Effect of Triple Therapy on Cardiovascular and Severe Cardiopulmonary Events in COPD: A Post-hoc Analysis of a Randomized, Double-Blind, Phase 3 Clinical Trial (ETHOS).

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular and cardiopulmonary events. In the Phase III, 52-week ETHOS trial (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) reduced rates of moderate/severe exacerbations and all-cause mortality versus dual therapy with glycopyrrolate/formoterol fumarate (GFF) or budesonide/formoterol fumarate (BFF). However, the effect of BGF on cardiovascular events versus GFF remains unevaluated. Further, the effect of BGF on time to first severe exacerbation has not been reported. Objective: Assess the effects of BGF 320/18/9.6 µg (BGF 320) and other ICS-containing arms on cardiovascular and severe cardiopulmonary endpoints versus GFF in patients with COPD from ETHOS. Methods: Patients with moderate-to-very severe COPD and a history of exacerbations were randomized to twice-daily BGF 320, BGF 160/18/9.6 µg, BFF 320/9.6 µg, or GFF 18/9.6 µg (GFF). Time to first severe COPD exacerbation was a pre-specified endpoint; post-hoc cardiovascular and severe cardiopulmonary endpoints included time to first major adverse cardiac event (MACE), time to first cardiovascular adverse event (AE) of special interest (CVAESI), time to first cardiac AE, and time to the composite endpoint of first severe cardiopulmonary event. Measurements and Main Results: BGF 320 reduced the rate of first occurrence (hazard ratio [95% confidence interval]) of cardiovascular and severe cardiopulmonary events versus GFF, including for CVAESI (0.63 [0.48, 0.82]), cardiac AE (0.60 [0.48, 0.76]), and severe cardiopulmonary event (0.80 [0.67, 0.95]). Conclusions: BGF had a benefit on cardiovascular endpoints and severe cardiopulmonary events versus GFF in patients with moderate-to-very severe COPD.

Sudden cardiac death after myocardial infarction: individual participant data from pooled cohorts.

BACKGROUND AND AIMS: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation. METHODS: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis. RESULTS: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor. CONCLUSIONS: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors.

Health outcomes after myocardial infarction: A population study of 56 million people in England.

BACKGROUND: The occurrence of a range of health outcomes following myocardial infarction (MI) is unknown. Therefore, this study aimed to determine the long-term risk of major health outcomes following MI and generate sociodemographic stratified risk charts in order to inform care recommendations in the post-MI period and underpin shared decision making. METHODS AND FINDINGS: This nationwide cohort study includes all individuals aged ≥18 years admitted to one of 229 National Health Service (NHS) Trusts in England between 1 January 2008 and 31 January 2017 (final follow-up 27 March 2017). We analysed 11 non-fatal health outcomes (subsequent MI and first hospitalisation for heart failure, atrial fibrillation, cerebrovascular disease, peripheral arterial disease, severe bleeding, renal failure, diabetes mellitus, dementia, depression, and cancer) and all-cause mortality. Of the 55,619,430 population of England, 34,116,257 individuals contributing to 145,912,852 hospitalisations were included (mean age 41.7 years (standard deviation [SD 26.1]); n = 14,747,198 (44.2%) male). There were 433,361 individuals with MI (mean age 67.4 years [SD 14.4)]; n = 283,742 (65.5%) male). Following MI, all-cause mortality was the most frequent event (adjusted cumulative incidence at 9 years 37.8% (95% confidence interval [CI] [37.6,37.9]), followed by heart failure (29.6%; 95% CI [29.4,29.7]), renal failure (27.2%; 95% CI [27.0,27.4]), atrial fibrillation (22.3%; 95% CI [22.2,22.5]), severe bleeding (19.0%; 95% CI [18.8,19.1]), diabetes (17.0%; 95% CI [16.9,17.1]), cancer (13.5%; 95% CI [13.3,13.6]), cerebrovascular disease (12.5%; 95% CI [12.4,12.7]), depression (8.9%; 95% CI [8.7,9.0]), dementia (7.8%; 95% CI [7.7,7.9]), subsequent MI (7.1%; 95% CI [7.0,7.2]), and peripheral arterial disease (6.5%; 95% CI [6.4,6.6]). Compared with a risk-set matched population of 2,001,310 individuals, first hospitalisation of all non-fatal health outcomes were increased after MI, except for dementia (adjusted hazard ratio [aHR] 1.01; 95% CI [0.99,1.02];p = 0.468) and cancer (aHR 0.56; 95% CI [0.56,0.57];p < 0.001). The study includes data from secondary care only-as such diagnoses made outside of secondary care may have been missed leading to the potential underestimation of the total burden of disease following MI. CONCLUSIONS: In this study, up to a third of patients with MI developed heart failure or renal failure, 7% had another MI, and 38% died within 9 years (compared with 35% deaths among matched individuals). The incidence of all health outcomes, except dementia and cancer, was higher than expected during the normal life course without MI following adjustment for age, sex, year, and socioeconomic deprivation. Efforts targeted to prevent or limit the accrual of chronic, multisystem disease states following MI are needed and should be guided by the demographic-specific risk charts derived in this study.

Risk calculator for incident atrial fibrillation across a range of prediction horizons.

BACKGROUND: The increasing burden of atrial fibrillation (AF) emphasizes the need to identify high-risk individuals for enrolment in clinical trials of AF screening and primary prevention. We aimed to develop prediction models to identify individuals at high-risk of AF across prediction horizons from 6-months to 10-years. METHODS: We used secondary-care linked primary care electronic health record data from individuals aged ≥30 years without known AF in the UK Clinical Practice Research Datalink-GOLD dataset between January 2, 1998 and November 30, 2018; randomly divided into derivation (80%) and validation (20%) datasets. Models were derived using logistic regression from known AF risk factors for incident AF in prediction periods of 6 months, 1-year, 2-years, 5-years, and 10-years. Performance was evaluated using in the validation dataset with bootstrap validation with 200 samples, and compared against the CHA2DS2-VASc and C2HEST scores. RESULTS: Of 2,081,139 individuals in the cohort (1,664,911 in the development dataset, 416,228 in the validation dataset), the mean age was 49.9 (SD 15.4), 50.7% were women, and 86.7% were white. New cases of AF were 7,386 (0.4%) within 6 months, 15,349 (0.7%) in 1 year, 38,487 (1.8%) in 5 years, and 79,997 (3.8%) by 10 years. Valvular heart disease and heart failure were the strongest predictors, and association of hypertension with AF increased at longer prediction horizons. The optimal risk models incorporated age, sex, ethnicity, and 8 comorbidities. The models demonstrated good-to-excellent discrimination and strong calibration across prediction horizons (AUROC, 95%CI, calibration slope: 6-months, 0.803, 0.789-0.821, 0.952; 1-year, 0.807, 0.794-0.819, 0.962; 2-years, 0.815, 0.807-0.823, 0.973; 5-years, 0.807, 0.803-0.812, 1.000; 10-years 0.780, 0.777-0.784, 1.010), and superior to the CHA2DS2-VASc and C2HEST scores. The models are available as a web-based FIND-AF calculator. CONCLUSIONS: The FIND-AF models demonstrate high discrimination and calibration across short- and long-term prediction horizons in 2 million individuals. Their utility to inform trial enrolment and clinical decisions for AF screening and primary prevention requires further study.

Risk factors for infection and outcomes in infants with neonatal encephalopathy: a cohort study.

BACKGROUND: To determine the association between early infection risk factors and short-term outcomes in infants with neonatal encephalopathy following perinatal asphyxia (NE). METHODS: A retrospective population-based cohort study utilizing the National Neonatal Research Database that included infants with NE admitted to neonatal units in England and Wales, Jan 2008-Feb 2018. EXPOSURE: one or more of rupture of membranes >18 h, maternal group B streptococcus colonization, chorioamnionitis, maternal pyrexia or antepartum antibiotics. PRIMARY OUTCOME: death or nasogastric feeds/nil by mouth (NG/NBM) at discharge. SECONDARY OUTCOMES: organ dysfunction; length of stay; intraventricular hemorrhage; antiseizure medications use. RESULTS: 998 (13.7%) out of 7265 NE infants had exposure to early infection risk factors. Primary outcome (20.3% vs. 23.1%, OR 0.87 (95% CI 0.71-1.08), p = 0.22), death (12.8% vs. 14.0%, p = 0.32) and NG/NBM (17.4% vs. 19.9%. p = 0.07) did not differ between the exposed and unexposed group. Time to full sucking feeds (OR 0.81 (0.69-0.95)), duration (OR 0.82 (0.71-0.95)) and the number of antiseizure medications (OR 0.84 (0.72-0.98)) were lower in exposed than unexposed infants after adjusting for confounders. Therapeutic hypothermia did not alter the results. CONCLUSIONS: Infants with NE exposed to risk factors for early-onset infection did not have worse short-term adverse outcomes. IMPACT: Risk factors for early-onset neonatal infection, including rupture of membranes >18 h, maternal group B streptococcus colonization, chorioamnionitis, maternal pyrexia or antepartum antibiotics, were not associated with death or short-term morbidity after cooling for NE. Despite exposure to risk factors for early-onset neonatal infection, infants with NE reached oral feeds earlier and needed fewer anti-seizure medications for a shorter duration than infants with NE but without such risk factors. This study supports current provision of therapeutic hypothermia for infants with NE and any risk factors for early-onset neonatal infection.

Antenatal and neonatal exposure to SARS-CoV-2 and children's development: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review of the impact of antenatal and neonatal exposure to SARS-CoV-2 on developmental outcomes in preterm and term-born infants. METHODS: We searched Embase, Emcare, MEDLINE, PsycINFO, Web of Science and grey literature on May 27, 2022 and updated on May 8, 2023. Studies defining exposure with a positive SARS-CoV-2 protein or genetic material, used a contemporaneous non-exposed cohort, and reported developmental outcomes up to 2 years of age were included. RESULTS: Four out of 828 screened studies were included. Meta-analysis included 815 infants screened for developmental delay (n = 306 exposed; n = 509 non-exposed) between 3- and 11-months of age. Among term-born infants, we did not find an increased risk of delay in communication (odd's ratio: 0.73 (95% CI: 0.24-2.24)), gross motor (1.50 (0.62, 3.62)), fine motor (2.90 (0.58, 14.43)), problem-solving (1.19 (0.54, 2.66)) or personal-social development (1.93 (0.78, 4.75)) in exposed infants. The number of preterm-born infants in the exposed (n = 37) and comparison cohorts (n = 41) were too few to report meaningful comparisons. CONCLUSION: Evidence regarding the potential impact of antenatal or neonatal exposure to SARS-CoV-2 infection on developmental outcomes in early infancy is limited and inconsistent. Larger cohorts with outcomes beyond the first year of life are needed. IMPACT: The current evidence examining associations between SARS-CoV-2 exposure during the neonatal period and developmental outcomes in infancy is limited by there being few studies with extremely small sample sizes. Based on sparse data there was no consistent association between antenatal or neonatal exposure to SARS-CoV-2 infection and an adverse impact on developmental outcomes below 12 months of age for babies born preterm or at term. This study highlights that larger cohorts with outcomes assessed beyond the first year are needed to determine the potential longer-term impact of SARS-CoV-2 infection exposure on child development.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

BACKGROUND: 'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modified Delphi approach to form a consensus definition for NE, and diagnostic criteria. METHODS: Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. DISCUSSION: A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modified Delphi technique, will enable more comparability of research results and improved communication among professionals and with families. IMPACT: The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Design and deployment of the STEEER-AF trial to evaluate and improve guideline adherence: a cluster-randomized trial by the European Society of Cardiology and European Heart Rhythm Association.

AIMS: The aim is to describe the rationale, design, delivery, and baseline characteristics of the Stroke prevention and rhythm control Treatment: Evaluation of an Educational programme of the European society of cardiology in a cluster-Randomized trial in patients with Atrial Fibrillation (STEEER-AF) trial. METHODS AND RESULTS: STEEER-AF is a pragmatic trial designed to objectively and robustly determine whether guidelines are adhered to in routine practice and evaluate a targeted educational programme for healthcare professionals. Seventy centres were randomized in six countries (France, Germany, Italy, Poland, Spain, and UK; 2022-23). The STEEER-AF centres recruited 1732 patients with a diagnosis of atrial fibrillation (AF), with a mean age of 68.9 years (SD 11.7), CHA2DS2-VASc score of 3.2 (SD 1.8), and 647 (37%) women. Eight hundred and forty-three patients (49%) were in AF at enrolment and 760 (44%) in sinus rhythm. Oral anticoagulant therapy was prescribed in 1543 patients (89%), with the majority receiving direct oral anticoagulants (1378; 89%). Previous cardioversion, antiarrhythmic drug therapy, or ablation was recorded in 836 patients (48.3%). Five hundred fifty-one patients (31.8%) were currently receiving an antiarrhythmic drug, and 446 (25.8%) were scheduled to receive a future cardioversion or ablation. The educational programme engaged 195 healthcare professionals across centres randomized to the intervention group, consisting of bespoke interactive online learning and reinforcement activities, supported by national expert trainers. CONCLUSION: The STEEER-AF trial was successfully deployed across six European countries to investigate guideline adherence in real-world practice and evaluate if a structured educational programme for healthcare professionals can improve patient-level care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04396418.

Maternal and neonatal outcomes among spontaneous vaginal births occurring in or out of water following intrapartum water immersion: The POOL cohort study.

OBJECTIVE: Warm water immersion during labour provides women with analgesia and comfort. This cohort study aimed to establish among women using intrapartum water immersion analgesia, without antenatal or intrapartum risk factors, whether waterbirth is as safe for them and their babies as leaving the water before birth. DESIGN: Cohort study with non-inferiority design. SETTING: Twenty-six UK NHS maternity services. SAMPLE: A total of 73 229 women without antenatal or intrapartum risk factors, using intrapartum water immersion, between 1 January 2015 and 30 June 2022. The analysis excluded 12 827 (17.5%) women who received obstetric or anaesthetic interventions before birth. METHODS: Non-inferiority analysis of retrospective and prospective data captured in NHS maternity and neonatal information systems. MAIN OUTCOME MEASURES: Maternal primary outcome: obstetric anal sphincter injury (OASI) by parity; neonatal composite primary outcome: fetal or neonatal death, neonatal unit admission with respiratory support or administration of antibiotics within 48 hours of birth. RESULTS: Rates of the primary outcomes were no higher among waterbirths compared with births out of water: rates of OASI among nulliparous women (waterbirth: 730/15 176 [4.8%] versus births out of water: 641/12 210 [5.3%]; adjusted odds ratio [aOR] 0.97, one-sided 95% CI, -∞ to 1.08); rates of OASI among parous women (waterbirth: 269/24 451 [1.1%] versus births out of water 144/8565 [1.7%]; aOR 0.64, one-sided 95% CI -∞ to 0.78) and rates of the composite adverse outcome among babies (waterbirth 263/9868 [2.7%] versus births out of water 224/5078 [4.4%]; aOR 0.65, one-sided 95% CI -∞ to 0.79). CONCLUSION: Among women using water immersion during labour, remaining in the pool and giving birth in water was not associated with an increase in the incidence of adverse primary maternal or neonatal outcomes.

Childhood outcomes after low-grade intraventricular haemorrhage: A systematic review and meta-analysis.

AIM: To undertake a systematic review and meta-analysis exploring school-age neurodevelopmental outcomes of children after low-grade intraventricular haemorrhage (IVH). METHOD: The published and grey literature was extensively searched to identify observational comparative studies exploring neurodevelopmental outcomes after IVH grades 1 and 2. Our primary outcome was neurodevelopmental impairment after 5 years of age, which included cognitive, motor, speech and language, behavioural, hearing, or visual impairments. RESULTS: This review included 12 studies and over 2036 infants born preterm with low grade IVH. Studies used 30 different neurodevelopmental tools to determine outcomes. There was conflicting evidence of the composite risk of neurodevelopmental impairment after low-grade IVH. There was evidence of an association between low-grade IVH and lower IQ at school age (-4.23, 95% confidence interval [CI] -7.53, -0.92, I2 = 0%) but impact on school performance was unclear. Studies reported an increased crude risk of cerebral palsy after low-grade IVH (odds ratio [OR] 2.92, 95% CI 1.95, 4.37, I2 = 41%). No increased risk of speech and language impairment or behavioural impairment was found. Few studies addressed hearing and visual impairment. INTERPRETATION: This systematic review presents evidence that low-grade IVH is associated with specific neurodevelopmental impairments at school age, lending support to the theory that low-grade IVH is not a benign condition. WHAT THIS PAPER ADDS: The functional impact of low-grade intraventricular haemorrhage (IVH) at school age is unknown. Low-grade IVH is associated with a lower IQ at school age. The risk of cerebral palsy is increased after low-grade IVH. Low-grade IVH is not associated with speech and language impairment.

Presentation, care, coronary intervention and outcomes of patients with NSTEMI according to age: insights from the international prospective ACVC-EAPCI EORP NSTEMI registry.

BACKGROUND: Older people less frequently receive invasive coronary angiography (ICA) for NSTEMI than younger patients. We describe care, ICA data, and in-hospital and 30-day outcomes of NSTEMI by age in a contemporary and geographically diverse cohort. METHODS: Prospective cohort study including 2947 patients with NSTEMI from 287 centres in 59 countries, stratified by age (≥75 years, n = 761). Quality of care was evaluated based on 12 guideline-recommended care interventions, and data collected on ICA. Outcomes included in hospital acute heart failure, cardiogenic shock, repeat myocardial infarction, stroke/transient ischaemic attack, BARC Type ≥3 bleeding and death, as well as 30-day mortality. RESULTS: Patients aged ≥75 years, compared with younger patients, at presentation had a higher prevalence of comorbidities and oral anticoagulation prescription (22.4% vs 7.6%, p < 0.001). Older patients less frequently received ICA than younger patients (78.6% vs 90.6%, p < 0.001) with the recorded reason more often being advanced age, comorbidities or frailty. Of those who underwent ICA, older patients more frequently demonstrated 3-vessel, 4-vessel and/or left main stem coronary artery disease compared to younger patients (49.7% vs 34.1%, p < 0.001) but less frequently received revascularisation (63.6% vs 76.9%, p < 0.001). Older patients experienced higher rates of in-hospital acute heart failure (15.0% vs 8.4%, p < 0.001) and bleeding (2.8% vs 1.3%, p = 0.006), as well as in-hospital and 30-day mortality (3.4% vs 1.3%, p < 0.001; 4.8% vs 1.7%, p < 0.001; respectively), than younger patients. CONCLUSIONS: Patients aged ≥75 years with NSTEMI, compared with younger patients, less frequently received ICA and guideline-recommended care, and had worse short-term outcomes.

Factors associated with posttraumatic stress and anxiety among the parents of babies admitted to neonatal care: a systematic review.

BACKGROUND: Posttraumatic stress (PTS) and anxiety are common mental health problems among parents of babies admitted to a neonatal unit (NNU). This review aimed to identify sociodemographic, pregnancy and birth, and psychological factors associated with PTS and anxiety in this population. METHOD: Studies published up to December 2022 were retrieved by searching Medline, Embase, PsychoINFO, Cumulative Index to Nursing and Allied Health electronic databases. The modified Newcastle-Ottawa Scale for cohort and cross-sectional studies was used to assess the methodological quality of included studies. This review was pre-registered in PROSPERO (CRD42021270526). RESULTS: Forty-nine studies involving 8,447 parents were included; 18 studies examined factors for PTS, 24 for anxiety and 7 for both. Only one study of anxiety factors was deemed to be of good quality. Studies generally included a small sample size and were methodologically heterogeneous. Pooling of data was not feasible. Previous history of mental health problems (four studies) and parental perception of more severe infant illness (five studies) were associated with increased risk of PTS, and had the strongest evidence. Shorter gestational age (≤ 33 weeks) was associated with an increased risk of anxiety (three studies) and very low birth weight (< 1000g) was associated with an increased risk of both PTS and anxiety (one study). Stress related to the NNU environment was associated with both PTS (one study) and anxiety (two studies), and limited data suggested that early engagement in infant's care (one study), efficient parent-staff communication (one study), adequate social support (two studies) and positive coping mechanisms (one study) may be protective factors for both PTS and anxiety. Perinatal anxiety, depression and PTS were all highly comorbid conditions (as with the general population) and the existence of one mental health condition was a risk factor for others. CONCLUSION: Heterogeneity limits the interpretation of findings. Until clearer evidence is available on which parents are most at risk, good communication with parents and universal screening of PTS and anxiety for all parents whose babies are admitted to NNU is needed to identify those parents who may benefit most from mental health interventions.

Implementing a Medicines at Transitions Intervention (MaTI) for patients with heart failure: a process evaluation of the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) cluster randomised controlled trial.

BACKGROUND: Heart failure is a major global health challenge incurring a high rate of mortality, morbidity and hospitalisation. Effective medicines management at the time of hospital discharge into the community could reduce poor outcomes for people with heart failure. Within the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) programme, the Medicines at Transitions Intervention (MaTI) was co-designed to improve such transitions, with a cluster randomised controlled trial to test effectiveness. The MaTI includes a patient toolkit and transfer of discharge medicines information to community pharmacy. This paper aims to determine the degree to which the intervention was delivered, and identify barriers and facilitators experienced by staff for the successful implementation of the intervention. METHODS: The study was conducted in six purposively selected intervention sites. A mixed-methods design was employed using hospital staff interviews, structured and unstructured ward observations, and routine trial data about adherence to the MaTI. A parallel mixed analysis was applied. Qualitative data were analysed thematically using the Framework method. Data were synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research (CFIR). RESULTS: With limited routines of communication between ward staff and community pharmacy, hospital staff found implementing community pharmacy-related steps of the intervention challenging. Staff time was depleted by attempts to bridge system barriers, sometimes leading to steps not being delivered. Whilst the introduction of the patient toolkit was often completed and valued as important patient education and a helpful way to explain medicines, the medicines discharge log within it was not, as this was seen as a duplication of existing systems. Within the CFIR the most applicable constructs were identified as 'intervention complexity' and 'cosmopolitanism' based on how well hospitals were networked with community pharmacies, and the availability of hospital resources to facilitate this. CONCLUSION: The MaTI was generally successfully implemented, particularly the introduction of the toolkit. However, implementation involving community pharmacy was more challenging and more effective communication systems are needed to support wider implementation. TRIAL REGISTRATION: 11/04/2018 ISRCTN66212970. https://www.isrctn.com/ISRCTN66212970 .

Temporal trends of cause-specific mortality after diagnosis of atrial fibrillation.

BACKGROUND AND AIMS: Reports of outcomes after atrial fibrillation (AF) diagnosis are conflicting. The aim of this study was to investigate mortality and hospitalization rates following AF diagnosis over time, by cause and by patient features. METHODS: Individuals aged ≥16 years with a first diagnosis of AF were identified from the UK Clinical Practice Research Datalink-GOLD dataset from 1 January 2001, to 31 December 2017. The primary outcomes were all-cause and cause-specific mortality and hospitalization at 1 year following diagnosis. Poisson regression was used to calculate rate ratios (RRs) for mortality and incidence RRs (IRRs) for hospitalization and 95% confidence intervals (CIs) comparing 2001/02 and 2016/17, adjusted for age, sex, region, socio-economic status, and 18 major comorbidities. RESULTS: Of 72 412 participants, mean (standard deviation) age was 75.6 (12.4) years, and 44 762 (61.8%) had ≥3 comorbidities. All-cause mortality declined (RR 2016/17 vs. 2001/02 0.72; 95% CI 0.65-0.80), with large declines for cardiovascular (RR 0.46; 95% CI 0.37-0.58) and cerebrovascular mortality (RR 0.41; 95% CI 0.29-0.60) but not for non-cardio/cerebrovascular causes of death (RR 0.91; 95% CI 0.80-1.04). In 2016/17, deaths caused from dementia (67, 8.0%), outstripped deaths from acute myocardial infarction, heart failure, and acute stroke combined (56, 6.7%, P < .001). Overall hospitalization rates increased (IRR 2016/17 vs. 2001/02 1.17; 95% CI, 1.13-1.22), especially for non-cardio/cerebrovascular causes (IRR 1.42; 95% CI 1.39-1.45). Older, more deprived, and hospital-diagnosed AF patients experienced higher event rates. CONCLUSIONS: After AF diagnosis, cardio/cerebrovascular mortality and hospitalization has declined, whilst hospitalization for non-cardio/cerebrovascular disease has increased.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Clinical Outcomes of Left Bundle Branch Area Pacing Compared with Biventricular Pacing in Patients with Heart Failure Requiring Cardiac Resynchronization Therapy: Systematic Review and Meta-Analysis.

Background: Biventricular pacing (BVP) is recommended for patients with heart failure (HF) who require cardiac resynchronization therapy (CRT). Left bundle branch area pacing (LBBAP) is a novel pacing strategy that appears to ensure better electrical and mechanical synchrony in these patients. Our aim was to systematically review and meta-analyze the existing evidence regarding the clinical outcomes of LBBAP-CRT compared with BVP-CRT. Methods: Medline, Embase, Cochrane Central Register of Controlled Trials and Web of Science databases were searched for studies comparing LBBAP-CRT with BVP-CRT. Outcomes were all-cause mortality, heart failure hospitalizations (HFH) and New York Heart Association (NYHA) class improvement. We included randomized controlled trials (RCTs) and observational studies with participants that had left ventricular ejection fraction (LVEF) ≤ 40% and (i) symptomatic HF or (ii) expected ventricular pacing > 40%. Random and fixed effects models pairwise meta-analysis was conducted. Cochrane Risk of Bias 2 assessment tool (ROB 2.0) and the Newcastle-Ottawa scale (NOS) were used to assess the quality of the studies. Results: Eleven studies (10 observational studies and 1 RCT) with 3141 patients were included in the analysis. Compared with BVP-CRT, LBBAP-CRT was associated with lower risk of all-cause mortality (risk ratio (RR): 0.71, 95% CI: 0.57 to 0.87; p = 0.001), lower risk of HFH (RR: 0.59, 95% CI: 0.50 to 0.71; p < 0.00001) and more improvement in NYHA class (weighed mean difference (WMD): -0.36, 95% CI: -0.59 to -0.13; p < 0.00001) compared with patients who received BVP-CRT. Conclusions: Compared with BVP-CRT, receipt of LBBAP-CRT in patients with HF is associated with a lower risk of mortality, and HFH and greater improvement in NHYA class.

Multisystem inflammatory syndrome in children (MIS-C) and neonates (MIS-N) associated with COVID-19: optimizing definition and management.

During the SARS-CoV-2-associated infection (COVID-19), pandemic initial reports suggested relative sparing of children inversely related to their age. Children and neonates have a decreased incidence of SARS-CoV-2 infection, and if infected they manifested a less severe phenotype, in part due to enhanced innate immune response. However, a multisystem inflammatory syndrome in children (MIS-C) or paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 emerged involving coronary artery aneurysms, cardiac dysfunction, and multiorgan inflammatory manifestations. MIS-C has many similarities to Kawasaki disease and other inflammatory conditions and may fit within a spectrum of inflammatory conditions based on immunological results. More recently neonates born to mothers with SARS-CoV-2 infection during pregnancy demonstrated evidence of a multisystem inflammatory syndrome with raised inflammatory markers and multiorgan, especially cardiac dysfunction that has been described as multisystem inflammatory syndrome in neonates (MIS-N). However, there is a variation in definitions and management algorithms for MIS-C and MIS-N. Further understanding of baseline immunological responses to allow stratification of patient groups and accurate diagnosis will aid prognostication, and inform optimal immunomodulatory therapies. IMPACT: Multisystem inflammatory system in children and neonates (MIS-C and MIS-N) post COVID require an internationally recognized consensus definition and international datasets to improve management and plan future clinical trials. This review incorporates the latest review of pathophysiology, clinical information, and management of MIS-C and MIS-N. Further understanding of the pathophysiology of MIS-C and MIS-N will allow future targeted therapies to prevent and limit clinical sequelae.

Neonatal outcomes of maternal SARS-CoV-2 infection in the UK: a prospective cohort study using active surveillance.

BACKGROUND: Newborns may be affected by maternal SARS-CoV-2 infection during pregnancy. We aimed to describe the epidemiology, clinical course and short-term outcomes of babies admitted to a neonatal unit (NNU) following birth to a mother with confirmed SARS-CoV-2 infection within 7 days of birth. METHODS: This is a UK prospective cohort study; all NHS NNUs, 1 March 2020 to 31 August 2020. Cases were identified via British Paediatric Surveillance Unit with linkage to national obstetric surveillance data. Reporting clinicians completed data forms. Population data were extracted from the National Neonatal Research Database. RESULTS: A total of 111 NNU admissions (1.98 per 1000 of all NNU admissions) involved 2456 days of neonatal care (median 13 [IQR 5, 34] care days per admission). A total of 74 (67%) babies were preterm. In all, 76 (68%) received respiratory support; 30 were mechanically ventilated. Four term babies received therapeutic hypothermia for hypoxic ischaemic encephalopathy. Twenty-eight mothers received intensive care, with four dying of COVID-19. Eleven (10%) babies were SARS-CoV-2 positive. A total of 105 (95%) babies were discharged home; none of the three deaths before discharge was attributed to SARS-CoV-2. CONCLUSION: Babies born to mothers with SARS-CoV-2 infection around the time of birth accounted for a low proportion of total NNU admissions over the first 6 months of the UK pandemic. Neonatal SARS-CoV-2 was uncommon. STUDY REGISTRATION: ISRCTN60033461; protocol available at http://www.npeu.ox.ac.uk/pru-mnhc/research-themes/theme-4/covid-19 . IMPACT: Neonatal unit admissions of babies born to mothers with SARS-CoV-2 infection comprised only a small proportion of total neonatal admissions in the first 6 months of the pandemic. A high proportion of babies requiring neonatal admission who were born to mothers with confirmed SARS-CoV-2 infection were preterm and had neonatal SARS-CoV-2 infection and/or other conditions associated with long-term sequelae. Adverse neonatal conditions were more common in babies whose SARS-CoV-2-positive mothers required intensive care compared to those whose SARS-CoV-2-positive mothers who did not.

European Society of Cardiology quality indicators for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.

To develop a suite of quality indicators (QIs) for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). The Working Group comprised experts in heart rhythm management including Task Force members of the 2022 European Society of Cardiology (ESC) Clinical Practice Guidelines for the management of patients with VA and the prevention of SCD, members of the European Heart Rhythm Association, international experts, and a patient representative. We followed the ESC methodology for QI development, which involves (i) the identification of the key domains of care for the management of patients with VA and the prevention of SCD by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. We identified eight domains of care for the management of patients with VA and the prevention of SCD: (i) structural framework, (ii) screening and diagnosis, (iii) risk stratification, (iv) patient education and lifestyle modification, (v) pharmacological treatment, (vi) device therapy, (vii) catheter ablation, and (viii) outcomes, which included 17 main and 4 secondary QIs across these domains. Following a standardized methodology, we developed 21 QIs for the management of patients with VA and the prevention of SCD. The implementation of these QIs will improve the care and outcomes of patients with VA and contribute to the prevention of SCD.

Attainment of NICE blood pressure targets among older people with newly diagnosed hypertension: nationwide linked electronic health records cohort study.

BACKGROUND: it is not known if clinical practice reflects guideline recommendations for the management of hypertension in older people and whether guideline adherence varies according to overall health status. AIMS: to describe the proportion of older people attaining National Institute for Health and Care Excellence (NICE) guideline blood pressure targets within 1 year of hypertension diagnosis and determine predictors of target attainment. METHODS: a nationwide cohort study of Welsh primary care data from the Secure Anonymised Information Linkage databank including patients aged ≥65 years newly diagnosed with hypertension between 1st June 2011 and 1st June 2016. The primary outcome was attainment of NICE guideline blood pressure targets as measured by the latest blood pressure recording up to 1 year after diagnosis. Predictors of target attainment were investigated using logistic regression. RESULTS: there were 26,392 patients (55% women, median age 71 [IQR 68-77] years) included, of which 13,939 (52.8%) attained a target blood pressure within a median follow-up of 9 months. Success in attaining target blood pressure was associated with a history of atrial fibrillation (OR 1.26, 95% CI 1.11, 1.43), heart failure (OR 1.25, 95% CI 1.06, 1.49) and myocardial infarction (OR 1.20, 95% CI 1.10, 1.32), all compared to no history of each, respectively. Care home residence, the severity of frailty, and increasing co-morbidity were not associated with target attainment following adjustment for confounder variables. CONCLUSIONS: blood pressure remains insufficiently controlled 1 year after diagnosis in nearly half of older people with newly diagnosed hypertension, but target attainment appears unrelated to baseline frailty, multi-morbidity or care home residence.