Associations of health-related quality of life with major adverse cardiovascular and cerebrovascular events for individuals with ischaemic heart disease: systematic review, meta-analysis and evidence mapping.

OBJECTIVE: To investigate the association between health-related quality of life (HRQoL) and major adverse cardiovascular and cerebrovascular events (MACCE) in individuals with ischaemic heart disease (IHD). METHODS: Medline(R), Embase, APA PsycINFO and CINAHL (EBSCO) from inception to 3 April 2023 were searched. Studies reporting association of HRQoL, using a generic or cardiac-specific tool, with MACCE or components of MACCE for individuals with IHD were eligible for inclusion. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale to assess the quality of the studies. Descriptive synthesis, evidence mapping and random-effects meta-analysis were performed stratified by HRQoL measures and effect estimates. Between-study heterogeneity was assessed using the Higgins I2 statistic. RESULTS: Fifty-one articles were included with a total of 134 740 participants from 53 countries. Meta-analysis of 23 studies found that the risk of MACCE increased with lower baseline HeartQoL score (HR 1.49, 95% CI 1.16 to 1.93) and Short Form Survey (SF-12) physical component score (PCS) (HR 1.39, 95% CI 1.28 to 1.51). Risk of all-cause mortality increased with a lower HeartQoL (HR 1.64, 95% CI 1.34 to 2.01), EuroQol 5-dimension (HR 1.17, 95% CI 1.12 to 1.22), SF-36 PCS (HR 1.29, 95% CI 1.19 to 1.41), SF-36 mental component score (HR 1.18, 95% CI 1.08 to 1.30). CONCLUSIONS: This study found an inverse association between baseline values or change in HRQoL and MACCE or components of MACCE in individuals with IHD, albeit with between-study heterogeneity. Standardisation and routine assessment of HRQoL in clinical practice may help risk stratify individuals with IHD for tailored interventions. PROSPERO REGISTRATION NUMBER: CRD42021234638.

The impact of hospital command centre on patient flow and data quality: findings from the UK National Health Service.

In the last 6 years, hospitals in developed countries have been trialling the use of command centres for improving organizational efficiency and patient care. However, the impact of these command centres has not been systematically studied in the past. It is a retrospective population-based study. Participants were patients who visited the Bradford Royal Infirmary hospital, Accident and Emergency (A&E) Department, between 1 January 2018 and 31 August 2021. Outcomes were patient flow (measured as A&E waiting time, length of stay, and clinician seen time) and data quality (measured by the proportion of missing treatment and assessment dates and valid transition between A&E care stages). Interrupted time-series segmented regression and process mining were used for analysis. A&E transition time from patient arrival to assessment by a clinician marginally improved during the intervention period; there was a decrease of 0.9 min [95% confidence interval (CI): 0.35-1.4], 3 min (95% CI: 2.4-3.5), 9.7 min (95% CI: 8.4-11.0), and 3.1 min (95% CI: 2.7-3.5) during 'patient flow program', 'command centre display roll-in', 'command centre activation', and 'hospital wide training program', respectively. However, the transition time from patient treatment until the conclusion of consultation showed an increase of 11.5 min (95% CI: 9.2-13.9), 12.3 min (95% CI: 8.7-15.9), 53.4 min (95% CI: 48.1-58.7), and 50.2 min (95% CI: 47.5-52.9) for the respective four post-intervention periods. Furthermore, the length of stay was not significantly impacted; the change was -8.8 h (95% CI: -17.6 to 0.08), -8.9 h (95% CI: -18.6 to 0.65), -1.67 h (95% CI: -10.3 to 6.9), and -0.54 h (95% CI: -13.9 to 12.8) during the four respective post-intervention periods. It was a similar pattern for the waiting and clinician seen times. Data quality as measured by the proportion of missing dates of records was generally poor (treatment date = 42.7% and clinician seen date = 23.4%) and did not significantly improve during the intervention periods. The findings of the study suggest that a command centre package that includes process change and software technology does not appear to have a consistent positive impact on patient safety and data quality based on the indicators and data we used. Therefore, hospitals considering introducing a command centre should not assume there will be benefits in patient flow and data quality.

The effects of computerised decision support systems on nursing and allied health professional performance and patient outcomes: a systematic review and user contextualisation.

Background: Computerised decision support systems (CDSS) are widely used by nurses and allied health professionals but their effect on clinical performance and patient outcomes is uncertain. Objectives: Evaluate the effects of clinical decision support systems use on nurses', midwives' and allied health professionals' performance and patient outcomes and sense-check the results with developers and users. Eligibility criteria: Comparative studies (randomised controlled trials (RCTs), non-randomised trials, controlled before-and-after (CBA) studies, interrupted time series (ITS) and repeated measures studies comparing) of CDSS versus usual care from nurses, midwives or other allied health professionals. Information sources: Nineteen bibliographic databases searched October 2019 and February 2021. Risk of bias: Assessed using structured risk of bias guidelines; almost all included studies were at high risk of bias. Synthesis of results: Heterogeneity between interventions and outcomes necessitated narrative synthesis and grouping by: similarity in focus or CDSS-type, targeted health professionals, patient group, outcomes reported and study design. Included studies: Of 36,106 initial records, 262 studies were assessed for eligibility, with 35 included: 28 RCTs (80%), 3 CBA studies (8.6%), 3 ITS (8.6%) and 1 non-randomised trial, a total of 1318 health professionals and 67,595 patient participants. Few studies were multi-site and most focused on decision-making by nurses (71%) or paramedics (5.7%). Standalone, computer-based CDSS featured in 88.7% of the studies; only 8.6% of the studies involved 'smart' mobile or handheld technology. Care processes - including adherence to guidance - were positively influenced in 47% of the measures adopted. For example, nurses' adherence to hand disinfection guidance, insulin dosing, on-time blood sampling, and documenting care were improved if they used CDSS. Patient care outcomes were statistically - if not always clinically - significantly improved in 40.7% of indicators. For example, lower numbers of falls and pressure ulcers, better glycaemic control, screening of malnutrition and obesity, and accurate triaging were features of professionals using CDSS compared to those who were not. Evidence limitations: Allied health professionals (AHPs) were underrepresented compared to nurses; systems, studies and outcomes were heterogeneous, preventing statistical aggregation; very wide confidence intervals around effects meant clinical significance was questionable; decision and implementation theory that would have helped interpret effects - including null effects - was largely absent; economic data were scant and diverse, preventing estimation of overall cost-effectiveness. Interpretation: CDSS can positively influence selected aspects of nurses', midwives' and AHPs' performance and care outcomes. Comparative research is generally of low quality and outcomes wide ranging and heterogeneous. After more than a decade of synthesised research into CDSS in healthcare professions other than medicine, the effect on processes and outcomes remains uncertain. Higher-quality, theoretically informed, evaluative research that addresses the economics of CDSS development and implementation is still required. Future work: Developing nursing CDSS and primary research evaluation. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in Health and Social Care Delivery Research; 2023. See the NIHR Journals Library website for further project information. Registration: PROSPERO [number: CRD42019147773].

Computerised decision support systems (CDSS) are software or computer-based technologies providing advice to professionals making clinical decisions ­ for example, which patients to treat first in emergency departments. CDSS improve some doctors' decisions and patients' outcomes, but we don't know if they improve nurses', midwives' and therapists' or other staff decisions and patient outcomes. Research into, and health professionals' use of, technology ­ for example, in video consultations ­ has grown since the last relevant systematic review in 2009. We systematically searched electronic databases for research measuring how well nurses, midwifes and other therapists/staff followed CDSS advice, how CDSS influence their decisions, how safe CDSS are, and their financial costs and benefits. We interviewed CDSS users and developers and some patient representatives from a general practice to help understand our findings. Of 35 relevant studies ­ from 36,106 initially found ­ most (71%) focused on nurses. Just over half (57%) involved hospital-based staff, and three-quarters (75%) were from richer countries like the USA or the UK. Research quality had not noticeably improved since 2009 and all studies were at risk of potentially misleading readers. CDSS improved care in just under half (47%) of professional behaviours, such as following hand-disinfection guidance, working out insulin doses, and sampling blood on time. Patient care ­ judged using outcomes like falls, pressure ulcers, diabetes control and triage accuracy ­ was better in 41% of the care measured. There wasn't enough evidence to judge CDSS safety or the financial costs and benefits of systems. CDSS can improve some nursing and therapist decisions and some patient outcomes. Studies mostly measure different behaviours and outcomes, making comparing them hard. Theories explaining or predicting how decision support systems might work are not used enough when designing, implementing or evaluating CDSS. More research into the financial costs and benefits of CDSS and higher-quality evidence of their effects are still needed. Whether decision support for nurses, midwives and other therapists reliably improves decision-making remains uncertain.

The effects of exposure to NO2, PM2.5 and PM10 on health service attendances with respiratory illnesses: A time-series analysis.

The associations of exposure to air-pollutants and respiratory illness remains inconsistent and studies have not adequately addressed the non-linearity and delayed effects of exposure. This is a retrospective cohort study using linked routine health and pollution data collected between January 2018 and December 2021. Participants were patients who visited General Practice (GP) or accident and emergency (A&E) services for respiratory illness. Time-series analysis, distributed lagged models, was used to address the potential non-linearity and delayed effects of exposure. There were 114,930 GP and 9878 A&E respiratory visits. For every 10 µg/m3 increase in NO2 and PM2.5 above the WHO recommended 24-hr thresholds, the immediate relative risk of GP respiratory visits was 1.09 (95% CI: 1.07 to 1.05) and 1.06 (95% CI: 1.01 to 1.10), respectively. The respective relative risk of A&E visit was 1.10 (95% CI: 1.07 to 1.14) and 1.07 (95% CI: 1.00 to 1.14). Exposure to 10-unit increases in NO2, PM2.5 and PM10 above the WHO recommended 24-hr thresholds, was associated with lagged relative risks of 1.49 (95% CI: 1.42 to 1.56), 5.26 (95% CI: 4.18 to 6.61) and 2.32 (95% CI: 1.66 to 3.26), respectively, for GP respiratory attendances. The lagged relative risk of A&E respiratory visits for same units of exposure in NO2, PM2.5, and PM10 at the peak lag days were 1.98 (95% CI: 1.82 to 2.15), 4.52 (95% CI: 3.37 to 6.07) and 3.55 (95% CI: 1.85 to 6.84). A third of GP and half of A&E respiratory visits were attributable to exposure to NO2 beyond the WHO threshold. The combined cost of these visits over the study period was 1.95 million (95% CI: 1.82 to 2.09). High pollution events are related to increased health service use for respiratory illness, with impacts persisting up to 100 days post exposure. The burden of respiratory illness related to air-pollution may be considerably higher than previously reported.

Effect of a hospital command centre on patient safety: an interrupted time series study.

BACKGROUND: Command centres have been piloted in some hospitals across the developed world in the last few years. Their impact on patient safety, however, has not been systematically studied. Hence, we aimed to investigate this. METHODS: This is a retrospective population-based cohort study. Participants were patients who visited Bradford Royal Infirmary Hospital and Calderdale & Huddersfield hospitals between 1 January 2018 and 31 August 2021. A five-phase, interrupted time series, linear regression analysis was used. RESULTS: After introduction of a Command Centre, while mortality and readmissions marginally improved, there was no statistically significant impact on postoperative sepsis. In the intervention hospital, when compared with the preintervention period, mortality decreased by 1.4% (95% CI 0.8% to 1.9%), 1.5% (95% CI 0.9% to 2.1%), 1.3% (95% CI 0.7% to 1.8%) and 2.5% (95% CI 1.7% to 3.4%) during successive phases of the command centre programme, including roll-in and activation of the technology and preparatory quality improvement work. However, in the control site, compared with the baseline, the weekly mortality also decreased by 2.0% (95% CI 0.9 to 3.1), 2.3% (95% CI 1.1 to 3.5), 1.3% (95% CI 0.2 to 2.4), 3.1% (95% CI 1.4 to 4.8) for the respective intervention phases. No impact on any of the indicators was observed when only the software technology part of the Command Centre was considered. CONCLUSION: Implementation of a hospital Command Centre may have a marginal positive impact on patient safety when implemented as part of a broader hospital-wide improvement programme including colocation of operations and clinical leads in a central location. However, improvement in patient safety indicators was also observed for a comparable period in the control site. Further evaluative research into the impact of hospital command centres on a broader range of patient safety and other outcomes is warranted.

Evaluating the safety and patient impacts of an artificial intelligence command centre in acute hospital care: a mixed-methods protocol.

INTRODUCTION: This paper presents a mixed-methods study protocol that will be used to evaluate a recent implementation of a real-time, centralised hospital command centre in the UK. The command centre represents a complex intervention within a complex adaptive system. It could support better operational decision-making and facilitate identification and mitigation of threats to patient safety. There is, however, limited research on the impact of such complex health information technology on patient safety, reliability and operational efficiency of healthcare delivery and this study aims to help address that gap. METHODS AND ANALYSIS: We will conduct a longitudinal mixed-method evaluation that will be informed by public-and-patient involvement and engagement. Interviews and ethnographic observations will inform iterations with quantitative analysis that will sensitise further qualitative work. Quantitative work will take an iterative approach to identify relevant outcome measures from both the literature and pragmatically from datasets of routinely collected electronic health records. ETHICS AND DISSEMINATION: This protocol has been approved by the University of Leeds Engineering and Physical Sciences Research Ethics Committee (#MEEC 20-016) and the National Health Service Health Research Authority (IRAS No.: 285933). Our results will be communicated through peer-reviewed publications in international journals and conferences. We will provide ongoing feedback as part of our engagement work with local trust stakeholders.

Effects of computerised clinical decision support systems (CDSS) on nursing and allied health professional performance and patient outcomes: a systematic review of experimental and observational studies.

OBJECTIVE: Computerised clinical decision support systems (CDSS) are an increasingly important part of nurse and allied health professional (AHP) roles in delivering healthcare. The impact of these technologies on these health professionals' performance and patient outcomes has not been systematically reviewed. We aimed to conduct a systematic review to investigate this. MATERIALS AND METHODS: The following bibliographic databases and grey literature sources were searched by an experienced Information Professional for published and unpublished research from inception to February 2021 without language restrictions: MEDLINE (Ovid), Embase Classic+Embase (Ovid), PsycINFO (Ovid), HMIC (Ovid), AMED (Allied and Complementary Medicine) (Ovid), CINAHL (EBSCO), Cochrane Central Register of Controlled Trials (Wiley), Cochrane Database of Systematic Reviews (Wiley), Social Sciences Citation Index Expanded (Clarivate), ProQuest Dissertations & Theses Abstracts & Index, ProQuest ASSIA (Applied Social Science Index and Abstract), Clinical Trials.gov, WHO International Clinical Trials Registry (ICTRP), Health Services Research Projects in Progress (HSRProj), OpenClinical(www.OpenClinical.org), OpenGrey (www.opengrey.eu), Health.IT.gov, Agency for Healthcare Research and Quality (www.ahrq.gov). Any comparative research studies comparing CDSS with usual care were eligible for inclusion. RESULTS: A total of 36 106 non-duplicate records were identified. Of 35 included studies: 28 were randomised trials, three controlled-before-and-after studies, three interrupted-time-series and one non-randomised trial. There were ~1318 health professionals and ~67 595 patient participants in the studies. Most studies focused on nurse decision-makers (71%) or paramedics (5.7%). CDSS as a standalone Personal Computer/LAPTOP-technology was a feature of 88.7% of the studies; only 8.6% of the studies involved 'smart' mobile/handheld-technology. DISCUSSION: CDSS impacted 38% of the outcome measures used positively. Care processes were better in 47% of the measures adopted; examples included, nurses' adherence to hand disinfection guidance, insulin dosing, on-time blood sampling and documenting care. Patient care outcomes in 40.7% of indicators were better; examples included, lower numbers of falls and pressure ulcers, better glycaemic control, screening of malnutrition and obesity and triaging appropriateness. CONCLUSION: CDSS may have a positive impact on selected aspects of nurses' and AHPs' performance and care outcomes. However, comparative research is generally low quality, with a wide range of heterogeneous outcomes. After more than 13 years of synthesised research into CDSS in healthcare professions other than medicine, the need for better quality evaluative research remains as pressing.

Peer mentorship to improve self-management of hip and knee osteoarthritis: a randomised feasibility trial.

OBJECTIVE: To determine the feasibility of conducting a randomised controlled trial (RCT) of a peer mentorship intervention to improve self-management of osteoarthritis (OA). DESIGN: Six-month parallel group non-blinded randomised feasibility trial. SETTING: One secondary care and one primary care UK National Health Service Trust. PARTICIPANTS: Fifty adults aged ≥55 years old with hip and/or knee OA. INTERVENTIONS: Participants were allocated 1:1 to the intervention or control group using an online randomisation service. Intervention group participants received usual care (information resources) and up to eight community-based self-management support sessions delivered by a peer mentor (trained volunteer with hip and/or knee OA). Control group participants received usual care only. OUTCOME MEASURES: Key feasibility outcomes were participant and peer mentor recruitment and attrition, intervention completion and the sample size required for a definitive RCT. Based on these feasibility outcomes, four success criteria for proceeding to a definitive RCT were prespecified. Patient-reported outcomes were collected via questionnaires at baseline, 8 weeks and 6 months. RESULTS: Ninety-six individuals were screened, 65 were eligible and 50 were randomised (25 per group). Of the 24 participants who commenced the intervention, 20 completed it. Four participants did not complete the 6-month questionnaire. Twenty-one individuals were eligible for the peer mentor role, 15 were trained and 5 withdrew prior to being matched with a participant. No intervention-related harms occurred. Allowing for 20% attrition, the sample size required for a definitive RCT was calculated as 170 participants. The intervention group showed improvements in self-management compared with the control group. CONCLUSIONS: The feasibility outcomes achieved the prespecified criteria for proceeding to an RCT. The exploratory analyses suggest peer mentorship may improve OA self-management. An RCT of the OA peer mentorship intervention is therefore warranted with minor modifications to the intervention and trial procedures. TRIAL REGISTRATION NUMBER: ISRCTN:50675542.

Oral glucocorticoids and incidence of hypertension in people with chronic inflammatory diseases: a population-based cohort study.

BACKGROUND: Only a few population-based studies have examined the association between glucocorticoids and hypertension, with inconsistent results. We aimed to investigate the effect of oral glucocorticoids on incidence of hypertension in adults with chronic inflammatory diseases. METHODS: We analyzed electronic health records from 389 practices in England during 1998-2017 of adults diagnosed with any of 6 chronic inflammatory diseases but with no previous diagnosis of hypertension. We used glucocorticoid prescription data to construct time-variant daily and cumulative variables of prednisolone-equivalent dose (cumulated from 1 year before the start of follow-up) and estimated incidence rates and adjusted hazard ratios (HRs) for hypertension using Cox regression analysis. RESULTS: Among 71 642 patients in the cohort, 24 896 (34.8%) developed hypertension during a median follow-up of 6.6 years. The incidence rate of hypertension was 46.7 (95% confidence interval [CI] 46.0-47.3) per 1000 person-years. Incidence rates increased with higher cumulative glucocorticoid prednisolone-equivalent dose, from 44.4 per 1000 person-years in periods of nonuse to 45.3 per 1000 person-years for periods with between > 0.0 and 959.9 mg (HR 1.14, 95% CI 1.09-1.19), to 49.3 per 1000 person-years for periods with 960-3054.9 mg (HR 1.20, 95% CI 1.14-1.27), and to 55.6 per 1000 person-years for periods with ≥ 3055 mg (HR 1.30, 95% CI 1.25-1.35). Cumulative effects were seen for the 6 diseases studied, but dose-response effects were not found for daily dose. INTERPRETATION: Cumulative dose of oral glucocorticoids was associated with increased incidence of hypertension, suggesting that blood pressure should be monitored closely in patients routinely treated with these drugs. Given that glucocorticoids are widely prescribed, the associated health burden could be high. Trial registration: ClinicalTrials. gov, no. NCT03760562.

Dose Dependency of Iatrogenic Glucocorticoid Excess and Adrenal Insufficiency and Mortality: A Cohort Study in England.

CONTEXT: Adrenal insufficiency and Cushing syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available. OBJECTIVE: To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids. DESIGN AND SETTING: Retrospective, record-linkage, open-cohort study spanning primary and hospital care in England. PATIENTS: A total of 70,638 oral glucocorticoid users and 41,166 nonusers aged ≥18 years registered in 389 practices in 1998 to 2017. MAIN OUTCOME MEASURES: Incidence rates and hazard ratios (HRs) of diagnosed adrenal dysfunction and death. RESULTS: During a median follow-up of 5.5 years, 183 patients had glucocorticoid-induced adrenal insufficiency and 248 had glucocorticoid-induced Cushing syndrome. A total of 22,317 (31.6%) and 7544 (18.3%) deaths occurred among glucocorticoid users and nonusers, respectively. The incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were 1.07 (95% CI: 1.04 to 1.09) for every increase of 5 mg per day and 2.25 (95% CI: 2.15 to 2.35) per 1000 mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing syndrome were 1.09 (95% CI: 1.08 to 1.11) and 2.31 (95% CI: 2.23 to 2.40) and for mortality 1.26 (95% CI: 2.24 to 1.28) and 2.05 (95% CI: 2.04 to 2.06). CONCLUSION: We report a high glucocorticoid dose-dependent increased risk of adrenal adverse events and death. The low observed absolute risk of adrenal insufficiency highlights a potential lack of awareness and a need for increased physician and patient education about the risks of adrenal dysfunction induced by glucocorticoids.

Ustekinumab for Treating Moderately to Severely Active Crohn's Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Janssen to submit evidence on the clinical and cost effectiveness of their drug ustekinumab, an interleukin-12/23 inhibitor, for treating moderate-to-severe active Crohn's disease (CD). The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the Company's submission, the ERG's critical review of submitted evidence, and the resulting NICE guidance. The main supporting clinical evidence was derived from four well conducted, randomised controlled trials, comparing ustekinumab with placebo in two sub-populations (conventional care failure and anti-TNFα failure patients) of adults with moderate-to-severe CD. Three trials assessed treatment induction over 8 weeks, while the fourth recruited successfully induced patients into a maintenance trial for 1 year. These trials showed ustekinumab to be more effective than placebo in terms of its ability to induce and maintain clinical response and remission. In the absence of any direct head-to-head data, the Company conducted a network meta-analysis (NMA), which synthesised induction trial data on ustekinumab and relevant comparators (vedolizumab, adalimumab and infliximab) using placebo data as a common comparator. This analysis found ustekinumab to be of comparable efficacy to previously approved biologics in treatment induction. A 'treatment sequence analysis' compared long-term treatment efficacy, finding ustekinumab to be comparable in maintaining treatment response and remission to the three other biologic therapies. However, the ERG had identified many limitations and potential bias in this analysis, and urged caution when interpreting the results. The Company's economic model estimated ustekinumab to be dominant in both sub-populations compared with conventional care; however, the ERG's preferred base-case estimated an incremental cost-effectiveness ratio of £109,279 in the conventional care failure sub-population, and £110,967 in the anti-TNFα failure sub-population when compared with conventional care. However, the ERG identified significant failings in both the model structure and data inputs, which could not be addressed without complete restructuring. The ERG considered that the economic analysis presented by the Company failed to adequately address the decision problem specified in NICE's scope. The NICE Appraisal Committee recommended ustekinumab within its market authorisation, on the grounds of sufficiently similar efficacy and costs to previously recommended biologic therapies. However, the ERG's analyses demonstrated that all currently recommended biologics are unlikely to be cost effective relative to conventional care, raising broader questions regarding the appropriateness of cost-comparison exercises for decision making.

Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation.

BACKGROUND: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. DATA SOURCES: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. REVIEW METHODS: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. RESULTS: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks' follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE's usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. LIMITATIONS: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. CONCLUSIONS: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016039494. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Crizotinib for Untreated Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence (NICE) single technology appraisal process, the manufacturer of crizotinib submitted evidence on the clinical and cost effectiveness of crizotinib in untreated anaplastic lymphoma kinase-positive (ALK-positive) non-small-cell lung cancer (NSCLC). Crizotinib has previously been assessed by NICE for patients with previously treated ALK-positive NSCLC (TA 296). It was not approved in this previous appraisal, but had been made available through the cancer drugs fund. As part of this new appraisal, the company included a price discount patient access scheme (PAS). The Centre for Reviews and Dissemination and Centre for Health Economics Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company's submission and the ERG's review and summarises the resulting NICE guidance issued in August 2016. The main clinical-effectiveness data were derived from a multicentre randomised controlled trial-PROFILE 1014-that compared crizotinib with pemetrexed chemotherapy in combination with carboplatin or cisplatin in patients with untreated non-squamous ALK-positive NSCLC. In the trial, crizotinib demonstrated improvements in progression-free survival (PFS) and overall survival (OS). The company's economic model was a three-state 'area under the curve' Markov model. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be greater than £50,000 per quality-adjusted life-year (QALY) gained (excluding the PAS discount). The ERG assessment of the evidence submitted by the company raised a number of concerns. In terms of the clinical evidence, the OS benefit was highly uncertain due to the cross-over permitted in the trial and the immaturity of the data; only 26% of events had occurred by the data cut-off point. In the economic modelling, the most significant concerns related to the analysis of OS and assumptions made regarding the duration of therapy. The ERG exploratory re-analysis of the OS data relaxed the assumption of proportional hazards made in the company submission, which demonstrated significant uncertainty regarding the OS gains from crizotinib. The ERG reconfigured the economic model so that duration of therapy was based on the area under the curve analysis of the PROFILE 1014 trial, dramatically increasing the cost associated with implementing crizotinib and consequently, substantially increasing the ICER. At the first appraisal meeting, the NICE Appraisal Committee concluded that crizotinib, while clinically effective, was not sufficiently cost effective for use in the UK NHS. Following the consultation, the company offered a revised PAS and conducted extensive re-analysis, resulting in a revised base-case ICER of £47,291 per QALY gained. The NICE Appraisal Committee concluded that crizotinib was likely to be a cost-effective use of NHS resources, despite the uncertainty that persisted around a number of factors, namely the long-term survival benefit of crizotinib. Crizotinib was therefore recommended as an option for untreated ALK-positive advanced NSCLC in adults.

Incidence and Burden of Wheezing Disorders, Eczema, and Rhinitis in Children: findings from the Born in Bradford Cohort.

BACKGROUND: Bradford city has high infant mortality and there is a major health concern in the community due to environmental pollution. The aim of the study was to investigate the incidence and burden of wheezing disorders, eczema, and rhinitis in children aged 3-7 years . METHODS: It is a prospective cohort study; the participants were 13 734 children from the Born in Bradford cohort. RESULTS: There were a total of 22.1% (95% Confidence Interval (CI) 21.4, 22.8%), 52.4% (95% CI 51.5%, 53.2%), and 19.3% (95% CI 18.6, 19.9%) incidence cases of wheezing disorders, eczema, and rhinitis respectively. A total of 37% (95% CI 36.2%, 37.8%), 19.5% (95% CI 18.9%, 20.2%,) and 5.9% (95% CI 5.5%, 6.3%) of the children were affected by only one, two, and three diseases respectively. Boys to girls incidence rate ratios for wheezing disorders, eczema, and rhinitis was 1.41 (95% CI 1.31, 1.51), 1.02 (95% CI 0.97, 1.07), and 1.18 (95% CI 1.09, 1.28) respectively. The respective incidence rate ratios of Pakistani to White British were 0.94 (95% CI 0.87, 1.02), 1.31 (95% CI 1.24, 1.39), and 2.03 (95% CI 1.83, 2.25) respectively. CONCLUSION: This study shows that the burden of wheezing disorders, eczema, and rhinitis in this cohort is higher than previously reported in earlier studies. In addition, it indicates that while boys are more likely to suffer from wheezing disorders, rhinitis, and multiple diseases than girls, Pakistani children are more likely to suffer from eczema, rhinitis, and multiple diseases than White British children.

Effects of birth weight and growth on childhood wheezing disorders: findings from the Born in Bradford Cohort.

OBJECTIVES: To examine the effects of birth weight and childhood growth on childhood wheezing disorders. We hypothesised that low birth weight and fast growth during early age would increase the risk of wheezing disorders. SETTING: Observational secondary analysis of data from the Born in Bradford cohort. PARTICIPANTS: All children who were born at the Bradford Royal Infirmary hospital between March 2007 and December 2010 were eligible for the study. A total of 13,734 and 1598 children participated in the analyses of the effects of birth weight and growth on wheezing disorders, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Wheezing disorders diagnosis (diagnosed as asthma or had wheezing symptom) during the ages of 0-7 years were the primary outcome measures. Diagnosis of asthma and occurrence of wheezing during the same period were secondary outcome measures. Birth weight was classified as normal (2.5-4.0 kg), low (<2.5 kg) and high (>4.0 kg). Growth mixture models were used to drive growth pattern outcomes which were classified as 'normal', 'fast' and 'slow' growth based on their velocities between birth and 36 months. RESULTS: The adjusted relative risks (RRs) of wheezing disorders diagnosis for the low and high birthweight children were 1.29 (95% CI 1.12 to 1.50; p=0.001) and 0.91 (95% CI 0.79 to 1.04; p=0.17), respectively. The adjusted RRs of wheezing disorders diagnosis were 1.30 (95% CI 0.56 to 3.06; p=0.54) and 0.60 (95% CI 0.16 to 2.18; p=0.44), respectively, for the 'fast' and 'slow' growth as compared with the 'normal' growth. CONCLUSIONS: Low birth weight is associated with an increased risk of wheezing disorders; however, there is a weak evidence that suggests high birthweight children have a reduced risk in this birth cohort. Low birth weight coupled with a slower growth until 3 months and a sharp growth between 3 and 12 months has an increased risk of wheezing disorders diagnosis.

Birth weight and childhood wheezing disorders: a systematic review and meta-analysis.

BACKGROUND: Previous observational studies have claimed that birth weight and childhood wheezing disorders are associated although the results remained inconsistent. One systematic review and two systematic reviews that included meta-analyses reported inconsistent results. We aimed to conduct a systematic review and meta-analysis to investigate this. METHODS: An online search of published papers linking childhood asthma and wheezing disorders with birth weight up to February 2014 was carried out using EMBASE and Medline medical research databases. Summary ORs were estimated using random-effects models. Subgroup meta-analyses were performed to assess the robustness of risk associations and between-study heterogeneity. RESULTS: A total of 37 studies comprising 1,71, 737 participants were included in our meta-analysis. The unadjusted summary ORs for risk of childhood wheezing disorders associated with low birth weight (<2.5 kg) were 1.60 (95% CI 1.39 to 1.85, p<0.001) and 1.37 (95% CI 1.05 to 1.79, p=0.02) when compared with ≥2.5 and 2.5-4.0 kg birthweight groups, respectively. The overall summary OR for high birth weight (>4 kg) as compared to the 2.5-4.0 kg birthweight group was 1.02 (95% CI 0.99 to 1.04, p=0.13). There was substantial heterogeneity in the unadjusted low birth weight risk estimates which was not accounted for by predefined study characteristics. There was no significant heterogeneity in the high birth weight risk estimates. There was some evidence of funnel plot asymmetry and small study effects in the low birth weight (2.5 vs ≥2.5 kg and <2.5 vs 2.5-4 kg) OR estimates. CONCLUSIONS: Our results suggest that low birth (<2.5 kg) is an independent risk factor for wheezing disorders during childhood and adolescence although there was substantial heterogeneity among the risk estimates. However, we found no significant association of high birth weight with wheezing disorders.

Childhood body mass index and wheezing disorders: a systematic review and meta-analysis.

BACKGROUND: It has been claimed that overweight/obesity, childhood asthma and wheezing disorders are associated, although the results of observational studies have remained inconsistent. We conducted a systematic review and meta-analysis to investigate this. METHODS: An online search of published papers linking childhood asthma and wheezing with overweight/obesity up to May 2014 using EMBASE and MEDLINE medical research databases was carried out. Summary odds ratios (OR) were estimated using random-effects models. Subgroup meta-analyses were performed to assess the robustness of risk associations and between-study heterogeneity. RESULTS: A total of 38 studies comprising 1,411,335 participants were included in our meta-analysis. The summary ORs of underweight (<5th percentile), overweight (>85th to <95th percentile) and obesity (≥ 95 th percentile) were 0.85 (95% CI: 0.75 to 0.97; p = 0.02), 1.23 (95% CI: 1.17 to 1.29; p < 0.001) and 1.46 (95% CI: 1.36 to 1.57, p < 0.001), respectively. Heterogeneity was significant and substantial in all three weight categories, and not accounted for by pre-defined study characteristics. CONCLUSION: Our results suggest that underweight is associated with a reduced risk of childhood asthma, and overweight and obesity are associated with an increased risk of childhood asthma. Although our findings assert that overweight/obesity and childhood asthma are associated, the causal pathway and temporal aspects of this relationship remain unanswered and deserve further epidemiological investigation.

Growth patterns of white British and Pakistani children in the Born in Bradford cohort: a latent growth modelling approach.

BACKGROUND: Childhood growth patterns have been proposed as a key predictor of health during childhood and adult life. In earlier studies, however, the statistical methodologies employed failed to uncover the more subtle patterns in growth trajectories. METHODS: Study participants were 1364 singleton term children (602 white British and 762 Pakistani origin) drawn from the Born in Bradford (BiB) prospective cohort. Weights were measured at 0, 1, 3, 6, 12, 18, 24 and 36 months. Age-specific and sex-specific standardised weight scores were derived based on the World Health Organisation growth standards. Missing growth data were estimated using Full Information Maximum Likelihood (FIML) method. Growth Mixture Model was used to analyse growth patterns of children from birth until 36 months. RESULTS: On average, Pakistani children were 190 g lighter than white British children at birth. Based on our Growth Mixture Model results, the study children had three distinct growth patterns: 'normal growers' (95.9%), 'fast growers' (2.5%) and 'slow growers' (1.6%). The Pakistani children were more likely to be in either the 'fast' (OR=2.90; 95% CI 0.91 to 9.25) or 'slow' (OR=15.63; 95% CI 1.06 to 230) grower class than the white British. Pakistani children showed faster growth than the white British between 3 and 36 months of age. CONCLUSIONS: In this growth study we have identified that the study children have three distinct growth patterns. These growth patterns may provide greater insight in predicting the risk of childhood or early adulthood diseases in life-course studies.

Weight-for-age distribution and case-mix adjusted outcomes of 14,307 paediatric intensive care admissions.

AIMS: To determine whether the paediatric intensive care (PIC) population weight distribution differs from the UK reference population and whether weight-for-age at admission is an independent risk factor for mortality. METHODS: Admission weight-for-age standard deviation scores (SDS) were calculated for all PIC admissions (March 2003-December 2011) to Great Ormond Street Hospital: this is the number of standard deviations (SD) between a child's weight and the UK mean weight-for-age. Categorised into nine SDS groups, standardised mortality ratios (SMR) and logistic regression were used to assess the relationship between weight-for-age at admission and risk-adjusted mortality. RESULTS: Out of 12,458 admissions, mean weight-for-age was 1.04 SD below the UK reference population mean (p < 0.0001). Based on 942 deaths, risk-adjusted mortality was lowest in those with mild-to-moderately raised weight-for-age (SDS 0.5-2.5) and highest in children with extreme under- or overweight (SDS < -3.5 and SDS > +3.5). Logistic regression indicated that age, gender, ethnicity and weight-for-age are independent risk factors for mortality. South Asian and 'other' ethnicities had significantly increased risk of death compared to children of white and black ethnic origin. CONCLUSION: The PIC population mean weight-for-age is significantly lower than the UK reference mean. The extremes of weight-for-age are over-represented, especially underweight. Weight-for-age at admission is an independent risk factor for mortality. A U-shaped association between weight and risk-adjusted mortality exists, with the lowest risk of death in children who are mild-to-moderately overweight. Future studies should determine the impact of malnutrition on risk-adjusted mortality and investigate the aetiology of risk disparities with ethnicity.