MIRACLE2 Score Compared With Downtime and Current Selection Criterion for Invasive Cardiovascular Therapies After OHCA.

BACKGROUND: The MIRACLE2 score is the only risk score that does not incorporate and can be used for selection of therapies after out-of-hospital cardiac arrest (OHCA). OBJECTIVES: This study sought to compare the discrimination performance of the MIRACLE2 score, downtime, and current randomized controlled trial (RCT) recruitment criteria in predicting poor neurologic outcome after out-of-hospital cardiac arrest (OHCA). METHODS: We used the EUCAR (European Cardiac Arrest Registry), a retrospective cohort from 6 centers (May 2012-September 2022). The primary outcome was poor neurologic outcome on hospital discharge (cerebral performance category 3-5). RESULTS: A total of 1,259 patients (total downtime = 25 minutes; IQR: 15-36 minutes) were included in the study. Poor outcome occurred in 41.8% with downtime <30 minutes and in 79.3% for those with downtime >30 minutes. In a multivariable logistic regression analysis, MIRACLE2 had a stronger association with outcome (OR: 2.23; 95% CI: 1.98-2.51; P < 0.0001) than zero flow (OR: 1.07; 95% CI: 1.01-1.13; P = 0.013), low flow (OR: 1.04; 95% CI: 0.99-1.09; P = 0.054), and total downtime (OR: 0.99; 95% CI: 0.95-1.03; P = 0.52). MIRACLE2 had substantially superior discrimination for the primary endpoint (AUC: 0.877; 95% CI: 0.854-0.897) than zero flow (AUC: 0.610; 95% CI: 0.577-0.642), low flow (AUC: 0.725; 95% CI: 0.695-0.754), and total downtime (AUC: 0.732; 95% CI: 0.701-0.760). For those modeled for exclusion from study recruitment, the positive predictive value of MIRACLE2 ≥5 for poor outcome was significantly higher (0.92) than the CULPRIT-SHOCK (Culprit lesion only PCI Versus Multivessel PCI in Cardiogenic Shock) (0.80), EUROSHOCK (Testing the value of Novel Strategy and Its Cost Efficacy In Order to Improve the Poor Outcomes in Cardiogenic Shock) (0.74) and ECLS-SHOCK (Extra-corporeal life support in Cardiogenic shock) criteria (0.81) (P < 0.001). CONCLUSIONS: The MIRACLE2 score has superior prediction of outcome after OHCA than downtime and higher discrimination of poor outcome than the current RCT recruitment criteria. The potential for the MIRACLE2 score to improve the selection of OHCA patients should be evaluated formally in future RCTs.

A Randomized Trial of Intravenous Iron Supplementation and Exercise on Exercise Capacity in Iron-Deficient Nonanemic Patients With CKD.

Introduction: Patients with chronic kidney disease (CKD) are often iron deficient, even when not anemic. This trial evaluated whether iron supplementation enhances exercise capacity of nonanemic patients with CKD who have iron-deficiency. Methods: Prospective, multicenter double-blind randomized controlled trial of nondialysis patients with CKD and iron-deficiency but without anemia (Hemoglobin [Hb] >110 g/l). Patients were assigned 1:1 to intravenous (IV) iron therapy, or placebo. An 8-week exercise program commenced at week 4. The primary outcome was the mean between-group difference in 6-minute walk test (6MWT) at 4 weeks. Secondary outcomes included 6MWT at 12 weeks, transferrin saturation (TSAT), serum ferritin (SF), Hb, renal function, muscle strength, functional capacity, quality of life, and adverse events at baseline, 4 weeks, and at 12 weeks. Mean between-group differences were analyzed using analysis of covariance models. Results: Among 75 randomized patients, mean (SD) age for iron therapy (n = 37) versus placebo (n = 38) was 54 (16) versus 61 (12) years; estimated glomerular filtration rate (eGFR) (34 [12] vs. 35 [11] ml/min per 1.73 m2], TSAT (23 [12] vs. 21 [6])%; SF (57 [64] vs. 62 [33]) µg/l; Hb (122.4 [9.2] vs. 127 [13.2] g/l); 6MWT (384 [95] vs. 469 [142] meters) at baseline, respectively. No significant mean between-group difference was observed in 6MWT distance at 4 weeks. There were significant increases in SF and TSAT at 4 and 12 weeks (P < 0.02), and Hb at 12 weeks (P = 0.009). There were no between-group differences in other secondary outcomes and no adverse events attributable to iron therapy. Conclusion: This trial did not demonstrate beneficial effects of IV iron therapy on exercise capacity at 4 weeks. A larger study is needed to confirm if IV iron is beneficial in nondialysis patients with CKD who are iron-deficient.

The Effectiveness and Cost-Effectiveness of a Universal Digital Parenting Intervention Designed and Implemented During the COVID-19 Pandemic: Evidence From a Rapid-Implementation Randomized Controlled Trial Within a Cohort.

BACKGROUND: Children's conduct and emotional problems increased during the COVID-19 pandemic. OBJECTIVE: We tested whether a smartphone parenting support app, Parent Positive, developed specifically for this purpose, reversed these effects in a cost-effective way. Parent Positive includes 3 zones. Parenting Boosters (zone 1) provided content adapted from standard face-to-face parent training programs to tackle 8 specific challenges identified by parents and parenting experts as particularly relevant for parents during the pandemic. The Parenting Exchange (zone 2) was a parent-to-parent and parent-to-expert communication forum. Parenting Resources (zone 3) provided access to existing high-quality web-based resources on a range of additional topics of value to parents (eg, neurodevelopmental problems, diet, and sleep). METHODS: Supporting Parents And Kids Through Lockdown Experiences (SPARKLE), a randomized controlled trial, was embedded in the UK-wide COVID-19: Supporting Parents, Adolescents and Children during Epidemics (Co-SPACE) longitudinal study on families' mental health during the pandemic. Parents of children aged 4 to 10 years were randomized 1:1 to Parent Positive or follow-up as usual (FAU) between May 19, 2021, and July 26, 2021. Parent Positive provided advice on common parenting challenges and evidence-based web-based resources and facilitated parent-to-parent and expert-to-parent support. Child conduct and emotional problems and family well-being were measured before randomization (T1) and at 1 (T2) and 2 (T3) months after randomization. Service use, costs, and adverse events were measured, along with app use and satisfaction. The primary outcome was T2 parent-reported child conduct problems, which were analyzed using linear mixed regression models. RESULTS: A total of 320 participants were randomized to Parent Positive, and 326 were randomized to FAU. The primary outcome analysis included 79.3% (512/646) of the participants (dropout: 84/320, 26% on Parent Positive and 50/326, 15% on FAU). There were no statistically significant intervention effects on conduct problems at either T2 (standardized effect=-0.01) or T3 (secondary outcome; standardized effect=-0.09) and no moderation by baseline conduct problems. Significant intervention-related reductions in emotional problems were observed at T2 and T3 (secondary outcomes; standardized effect=-0.13 in both cases). Parent Positive, relative to FAU, was associated with more parental worries at T3 (standardized effect=0.14). Few intervention-attributable adverse events were reported. Parent Positive was cost-effective once 4 outliers with extremely high health care costs were excluded. CONCLUSIONS: Parent Positive reduced child emotional problems and was cost-effective compared with FAU once outliers were removed. Although small when considered against targeted therapeutic interventions, the size of these effects was in line with trials of nontargeted universal mental health interventions. This highlights the public health potential of Parent Positive if implemented at the community level. Nevertheless, caution is required before making such an interpretation, and the findings need to be replicated in large-scale, whole-community studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04786080; https://clinicaltrials.gov/ct2/show/NCT04786080.

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study.

BACKGROUND: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αß, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. METHODS: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1-4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107-1×109 T4+ T-cells, administered without prior lymphodepletion. RESULTS: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. CONCLUSIONS: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

The HAVEN study-hydroxychloroquine in ANCA vasculitis evaluation-a multicentre, randomised, double-blind, placebo-controlled trial: study protocol and statistical analysis plan.

BACKGROUND: Patients with non-severe ANCA-associated vasculitis (AAV) are often prescribed immunosuppressive medications that are associated with severe side effects and a reduced quality of life. There is an unmet need for safer effective treatments for these patients. Hydroxychloroquine is being explored due to its effect in similar autoimmune conditions such as systemic lupus erythematosus. METHODS: Double-blind, placebo-controlled multicentre trial recruiting 76 patients across 20 sites. Participants will be randomised 1:1 to hydroxychloroquine or placebo in addition to standard of care immunosuppressive therapies over the course of 52 weeks. A phase II selection design will be used to determine hdroxychloroquine's efficacy, using prednisolone dosage and Birmingham Vasculitis Activity Score as a measure of disease activity. Secondary outcomes will explore other elements of AAV progression, including disease flares and time to remission. DISCUSSION: This trial aims to explore Hydroxychloroquine as a treatment for patients with AAV. If effective, the need for immunosuppressive treatments such as prednisolone could be reduced. Hydroxychloroquine is safer, cheaper and has fewer adverse effects than conventional immunosuppressive treatments. This could improve patient outcomes while saving money for the NHS. TRIAL REGISTRATION: ISRCTN: ISRCTN79334891. Registered 07 June 2021. EudraCT: 2018-001268-40. Registered 13 September 2019. CLINICALTRIALS: gov: NCT04316494. Registered 20 March 2020.

The effect of intravenous iron supplementation on exercise capacity in iron-deficient but not anaemic patients with chronic kidney disease: study design and baseline data for a multicentre prospective double-blind randomised controlled trial.

BACKGROUND: Many people living with chronic kidney disease (CKD) are iron deficient, even though they may not be anaemic. The Iron and Muscle study aims to evaluate whether iron supplementation reduces symptoms of fatigue, improves muscle metabolism, and leads to enhanced exercise capacity and physical function. We report here the trial design and baseline characteristics. METHODS: This is a prospective, double-blind multicentre randomised controlled trial (RCT) including 75 non-dialysis stage 3-4 CKD patients with iron deficiency but without anaemia. Patients were randomly (1:1) assigned to either: i) intravenous iron therapy, or ii) placebo, with concurrent recruitment of eight CKD non-iron deficient participants and six healthy volunteers. The primary outcome of the study is the six-minute walk test (6MWT) distance between baseline and four-weeks. An additional exercise training programme for patients in both groups was initiated and completed between 4 and 12 weeks, to determine the effect of iron repletion compared to placebo treatment in the context of patients undertaking an exercise programme. Additional secondary outcomes include fatigue, physical function, muscle strength, muscle metabolism, quality of life, resting blood pressure, clinical chemistry, safety and harms associated with the iron therapy intervention and the exercise training intervention, and hospitalisations. All outcomes were conducted at baseline, 4, and 12 weeks, with a nested qualitative study, to investigate the experience of living with iron deficiency and intervention acceptability. The cohort have been recruited and baseline assessments undertaken. RESULTS: Seventy-five individuals were recruited. 44% of the randomised cohort were male, the mean (SD) age was 58 (14) years, and 56% were White. Body mass index was 31 (7) kg/m2; serum ferritin was 59 (45) µg/L, transferrin saturation was 22 (10) %, and haemoglobin was 125 (12) g/L at randomisation for the whole group. Estimated glomerular filtration rate was 35 (12) mL/min/1.73 m2 and the baseline 6MWT distance was 429 (174) m. CONCLUSION: The results from this study will address a substantial knowledge gap in the effects of intravenous iron therapy, and offer potential clinical treatment options, to improve exercise capacity, physical function, fatigue, and muscle metabolism, for non-dialysis patients with CKD who are iron-deficient but not anaemic. It will also offer insight into the potential novel effects of an 8-week exercise training programme. TRIAL REGISTRATION: EudraCT: 2018-000,144-25 Registered 28/01/2019.

MIRACLE2 Score and SCAI Grade to Identify Patients With Out-of-Hospital Cardiac Arrest for Immediate Coronary Angiography.

OBJECTIVES: The purpose of this study was to evaluate the impact of performing immediate coronary angiography (CAG) after out-of-hospital cardiac arrest (OHCA) with stratification of predicted neurologic injury and cardiogenic shock on arrival to a center. BACKGROUND: The role of immediate CAG for patients with OHCA is unclear, which may in part be explained by the majority of patients dying of hypoxic brain injury. METHODS: Between May 2012 and July 2020, patients from 5 European centers were included in the EUCAR (European Cardiac Arrest Registry). Patients were retrospectively classified into low vs high neurologic risk (MIRACLE2 score 0-3 vs ≥4) and degree of cardiogenic shock on arrival (Society for Cardiovascular Angiography and Interventions [SCAI] grade A vs B-E). A multivariable logistic regression analysis including immediate CAG was performed for the primary outcome of survival with good neurologic outcome (Cerebral Performance Category 1 or 2) at hospital discharge. RESULTS: Nine hundred twenty-six patients were included in the registry, with 405 (43.7%) in the low-risk group and 521 (56.3%) in the high-risk group. Immediate CAG was independently associated with improved survival with good neurologic outcome in the low MIRACLE2 risk group with ST-segment elevation myocardial infarction (OR: 11.80; 95% CI: 2.24-76.74; P = 0.048) and with SCAI grade B to E shock (OR: 3.23; 95% CI: 1.10-9.50; P = 0.031). No subgroups, including those with ST-segment elevation myocardial infarction and with SCAI grade B to E shock, achieved any benefit from early CAG in the high MIRACLE2 group. CONCLUSIONS: Combined classification of patients with OHCA with 12-lead electrocardiography, MIRACLE2 score 0 to 3, and SCAI grade B to E identifies a potential cohort of patients at low risk for neurologic injury who benefit most from immediate CAG.

Healthy Eating and Active Lifestyles for Diabetes (HEAL-D), a culturally tailored self-management education and support program for type 2 diabetes in black-British adults: a randomized controlled feasibility trial.

INTRODUCTION: Black-British communities are disproportionately affected by type 2 diabetes (T2D). Structured education programs are a core component of T2D healthcare but they are less successful in people from minority ethnic groups. Culturally tailored T2D education has demonstrated greater benefits than usual care. The aim of our study was to evaluate acceptability, fidelity and trial feasibility of the Healthy Eating and Active Lifestyles for Diabetes ('HEAL-D') culturally tailored T2D self-management education and support (DSMES) program. RESEARCH DESIGN AND METHODS: A mixed-methods randomized controlled feasibility trial in black-British adults with T2D was conducted. Participants were assigned to control (usual care) or intervention (HEAL-D; 7 sessions, 14 hours of group-based culturally tailored diet and lifestyle education, behavior change support and supervised physical activity), in a ratio of 1:1. Primary outcomes were recruitment and retention rates, intervention attendance and completion. Fidelity was assessed through observations and qualitative evaluation was undertaken with participants and educators. RESULTS: 102 patients responded to invitation letters (n=1335); 63 were randomized but 8 were subsequently deemed ineligible due to high baseline glycosylated hemoglogin (HbA1c) requiring intensive medical management or missing baseline HbA1c measurement. Of the remaining 55 participants (27 intervention, 28 control), 69% were female, 47% were of African and 51% were of Caribbean ethnicity. 93% completed the trial, providing end point data. Intervention attendance was high; 85% completed the program (attendance at ≥5 sessions), and 74% attended ≥6 sessions. The intervention was delivered with acceptable fidelity, although the qualitative evaluations identified some areas of structure and format in need of refinement. CONCLUSIONS: We have shown it is feasible to recruit and randomize black-British adults with T2D to a trial of a culturally tailored DSMES program. We have shown the intervention is highly acceptable for both patients and healthcare providers. A future trial should assess clinical and cost-effectiveness of HEAL-D. TRIAL REGISTRATION NUMBER: NCT03531177.

Alcohol use, cigarette smoking, vaping and number of sexual partners: A cross-sectional study of sexually active, ethnically diverse, inner city adolescents.

CONTEXT: There are few UK data on the prevalence and clustering of risky behaviours in ethnically diverse adolescents. OBJECTIVES: To investigate the prevalence of reported alcohol use, smoking and vaping, and explore whether these behaviours are associated with increased numbers of sexual partners. DESIGN: Questionnaire survey of 'Test n Treat' chlamydia screening trial participants. SETTING AND PARTICIPANTS: Sexually active students attending six London technical colleges completed confidential questionnaires and provided genitourinary samples. RESULTS: The median age of the 509 participants was 17 years (IQR: 16-18), 47% were male, 50% were of black ethnicity, 55% reported ≥2 sexual partners in the past year (67% of males and 45% of females) and 6.2% had chlamydia infection and 0.6% gonorrhoea. Almost half (48%) reported getting drunk in the past month, 33% smoked cigarettes and 7% had ever vaped. A larger percentage of students with ≥2 sexual partners than 0-1 partners reported getting drunk in the past month (53.7%, 144/268% versus 42.2% 94/223, adjusted prevalence ratio: 1.33, 95% confidence interval: 1.11-1.61) and smoking cigarettes (36.6%, 100/273% versus 30.2%, 67/222, 1.34 (1.05-1.70)). By contrast, multiple sexual partners were not associated with vaping or chlamydia infection, but numbers were small. CONCLUSIONS: We found high prevalences of risky behaviour and an association between multiple sexual partners and smoking and/or getting drunk. Findings support the introduction of compulsory sex and relationship education in UK secondary schools, including information about the adverse effects of alcohol and smoking. PUBLIC CONTRIBUTION: Participants helped with study design, conduct and interpretation.

Human papillomavirus (HPV) vaccination and oropharyngeal HPV in ethnically diverse, sexually active adolescents: community-based cross-sectional study.

OBJECTIVES: Oropharyngeal squamous cell carcinoma is the most common human papillomavirus (HPV)-associated cancer in the UK, but little is known about the prevalence of oropharyngeal HPV in sexually active teenagers. We investigated reported HPV vaccination coverage (in females) and prevalence of oropharyngeal HPV in sexually active students attending six technical colleges in London, UK. METHODS: In 2017, we obtained mouthwash samples and questionnaires from male and female students taking part in the 'Test n Treat' chlamydia screening trial. Samples were subjected to HPV genotyping. RESULTS: Of 232 participants approached, 202 (87%) provided a mouthwash sample and questionnaire. Participants' median age was 17 years and 47% were male. Most (73%) were from black and minority ethnic groups, 64% gave a history of oral sex, 52% reported having a new sexual partner in the past 6 months, 33% smoked cigarettes, 5.9% had concurrent genitourinary Chlamydia trachomatis infection and 1.5% Neisseria gonorrhoeae and 5.0% were gay or bisexual. Only 47% (50/107) of females reported being vaccinated against HPV 16/18, of whom 74% had received ≥2 injections. HPV genotyping showed three mouthwash samples (1.5%, 95% CI 0.3% to 4.3%) were positive for possible high-risk human papillomavirus (HR-HPV), one (0.5%, 0.0% to 2.7%) for low-risk HPV 6/11, but none (0.0%, 0.0% to 1.8%) for HR-HPV. Four samples (2.0%, 0.5% to 5.0%) were positive for HPV16 using a HPV16 type-specific quantitative PCR, but these were at a very low copy number and considered essentially negative. CONCLUSIONS: Despite the high prevalence of oral sex and genitourinary chlamydia and low prevalence of HPV vaccination, the prevalence of oropharyngeal HR-HPV in these adolescents was negligible.

A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE2.

AIMS: The purpose of this study was to develop a practical risk score to predict poor neurological outcome after out-of-hospital cardiac arrest (OOHCA) for use on arrival to a Heart Attack Centre. METHODS AND RESULTS: From May 2012 to December 2017, 1055 patients had OOHCA in our region, of whom 373 patients were included in the King's Out of Hospital Cardiac Arrest Registry (KOCAR). We performed prediction modelling with multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was externally validated in two independent cohorts comprising 473 patients. The primary endpoint was poor neurological outcome at 6-month follow-up (Cerebral Performance Category 3-5). Seven independent predictors of outcome were identified: missed (unwitnessed) arrest, initial non-shockable rhythm, non-reactivity of pupils, age (60-80 years-1 point; >80 years-3 points), changing intra-arrest rhythms, low pH <7.20, and epinephrine administration (2 points). The MIRACLE2 score had an area under the curve (AUC) of 0.90 in the development and 0.84/0.91 in the validation cohorts. Three risk groups were defined-low risk (MIRACLE2 ≤2-5.6% risk of poor outcome); intermediate risk (MIRACLE2 of 3-4-55.4% of poor outcome); and high risk (MIRACLE2 ≥5-92.3% risk of poor outcome). The MIRACLE2 score had superior discrimination than the OHCA [median AUC 0.83 (0.818-0.840); P < 0.001] and Cardiac Arrest Hospital Prognosis models [median AUC 0.87 (0.860-0.870; P = 0.001] and equivalent performance with the Target Temperature Management score [median AUC 0.88 (0.876-0.887); P = 0.092]. CONCLUSIONS: The MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on admission.

Comparing Factors Related to Any Conventional Cigarette Smokers, Exclusive New Alternative Product Users, and Non-Users among Japanese Youth: A Nationwide Survey.

The impact of heated-tobacco-products (HTPs) and electronic cigarettes (e-cigarettes) on youth is a controversial public health issue, as it is unknown whether alternative products result in more youth using such products or smoking. In Japan, e-cigarettes with nicotine are prohibited, but e-cigarettes without nicotine are available. HTPs are marketed as tobacco products. Within this unique context, we aimed to compare any conventional cigarette smokers (including those who also used alternative products) with exclusive users of alternative products and examine factors relating to their use in Japan. In 2017, 22,275 students in grades 7-9 (age 12-15) and 42,142 in grades 10-12 (age 15-18) nationwide were surveyed. Overall, 1.8% were current users of any of the three products over the last month. Multivariable analysis revealed that risk factors for alternative product use were the same as those for cigarette use. Among all users, exclusive new product users were more likely to participate in club activities and intend to continue to higher education; any conventional cigarette users (including those who also used alternative products) were more likely to be exposed to secondhand smoke at home and to drink alcohol. Reducing adult smoking and disseminating health education remain relevant as strategies for preventing adolescents' future tobacco use.