GBS vaccines in the UK: a round table discussion.

BACKGROUND: Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. MEETING: A round-table discussion, held at St George's University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation.Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. CONCLUSIONS: With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study.

BACKGROUND: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. METHODS: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. FINDINGS: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. INTERPRETATION: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. FUNDING: Pfizer, Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron

Do maternal haemodynamics have a causal influence on treatment for gestational diabetes?

BACKGROUND: Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM. METHODS: We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis. RESULTS: 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 - 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm, p = 0.014) and PWV (7.8 ± 1.04 vs. 8.4 ± 1.61 m/s, p = 0.029) were both significantly higher amongst the women requiring pharmacological management, though these relationships did not remain significant in causal logistic regression. CONCLUSIONS: Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment

Vaccine value profile for Klebsiella pneumoniae

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91–1.71) and 4.95 million (95% UI: 3.62–6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K. pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A ‘Vaccine Value Profile’ (VVP) for K. pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public–private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K. pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information

Implementation of chronic kidney disease guidelines for sodium-glucose co-transporter-2 inhibitor use in primary care in the UK: a cross-sectional study.

BACKGROUND: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. METHODS: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). FINDINGS: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). INTERPRETATION: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. FUNDING: None

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolaemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia, von Hippel-Lindau. Here we report disclosure processes, manifestation of AF-related disease, outcomes and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88% respectively had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, four cancer-AF recipients had evidence of disease, including one medullary thyroid cancer. Six women with an HBOC AF, three women with a Lynch syndrome AF, and two individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidaemia diagnoses were made in six FH-AF recipients, and treatment (re-)initiated for seven with prior hyperlipidaemia. Generating and disclosing AFs in this region cost £1.4m; £8,680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with, and without personal or familial evidence of disease, and prompts appropriate clinical interventions. Results can inform policy towards secondary findings

Post-traumatic stress trajectories of children and their parents over the year following intensive care discharge: A secondary analysis

Background New research in the field of psychological trauma has emphasized (a) the heterogeneity of psychological reactions after traumatic events and (b) the existence of distinct symptom trajectories. Aims In this study, existing data on post-traumatic stress disorder (PTSD) symptoms in 66 parent–child dyads were re-examined in the light of this literature in order to establish whether a similar pattern of symptom trajectories also applies to this population. Study Design A prospective observational cohort study. Participants' PTSD symptoms were assessed 3 and 12 months after discharge from a paediatric intensive care unit (PICU), using a short form of the Davidson Trauma Scale with parents and the Child Revised Impact of Events Scale with children aged 7–17 years. Results Results confirmed that the majority of children (58%) and parents (46%) exhibited a ‘Resilient’ PTSD trajectory over the year, in the sense that their scores remained in the non-clinical range at both timepoints. Children displaying a ‘Resilient’ trajectory were more likely to have a parent who also displayed a ‘Resilient’ trajectory (p = .018). However, there was also evidence of a ‘Recovery’ trajectory in a significant minority in this sample and over 1 in 4 children and parents exhibited a ‘Chronic’ or ‘Delayed’ symptom trajectory. Conclusions Although average PTSD scores reduced over time in this sample and ‘Resilient’ trajectories were common, a significant proportion of children and parents exhibited ‘Chronic’ and ‘Delayed’ symptom trajectories. Relevance to Clinical Practice These results suggest that, although the majority do well, a significant number of children and family members may develop chronic or delayed symptoms of PTSD in the year following PICU discharge. The monitoring of individual family members' symptoms beyond 3 months post-discharge may help to determine those who might most benefit from further support

Assessing the effects of distinct biologic therapies on rheumatoid arthritis pain by nociceptive, neuropathic and nociplastic pain components: a randomised feasibility study.

BACKGROUND: Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS), including biologic therapies, many people with RA continue to experience significant pain. We aimed to determine whether performing a comprehensive pain evaluation is feasible in people with active RA receiving conventional DMARDs and biologic therapies. METHODS: The BIORA-PAIN feasibility study was an open-label, randomised trial, which recruited participants suitable for treatment with biologic therapy. The primary feasibility outcomes were recruitment, randomisation and retention of eligible participants. All participants underwent pain assessment for nociceptive, neuropathic and nociplastic pain during the 12-month study period, with quarterly assessments for VAS (Visual Analogue Scale) pain, painDETECT and QST (quantitative sensory testing). This trial was registered in clinicaltrials.gov NCT04255134. RESULTS: During the study period, 93 participants were screened of whom 25 were eligible: 13 were randomised to adalimumab and 12 to abatacept. Participant recruitment was lower than expected due to the COVID-19 pandemic. Pain assessments were practical in the clinical trial setting. An improvement was observed for VAS pain from baseline over 12 months, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.1) in the adalimumab group. There was a reduction in painDETECT and improvement in QST measures in both treatment groups during the study. Participant feedback included that some of the questionnaire-based pain assessments were lengthy and overlapped in their content. Adverse events were similar in both groups. There was one death due to COVID-19. CONCLUSIONS: This first-ever feasibility study of a randomised controlled trial assessing distinct modalities of pain in RA met its progression criteria. This study demonstrates that it is feasible to recruit and assess participants with active RA for specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Our data suggests that it is possible to stratify people for RA based on pain features. The differences in pain outcomes between abatacept and adalimumab treated groups warrant further investigation. TRIAL REGISTRATION: NCT04255134, Registered on Feb 5, 2020

How to tackle therapeutic inertia in heart failure with reduced ejection fraction. A scientific statement of the Heart Failure Association of the ESC.

Guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set-up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up-to-date evidence