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OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury scoring by radiologists. Materials and Methods In this secondary analysis, brain diffusion-weighted MRI data from neonates in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which recruited participants between January 2017 and October 2019, were analyzed. Volume of acute brain injury, defined as brain with apparent diffusion coefficient (ADC) less than 800 × 10-6 mm2/sec, was automatically computed across the whole brain and within the thalami and white matter. Outcomes of death and neurodevelopmental impairment (NDI) were recorded at 24-month follow-up. Associations between the presence and volume (in milliliters) of acute brain injury with 24-month outcomes were evaluated using multiple logistic regression. The correlation between quantitative acute brain injury volume and qualitative MRI scores was assessed using the Kendall tau-b test. Results A total of 416 neonates had available MRI data (mean gestational age, 39.1 weeks ± 1.4 [SD]; 235 male) and 113 (27%) showed evidence of acute brain injury at MRI. Of the 387 participants with 24-month follow-up data, 185 (48%) died or had any NDI. Volume of acute injury greater than 1 mL (odds ratio [OR], 13.9 [95% CI: 5.93, 32.45]; P < .001) and presence of any acute injury in the brain (OR, 4.5 [95% CI: 2.6, 7.8]; P < .001) were associated with increased odds of death or any NDI. Quantitative whole-brain acute injury volume was strongly associated with radiologists qualitative scoring of diffusion-weighted images (Kendall tau-b = 0.56; P < .001). Conclusion Automated quantitative volume of brain injury is associated with death, moderate to severe NDI, and cerebral palsy in neonates with hypoxic ischemic encephalopathy and correlated well with qualitative MRI scoring of acute brain injury. Clinical trial registration no. NCT02811263 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

ObjectiveTo compare secondary patient reported outcomes of perceptions of treatment success and function for patients treated for appendicitis with appendectomy vs. antibiotics at 30 days.Summary background dataThe Comparison of Outcomes of antibiotic Drugs and Appendectomy trial found antibiotics noninferior to appendectomy based on 30-day health status. To address questions about outcomes among participants with lower socioeconomic status, we explored the relationship of sociodemographic and clinical factors and outcomes.MethodsWe focused on 4 patient reported outcomes at 30 days: high decisional regret, dissatisfaction with treatment, problems performing usual activities, and missing >10 days of work. The randomized (RCT) and observational cohorts were pooled for exploration of baseline factors. The RCT cohort alone was used for comparison of treatments. Logistic regression was used to assess associations.ResultsThe pooled cohort contained 2062 participants; 1552 from the RCT. Overall, regret and dissatisfaction were low whereas problems with usual activities and prolonged missed work occurred more frequently. In the RCT, those assigned to antibiotics had more regret (Odd ratios (OR) 2.97, 95% Confidence intervals (CI) 2.05-4.31) and dissatisfaction (OR 1.98, 95%CI 1.25-3.12), and reported less missed work (OR 0.39, 95%CI 0.27-0.56). Factors associated with function outcomes included sociodemographic and clinical variables for both treatment arms. Fewer factors were associated with dissatisfaction and regret.ConclusionsOverall, participants reported high satisfaction, low regret, and were frequently able to resume usual activities and return to work. When comparing treatments for appendicitis, no single measure defines success or failure for all people. The reported data may inform discussions regarding the most appropriate treatment for individuals.Trial registrationClinicaltrials.gov Identifier: NCT02800785.

Background Cardiac rehabilitation improves health and quality of life and reduces risk of further cardiac events. Twenty-eight per cent of cardiac rehabilitation patients experience clinically significant anxiety and 19% suffer depression. Such patients are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. The available psychological treatments for cardiac patients have small effects on anxiety and depression and quality of life; therefore, more effective treatments are needed. Research shows that a thinking style dominated by rumination and worry maintains anxiety and depression. A psychological intervention (metacognitive therapy) effectively reduces this style of thinking and alleviates depression and anxiety in mental health settings. The PATHWAY study evaluated two versions of metacognitive therapy applied in cardiac rehabilitation services. Objectives The primary aim was to improve psychological outcomes for cardiac rehabilitation patients. We evaluated two formats of metacognitive therapy: (1) a group-based face-to-face intervention delivered by cardiac rehabilitation staff (group-based metacognitive therapy) and (2) a paper-based, self-directed intervention (home-based metacognitive therapy). Each was compared with usual cardiac rehabilitation alone in separate randomised controlled trials. Design A randomised feasibility trial (work stream 1) and a full-scale randomised controlled trial (work stream 2) evaluated group-metacognitive therapy, while separate feasibility and full-scale trials (work stream 3 and work stream 3+, respectively) evaluated home-based metacognitive therapy. A cost-effectiveness analysis of group-metacognitive therapy was conducted, along with stated preference surveys and qualitative studies examining patient psychological needs and therapists’ perspectives on metacognitive therapy. Setting Seven NHS cardiac rehabilitation services across the north-west of England. Participants Adults aged ≥ 18 years who met cardiac rehabilitation eligibility criteria, scored ≥ 8 on depression or anxiety subscales of the Hospital Anxiety and Depression Scale, and were able to read, understand and complete questionnaires in English. Interventions Work stream 1 and work stream 2 – a 6-week group-metacognitive therapy intervention delivered by cardiac rehabilitation staff plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Group-metacognitive therapy was delivered once per week for 6 weeks, with each session lasting 90 minutes. Work stream 3 and work stream 3+ – home-based metacognitive therapy plus usual cardiac rehabilitation compared with usual cardiac rehabilitation alone. Home-metacognitive therapy was a paper-based manual that included six modules and two supportive telephone calls delivered by cardiac rehabilitation staff. Main outcome measures The Hospital Anxiety and Depression Scale total score at 4-month follow-up was the primary outcome in all trials. A range of secondary outcomes were also evaluated. Results Our qualitative study with 46 patients across three cardiac rehabilitation services suggested that cardiac rehabilitation patients’ psychological needs were not met by current approaches and that metacognitive therapy might offer an improved fit with their psychological symptoms. The internal pilot feasibility study (work stream 1; n = 54) demonstrated that a full-scale randomised controlled trial was feasible and acceptable and confirmed our sample size estimation. A subsequent full-scale, single-blind randomised controlled trial (work stream 2; n = 332) showed that adding group-based metacognitive therapy to cardiac rehabilitation was associated with statistically significant improvements on the Hospital Anxiety and Depression Scale (primary outcome) in anxiety and depression compared with cardiac rehabilitation alone at 4-month (adjusted mean difference −3.24, 95% confidence interval −4.67 to −1.81, p < 0.001; standardised mean difference 0.52) and 12-month follow-up (adjusted mean difference −2.19, 95% confidence interval −3.72 to −0.66, p = 0.005; standardised mean difference 0.33). The cost-effectiveness analysis suggested that group-metacognitive therapy was dominant, that it could be cost saving (net cost −£219, 95% confidence interval −£1446 to £1007) and health increasing (net quality-adjusted life-year 0.015, 95% confidence interval −0.015 to 0.045). However, confidence intervals were wide and overlapped zero, indicating high variability in the data and uncertainty in the estimates. A pilot feasibility trial (work stream 3; n = 108) supported a full-scale trial of home-metacognitive therapy and was extended (work stream 3+; n = 240). In the full trial, the adjusted mean difference on the Hospital and Anxiety and Depression Scale favoured the metacognitive therapy + cardiac rehabilitation arm (adjusted mean difference −2.64, 95% confidence interval −4.49 to −0.78, p = 0.005; standardised mean difference 0.38), with statistically significant greater improvements in anxiety and depression in home-metacognitive therapy plus cardiac rehabilitation than in cardiac rehabilitation alone at 4-month follow-up. A stated preference survey on clinic-delivered psychological therapy (not specific to metacognitive therapy) indicated a preference for including psychological therapy as part of cardiac rehabilitation. Participants favoured individual therapy, delivered by cardiac rehabilitation staff, with information provided prior to therapy and at a lower cost to the NHS. A pilot stated preference study focused on preferences for home- or clinic-based psychological therapy. Preferences were stronger for home-based therapy than for centre-based, but this was not statistically significant and participants highly valued receiving therapy and having reduced waiting times. Limitations Limitations include no control for additional contact as part of metacognitive therapy to estimate non-specific effects. Work stream 3+ did not include 12-month follow-up and therefore the long-term effects of home-based metacognitive therapy are unknown. The health economics analysis was limited by sample size and large amount of missing data in the final follow up. Findings from the qualitative study cannot necessarily be generalised. Conclusions Both group-based and home-based metacognitive therapy were associated with significantly greater reductions in anxiety and depression symptoms at 4 months, compared with cardiac rehabilitation alone. The results in group-based metacognitive therapy appeared to be stable over 12 months. Introducing metacognitive therapy into cardiac rehabilitation has the potential to improve mental health outcomes. Future work Future studies should evaluate the long-term effects of home-metacognitive therapy and the effect of metacognitive therapy against other treatments offered in cardiac rehabilitation. Given the uncertainty in the economic evaluation, further work is needed to determine the cost-effectiveness of metacognitive therapy. Trial registration Work stream 1/work stream 2: NCT02420431 and ISRCTN74643496; work stream 3: NCT03129282; work stream 3+: NCT03999359. The trial is registered with clinicaltrials.gov NCT03999359. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-1211-20011) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information. Plain language summary Depression and anxiety are common among cardiac rehabilitation patients. Cardiac patients with anxiety and depression are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. Current talking-based therapies have small effects on anxiety and depression in patients with cardiovascular disease. It is important that more effective treatments for mental health are added to cardiac rehabilitation. We applied two versions of a recent treatment called metacognitive therapy in cardiac rehabilitation: a group version and a home-based (self-help) paper-based manual. The programme had three work streams conducted across seven NHS trusts. In work stream 1, we ran a pilot trial showing that adding group-metacognitive therapy to cardiac rehabilitation was feasible and acceptable A full-scale trial (work stream 2) followed, and this showed that adding group-metacognitive therapy to cardiac rehabilitation was associated with greater improvement in anxiety and depression than cardiac rehabilitation alone. In work stream 3, we created a home-based version of metacognitive therapy and ran a feasibility trial, which was extended to a full-scale trial and showed that home-metacognitive therapy plus cardiac rehabilitation was associated with improved anxiety and depression outcomes compared with cardiac rehabilitation alone. Interview studies of patients’ needs, treatment preferences and reactions to treatment were included, and our patient and public involvement group advised the research team throughout the trial. The originator of metacognitive therapy, Adrian Wells, was the chief investigator of the study and is the director of the Metacognitive Therapy Institute. He has funding for the study ‘Implementing Group Metacognitive Therapy in Cardiac Rehabilitation Services (PATHWAY-Beacons; NIHR29567)’ as chief investigator. To maintain objectivity along with the trial statistician and research assistants he did not know patient treatment allocation, data were managed by a separate clinical trials unit and a plan for analysis was devised before analysis took place. Project oversight and monitoring were undertaken by an independent Trial Steering Committee. Scientific summary Background Cardiac rehabilitation (CR) aims to improve heart disease patients’ health and quality of life and reduce the risk of further cardiac events: 28% of cardiac patients have clinically significant anxiety and 19% have depression. Such patients are at greater risk of death, further cardiac events and poorer quality of life and use more health care, leading to higher NHS costs. Available psychological treatments for patients with heart disease have small effects on improving anxiety, depression and quality of life. Therefore, more effective treatments for depression and anxiety need to be explored and made available in CR services. Research in mental health contexts shows that a style of thinking dominated by rumination and worry maintains distress. A psychological intervention [metacognitive therapy (MCT)] reduces this style of thinking and alleviates depression and anxiety. The PATHWAY study evaluated two versions of MCT applied in heart disease patients attending CR: (1) a 6-week intervention delivered face to face in a group setting by CR staff (group-based MCT) and (2) a paper-based, six-module, self-directed intervention (home-based MCT). Objectives The primary aim is to improve access to more effective psychological interventions for the range of heart disease patients attending CR services. The specific objectives were to: conduct a pilot randomised controlled trial (RCT) of group-based MCT (Group-MCT) to evaluate the acceptability and feasibility of delivering the intervention to CR patients who have symptoms of anxiety and depression establish evidence of the effectiveness and cost-effectiveness of Group-MCT in CR in a full-scale RCT produce a rigorous, well-specified Group-MCT package develop a home-based metacognitive intervention (Home-MCT) for CR patients with depression and/or anxiety establish the feasibility and acceptability of integrating Home-MCT into the CR pathway in a pilot RCT establish provisional evidence of the effectiveness and cost-effectiveness of Home-MCT develop a protocol and manual for Home-MCT to inform a full-scale RCT conduct a full-scale RCT evaluating the effectiveness of Home-MCT. Methods We conducted a randomised controlled pilot trial and a full-scale RCT comparing usual CR alone against CR plus group-based MCT [work stream (WS) 1 and WS2; n = 332)]. We also conducted a randomised controlled pilot trial and a full-scale RCT of home-based metacognitive therapy (WS3 and WS3+; n = 240). All trials included integrated qualitative (n = 52) and economic evaluations (n = 339; stated preference survey). Participants A total of seven NHS trusts that provided a routine CR service participated in the research, with the number of participants and specific sites varying by trial. Work streams 1 and 2 explored the acceptability and effectiveness of Group-MCT integrated into usual CR in hospital settings, whereas WS3 and WS3+ explored the acceptability and effectiveness of Home-MCT integrated into usual CR in hospital and community settings. Work stream 1 recruited participants from three NHS trusts in north-west England. Participant recruitment for WS2 took place in five NHS trusts across north-west England. WS3 and WS3+ patients were recruited from CR services at five NHS hospital trusts across north-west England. Participating CR patients in all trials had to score ≥ 8 on the anxiety and/or depression subscale of the Hospital Anxiety and Depression Scale (HADS), be aged ≥ 18 years and meet the British Association for Cardiovascular Prevention and Rehabilitation criteria for attending CR. Participants were randomly allocated in a one-to-one ratio to receive either MCT plus usual CR or usual CR only using a randomisation procedure that balanced the trial arms with respect to gender, HADS scores and trial sites. Interventions Group-MCT: a 6-week manualised MCT intervention delivered face to face in a group setting. Therapists were CR staff who were not mental health specialists (e.g. clinical psychologists) but were trained to deliver the intervention. The intervention was developed by Adrian Wells based on the metacognitive model of psychological disorder and uses effective metacognitive therapy methods tested in mental health settings. Home-MCT: a paper-based, self-directed MCT intervention consisting of six modules in a treatment manual following a structure and content like that of the group-based MCT intervention. Adrian Wells provided pre-trial training for staff but was not involved in the ongoing supervision of staff delivering the intervention to maintain blinding and objectivity. Outcome measures The primary outcome was HADS total score at 4 months, with HADS total scores at 12 months as a secondary outcome (WS1 and WS2, i.e. Group-MCT only). Other secondary outcomes were the separate HADS anxiety and depression subscales, traumatic stress symptoms, and psychological mechanisms including metacognitive beliefs and repetitive negative thinking. For both interventions, qualitative interviews were conducted to assess patients’ emotional experiences and needs following cardiac events, and their understanding and experience of MCT. In Group-MCT, practitioners were interviewed to understand their experience of delivering the intervention and their understanding of patients’ responses to it and patients’ emotional needs. Statistical analysis For the pilot studies, statistical analysis was principally descriptive. We assessed the acceptability of adding Group-MCT and Home-MCT to usual CR regarding rates of recruitment into the study, attrition by the primary end point, and numbers of MCT and CR modules/sessions completed. The feasibility of conducting a full RCT was assessed against the completion of follow-up questionnaires, adequate variability in the outcome measures, and re-estimation of the required sample size based on pilot study findings. Therapist adherence to the Group-MCT treatment protocol was also assessed. The full-scale RCTs of Group-MCT and Home-MCT were designed to detect a standardised mean difference (SMD) between trial arms of 0.4 in HADS total score at 4-month follow-up with 90% power, based on effect sizes reported for other psychological interventions for depression. Analysis was conducted following a prespecified plan detailing the analytic models, primary and secondary outcomes, choice of covariates, sensitivity analyses, and all other key aspects of the analysis. The primary analyses used intention-to-treat principles. To reduce bias, data from the trial were managed by a separate clinical trials unit and locked prior to analysis. The chief investigator (AW), trial statisticians and research assistants were kept unaware of patient treatment allocation throughout the programme and the analyses followed a prespecified plan. Cost-effectiveness analysis For Group-MCT only, a within-trial cost-effectiveness analysis with a 12-month time horizon compared the cost-effectiveness of MCT plus usual CR with that of CR alone, from a UK health and social care perspective. Key measures included health status (measured using the EuroQol-5 Dimensions, five-level) and self-reported health and social care use. Total costs and quality-adjusted life-years (QALYs) were calculated for the trial follow-up. Missing values were addressed using multiple imputation. The primary outcome was the incremental cost-effectiveness ratio. Regression analysis was used to estimate net costs and net QALYs, and 10,000 bootstrapped pairs of net costs and QALYs were generated to inform the probability of cost-effectiveness. For the home-based MCT pilot study, a simple between-group comparison of the available economic data (health status and NHS and social care costs), using summary statistics, was performed. Two stated preference studies (using discrete choice experiment designs), one focused on Group-MCT and the other on Home-MCT, were conducted to explore patient preferences for the delivery of psychological therapy in CR. Participants were asked to choose between two hypothetical interventions, described using five attributes. The cost to the NHS was used to estimate willingness to pay for aspects of intervention delivery. Results Group-MCT Fifty-two CR patients were consented to the pilot trial of Group-MCT + CR versus CR alone, of whom 23 were randomly allocated to Group-MCT + CR and 29 to CR. The trial recruited to target, and > 70% of participants completed the 4-month follow-up questionnaire. More than half of the patients in both arms attended at least six CR sessions, and 57% of Group-MCT participants completed an a priori defined minimal dose of the intervention likely to produce the benefit of at least four of the six MCT sessions. The addition of MCT to rehabilitation did not negatively impact on CR attendance, and we observed high therapist adherence to the protocol. The trial concluded that Group-MCT is an acceptable and feasible intervention to deliver in CR services. The Trial Steering Committee and NIHR as funder agreed to support the progression to a full-scale RCT of the Group-MCT intervention. No substantive changes were required to the trial procedures; therefore, the pilot and full RCT samples were pooled for final analysis. A total of 332 patients (including 52 from the pilot trial) consented to the full-scale RCT of Group-MCT + CR versus CR alone, with 163 randomly allocated to Group-MCT + CR and 169 randomly allocated to CR alone; 81% returned data at 4-month follow-up. The adjusted group difference on the primary outcome of HADS total score at 4 months significantly favoured Group-MCT + CR [–3.24, 95% confidence interval (CI) –4.67 to –1.81, p < 0.001; SMD 0.52], as did the difference at the 12-month secondary outcome point (–2.19, 95% CI –3.72 to –0.66, p < 0.01; SMD 0.33). Patients in the Group-MCT + CR arm also had lower mean HADS anxiety and depression subscale scores at 4 months (p < 0.001). Differences in anxiety remained statistically significant at 12 months (p < 0.01), but those in depression did not (p = 0.065). Most of the other secondary outcomes also favoured the MCT intervention. Attendance at CR sessions did not differ between trial arms. Over 60% of Group-MCT + CR participants attended four or more of the six MCT intervention sessions. However, Group-MCT did not appeal to some patients, with 40 (25%) of the 163 patients randomised to receive MCT attending no MCT intervention sessions. Home-MCT One hundred and eight CR patients consented to the pilot trial of Home-MCT, with 54 randomised to Home-MCT + CR and 54 randomised to CR alone. The trial recruited to target, with 96% of CR only and 83% of Home-MCT + CR participants completing 4-month follow-up measures. Forty-four per cent of patients in the MCT arm completed a minimally effective dose of more than four out of six modules. Exit questionnaire ratings were good. However, views about telephone support were mixed and the quality of calls was rated low. Home-MCT appeared to be acceptable and feasible to deliver in CR services. The Trial Steering Committee and NIHR as funder agreed to support the progression to a full-scale RCT of the Home-MCT intervention. We submitted a no-additional-cost variation to contract (VTC) on 29 January 2019 to progress WS3 to a full-scale RCT (WS3+). The VTC was awarded on 12 March 2019. No substantive changes were required to the trial procedures; therefore, the pilot sample was pooled with the sample from the full RCT in final analysis. A total of 240 patients (including 108 from the pilot trial) were consented to the full-scale RCT of Home-MCT, with 118 randomly allocated to Home-MCT + CR and 122 randomly allocated to CR alone; 89% returned 4-month follow-up data. The adjusted group difference on the primary outcome of HADS total score at 4 months significantly favoured the MCT + CR arm (−2.64, 95% CI −4.49 to −0.78, p = 0.005; SMD 0.38). Patients in the MCT + CR arm also reported significantly lower mean HADS anxiety and depression scores (p < 0.05). Most other secondary outcomes also favoured the MCT intervention. Attendance at CR sessions did not differ between the trial arms. Over 70% of participants in the Home-MCT arm completed more than four MCT modules, but the intervention did not appeal to some patients; 21 participants (18%) withdrew or were not contactable at 4 months, compared with only one in the CR-alone arm. An investigation of the impact of differential attrition on the findings using last-observation-carried-forward resulted in no changes in statistical significance for the primary outcome and most of the secondary outcomes. In the primary cost-effectiveness analysis, the Group-MCT intervention was dominant, that is cost saving (net cost −219, 95% CI −£1446 to £1007) and health increasing (net QALY 0.015, 95% CI −0.015 to 0.045). However, the CIs are wide and overlap zero, indicating a high level of variability in the data and uncertainty in the estimates. Stated preference research indicated a preference for the inclusion of psychological therapy as part of a programme of CR. Conclusions There is not currently a standardised approach for psychological interventions in CR, and interventions can vary. There is a preference for the inclusion of psychological therapy in rehabilitation. Group-based MCT and Home-MCT were associated with significantly better anxiety and depression outcomes when added to CR compared with CR alone. The implications for health care are (1) MCT could be provided as part of the menu of approaches used in CR and (2) patients could be given the option to choose between group-based or home-based treatment to increase access. The recommendations for future research are (1) implementation studies that assess barriers to and enablers of roll-out in the NHS, (2) studies of longer-term outcomes of home-based MCT and (3) an evaluation of MCT against alternative therapies. Trial registration Work stream 1/work stream 2: NCT02420431 and ISRCTN74643496; work stream 3: NCT03129282; work stream 3+: NCT03999359. The trial is registered with clinicaltrials.gov NCT03999359. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1211-20011) and is published in full in Programme Grants for Applied Research; Vol. 12, No. 7. See the NIHR Funding and Awards website for further award information.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Background Acute kidney injury (AKI) is common and is associated with poor clinical outcomes in premature neonates. Urine biomarkers hold the promise to improve our understanding and care of patients with kidney disease. Because kidney maturation and gender can impact urine biomarker values in extremely low gestational age neonates (ELGANs), careful control of gestational age (GA) and time is critical to any urine biomarker studies in neonates. Methods To improve our understanding of the potential use of urine biomarkers to detect AKI during the first postnatal weeks, we performed a nested case-control study to evaluate 21 candidate urine AKI biomarkers. Cases include 20 ELGANs with severe AKI. Each case was matched with 2 controls for the same GA week (rounded down to the nearest week), gender, and birth weight (BW) (± 50 g). Results Urine cystatin C, creatinine, ghrelin, fibroblast growth factor-23 (FGF23), tissue metalloproteinase 2 (TIMP2) and vascular endothelial growth factor A (VEGFa) concentrations were higher in ELGANs with early severe AKI compared to matched control subjects without AKI. Urine epidermal growth factor (EGF) and uromodulin (UMOD) concentrations are lower in cases than controls. Interleukin (IL)-15 was lower on day 1, but higher on day 8 in cases than controls; while VEGFa was lower on day 1, but higher on day 5 in cases than controls. Conclusion Urine biomarkers hold the promise to improve our ability to reliably detect kidney injury. Interventional studies are needed to determine the biomarkers' ability to predict outcomes, enhance AKI phenotypes, and improve timely interventions which can prevent the sequalae of AKI in ELGANs. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): David J. Askenazi [sup.1] , Brian A. Halloran [sup.1] , Patrick J. Heagerty [sup.2] , Robert H. Schmicker [sup.2] , Sandra E. Juul [sup.3] , Sangeeta Hingorani [sup.3] , [...]

ObjectiveThe association of sarcopenia with development of knee osteoarthritis (OA) or knee pain in older adults is uncertain. We examined the relationship of grip strength and appendicular lean mass (ALM) with the likelihood of developing knee OA and knee pain in older adults in the Health ABC (Health, Aging, and Body Composition) Study.MethodsALM and grip strength were assessed at baseline by dual-energy x-ray absorptiometry and handheld dynamometry, respectively. Incident clinically diagnosed, symptomatic knee OA, defined as new participant report of physician-diagnosed knee OA and concurrent frequent knee pain, and incident frequent knee pain over 5 years of follow-up were examined. Separate regression analyses, stratified by sex, modeled associations of baseline ALM and grip strength with the likelihood of incident clinically diagnosed, symptomatic knee OA and incident knee pain over follow-up, adjusting for covariates.ResultsAmong the 2779 subjects without OA at baseline, 95 men (6.9%) and 158 women (11.3%) developed clinically diagnosed, symptomatic knee OA, and, among the 2182 subjects without knee pain at baseline, 315 men (28.3%) and 385 women (36.1%) developed knee pain over follow-up. Among men only, each SD decrement of ALM was associated with decreasing likelihood of incident knee OA (odds ratio [OR] per SD decrement: 0.68; 95% confidence interval [CI]: 0.47-0.97), and each SD decrement of grip strength was associated with increasing likelihood of incident knee pain (OR per SD decrement: 1.20; 95% CI: 1.01-1.42).ConclusionIn older men, ALM and grip strength may be associated with the development of knee OA and knee pain, respectively.

OBJECTIVE: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo. STUDY DESIGN: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. RESULTS: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) 30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P 95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit. CONCLUSIONS: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.

IntroductionMRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.Methods and analysisNeonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans.Ethics and disseminationIRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor.Trial registration numberNCT02811263; Pre-result.

Abstract Background Chronic low back pain (cLBP) is widespread, costly, and burdensome to patients and health systems. Little is known about non-pharmacological treatments for the secondary prevention of cLBP. There is some evidence that treatments addressing psychosocial factors in higher risk patients are more effective than usual care. However, most clinical trials on acute and subacute LBP have evaluated interventions irrespective of prognosis. Methods We have designed a phase 3 randomized trial with a 2 × 2 factorial design. The study is also a Hybrid type 1 trial with focus on intervention effectiveness while simultaneously considering plausible implementation strategies. Adults (n = 1000) with acute/subacute LBP at moderate to high risk of chronicity based on the STarT Back screening tool will be randomized in to 1 of 4 interventions lasting up to 8 weeks: supported self-management (SSM), spinal manipulation therapy (SMT), both SSM and SMT, or medical care. The primary objective is to assess intervention effectiveness; the secondary objective is to assess barriers and facilitators impacting future implementation. Primary effectiveness outcome measures are: (1) average pain intensity over 12 months post-randomization (pain, numerical rating scale); (2) average low back disability over 12 months post-randomization (Roland-Morris Disability Questionnaire); (3) prevention of cLBP that is impactful at 10–12 months follow-up (LBP impact from the PROMIS-29 Profile v2.0). Secondary outcomes include: recovery, PROMIS-29 Profile v2.0 measures to assess pain interference, physical function, anxiety, depression, fatigue, sleep disturbance, and ability to participate in social roles and activities. Other patient-reported measures include LBP frequency, medication use, healthcare utilization, productivity loss, STarT Back screening tool status, patient satisfaction, prevention of chronicity, adverse events, and dissemination measures. Objective measures include the Quebec Task Force Classification, Timed Up & Go Test, the Sit to Stand Test, and the Sock Test assessed by clinicians blinded to the patients’ intervention assignment. Discussion By targeting those subjects at higher risk this trial aims to fill an important gap in the scientific literature regarding the effectiveness of promising non-pharmacological treatments compared to medical care for the management of patients with an acute episode of LBP and the prevention of progression to a severe chronic back problem. Trial registration ClinicalTrials.gov Identifier: NCT03581123.

Fibrotic diseases account for 45% of all deaths in the developed world, and progressive scarring conditions, such as dystrophic epidermolysis bullosa (EB), result in a significant reduction in quality of life. There is thus a need for novel approaches in fibrosis prevention. Herein, it is shown that iota carrageenan, a low‐cost, regulatory approved polysaccharide, is effective at preventing scarring by inhibiting collagen fibrillogenesis, abrogating the transforming growth factor beta 1 (TGFβ1) pathway, and lubricating the epithelium. It is demonstrated that iota carrageenan, and other anionic polysaccharides, can prevent collagen fibril formation, a key step in scar formation. It also binds TGFβ1 to prevent myofibroblast transdifferentiation, evidenced by a significant reduction in both transcription and translation of collagen 1 and alpha smooth muscle actin. Iota carrageenan may be formulated as a microparticle suspension, to allow spraying for even coverage on hard‐to‐reach anatomical sites, like the oral mucosa. This formulation provides good lubrication, to reduce the shear forces that initiate the progressive oral scarring in EB. This study not only provides a novel therapy for fibrosis prevention, but also demonstrates the potential of self‐delivering immunomodulatory polysaccharides as a safe, cost‐effective, and stable platform, which can be more easily translated for clinical benefit.

Abstract Background Low back pain (LBP) is a common condition made up of a variety of anatomic and clinical subtypes. Lumbar disc herniation (LDH) and lumbar spinal stenosis (LSS) are two subtypes highly associated with LBP. Patients with LDH/LSS are often started with non-surgical treatments and if those are not effective then go on to have decompression surgery. However, recommendation of surgery is complicated as the outcome may depend on the patient’s health characteristics. We developed a deep learning (DL) model to predict decompression surgery for patients with LDH/LSS. Materials and method We used datasets of 8387 and 8620 patients from a prospective study that collected data from four healthcare systems to predict early (within 2 months) and late surgery (within 12 months after a 2 month gap), respectively. We developed a DL model to use patients’ demographics, diagnosis and procedure codes, drug names, and diagnostic imaging reports to predict surgery. For each prediction task, we evaluated the model’s performance using classical and generalizability evaluation. For classical evaluation, we split the data into training (80%) and testing (20%). For generalizability evaluation, we split the data based on the healthcare system. We used the area under the curve (AUC) to assess performance for each evaluation. We compared results to a benchmark model (i.e. LASSO logistic regression). Results For classical performance, the DL model outperformed the benchmark model for early surgery with an AUC of 0.725 compared to 0.597. For late surgery, the DL model outperformed the benchmark model with an AUC of 0.655 compared to 0.635. For generalizability performance, the DL model outperformed the benchmark model for early surgery. For late surgery, the benchmark model outperformed the DL model. Conclusions For early surgery, the DL model was preferred for classical and generalizability evaluation. However, for late surgery, the benchmark and DL model had comparable performance. Depending on the prediction task, the balance of performance may shift between DL and a conventional ML method. As a result, thorough assessment is needed to quantify the value of DL, a relatively computationally expensive, time-consuming and less interpretable method.

Abstract Background Multiple-period parallel group randomized trials (GRTs) analyzed with linear mixed models can represent time in mean models as continuous or categorical. If time is continuous, random effects are traditionally group- and member-level deviations from condition-specific slopes and intercepts and are referred to as random coefficients (RC) analytic models. If time is categorical, random effects are traditionally group- and member-level deviations from time-specific condition means and are referred to as repeated measures ANOVA (RM-ANOVA) analytic models. Longstanding guidance recommends the use of RC over RM-ANOVA for parallel GRTs with more than two periods because RC exhibited nominal type I error rates for both time parameterizations while RM-ANOVA exhibited inflated type I error rates when applied to data generated using the RC model. However, this recommendation was developed assuming a variance components covariance matrix for the RM-ANOVA, using only cross-sectional data, and explicitly modeling time × group variation. Left unanswered were how well RM-ANOVA with an unstructured covariance would perform on data generated according to the RC mechanism, if similar patterns would be observed in cohort data, and the impact of not modeling time × group variation if such variation was present in the data-generating model. Methods Continuous outcomes for cohort and cross-sectional parallel GRT data were simulated according to RM-ANOVA and RC mechanisms at five total time periods. All simulations assumed time × group variation. We varied the number of groups, group size, and intra-cluster correlation. Analytic models using RC, RM-ANOVA, RM-ANOVA with unstructured covariance, and a Saturated random effects structure were applied to the data. All analytic models specified time × group random effects. The analytic models were then reapplied without specifying random effects for time × group. Results Results indicated the RC and saturated analytic models maintained the nominal type I error rate in all data sets, RM-ANOVA with an unstructured covariance did not avoid type I error rate inflation when applied to cohort RC data, and analytic models omitting time-varying group random effects when such variation exists in the data were prone to substantial type I error inflation unless the residual error variance is high relative to the time × group variance. Conclusion The time × group RC and saturated analytic models are recommended as the default for multiple period parallel GRTs.