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Aims:Heart failure (HF) is a global health burden and new strategies to achieve timely diagnosis and early intervention are urgently needed. Natriuretic peptide (NP) testing can be used to screen for left ventricular systolic dysfunction (LVSD), but evidence on test performance is mixed, and international HF guidelines differ in their recommendations. Our aim was to summarize the evidence on diagnostic accuracy of NP screening for LVSD in general and high-risk community populations and estimate optimal screening thresholds. Methods:We searched relevant databases up to August 2020 for studies with a screened community population of over 100 adults reporting NP performance to diagnose LVSD. Study inclusion, quality assessment, and data extraction were conducted independently and in duplicate. Diagnostic test meta-analysis used hierarchical summary receiver operating characteristic curves to obtain estimates of pooled accuracy to detect LVSD, with optimal thresholds obtained to maximize the sum of sensitivity and specificity. Results:Twenty-four studies were identified, involving 26 565 participants: eight studies in high-risk populations (at least one cardiovascular risk factor), 12 studies in general populations, and four in both high-risk and general populations combined. For detecting LVSD in screened high-risk populations with N-terminal prohormone brain natriuretic peptide (NT-proBNP), the pooled sensitivity was 0.87 [95% confidence interval (CI) 0.73–0.94] and specificity 0.84 (95% CI 0.55–0.96); for BNP, sensitivity was 0.75 (95% CI 0.65–0.83) and specificity 0.78 (95% CI 0.72–0.84). Heterogeneity between studies was high with variations in positivity threshold. Due to a paucity of high-risk studies that assessed NP performance at multiple thresholds, it was not possible to calculate optimal thresholds for LVSD screening in high-risk populations alone. To provide an indication of where the positivity threshold might lie, the pooled accuracy for LVSD screening in high-risk and general community populations were combined and gave an optimal cut-off of 311pg/mL [sensitivity 0.74 (95% CI 0.53–0.88), specificity 0.85 (95% CI 0.68–0.93)] for NT-proBNP and 49pg/mL [sensitivity 0.68 (95% CI 0.45–0.85), specificity 0.81 (0.67–0.90)] for BNP. Conclusions:Our findings suggest that in high-risk community populations NP screening may accurately detect LVSD, potentially providing an important opportunity for diagnosis and early intervention. Our study highlights an urgent need for further prospective studies, as well as an individual participant data meta-analysis, to more precisely evaluate diagnostic accuracy and identify optimal screening thresholds in specifically defined community-based populations to inform future guideline recommendations.

Childhood pneumococcal conjugate vaccine (PCV) protects against invasive pneumococcal disease caused by vaccine-serotype (VT) Streptococcus pneumoniae by generating opsonophagocytic anti-capsular antibodies, but how vaccination protects against and reduces VT carriage is less well understood. Using serological samples from PCV-vaccinated Malawian individuals and a UK human challenge model, we explored whether antibody quality (IgG subclass, opsonophagocytic killing, and avidity) is associated with protection from carriage. Following experimental challenge of adults with S. pneumoniae serotype 6B, 3/21 PCV13-vaccinees were colonised with pneumococcus compared to 12/24 hepatitis A-vaccinated controls; PCV13-vaccination induced serotype-specific IgG, IgG1, and IgG2, and strong opsonophagocytic responses. However, there was no clear relationship between antibody quality and protection from carriage or carriage intensity after vaccination. Similarly, among PCV13-vaccinated Malawian infants there was no relationship between serotype-specific antibody titre or quality and carriage through exposure to circulating serotypes. Although opsonophagocytic responses were low in infants, antibody titre and avidity to circulating serotypes 19F and 6A were maintained or increased with age. These data suggest a complex relationship between antibody-mediated immunity and pneumococcal carriage, and that PCV13-driven antibody quality may mature with age and exposure.

Aims: In people with heart failure (HF), a high body mass index (BMI) has been linked with better outcomes (‘obesity paradox’), but there is limited evidence in community populations across long-term follow-up. We aimed to examine the association between BMI and long-term survival in patients with HF in a large primary care cohort. Methods: We included patients with incident HF aged ≥45 years from the Clinical Practice Research Datalink (2000-2017). We used Kaplan-Meier curves, Cox regression, and penalised splines methods to assess the association of pre-diagnostic BMI, based on WHO classification, with all-cause mortality. Results: There were 47,531 participants with HF (median age 78.0 years (IQR 70-84), 45.8% female, 79.0% white ethnicity, median BMI 27.1 (IQR 23.9-31.0)) and 25,013 (52.6%) died during follow-up. Compared to healthy weight, people with overweight (HR 0.78, 95%CI 0.75-0.81, risk difference (RD) -4.1%), obesity class I (HR 0.76, 95%CI 0.73-0.80, RD -4.5%) and class II (HR 0.76, 95%CI 0.71-0.81, RD -4.5%) were at decreased risk of death, whereas people with underweight were at increased risk (HR 1.59, 95%CI 1.45-1.75, RD 11.2%). In those underweight, this risk was greater among men than women (p-value for interaction = 0.02). Class III obesity was associated with increased risk of all-cause mortality compared to overweight (HR 1.23, 95%CI 1.17-1.29). Conclusion: The U-shaped relationship between BMI and long-term all-cause mortality suggests a personalised approach to identifying optimal weight may be needed for patients with HF in primary care. Underweight people have the poorest prognosis and should be recognised as high-risk.

Background People with chronic heart failure (HF) have a poor prognosis, with survival rates at five year follow-up close to 50%.1 More than half of patients with HF will develop atrial fibrillation (AF). The presence of AF in people with HF has been associated with a poor prognosis, irrespective of left ventricular ejection fraction. 2,3 However, the majority of studies to date have analysed prognosis among secondary care cohorts or randomised trial participants, who may not be representative of patients with chronic HF in the community.2 Purpose To examine the association between survival in patients with HF and AF compared to either condition alone, among a large primary care cohort. Methods We extracted data from the Clinical Practice Research Datalink of primary care records from 1st January 2000 to 31st December 2018 and included all patients aged 45 years and over who were registered at an up-to-standard practice for a minimum of 12 months. Records were linked to Hospital Episode Statistics for secondary care data. The primary outcome was all-cause mortality. Exposure groups were defined as HF+AF, HF or AF, with exposure status treated as a time-varying covariate across follow-up. We used Cumulative Hazard plots to compare survival in people with HF and AF, compared to people with either condition alone or neither. We also report a Cox regression model for risk of all-cause mortality among people with HF and AF, adjusting for age, sex, ethnicity, smoking status and comorbid cardiovascular disease. Results There were 314,042 deaths during the study follow-up. The average age of participants was 58.0 years (SD 10.6) and 51.4% were women. At some point across follow-up, 94,990 people had HF alone, 147,815 had AF alone and 74,470 had both HF and AF. In an unadjusted Cox regression analysis, people with HF and AF were at the greatest risk of death (HR 17.94, 95% CI 17.75 to 18.13), followed by people with HF alone (HR 12.00, 95% CI 11.87 to 12.13), and AF alone (HR 6.14, 95% CI 6.08 to 6.21) compared to people with neither HF nor AF. In the fully adjusted analysis, the risk of death remained highest among people with HF and AF (HR 3.78, 95% CI 3.73 to 3.83), followed by people with HF alone (HR 3.06, 95% CI 3.02 to 3.10), then people with AF alone (HR 1.85, 95%, CI 1.82 to 1.87). In a cumulative hazard plot, the risk of death across follow-up was similar among people with HF and AF, compared to those with HF alone. Conclusion In our large community cohort, we found HF and AF was associated with a worse prognosis than either condition alone. Both HF and AF were also associated with a poor prognosis. These results support the findings of previous secondary care and trial studies regarding the importance of AF as a prognostic indicator among people with HF. Further research could aim to identify preventive strategies that might improve prognosis among this high-risk group of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The study was undertaken as part of NRJ's Doctoral Research Fellowship, supported by the Wellcome Trust (grant number 203921/Z/16/Z), with additional funding for this project from the National Institute for Health Research (NIHR) Collaboration for Applied Health Research (CLAHRC) Oxford at Oxford Health NHS Foundation Trust (P2-001).

Background People with obesity are twice as likely to develop heart failure (HF) compared to people with a healthy body mass index (BMI) [1]. However, among people with HF a higher BMI has been linked to a reduced risk of all-cause mortality, a concept known as the “obesity paradox” [2]. Purpose To examine the association between BMI and survival in patients with chronic HF among a large primary care cohort. Methods We extracted data from the Clinical Practice Research Datalink of primary care records from 1st January 2000 to 31st December 2017 and included 47,531 patients with an incident diagnosis of HF, who were aged 45 years and over and who had a recorded BMI. Patients were stratified into categories of baseline BMI as underweight (BMI Results There were 25,013 deaths during the study follow-up. The average age of participants was 77.1 years (SD 10.6) and mean BMI was 27.9 (SD 6.1). In an age- and sex-adjusted analysis, people who were underweight were at increased risk of all-cause mortality compared to people with healthy weight (HR 1.52, 95% CI 1.41 to 1.64). People with overweight (HR 0.81, 95% CI 0.79 to 0.84), obesity class I (HR 0.79, 95% CI 0.76 to 0.82) and obesity class II (HR 0.78, 95% CI 0.74 to 0.82) were at decreased risk of all-cause mortality. People with obesity class III had no difference in risk of death compared to people with healthy weight (HR 0.95, 95% CI 0.88 to 1.02). In a Kaplan-Meier analysis, there was an inverse relationship between body weight and risk of death, even within the first year of follow-up. Conclusion In our large community cohort of people with HF, we found an inverse relationship between BMI and survival. Underweight people with HF have the poorest prognosis and should be identified as high-risk. Conversely, people with HF who are overweight or obese (class I and II) are at lower risk of death confirming the obesity paradox in a real-world primary care population. These findings suggest a more cautious approach to weight management in overweight and obese patients may be needed for people with HF in primary care. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The SurviveHF study was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) Oxford at Oxford Health NHS Foundation Trust and the Wellcome Institutional Strategic Fund. The funders did not have any role in the design of the study, analysis and interpretation of the data, or writing of the results for publication.

ObjectiveHeart failure (HF) is a malignant condition requiring urgent treatment. Guidelines recommend natriuretic peptide (NP) testing in primary care to prioritise referral for specialist diagnostic assessment. We aimed to assess association of baseline NP with hospitalisation and mortality in people with newly diagnosed HF.MethodsPopulation-based cohort study of 40 007 patients in the Clinical Practice Research Datalink in England with a new HF diagnosis (48% men, mean age 78.5 years). We used linked primary and secondary care data between 1 January 2004 and 31 December 2018 to report one-year hospitalisation and 1-year, 5-year and 10-year mortality by NP level.Results22 085 (55%) participants were hospitalised in the year following diagnosis. Adjusted odds of HF-related hospitalisation in those with a high NP (NT-proBNP >2000 pg/mL) were twofold greater (OR 2.26 95% CI 1.98 to 2.59) than a moderate NP (NT-proBNP 400–2000 pg/mL). All-cause mortality rates in the high NP group were 27%, 62% and 82% at 1, 5 and 10 years, compared with 19%, 50% and 77%, respectively, in the moderate NP group and, in a competing risks model, risk of HF-related death was 50% higher at each timepoint. Median time between NP test and HF diagnosis was 101 days (IQR 19–581).ConclusionsHigh baseline NP is associated with increased HF-related hospitalisation and poor survival. While healthcare systems remain under pressure from the impact of COVID-19, research to test novel strategies to prevent hospitalisation and improve outcomes—such as a mandatory two-week HF diagnosis pathway—is urgently needed.

In most countries worldwide, pneumococcal conjugate vaccines have been included in the infant immunization program, resulting in a significant reduction in the burden of pneumococcal disease in children and adults. Shifting serotype distribution due to the indirect effect of infant vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) may continue to increase the gap between 23-valent pneumococcal polysaccharide vaccine (PPSV23) and PCV13 serotype coverage for older adults in the coming years. This clinical study (V110-029; NCT02225587) evaluated the safety and immunogenicity of sequential administration of PCV13 followed approximately 8 weeks later, or approximately 26 weeks later, by PPSV23 in healthy adults ≥50 years of age. Both dosing intervals were generally well tolerated as measured by the nature, frequency, and intensity of reported adverse events (AEs) in both vaccination groups. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) measured 30 days following receipt of PPSV23 in either group and at Week 30 were generally comparable between the 2 groups for 6 serotypes unique to PPSV23 and 12 serotypes shared between PCV13 and PPSV23, regardless of the interval between receipt of PCV13 and PPSV23. In addition, administration of PPSV23 given either 8 weeks or 26 weeks following PCV13 did not negatively impact immune responses induced by PCV13. Furthermore, administration of PPSV23 given either 8 weeks or 26 weeks after PCV13 elicited serotype-specific OPA GMTs to serotypes unique to PPSV23, which could provide earlier protection against pneumococcal disease caused by these serotypes in comparison with the current Advisory Committee on Immunization Practices recommended interval of at least 12 months.

Plasma-derived polyclonal antibody therapeutics, such as intravenous immunoglobulin, have multiple drawbacks, including low potency, impurities, insufficient supply, and batch-to-batch variation. Here we describe a microfluidics and molecular genomics strategy for capturing diverse mammalian antibody repertoires to create recombinant multivalent hyperimmune globulins. Our method generates thousands-diverse mixtures of recombinant antibodies, enriched for specificity and activity against therapeutic targets. Each hyperimmune globulin product comprised thousands to tens of thousands of antibodies derived from convalescent or vaccinated human donors, or immunized mice. Using this approach, we generated hyperimmune globulins with potent neutralizing activity against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in under three months, Fc-engineered hyperimmune globulins specific for Zika virus that lacked antibody-dependent enhancement of disease, and hyperimmune globulins specific for lung pathogens present in patients with primary immune deficiency. To address the limitations of rabbit-derived anti-thymocyte globulin (ATG), we generated a recombinant human version and demonstrated its efficacy in mice against graft-versus-host disease.

BackgroundNatriuretic peptide (NP) testing is recommended for patients presenting to primary care with symptoms of chronic heart failure (HF) to prioritise referral for diagnosis.AimTo report NP test performance at European Society of Cardiology (ESC) and National Institute for Health and Care Excellence (NICE) guideline referral thresholds.Design and settingDiagnostic accuracy study using linked primary and secondary care data (2004 to 2018).MethodThe sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NP testing for HF diagnosis was assessed.ResultsIn total, 229 580 patients had an NP test and 21 102 (9.2%) were diagnosed with HF within 6 months. The ESC NT-proBNP threshold ≥125 pg/mL had a sensitivity of 94.6% (95% confidence interval [CI] = 94.2 to 95.0) and specificity of 50.0% (95% CI = 49.7 to 50.3), compared with sensitivity of 81.7% (95% CI = 81.0 to 82.3) and specificity of 80.3% (95% CI = 80.0 to 80.5) for the NICE NT-proBNP ≥400 pg/mL threshold. PPVs for an NT-proBNP test were 16.4% (95% CI = 16.1 to 16.6) and 30.0% (95% CI = 29.6 to 30.5) for ESC and NICE thresholds, respectively. For both guidelines, nearly all patients with an NT-proBNP level below the threshold did not have HF (NPV: ESC 98.9%, 95% CI = 98.8 to 99.0 and NICE 97.7%, 95% CI = 97.6 to 97.8).ConclusionAt the higher NICE chronic HF guideline NP thresholds, one in five cases are initially missed in primary care but the lower ESC thresholds require more diagnostic assessments. NP is a reliable ‘rule-out’ test at both cut-points. The optimal NP threshold will depend on the priorities and capacity of the healthcare system.

BACKGROUND: Newer flow diverters are enhanced with antithrombogenic surface modifications like the Pipeline Embolization Device with Shield Technology and the Derivo Embolization Device and are purported to facilitate deployment and reduce ischemic events. PURPOSE: Our aim was to review the safety and efficacy of surface-modified flow diverters in treating patients with cerebral aneurysms. DATA SOURCES: We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses–compliant systematic review and meta-analysis covering 3 major data bases and gray literature between 2014 and 2019. STUDY SELECTION: Two reviewers independently reviewed human studies of surface-modified flow diverters for eligibility based on predetermined criteria. DATA ANALYSIS: The random effects model and Freeman-Tukey arcsine transformation were used to pool efficacy outcomes (technical success, aneurysm occlusion at 6 and 12 months) and safety outcomes (mortality, morbidity, all ischemia, and serious ischemia). Subgroup analysis was performed to compare outcomes between 2 different flow diverters. DATA SYNTHESIS: Eight single-arm case series involving 911 patients and 1060 aneurysms were included. The median follow-up was 8.24 months. Pooled estimate for technical success was 99.6%, while the aneurysm occlusion at 6 and 12 months were 80.5%, and 85.6%, respectively. Pooled estimates for mortality, morbidity, total ischemia, and serious ischemia rates were 0.7%, 6.0%, 6.7%, and 1.8%, respectively. Most studies were of good quality, and no significant heterogeneity was observed. LIMITATIONS: Limitations include a retrospective, observational design in some studies; heterogeneous and underreported antiplatelet therapy; and potential performance and ecologic bias. CONCLUSIONS: Early-to-midterm safety and efficacy for surface-modified flow diverters appear comparable with older devices, especially for small, unruptured anterior circulation aneurysms. Long-term clinical data are required to further corroborate these results.

Summary Background Routine childhood immunisation with pneumococcal conjugate vaccine (PCV) has changed the epidemiology of pneumococcal disease across age groups, providing an opportunity to reconsider PCV dosing schedules. We aimed to evaluate the post-booster dose immunogenicity of ten-valent (PCV10) and 13-valent (PCV13) PCVs between infants randomly assigned to receive a single-dose compared with a two-dose primary series. Methods We did an open-label, non-inferiority, randomised study in HIV-unexposed infants at a single centre in Soweto, South Africa. Infants were randomly assigned to receive one priming dose of PCV10 or PCV13 at ages 6 weeks (6w + 1 PCV10 and 6w + 1 PCV13 groups) or 14 weeks (14w + 1 PCV10 and 14w + 1 PCV13 groups) or two priming doses of PCV10 or PCV13, one each at ages 6 weeks and 14 weeks (2 + 1 PCV10 and 2 + 1 PCV13 groups); all participants then received a booster dose of PCV10 or PCV13 at 40 weeks of age. The primary endpoint was geometric mean concentrations (GMCs) of serotype-specific IgG 1 month after the booster dose, which was assessed in all participants who received PCV10 or PCV13 as per the assigned randomisation group and for whom laboratory results were available at that timepoint. The 1 + 1 vaccine schedule was considered non-inferior to the 2 + 1 vaccine schedule if the lower bound of the 96% CI for the GMC ratio was greater than 0·5 for at least ten PCV13 serotypes and eight PCV10 serotypes. Safety was a secondary endpoint. This trial is registered with ClinicalTrials.gov ( NCT02943902 ) and is ongoing. Findings Of 1695 children assessed, 600 were enrolled and randomly assigned to one of the six groups between Jan 9 and Sept 20, 2017; 542 were included in the final analysis of the primary endpoint (86–93 per group). For both PCV13 and PCV10, a 1+1 dosing schedule (either beginning at 6 or 14 weeks) was non-inferior to a 2 + 1 schedule. For PCV13, the lower limit of the 96% CI for the ratio of GMCs between the 1 + 1 and 2 + 1 groups was higher than 0·5 for ten serotypes in the 6w+1 group (excluding 6B, 14, and 23F) and 11 serotypes in the 14w + 1 group (excluding 6B and 23F). For PCV10, the lower limit of the 96% CI for the ratio of GMCs was higher than 0·5 for all ten serotypes in the 6w+1 and 14w + 1 groups. 84 serious adverse events were reported in 72 (12%) of 600 participants. 15 occurred within 28 days of vaccination, but none were considered to be related to PCV injection. There were no cases of culture-confirmed invasive pneumococcal disease. Interpretation The non-inferiority in post-booster immune responses following a single-dose compared with a two-dose primary series of PCV13 or PCV10 indicates the potential for reducing PCV dosing schedules from a 2 + 1 to 1 + 1 series in low-income and middle-income settings with well established PCV immunisation programmes. Funding The Bill & Melinda Gates Foundation (OPP1 + 152352).

Aims Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. Methods and results We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71–76%, n = 46 paired samples, P, Graphical Abstract