial evidence of a neuroprotective effect of marine-derived n-3 polyunsaturated fatty acids (PUFAs) in animal models of stroke, leading to a better functional outcome. OBJECTIVES: To assess the effects of administration of marine-derived n-3 PUFAs on functional outcomes and dependence in people with stroke. SEARCH METHODS: We searched the Cochrane Stroke Trials Register (last searched 31 May 2021), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 5), MEDLINE Ovid (from 1948 to 31 May 2021), Embase Ovid (from 1980 to 31 May 2021), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; from 1982 to 31 May 2021), Science Citation Index Expanded ‒ Web of Science (SCI-EXPANDED), Conference Proceedings Citation Index-Science - Web of Science (CPCI-S), and BIOSIS Citation Index. We also searched ongoing trial registers, reference lists, relevant systematic reviews, and used the Science Citation Index Reference Search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing marine-derived n-3 PUFAs to placebo or open control (no placebo) in people with a history of stroke or transient ischaemic attack (TIA), or both. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected trials for inclusion, extracted data, assessed risk of bias, and used the GRADE approach to assess the certainty of the body of evidence. We contacted study authors for clarification and additional information on stroke/TIA participants. We conducted random-effects meta-analysis or narrative synthesis, as appropriate. The primary outcome was efficacy (functional outcome) assessed using a validated scale, for example, the Glasgow Outcome Scale Extended (GOSE) dichotomised into poor or good clinical outcome, the Barthel Index (higher score is better; scale from 0 to 100), or the Rivermead Mobility Index (higher score is better; scale from 0 to 15). Our secondary outcomes were vascular-related death, recurrent events, incidence of other type of stroke, adverse events, quality of life, and mood. MAIN RESULTS: We included 30 RCTs; nine of them provided outcome data (3339 participants). Only one study included participants in the acute phase of stroke (haemorrhagic). Doses of marine-derived n-3 PUFAs ranged from 400 mg/day to 3300 mg/day. Risk of bias was generally low or unclear in most trials, with a higher risk of bias in smaller studies. We assessed results separately for short (up to three months) and longer (more than three months) follow-up studies. Short follow-up (up to three months) Functional outcome was reported in only one pilot study as poor clinical outcome assessed with the GOSE (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.36 to 1.68, P = 0.52; 40 participants; very low-certainty evidence). Mood (assessed with the GHQ-30, lower score better) was reported by only one study and favoured control (mean difference (MD) 1.41, 95% CI 0.07 to 2.75, P = 0.04; 102 participants; low-certainty evidence). We found no evidence of an effect of the intervention for the remainder of the secondary outcomes: vascular-related death (two studies, not pooled due to differences in population, RR 0.33, 95% CI 0.01 to 8.00, P = 0.50, and RR 0.33, 95% CI 0.01 to 7.72, P = 0.49; 142 participants; low-certainty evidence); recurrent events (RR 0.41, 95% CI 0.02 to 8.84, P = 0.57; 18 participants; very low-certainty evidence); incidence of other type of stroke (two studies, not pooled due to different type of index stroke, RR 6.11, 95% CI 0.33 to 111.71, P = 0.22, and RR 0.63, 95% CI 0.25 to 1.58, P = 0.32; 58 participants; very low-certainty evidence); and quality of life (physical component, MD -2.31, 95% CI -4.81 to 0.19, P = 0.07, and mental component, MD -2.16, 95% CI -5.91 to 1.59, P = 0.26; 1 study; 102 participants; low-certainty evidence). Adverse events were reported by two studies (57 participants; very low-certainty evidence), one trial reporting extracranial haemorrhage (RR 0.25, 95% CI 0.04 to 1.73, P = 0.16) and the other one reporting bleeding complications (RR 0.32, 95% CI 0.01 to 7.35, P = 0.47). Longer follow-up (more than three months) One small trial assessed functional outcome with both the Barthel Index for activities of daily living (MD 7.09, 95% CI -5.16 to 19.34, P = 0.26), and the Rivermead Mobility Index for mobility (MD 1.30, 95% CI -1.31 to 3.91, P = 0.33) (52 participants; very low-certainty evidence). We carried out meta-analysis for vascular-related death (RR 1.02, 95% CI 0.78 to 1.35, P = 0.86; 5 studies; 2237 participants; low-certainty evidence) and fatal recurrent events (RR 0.69, 95% CI 0.31 to 1.55, P = 0.37; 3 studies; 1819 participants; low-certainty evidence). We found no evidence of an effect of the intervention for mood (MD 1.00, 95% CI -2.07 to 4.07, P = 0.61; 1 study; 14 participants; low-certainty evidence). Incidence of other type of stroke and quality of life were not reported. Adverse events (all combined) were reported by only one study (RR 0.94, 95% CI 0.56 to 1.58, P = 0.82; 1455 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: We are very uncertain of the effect of marine-derived n-3 PUFAs therapy on functional outcomes and dependence after stroke as there is insufficient high-certainty evidence. More well-designed RCTs are needed, specifically in acute stroke, to determine the efficacy and safety of the intervention. Studies assessing functional outcome might consider starting the intervention as early as possible after the event, as well as using standardised, clinically relevant measures for functional outcomes, such as the modified Rankin Scale. Optimal doses remain to be determined; delivery forms (type of lipid carriers) and mode of administration (ingestion or injection) also need further consideration.

Digital smartphone intervention to recognise and manage early warning signs in schizophrenia to prevent relapse: the EMPOWER feasibility cluster RCT.

BACKGROUND: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse. OBJECTIVE: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse? DESIGN: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up. SETTINGS: Glasgow, UK, and Melbourne, Australia. PARTICIPANTS: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user. INTERVENTIONS: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted. MAIN OUTCOME MEASURES: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse. RESULTS: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference -4.29, 95% confidence interval -7.29 to -1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained. LIMITATIONS: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness. CONCLUSIONS: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible. FUTURE WORK: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3-0.4). TRIAL REGISTRATION: This trial is registered as ISRCTN99559262. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

WHAT WAS THE PROBLEM?: Relapse is a considerable problem for people with a diagnosis of schizophrenia. Relapse can be predicted by early warning signs that are unique to the person. They include withdrawal, fear and paranoia. WHAT WAS THE QUESTION?: Is it possible to investigate the effectiveness of an intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse? WHAT DID WE DO?: We spoke with 88 mental health staff, 40 carers and 21 service users before we designed a system that used a mobile phone to help people monitor early warning signs. We included peer support to help people using the system reflect on their experiences. We hoped the overall system, called EMPOWER, would help people to be more in charge of their mental health. After consenting 86 people to the study, we were able to randomly assign 73 people either to use the EMPOWER system (42 people) or to receive their normal treatment alone (31 people). We used research measures over 1 year to help us better understand people's experiences. We also involved carers (for example family or friends) and mental health service providers in the research. WHAT DID WE FIND?: We found that it was possible to recruit people to the study and to gather research data. We also found that people used the EMPOWER system and found it acceptable. We found that those who used EMPOWER had a lower rate of relapse over 12 months than people who did not. They were also less likely to be fearful of relapse. We found that EMPOWER was likely to be cost-effective. WHAT DOES THIS MEAN?: This means that a study to investigate the effectiveness of a system to recognise and respond to early warning signs of relapse in schizophrenia is possible.

The EMPOWER blended digital intervention for relapse prevention in schizophrenia: a feasibility cluster randomised controlled trial in Scotland and Australia.

BACKGROUND: Early warning signs monitoring by service users with schizophrenia has shown promise in preventing relapse but the quality of evidence is low. We aimed to establish the feasibility of undertaking a definitive randomised controlled trial to determine the effectiveness of a blended digital intervention for relapse prevention in schizophrenia. METHODS: This multicentre, feasibility, cluster randomised controlled trial aimed to compare Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) with treatment as usual in community mental health services (CMHS) in Glasgow and Melbourne. CMHS were the unit of randomisation, selected on the basis of those that probably had five or more care coordinators willing to participate. Participants were eligible if they were older than 16 years, had a schizophrenia or related diagnosis confirmed via case records, were able to provide informed consent, had contact with CMHS, and had had a relapse within the previous 2 years. Participants were randomised within stratified clusters to EMPOWER or to continue their usual approach to care. EMPOWER blended a smartphone for active monitoring of early warning signs with peer support to promote self-management and clinical triage to promote access to relapse prevention. Main outcomes were feasibility, acceptability, usability, and safety, which was assessed through face-to-face interviews. App usage was assessed via the smartphone and self-report. Primary end point was 12 months. Participants, research assistants and other team members involved in delivering the intervention were not masked to treatment conditions. Assessment of relapse was done by an independent adjudication panel masked to randomisation group. The study is registered at ISRCTN (99559262). FINDINGS: We identified and randomised eight CMHS (six in Glasgow and two in Melbourne) comprising 47 care coordinators. We recruited 86 service users between Jan 19 and Aug 8, 2018; 73 were randomised (42 [58%] to EMPOWER and 31 [42%] to treatment as usual). There were 37 (51%) men and 36 (49%) women. At 12 months, main outcomes were collected for 32 (76%) of service users in the EMPOWER group and 30 (97%) of service users in the treatment as usual group. Of those randomised to EMPOWER, 30 (71%) met our a priori criterion of more than 33% adherence to daily monitoring that assumed feasibility. Median time to discontinuation of these participants was 31·5 weeks (SD 14·5). There were 29 adverse events in the EMPOWER group and 25 adverse events in the treatment as usual group. There were 13 app-related adverse events, affecting 11 people, one of which was serious. Fear of relapse was lower in the EMPOWER group than in the treatment as usual group at 12 months (mean difference -7·53 (95% CI -14·45 to 0·60; Cohen's d -0·53). INTERPRETATION: A trial of digital technology to monitor early warning signs blended with peer support and clinical triage to detect and prevent relapse appears to be feasible, safe, and acceptable. A further main trial is merited. FUNDING: UK National Institute for Health Research Health Technology Assessment programme and the Australian National Health and Medical Research Council.

Household income, fetal size and birth weight: an analysis of eight populations.

BACKGROUND: The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth. METHODS: Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis. RESULTS: The eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model. CONCLUSIONS: The association between HI, an index of poverty, and fetal size is already present in the second trimester.

Pre-hospital and emergency department treatment of convulsive status epilepticus in adults: an evidence synthesis.

BACKGROUND: Convulsive status epilepticus is defined as ≥ 5 minutes of either continuous seizure activity or repetitive seizures without regaining consciousness. It is regarded as an emergency condition that requires prompt treatment to avoid hospitalisation and to reduce morbidity and mortality. Rapid pre-hospital first-line treatment of convulsive status epilepticus is currently benzodiazepines, administered either by trained caregivers in the community (e.g. buccal midazolam, rectal diazepam) or by trained health professionals via intramuscular or intravenous routes (e.g. midazolam, lorazepam). There is a lack of clarity about the optimal treatment for convulsive status epilepticus in the pre-hospital setting. OBJECTIVES: To assess the current evidence on the clinical effectiveness and cost-effectiveness of treatments for adults with convulsive status epilepticus in the pre-hospital setting. DATA SOURCES: We searched major electronic databases, including MEDLINE, EMBASE, PsycInfo®, CINAHL, CENTRAL, NHS Economic Evaluation Database, Health Technology Assessment Database, Research Papers in Economics, and the ISPOR Scientific Presentations Database, with no restrictions on publication date or language of publication. Final searches were carried out on 21 July 2020. REVIEW METHODS: Systematic review of randomised controlled trials assessing adults with convulsive status epilepticus who received treatment before or on arrival at the emergency department. Eligible treatments were any antiepileptic drugs offered as first-line treatments, regardless of their route of administration. Primary outcomes were seizure cessation, seizure recurrence and adverse events. Two reviewers independently screened all citations identified by the search strategy, retrieved full-text articles, extracted data and assessed the risk of bias of the included trials. Results were described narratively. RESULTS: Four trials (1345 randomised participants, of whom 1234 were adults) assessed the intravenous or intramuscular use of benzodiazepines or other antiepileptic drugs for the pre-hospital treatment of convulsive status epilepticus in adults. Three trials at a low risk of bias showed that benzodiazepines were effective in stopping seizures. In particular, intramuscular midazolam was non-inferior to intravenous lorazepam. The addition of levetiracetam to clonazepam did not show clear advantages over clonazepam alone. One trial at a high risk of bias showed that phenobarbital plus optional phenytoin was more effective in terminating seizures than diazepam plus phenytoin. The median time to seizure cessation from drug administration varied from 1.6 minutes to 15 minutes. The proportion of people with recurrence of seizures ranged from 10.4% to 19.1% in two trials reporting this outcome. Across trials, the rates of respiratory depression among participants receiving active treatments were generally low (from 6.4% to 10.6%). The mortality rate ranged from 2% to 7.6% in active treatment groups and from 6.2% to 15.5% in control groups. Only one study based on retrospective observational data met the criteria for economic evaluation; therefore, it was not possible to draw any robust conclusions on cost-effectiveness. LIMITATIONS: The limited number of identified trials and their differences in terms of treatment comparisons and outcomes hindered any meaningful pooling of data. None of the included trials was conducted in the UK and none assessed the use of buccal midazolam or rectal diazepam. The review of economic evaluations was hampered by lack of suitable data. CONCLUSIONS: Both intravenous lorazepam and intravenous diazepam administered by paramedics are more effective than a placebo in the treatments of adults with convulsive status epilepticus, and intramuscular midazolam is non-inferior to intravenous lorazepam. Large well-designed clinical trials are needed to establish which benzodiazepines are more effective and preferable in the pre-hospital setting. STUDY REGISTRATION: This study is registered as PROSPERO CRD42020201953. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 20. See the NIHR Journals Library website for further project information.

Epilepsy is a common condition that results from abnormal electrical activity in the brain and causes seizures (stiffening and uncontrolled jerking ­ known as a 'fit'). The most severe form of epilepsy is called 'convulsive status epilepticus', which involves continuous seizure activity for 5 minutes or more, or repetitive seizures without recovery of consciousness. Convulsive status epilepticus can be very dangerous and requires prompt treatment to avoid hospitalisation and prevent complications. Although several drugs are available for the treatment of convulsive status epilepticus in the community or in the emergency department, it is unclear which one is most effective in stopping seizures. We brought together results from all available clinical studies that looked at the use of drugs to treat adults with convulsive status epilepticus either before arriving at hospital or on arrival at the emergency department. In the literature, we found four studies (1234 adults) assessing drugs delivered by paramedics through an injection into a vein or into muscle. In general, the drugs used by paramedics (benzodiazepines) were effective in stopping seizures, but we were unable to identify any particular drug or way of administering it as being more successful than others. Future research is needed to establish which drugs are most effective and preferable. It is also important to improve adherence to clinical guidelines with regard to the use of these drugs. For the pre-hospital treatment of convulsive status epilepticus, little evidence was available to decide which drug treatment is the best in terms of value for money. Future studies could assess the (1) impact of treatments on costs and outcomes over the whole course of a seizure episode (2) long-term impact of different treatments on patients' quality of life and (3) health and social care needs.

Shockwave lithotripsy compared with ureteroscopic stone treatment for adults with ureteric stones: the TISU non-inferiority RCT.

BACKGROUND: Urinary stone disease affects 2-3% of the general population. Ureteric stones are associated with severe pain and can have a significant impact on a patient's quality of life. Most ureteric stones are expected to pass spontaneously with supportive care; however, between one-fifth and one-third of patients require an active intervention. The two standard interventions are shockwave lithotripsy and ureteroscopic stone treatment. Both treatments are effective, but they differ in terms of invasiveness, anaesthetic requirement, treatment setting, number of procedures, complications, patient-reported outcomes and cost. There is uncertainty around which is the more clinically effective and cost-effective treatment. OBJECTIVES: To determine if shockwave lithotripsy is clinically effective and cost-effective compared with ureteroscopic stone treatment in adults with ureteric stones who are judged to require active intervention. DESIGN: A pragmatic, multicentre, non-inferiority, randomised controlled trial of shockwave lithotripsy as a first-line treatment option compared with primary ureteroscopic stone treatment for ureteric stones. SETTING: Urology departments in 25 NHS hospitals in the UK. PARTICIPANTS: Adults aged ≥ 16 years presenting with a single ureteric stone in any segment of the ureter, confirmed by computerised tomography, who were able to undergo either shockwave lithotripsy or ureteroscopic stone treatment and to complete trial procedures. INTERVENTION: Eligible participants were randomised 1 : 1 to shockwave lithotripsy (up to two sessions) or ureteroscopic stone treatment. MAIN OUTCOME MEASURES: The primary clinical outcome measure was resolution of the stone episode (stone clearance), which was operationally defined as 'no further intervention required to facilitate stone clearance' up to 6 months from randomisation. This was determined from 8-week and 6-month case report forms and any additional hospital visit case report form that was completed by research staff. The primary economic outcome measure was the incremental cost per quality-adjusted life-year gained at 6 months from randomisation. We estimated costs from NHS resources and calculated quality-adjusted life-years from participant completion of the EuroQol-5 Dimensions, three-level version, at baseline, pre intervention, 1 week post intervention and 8 weeks and 6 months post randomisation. RESULTS: In the shockwave lithotripsy arm, 67 out of 302 (22.2%) participants needed further treatment. In the ureteroscopic stone treatment arm, 31 out of 302 (10.3%) participants needed further treatment. The absolute risk difference was 11.4% (95% confidence interval 5.0% to 17.8%); the upper bound of the 95% confidence interval ruled out the prespecified margin of non-inferiority (which was 20%). The mean quality-adjusted life-year difference (shockwave lithotripsy vs. ureteroscopic stone treatment) was -0.021 (95% confidence interval 0.033 to -0.010) and the mean cost difference was -£809 (95% confidence interval -£1061 to -£551). The probability that shockwave lithotripsy is cost-effective is 79% at a threshold of society's willingness to pay for a quality-adjusted life-year of £30,000. The CEAC is derived from the joint distribution of incremental costs and incremental effects. Most of the results fall in the south-west quadrant of the cost effectiveness plane as SWL always costs less but is less effective. LIMITATIONS: A limitation of the trial was low return and completion rates of patient questionnaires. The study was initially powered for 500 patients in each arm; however, the total number of patients recruited was only 307 and 306 patients in the ureteroscopic stone treatment and shockwave lithotripsy arms, respectively. CONCLUSIONS: Patients receiving shockwave lithotripsy needed more further interventions than those receiving primary ureteroscopic retrieval, although the overall costs for those receiving the shockwave treatment were lower. The absolute risk difference between the two clinical pathways (11.4%) was lower than expected and at a level that is acceptable to clinicians and patients. The shockwave lithotripsy pathway is more cost-effective in an NHS setting, but results in lower quality of life. FUTURE WORK: (1) The generic health-related quality-of-life tools used in this study do not fully capture the impact of the various treatment pathways on patients. A condition-specific health-related quality-of-life tool should be developed. (2) Reporting of ureteric stone trials would benefit from agreement on a core outcome set that would ensure that future trials are easier to compare. TRIAL REGISTRATION: This trial is registered as ISRCTN92289221. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 19. See the NIHR Journals Library website for further project information.

Approximately 1 in 20 people suffers from kidney stones that pass down the urine drainage tube (ureter) into the urinary bladder and cause episodes of severe pain (ureteric colic). People with ureteric colic attend hospital for pain relief and diagnosis. Although most stones smaller than 10 mm eventually reach the bladder and are passed during urination, some get stuck and have to be removed using telescopic surgery (called ureteroscopic stone treatment) or shockwave therapy (called shockwave lithotripsy). Ureteroscopic stone treatment involves passing a telescope-containing instrument through the bladder and into the ureter to fragment and/or remove the stone. This is usually carried out under general anaesthetic as a day case. For shockwave lithotripsy, the patient lies flat on a couch and the apparatus underneath them generates shockwaves that pass through the skin to the ureter and break the stones into smaller fragments, which can be passed naturally in the urine. This involves using X-ray or ultrasound to locate the stone, but can be carried out on an outpatient basis and without general anaesthetic. Telescopic surgery is known to be more successful at removing stones after just one treatment, but it requires more time in hospital and has a higher risk of complications than shockwave lithotripsy (however, shockwave lithotripsy may require more than one session of treatment). Our study, the Therapeutic Interventions for Stones of the Ureter trial, was designed to establish if treatment for ureteric colic should start with telescopic surgery or shockwave therapy. Over 600 NHS patients took part and they were split into two groups. Each patient had an equal chance of their treatment starting with either telescopic surgery or shockwave lithotripsy, which was decided by a computer program (via random allocation). We counted how many patients in each group had further procedures to remove their stone. We found that telescopic surgery was 11% more effective overall, with an associated slightly better quality of life (10 more healthy days over the 6-month period), but was more expensive in an NHS setting. The finding of a lack of any significant additional clinical benefit leads to the conclusion that the more cost-effective treatment pathway is shockwave lithotripsy with telescopic surgery used only in those patients in whom shockwave lithotripsy is unsuccessful.

Biomarkers for assessing acute kidney injury for people who are being considered for admission to critical care: a systematic review and cost-effectiveness analysis.

BACKGROUND: Acute kidney injury is a serious complication that occurs in the context of an acute critical illness or during a postoperative period. Earlier detection of acute kidney injury may facilitate strategies to preserve renal function, prevent further disease progression and reduce mortality. Acute kidney injury diagnosis relies on a rise in serum creatinine levels and/or fall in urine output; however, creatinine is an imperfect marker of kidney function. There is interest in the performance of novel biomarkers used in conjunction with existing clinical assessment, such as NephroCheck® (Astute Medical, Inc., San Diego, CA, USA), ARCHITECT® urine neutrophil gelatinase-associated lipocalin (NGAL) (Abbott Laboratories, Abbott Park, IL, USA), and urine and plasma BioPorto NGAL (BioPorto Diagnostics A/S, Hellerup, Denmark) immunoassays. If reliable, these biomarkers may enable earlier identification of acute kidney injury and enhance management of those with a modifiable disease course. OBJECTIVE: The objective was to evaluate the role of biomarkers for assessing acute kidney injury in critically ill patients who are considered for admission to critical care. DATA SOURCES: Major electronic databases, conference abstracts and ongoing studies were searched up to June 2019, with no date restrictions. MEDLINE, EMBASE, Health Technology Assessment Database, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Web of Science, World Health Organization Global Index Medicus, EU Clinical Trials Register, International Clinical Trials Registry Platform and ClinicalTrials.gov were searched. REVIEW METHODS: A systematic review and meta-analysis were conducted to evaluate the performance of novel biomarkers for the detection of acute kidney injury and prediction of other relevant clinical outcomes. Random-effects models were adopted to combine evidence. A decision tree was developed to evaluate costs and quality-adjusted life-years accrued as a result of changes in short-term outcomes (up to 90 days), and a Markov model was used to extrapolate results over a lifetime time horizon. RESULTS: A total of 56 studies (17,967 participants), mainly prospective cohort studies, were selected for inclusion. No studies addressing the clinical impact of the use of biomarkers on patient outcomes, compared with standard care, were identified. The main sources of bias across studies were a lack of information on blinding and the optimal threshold for NGAL. For prediction studies, the reporting of statistical details was limited. Although the meta-analyses results showed the potential ability of these biomarkers to detect and predict acute kidney injury, there were limited data to establish any causal link with longer-term health outcomes and there were considerable clinical differences across studies. Cost-effectiveness results were highly uncertain, largely speculative and should be interpreted with caution in the light of the limited evidence base. To illustrate the current uncertainty, 15 scenario analyses were undertaken. Incremental quality-adjusted life-years were very low across all scenarios, ranging from positive to negative increments. Incremental costs were also small, in general, with some scenarios generating cost savings with tests dominant over standard care (cost savings with quality-adjusted life-year gains). However, other scenarios generated results whereby the candidate tests were more costly with fewer quality-adjusted life-years, and were thus dominated by standard care. Therefore, it was not possible to determine a plausible base-case incremental cost-effectiveness ratio for the tests, compared with standard care. LIMITATIONS: Clinical effectiveness and cost-effectiveness results were hampered by the considerable heterogeneity across identified studies. Economic model predictions should also be interpreted cautiously because of the unknown impact of NGAL-guided treatment, and uncertain causal links between changes in acute kidney injury status and changes in health outcomes. CONCLUSIONS: Current evidence is insufficient to make a full appraisal of the role and economic value of these biomarkers and to determine whether or not they provide cost-effective improvements in the clinical outcomes of acute kidney injury patients. FUTURE WORK: Future studies should evaluate the targeted use of biomarkers among specific patient populations and the clinical impact of their routine use on patient outcomes and management. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019147039. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 26, No. 7. See the NIHR Journals Library website for further project information.

Among people who are very ill or have undergone surgery, the kidneys may suddenly stop working properly. This is known as acute kidney injury. Acute kidney injury can progress to serious kidney problems and can be fatal. Currently, to decide whether or not acute kidney injury is present, doctors use the level of creatinine (a waste product filtered by the kidneys) in the blood or urine. However, creatinine levels are not a precise indicator and they can take hours or days to rise; this may lead to delays in acute kidney injury recognition. Novel biomarkers may help doctors to recognise the presence of acute kidney injury earlier and treat patients promptly. This work evaluates current evidence on the use of biomarkers for acute kidney injury with respect to clinical usefulness and costs. We reviewed the current evidence on the use of biomarkers for assessing the risk of acute kidney injury among people who are very ill, and assessed whether or not the evidence was of good value for the NHS. We assessed the ARCHITECT^® urine neutrophil gelatinase-associated lipocalin (NGAL) (Abbott Laboratories, Abbott Park, IL, USA), urine and plasma BioPorto NGAL (BioPorto Diagnostics A/S, Hellerup, Denmark) and urine NephroCheck^® (Astute Medical, Inc., San Diego, CA, USA) biomarkers. We checked studies published up to June 2019 and found 56 relevant studies (17,967 patients). Most studies were conducted outside the UK and investigated people already admitted to critical care. We combined the results of the studies and found that NephroCheck and NGAL biomarkers might be useful in identifying acute kidney injury or pre-empting acute kidney injury in some circumstances. However, studies differed in patient characteristics, clinical setting and the way in which biomarkers were used. This could explain why the number of people correctly identified and missed by the biomarkers varied across studies. Hence, we do not completely trust the pooled results. We also found that acute kidney injury is associated with substantial costs for the NHS, but there was insufficient good-quality evidence to decide which biomarker (if any) offered the best value for money.