Conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU): a UK multicentre, open, parallel-group, randomised clinical trial.

BACKGROUND: The optimal target for systemic oxygenation in critically ill children is unknown. Liberal oxygenation is widely practiced, but has been associated with harm in paediatric patients. We aimed to evaluate whether conservative oxygenation would reduce duration of organ support or incidence of death compared to standard care. METHODS: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in 15 UK paediatric intensive care units (PICUs). Children admitted as an emergency, who were older than 38 weeks corrected gestational age and younger than 16 years receiving invasive ventilation and supplemental oxygen were randomly allocated in a 1:1 ratio via a concealed, central, web-based randomisation system to conservative peripheral oxygen saturations ([SpO2] 88-92%) or liberal (SpO2 >94%) targets. The primary outcome was the duration of organ support at 30 days following random allocation, a rank-based endpoint with death either on or before day 30 as the worst outcome (a score equating to 31 days of organ support), with survivors assigned a score between 1 and 30 depending on the number of calendar days of organ support received. The primary effect estimate was the probabilistic index, a value greater than 0·5 indicating more than 50% probability that conservative oxygenation is superior to liberal oxygenation for a randomly selected patient. All participants in whom consent was available were included in the intention-to-treat analysis. The completed study was registered with the ISRCTN registry (ISRCTN92103439). FINDINGS: Between Sept 1, 2020, and May 15, 2022, 2040 children were randomly allocated to conservative or liberal oxygenation groups. Consent was available for 1872 (92%) of 2040 children. The conservative oxygenation group comprised 939 children (528 [57%] of 927 were female and 399 [43%] of 927 were male) and the liberal oxygenation group included 933 children (511 [56%] of 920 were female and 409 [45%] of 920 were male). Duration of organ support or death in the first 30 days was significantly lower in the conservative oxygenation group (probabilistic index 0·53, 95% CI 0·50-0·55; p=0·04 Wilcoxon rank-sum test, adjusted odds ratio 0·84 [95% CI 0·72-0·99]). Prespecified adverse events were reported in 24 (3%) of 939 patients in the conservative oxygenation group and 36 (4%) of 933 patients in the liberal oxygenation group. INTERPRETATION: Among invasively ventilated children who were admitted as an emergency to a PICU receiving supplemental oxygen, a conservative oxygenation target resulted in a small, but significant, greater probability of a better outcome in terms of duration of organ support at 30 days or death when compared with a liberal oxygenation target. Widespread adoption of a conservative oxygenation saturation target (SpO2 88-92%) could help improve outcomes and reduce costs for the sickest children admitted to PICUs. FUNDING: UK National Institute for Health and Care Research Health Technology Assessment Programme.

Exploring Heterogeneity in Cost-Effectiveness Using Machine Learning Methods: A Case Study Using the FIRST-ABC Trial.

OBJECTIVE: The aim of this study was to explore heterogeneity in the cost-effectiveness of high-flow nasal cannula (HFNC) therapy compared with continuous positive airway pressure (CPAP) in children following extubation. DESIGN: Using data from the FIRST-line support for Assistance in Breathing in Children (FIRST-ABC) trial, we explore heterogeneity at the individual and subgroup levels using a causal forest approach, alongside a seemingly unrelated regression (SUR) approach for comparison. SETTINGS: FIRST-ABC is a noninferiority randomized controlled trial (ISRCTN60048867) including children in UK paediatric intensive care units, which compared HFNC with CPAP as the first-line mode of noninvasive respiratory support. PATIENTS: In the step-down FIRST-ABC, 600 children clinically assessed to require noninvasive respiratory support were randomly assigned to HFNC and CPAP groups with 1:1 treatment allocation ratio. In this analysis, 118 patients were excluded because they did not consent to accessing their medical records, did not consent to follow-up questionnaire or did not receive respiratory support. MEASUREMENTS AND MAIN RESULTS: The primary outcome of this study is the incremental net monetary benefit (INB) of HFNC compared with CPAP using a willingness-to-pay threshold of £20,000 per QALY gain. INB is calculated based on total costs and quality adjusted life years (QALYs) at 6 months. The findings suggest modest heterogeneity in cost-effectiveness of HFNC compared with CPAP at the subgroup level, while greater heterogeneity is detected at the individual level. CONCLUSIONS: The estimated overall INB of HFNC is smaller than the INB for patients with better baseline status suggesting that HFNC can be more cost-effective among less severely ill patients.

Protocol for a Randomized Controlled Trial to Evaluate a Permissive Blood Pressure Target Versus Usual Care in Critically Ill Children with Hypotension (PRESSURE).

OBJECTIVES: Management of hypotension is a fundamental part of pediatric critical care, with cardiovascular support in the form of fluids or vasoactive drugs offered to every hypotensive child. However, optimal blood pressure (BP) targets are unknown. The PRotocolised Evaluation of PermiSSive BP Targets Versus Usual CaRE (PRESSURE) trial aims to evaluate the clinical and cost-effectiveness of a permissive mean arterial pressure (MAP) target of greater than a fifth centile for age compared with usual care. DESIGN: Pragmatic, open, multicenter, parallel-group randomized control trial (RCT) with integrated economic evaluation. SETTING: Eighteen PICUs across the United Kingdom. PATIENTS: Infants and children older than 37 weeks corrected gestational age to 16 years accepted to a participating PICU, on mechanical ventilation and receiving vasoactive drugs for hypotension. INTERVENTIONS: Adjustment of hemodynamic support to achieve a permissive MAP target greater than fifth centile for age during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a permissive MAP target or usual care, stratified by site and age group. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred until after randomization. The primary clinical outcome is a composite of death and days of ventilatory support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of BP and organ support, and discharge outcomes. This RCT received Health Research Authority approval (reference 289545), and a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee on May 10, 2021 (reference number 21/EE/0084). The trial is registered and has an International Standard RCT Number (reference 20609635). CONCLUSIONS: Trial findings will be disseminated in U.K. national and international conferences and in peer-reviewed journals.

Estimating the hospital costs of care for people living with HIV in England using routinely collected data.

BACKGROUND: Understanding the health care activity and associated hospital costs of caring for people living with HIV is an important component of assessing the cost effectiveness of new technologies and for budget planning. METHODS: Data collected between 2010 and 2017 from an English HIV treatment centre were combined with national reference costs to estimate the rate of hospital attendances and costs per quarter year, according to demographic and clinical factors. The final dataset included records for 1763 people living with HIV, which was analysed using negative binomial regression models and general estimating equations. RESULTS: People living with HIV experienced an unadjusted average of 0.028 (standard deviation [SD] 0.20) inpatient episodes per quarter, equivalent to one every 9 years, and 1.85 (SD 2.30) outpatient visits per quarter. The unadjusted mean quarterly cost per person with HIV (excluding antiretroviral drug costs) was £439 (SD 604). Outpatient appointments and inpatient episodes accounted for 88% and 6% of total costs, respectively. In adjusted models, low CD4 count was the strongest predictor of inpatient stays and outpatient visits. Low CD4 count and new patient status (having a first visit at the Trust in the last 6 months) were the factors that most increased estimated costs. Associations were weaker or less consistent for demographic factors (age, sex/sexual orientation/ethnicity). Sensitivity analyses suggest that the findings were generally robust to alternative parameter and modelling assumptions. CONCLUSION: A number of factors predicted hospital activity and costs, but CD4 cell count and new patient status were the strongest. The study results can be incorporated into future economic evaluations and budget impact assessments of HIV-related technologies.

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Pediatric Intensive Care.

OBJECTIVES: Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Sp o2 ) target of 88-92% compared with a liberal target of more than 94%. DESIGN: Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation. SETTING: Fifteen PICUs across England, Wales, and Scotland. PATIENTS: Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. INTERVENTION: Adjustment of ventilation and inspired oxygen settings to achieve an Sp o2 target of 88-92% during invasive mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Randomization is 1:1 to a liberal Sp o2 target of more than 94% or a conservative Sp o2 target of 88-92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England-Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals.

Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Therapy on Liberation From Respiratory Support in Acutely Ill Children Admitted to Pediatric Critical Care Units: A Randomized Clinical Trial.

Importance: The optimal first-line mode of noninvasive respiratory support for acutely ill children is not known. Objective: To evaluate the noninferiority of high-flow nasal cannula therapy (HFNC) as the first-line mode of noninvasive respiratory support for acute illness, compared with continuous positive airway pressure (CPAP), for time to liberation from all forms of respiratory support. Design, Setting, and Participants: Pragmatic, multicenter, randomized noninferiority clinical trial conducted in 24 pediatric critical care units in the United Kingdom among 600 acutely ill children aged 0 to 15 years who were clinically assessed to require noninvasive respiratory support, recruited between August 2019 and November 2021, with last follow-up completed in March 2022. Interventions: Patients were randomized 1:1 to commence either HFNC at a flow rate based on patient weight (n = 301) or CPAP of 7 to 8 cm H2O (n = 299). Main Outcomes and Measures: The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which a participant was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio of 0.75. Seven secondary outcomes were assessed, including mortality at critical care unit discharge, intubation within 48 hours, and use of sedation. Results: Of the 600 randomized children, consent was not obtained for 5 (HFNC: 1; CPAP: 4) and respiratory support was not started in 22 (HFNC: 5; CPAP: 17); 573 children (HFNC: 295; CPAP: 278) were included in the primary analysis (median age, 9 months; 226 girls [39%]). The median time to liberation in the HFNC group was 52.9 hours (95% CI, 46.0-60.9 hours) vs 47.9 hours (95% CI, 40.5-55.7 hours) in the CPAP group (absolute difference, 5.0 hours [95% CI -10.1 to 17.4 hours]; adjusted hazard ratio 1.03 [1-sided 97.5% CI, 0.86-∞]). This met the criterion for noninferiority. Of the 7 prespecified secondary outcomes, 3 were significantly lower in the HFNC group: use of sedation (27.7% vs 37%; adjusted odds ratio, 0.59 [95% CI, 0.39-0.88]); mean duration of critical care stay (5 days vs 7.4 days; adjusted mean difference, -3 days [95% CI, -5.1 to -1 days]); and mean duration of acute hospital stay (13.8 days vs 19.5 days; adjusted mean difference, -7.6 days [95% CI, -13.2 to -1.9 days]). The most common adverse event was nasal trauma (HFNC: 6/295 [2.0%]; CPAP: 18/278 [6.5%]). Conclusions and Relevance: Among acutely ill children clinically assessed to require noninvasive respiratory support in a pediatric critical care unit, HFNC compared with CPAP met the criterion for noninferiority for time to liberation from respiratory support. Trial Registration: ISRCTN.org Identifier: ISRCTN60048867.

Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Following Extubation on Liberation From Respiratory Support in Critically Ill Children: A Randomized Clinical Trial.

Importance: The optimal first-line mode of noninvasive respiratory support following extubation of critically ill children is not known. Objective: To evaluate the noninferiority of high-flow nasal cannula (HFNC) therapy as the first-line mode of noninvasive respiratory support following extubation, compared with continuous positive airway pressure (CPAP), on time to liberation from respiratory support. Design, Setting, and Participants: This was a pragmatic, multicenter, randomized, noninferiority trial conducted at 22 pediatric intensive care units in the United Kingdom. Six hundred children aged 0 to 15 years clinically assessed to require noninvasive respiratory support within 72 hours of extubation were recruited between August 8, 2019, and May 18, 2020, with last follow-up completed on November 22, 2020. Interventions: Patients were randomized 1:1 to start either HFNC at a flow rate based on patient weight (n = 299) or CPAP of 7 to 8 cm H2O (n = 301). Main Outcomes and Measures: The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio (HR) of 0.75. There were 6 secondary outcomes, including mortality at day 180 and reintubation within 48 hours. Results: Of the 600 children who were randomized, 553 children (HFNC, 281; CPAP, 272) were included in the primary analysis (median age, 3 months; 241 girls [44%]). HFNC failed to meet noninferiority, with a median time to liberation of 50.5 hours (95% CI, 43.0-67.9) vs 42.9 hours (95% CI, 30.5-48.2) for CPAP (adjusted HR, 0.83; 1-sided 97.5% CI, 0.70-∞). Similar results were seen across prespecified subgroups. Of the 6 prespecified secondary outcomes, 5 showed no significant difference, including the rate of reintubation within 48 hours (13.3% for HFNC vs 11.5 % for CPAP). Mortality at day 180 was significantly higher for HFNC (5.6% vs 2.4% for CPAP; adjusted odds ratio, 3.07 [95% CI, 1.1-8.8]). The most common adverse events were abdominal distension (HFNC: 8/281 [2.8%] vs CPAP: 7/272 [2.6%]) and nasal/facial trauma (HFNC: 14/281 [5.0%] vs CPAP: 15/272 [5.5%]). Conclusions and Relevance: Among critically ill children requiring noninvasive respiratory support following extubation, HFNC compared with CPAP following extubation failed to meet the criterion for noninferiority for time to liberation from respiratory support. Trial Registration: isrctn.org Identifier: ISRCTN60048867.

Cost-Utility Analysis of a Complex Intervention to Reduce School-Based Bullying and Aggression: An Analysis of the Inclusive RCT.

OBJECTIVES: Bullying and aggression among children and young people are key public mental health priorities. In this study, we evaluated the cost-effectiveness of a complex school-based intervention to address these outcomes within a large-cluster randomized trial (Inclusive). METHODS: Forty state secondary schools were randomly allocated (1:1) to receive the intervention or continue with current practice as controls. Data were collected using paper questionnaires completed in classrooms including measures of their health-related quality of life using the Childhood Utility Index and police and National Health Service resource use. Further detailed data were collected on the cost of delivering the intervention. We calculated incremental cost-effectiveness ratios following the intention-to-treat principle using multilevel linear regression models that allowed for clustering of pupils at the school level. RESULTS: Overall, we found that the intervention was highly cost-effective, with cost-per quality-adjusted life year thresholds of £13 284 and £1875 at 2 years and 3 years, respectively. Analysis of uncertainty in the result at 2 years revealed a 65% chance of being cost-effective, but after 3 years there was a 90% chance that it was cost-effective. CONCLUSION: This study provides strong evidence collected prospectively from a randomized study that this school-based intervention is highly cost-effective. Education- and health-sector policy makers should consider investment in scaling up this intervention.

An International Comparison of EQ-5D-5L and EQ-5D-3L for Use in Cost-Effectiveness Analysis.

OBJECTIVES: To estimate the impact of using EQ5D-5L (5L) compared with EQ5D-3L (3L) in cost-effectiveness analyses in 6 countries with 3L and 5L values: Germany, Japan, Korea, The Netherlands, China, and Spain. METHODS: Eight cost-effectiveness analyses based on clinical studies with 3L provided 11 pairwise comparisons. We estimated cost-effectiveness by applying the appropriate country values for 3L to observed responses. We re-estimated cost-effectiveness for each country by predicting the 5L tariff score for each respondent, for each country, using a previously published mapping method. We compared results in terms of impact on estimated incremental quality-adjusted life-year (QALY) gain and cost-effectiveness ratios. RESULTS: For most countries the impact of moving from 3L to 5L is to lower the incremental QALY gain in the majority of comparisons. The only exception to this was Japan, where 4 out of 11 cases (37%) saw lower QALYs gained when using 5L. The mean and median reductions in health gain, in those case studies where 5L does lead to lower health gain, are largest in The Netherlands (84% mean reduction, 41% median reduction), Germany (68% and 27%), and Spain (30% and 31%). For most countries, those studies where 5L leads to lower health gain see larger reductions than the gains in studies showing the opposite tendency. CONCLUSIONS: Overall, 3L and 5L are not interchangeable in these countries. Differences between results are large, but the direction of change can be unpredictable. These findings should prompt further investigation into the reasons for differences.

Costs of Early Invasive Breast Cancer in England Using National Patient-Level Data.

OBJECTIVES: This study aimed to use patient-level data to provide up-to-date estimates of early invasive breast cancer care costs by stage in England and to explore to what extent these costs varied based on patients' ages and geographic regions. METHODS: This study identified women aged 50 years and older who had been diagnosed with early invasive breast cancer between January 1, 2014, and December 31, 2015, using linked cancer registrations and routine hospital data sets generated from the usual care for all National Health Service trusts in England. Cost estimates were derived from hospital records in Hospital Episodes Statistics with additional chemotherapy and radiotherapy information from the national data sets. We fitted general linear regression models to analyze the cost data. The model that best fit the data was selected using the model selection criteria of Akaike information criterion. RESULTS: 55 662 women with early invasive breast cancer in England were included. The generalized linear model with log-gamma distribution fit the data best. The costs of breast cancer care for 1 year after diagnosis were strongly dependent on stage at diagnosis, controlling for other covariates. The estimated average per-patient hospital-related costs were £5167 at stage I, £7613 at stage II, and £13 330 at stage IIIA. Costs decreased with increasing age (P < .001) and varied across region (P < .001), deprivation level (P < .001), referral source (P < .01), presence of comorbidities (P< .001), and tumor receptor (ER/PR/HER2) status (P < .001). CONCLUSIONS: In England, the costs of breast cancer care increased with advancing stage of the disease at diagnosis. Breast cancer costs varied by age and geographic region.

Cost-effectiveness of breast cancer screening programme for women in rural China.

In low and middle-income countries mammographic breast cancer screening is prohibitively expensive and a cheaper alternative option is to use ultrasound as the primary screening test. In 2009, China launched a breast cancer screening programme for rural women aged 35-64 years with clinical breast examination coupled with ultrasound as the primary tool. Our study aimed to analyse the cost-effectiveness of breast screening compared to no screening among Chinese rural women. We developed a Markov model to estimate the lifetime costs and effects for rural women aged 35 years from a societal perspective. Asymptomatic women in the intervention arm were screened every 3 years before age 64 years. Breast cancer in the non-screening arm can only be diagnosed on presentation of symptoms. Parameter uncertainty was explored using one-way and probabilistic sensitivity analyses. Compared to no screening, breast cancer screening cost $186.7 more and led to a loss of 0.20 quality-adjusted life years (QALYs). Breast screening was more expensive and did harm to health among rural women with an incremental cost-effectiveness ratio (ICER) of $-916/QALY. The sensitivity analysis identified utility loss from false positives as the factor that most influenced the results, but this did not affect the conclusions. In a rural setting with such low breast cancer incidence, screening for asymptomatic disease is not cost-effective with current screening tools. Priority should be given to ensure that symptomatic women have proper access to diagnosis and treatment at an early stage as this will lead to mortality reductions without the usual screening harms.

Effects of the Learning Together intervention on bullying and aggression in English secondary schools (INCLUSIVE): a cluster randomised controlled trial.

BACKGROUND: Bullying, aggression, and violence among children and young people are some of the most consequential public mental health problems. We tested the Learning Together intervention, which involved students in efforts to modify their school environment using restorative practice and by developing social and emotional skills. METHODS: We did a cluster randomised trial, with economic and process evaluations, of the Learning Together intervention compared with standard practice (controls) over 3 years in secondary schools in south-east England. Learning Together consisted of staff training in restorative practice; convening and facilitating a school action group; and a student social and emotional skills curriculum. Primary outcomes were self-reported experience of bullying victimisation (Gatehouse Bullying Scale; GBS) and perpetration of aggression (Edinburgh Study of Youth Transitions and Crime (ESYTC) school misbehaviour subscale) measured at 36 months. We analysed data using intention-to-treat longitudinal mixed-effects models. This trial was registered with the ISRCTN registry (10751359). FINDINGS: We included 40 schools (20 in each group); no schools withdrew. 6667 (93·6%) of 7121 students participated at baseline and 5960 (83·3%) of 7154 at 36 months. Mean GBS bullying score at 36 months was 0·34 (SE 0·02) in the control group versus 0·29 (SE 0·02) in the intervention group, with a significant adjusted mean difference (-0·03, 95% CI -0·06 to -0·001; adjusted effect size -0·08). Mean ESYTC score at 36 months was 4·33 (SE 0·20) in the control group versus 4·04 (0·21) in the intervention group, with no evidence of a difference between groups (adjusted difference -0·13, 95% CI -0·43 to 0·18; adjusted effect size -0·03). Costs were an additional £58 per pupil in intervention schools than in control schools. INTERPRETATION: Learning Together had small but significant effects on bullying, which could be important for public health, but no effect on aggression. Interventions to promote student health by modifying the whole-school environment are likely to be one of the most feasible and efficient ways of addressing closely related risk and health outcomes in children and young people. FUNDING: National Institute for Health Research, Educational Endowment Foundation.

Cost-effectiveness of risk-based breast cancer screening programme, China.

OBJECTIVE: To model the cost-effectiveness of a risk-based breast cancer screening programme in urban China, launched in 2012, compared with no screening. METHODS: We developed a Markov model to estimate the lifetime costs and effects, in terms of quality-adjusted life years (QALYs), of a breast cancer screening programme for high-risk women aged 40-69 years. We derived or adopted age-specific incidence and transition probability data, assuming a natural history progression between the stages of cancer, from other studies. We obtained lifetime direct and indirect treatment costs in 2014 United States dollars (US$) from surveys of breast cancer patients in 37 Chinese hospitals. To calculate QALYs, we derived utility scores from cross-sectional patient surveys. We evaluated incremental cost-effectiveness ratios for various scenarios for comparison with a willingness-to-pay threshold. FINDINGS: Our baseline model of annual screening yielded an incremental cost-effectiveness ratio of US$ 8253/QALY, lower than the willingness-to-pay threshold of US$ 23 050/QALY. One-way and probabilistic sensitivity analyses demonstrated that the results are robust. In the exploration of various scenarios, screening every 3 years is the most cost-effective with an incremental cost-effectiveness ratio of US$ 6671/QALY. The cost-effectiveness of the screening is reduced if not all diagnosed women seek treatment. Finally, the economic benefit of screening women aged 45-69 years with both ultrasound and mammography, compared with mammography alone, is uncertain. CONCLUSION: High-risk population-based breast cancer screening is cost-effective compared with no screening.

EQ-5D-5L versus EQ-5D-3L: The Impact on Cost Effectiveness in the United Kingdom.

OBJECTIVES: To model the relationship between the three-level (3L) and the five-level (5L) EuroQol five-dimensional questionnaire and examine how differences have an impact on cost effectiveness in case studies. METHODS: We used two data sets that included the 3L and 5L versions from the same respondents. The EuroQol Group data set (n = 3551) included patients with different diseases and a healthy cohort. The National Data Bank data set included patients with rheumatoid disease (n = 5205). We estimated a system of ordinal regressions in each data set using copula models to link responses of the 3L instrument to those of the 5L instrument and its UK tariff, and vice versa. Results were applied to nine cost-effectiveness studies. RESULTS: Best-fitting models differed between the EuroQol Group and the National Data Bank data sets in terms of the explanatory variables, copulas, and coefficients. In both cases, the coefficients of the covariates and latent factors between the 3L and the 5L instruments were significantly different, indicating that moving between instruments is not simply a uniform re-alignment of the response levels for most dimensions. In the case studies, moving from the 3L to the 5L caused a decrease of up to 87% in incremental quality-adjusted life-years gained from effective technologies in almost all cases. Incremental cost-effectiveness ratios increased, often substantially. Conversely, one technology with a significant mortality gain saw increased incremental quality-adjusted life-years. CONCLUSIONS: The 5L shifts mean utility scores up the utility scale toward full health and compresses them into a smaller range, compared with the 3L. Improvements in quality of life are valued less using the 5L than using the 3L. The 3L and the 5L can produce substantially different estimates of cost effectiveness. There is no simple proportional adjustment that can be made to reconcile these differences.

A randomized trial of hyperglycemic control in pediatric intensive care.

BACKGROUND: Whether an insulin infusion should be used for tight control of hyperglycemia in critically ill children remains unclear. METHODS: We randomly assigned children (≤16 years of age) who were admitted to the pediatric intensive care unit (ICU) and were expected to require mechanical ventilation and vasoactive drugs for at least 12 hours to either tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter), or conventional glycemic control, with a target level below 216 mg per deciliter (12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days after randomization. The main prespecified subgroup analysis compared children who had undergone cardiac surgery with those who had not. We also assessed costs of hospital and community health services. RESULTS: A total of 1369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], -0.42 to 1.14); the effects did not differ according to subgroup. Severe hypoglycemia (blood glucose, <36 mg per deciliter [2.0 mmol per liter]) occurred in a higher proportion of children in the tight-glycemic-control group than in the conventional-glycemic-control group (7.3% vs. 1.5%, P<0.001). Overall, the mean 12-month costs were lower in the tight-glycemic-control group than in the conventional-glycemic-control group. The mean 12-month costs were similar in the two groups in the cardiac-surgery subgroup, but in the subgroup that had not undergone cardiac surgery, the mean cost was significantly lower in the tight-glycemic-control group than in the conventional-glycemic-control group: -$13,120 (95% CI, -$24,682 to -$1,559). CONCLUSIONS: This multicenter, randomized trial showed that tight glycemic control in critically ill children had no significant effect on major clinical outcomes, although the incidence of hypoglycemia was higher with tight glucose control than with conventional glucose control. (Funded by the National Institute for Health Research, Health Technology Assessment Program, U.K. National Health Service; CHiP Current Controlled Trials number, ISRCTN61735247.).

Cost-effectiveness of Ward Closure to Control Outbreaks of Norovirus Infection in United Kingdom National Health Service Hospitals.

BACKGROUND: Norovirus is the most common cause of outbreaks of acute gastroenteritis in National Health Service hospitals in the United Kingdom. Wards (units) are often closed to new admissions to stop the spread of the virus, but there is limited evidence describing the cost-effectiveness of ward closure. METHODS: An economic analysis based on the results from a large, prospective, active-surveillance study of gastroenteritis outbreaks in hospitals and from an epidemic simulation study compared alternative ward closure options evaluated at different time points since first infection, assuming different efficacies of ward closure. RESULTS: A total of 232 gastroenteritis outbreaks occurring in 14 hospitals over a 1-year period were analyzed. The risk of a new outbreak in a hospital is significantly associated with the number of admission, general medical, and long-stay wards that are concurrently affected but is less affected by the level of community transmission. Ward closure leads to higher costs but reduces the number of new outbreaks by 6%-56% and the number of clinical cases by 1%-55%, depending on the efficacy of the intervention. The incremental cost per outbreak averted varies from £10 000 ($14 000) to £306 000 ($428 000), and the cost per case averted varies from £500 ($700) to £61 000 ($85 000). The cost-effectiveness of ward closure decreases as the efficacy of the intervention increases, and the cost-effectiveness increases with the timing of the intervention. The efficacy of ward closure is critical from a cost-effectiveness perspective. CONCLUSIONS: Ward closure may be cost-effective, particularly if targeted to high-throughput units.

Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu).

RATIONALE: Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. OBJECTIVE: To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks ('schemes') and their carers in London, UK. MEASUREMENTS AND METHODS: Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 µg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 µg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. MAIN RESULTS: Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT01069874.

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs).

RATIONALE: Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking. OBJECTIVE: To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes). MEASUREMENTS AND METHODS: 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes. MAIN RESULTS: 206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. CONCLUSIONS: Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency. TRIAL REGISTRATION NUMBER: NCT00978315 (ClinicalTrials.gov).

Prospective evaluation of the cost of diagnosis and treatment of invasive fungal disease in a cohort of adult haematology patients in the UK.

OBJECTIVES: The direct cost of invasive fungal disease (IFD) includes antifungal drugs as well as diagnostic tests. The aim of this study was to determine these costs. METHODS: A total of 203 haematology patients were enrolled into the study and followed for a median of 556 days. Data were prospectively collected on antifungal drugs, diagnostic tests, length of stay and antibiotic usage. RESULTS: The overall mean (IQR) cost of care per patient (using UK-based reference costs) was £88 911 (45 339-121 594), £61 509 (39 748-78 383), £50 332 (23 037-72 057) and £34 075 (19 928-43 900) for proven/probable IFD, possible IFD, not classified and no evidence of IFD, respectively (P<0.001). The attributable cost of IFD was £54 836. Inpatient hospital stay accounted for nearly 74% of costs. In proven/probable IFD inpatient care, antifungals, antibiotics and IFD status accounted for 68%, 25%, 5% and 2%, respectively, compared with 85%, 11%, 2% and 2%, respectively, for no IFD (P<0.001). Among the allogeneic transplant patients, £36 914 (60%) of the total cost (£60 917) was used during the first 100 days. CONCLUSIONS: IFD was associated with longer length of stay and higher total overall cost of care, with attributable costs greater than £50 000 per case of IFD. Costs for inpatient stay far outstrip the cost of antifungal agents.