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Background: Increasing demand for transcatheter aortic valve implantation (TAVI) places greater emphasis on the efficiency of pathways and services. A significant limitation to increasing TAVI capacity is the availability of cardiac catheterisation laboratory time. We have developed a novel complexity scoring system (TAVI ComplEXity; TEX score) which can aid in planning lists with appropriate case selection. To validate the TEX score, we have undertaken a retrospective analysis of TAVI cases. The hypothesis is that increasing TEX score correlates with increased procedural duration and reduced valve academic research consortium (VARC) 3 technical and device success., Methods: The TEX score assigns patients to a complexity level of 1 (low), 2 (intermediate) or 3 (high) based on the presence of specific clinical and anatomical variables. For validation purposes, comparisons were made between patients in the three complexity levels with respect to procedural duration as well as VARC-3 technical success, device success and early safety., Results: The validation study included 1034 consecutive patients who underwent TAVI between June 2021 and October 2023. Of these, 582 (56.3%) were classified as level 1 complexity, 377 (36.5%) level 2 and 75 (7.3%) level 3. Significant differences were observed between the three groups with respect to procedural duration (73.7 min vs 85.6 min vs 136 min; p<0.001), VARC-3 technical success (97.9% vs 96.6% vs 92%; p<0.05) and VARC-3 device success (96.2% vs 92.3% vs 86.6%; p<0.001)., Conclusion: The TEX score is a simple tool which allows stratification of patients into three levels of complexity. Increasing complexity levels correlate with increasing procedural duration and reduced VARC-3 technical and device success. This is potentially useful for scheduling patients onto appropriate lists., Competing Interests: Competing interests: DJB is a consultant and proctor for Medtronic plc and Abbott Vascular, as well as a consultant for Edwards Lifesciences and Boston Scientific. CM is a proctor for Edwards Lifesciences, Medtronic plc and Abbott Vascular and has received honorary speaking fees from Boston Scientific. MC has received educational speaking fees from Medtronic plc, Abbott Vascular and Boston Scientific. NA has received honorary speaking fees from Medtronic and Abbott Vascular., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Cardiovascular disease is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), each prevent cardiovascular disease. However, trial results may not be generalizable, and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored the generalizability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD dataset from January 1, 2001, to July 31, 2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB with ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure) and secondary outcomes. Because the prespecified criteria were met, confirming trial emulation, we then explored treatment heterogeneity among 3 trial-underrepresented subgroups: females, persons aged ≥75 years, and those with chronic kidney disease. In the trial-eligible population (n = 137 155), results for the primary outcome demonstrated similar effects of ARB and ACEi (hazard ratio = 0.97; 95% CI, 0.93-1.01), meeting the prespecified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age, and chronic kidney disease. This suggests that ONTARGET trial findings are generalizable to trial-underrepresented subgroups. This article is part of a Special Collection on Pharmacoepidemiology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Guidelines by the National Institute for Health and Care Excellence recommend an angiotensin receptor blocker (ARB) rather than an angiotensin-converting enzyme inhibitor (ACEi) for the treatment of hypertension for people of African and Caribbean descent, due to an increased risk of angioedema associated with ACEi use observed in US trials. However, the effectiveness and risk of these drugs in Black populations in UK routine care is unknown., Methods and Findings: We applied a reference trial emulation approach to UK Clinical Practice Research Datalink Aurum data (linked with data from Hospital Episode Statistics and Office for National Statistics) to study the comparative effectiveness of ARB and ACEi in ethnic minority groups in England, after benchmarking results against the ONTARGET trial. Approximately 17,593 Black, 30,805 South Asian, and 524,623 White patients receiving a prescription for ARB/ACEi between 1 January 2001 and 31 July 2019 were included with a median follow-up of 5.2 years. The primary composite outcome was cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using an inverse-probability-weighted Cox proportional hazards model for ARB versus ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale. For the primary outcome, 27,327 (18.0%) events were recorded in the ARB group (event rate: 25% per 5.5 person-years) and 80,624 (19.1%) events (event rate: 26% per 5.5 person-years) in the ACEi group. We benchmarked results against ONTARGET and observed hazard ratio (HR) 0.96 (95% CI: 0.95, 0.98) for the primary outcome, with an absolute incidence rate difference (IRD)% of -1.01 (95% CI: -1.42, -0.60) per 5.5 person-years. We found no evidence of treatment effect heterogeneity by ethnicity for the primary outcome on the multiplicative (Pint = 0.422) or additive scale (Pint = 0.287). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, which occurred in 37,554 (6.6%) people, there was strong evidence of heterogeneity on the multiplicative (Pint = 0.002) and additive scale (Pint < 0.001). Compared to ACEi, ARB were associated with more events in Black individuals (HR 1.20 (95% CI: 1.02, 1.40); IRD% 1.07 (95% CI: 0.10, 2.04); number-needed-to-harm (NNH): 93) and associated with fewer events in White individuals (HR 0.91 (95% CI: 0.88, 0.93); IRD% -0.87 (95% CI: -1.10, -0.63); number-needed-to-treat (NNT): 115), and no differences in South Asian individuals (HR 0.97 (95% CI: 0.86, 1.09); IRD% -0.17 (95% CI: -0.87, 0.53)). For angioedema, HR 0.56 (95% CI: 0.46, 0.67) with no heterogeneity for ARB versus ACEi on the multiplicative scale (Pint = 0.306). However, there was heterogeneity on the additive scale (Pint = 0.023). Absolute risks were higher in Black individuals (IRD% -0.49 (95% CI: -0.79, -0.18); NNT: 204) compared with White individuals (IRD% -0.06 (95% CI: -0.09, -0.03); NNT: 1667) and no difference among South Asian individuals (IRD% -0.05 (95% CI: -0.15, 0.05) for ARB versus ACEi., Conclusions: These results demonstrate variation in drug effects of ACEi and ARB for some outcomes by ethnicity and suggest the potential for adverse consequences from current UK guideline recommendations for ARB in preference to ACEi for Black individuals., Competing Interests: PB was funded by a GSK PhD studentship at the time of analysis. AS is employed by LSHTM on a fellowship sponsored by GSK. EP was an employee of Compass Pathways at the time of the review. CC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter. In 2018 CC co-chaired a KDIGO potassium controversies conference sponsored at arm’s length by Fresenius Medical Care, AstraZeneca, Vifor Fresenius Medical Care, Relypsa, Bayer HealthCare and Boehringer Ingelheim. JFEM reports honoraria from AstraZeneca, Bayer, Boehringer, Novo Nordisk, UpToDate Inc., Idorisia, Labchem, Parexel, Roche, Sanofi. MC was an employee of GSK at the time of the study. All other authors have no conflicts., (Copyright: © 2024 Baptiste et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Confounding by indication is a key challenge for pharmacoepidemiologists. Although self-controlled study designs address time-invariant confounding, indications sometimes vary over time. For example, infection might act as a time-varying confounder in a study of antibiotics and uveitis, because it is time-limited and a direct cause both of receiving antibiotics and uveitis. Methods for incorporating active comparators in self-controlled studies to address such time-varying confounding by indication have only recently been developed. In this paper we formalize these methods, and provide a detailed description for how the active comparator rate ratio can be derived in a self-controlled case series (SCCS): either by explicitly comparing the regression coefficients for a drug of interest and an active comparator under certain circumstances using a simple ratio approach, or through the use of a nested regression model. The approaches are compared in two case studies, one examining the association between thiazolidinediones and fractures, and one examining the association between fluoroquinolones and uveitis using the UK Clinical Practice Research DataLink. Finally, we provide recommendations for the use of these methods, which we hope will support the design, execution and interpretation of SCCS using active comparators and thereby increase the robustness of pharmacoepidemiological studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Transcatheter aortic valve implantation (TAVI) serves a growing range of patients with severe aortic stenosis (AS). TAVI has evolved to a streamlined procedure minimizing length of hospital stay., Aims: To evaluate the safety and efficacy of an early discharge (ED) strategy after TAVI., Methods: We performed an international, multi-center, prospective observational single-arm study in AS patients undergoing TAVI with the ACURATE valve platform. Eligibility for ED was assessed prior to TAVI and based on prespecified selection criteria. Discharge ≤ 48 h was defined as ED. Primary Valve Academic Research Consortium (VARC)-3-defined 30-day safety and efficacy composite endpoints were landmarked at 48 h and compared between ED and non-ED groups., Results: A total of 252 patients were included. The median age was 82 [25th-75th percentile, 78-85] years and the median Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score was 2.2% [25th-75th percentile, 1.6-3.3]. ED and non-ED were achieved in 173 (69%) and 79 (31%) patients respectively. Monitoring for conduction disturbances was the principal reason for non-ED (33%). Overall, at 30 days, all-cause mortality was 1%, new permanent pacemaker rate was 4%, and valve- or procedure-related rehospitalization was 4%. There was no difference in the primary safety and efficacy endpoint between the ED and non-ED cohorts (OR 0.84 [25th-75th percentile, 0.31-2.26], p = 0.73, and OR 0.97 [25th-75th percentile, 0.46-2.06], p = 0.94). The need for rehospitalization was similarly low for ED and non-ED groups., Conclusion: Early discharge after TAVI with the ACURATE valve is safe and feasible in selected patients. Rhythm monitoring and extended clinical observation protracted hospital stay., (© 2024. The Author(s).)

Background: In many areas of health care, learning health care systems (LHSs) are seen as promising ways to accelerate research and outcomes for patients by reusing health and research data. For example, considering pregnant and lactating people, for whom there is still a poor evidence base for medication safety and efficacy, an LHS presents an interesting way forward. Combining unique data sources across Europe in an LHS could help clarify how medications affect pregnancy outcomes and lactation exposures. In general, a remaining challenge of data-intensive health research, which is at the core of an LHS, has been obtaining meaningful access to data. These unique data sources, also called data access providers (DAPs), are both public and private organizations and are important stakeholders in the development of a sustainable and ethically responsible LHS. Sustainability is often discussed as a challenge in LHS development. Moreover, DAPs are increasingly expected to move beyond regulatory compliance and are seen as moral agents tasked with upholding ethical principles, such as transparency, trustworthiness, responsibility, and community engagement., Objective: This study aims to explore the views of people working for DAPs who participate in a public-private partnership to build a sustainable and ethically responsible LHS., Methods: Using a qualitative interview design, we interviewed 14 people involved in the Innovative Medicines Initiative (IMI) ConcePTION (Continuum of Evidence from Pregnancy Exposures, Reproductive Toxicology and Breastfeeding to Improve Outcomes Now) project, a public-private collaboration with the goal of building an LHS for pregnant and lactating people. The pseudonymized transcripts were analyzed thematically., Results: A total of 3 themes were identified: opportunities and responsibilities, conditions for participation and commitment, and challenges for a knowledge-generating ecosystem. The respondents generally regarded the collaboration as an opportunity for various reasons beyond the primary goal of generating knowledge about medication safety during pregnancy and lactation. Respondents had different interpretations of responsibility in the context of data-intensive research in a public-private network. Respondents explained that resources (financial and other), scientific output, motivation, agreements collaboration with the pharmaceutical industry, trust, and transparency are important conditions for participating in and committing to the ConcePTION LHS. Respondents also discussed the challenges of an LHS, including the limitations to (real-world) data analyses and governance procedures., Conclusions: Our respondents were motivated by diverse opportunities to contribute to an LHS for pregnant and lactating people, primarily centered on advancing knowledge on medication safety. Although a shared responsibility for enabling real-world data analyses is acknowledged, their focus remains on their work and contribution to the project rather than on safeguarding ethical data handling. The results of our interviews underline the importance of a transparent governance structure, emphasizing the trust between DAPs and the public for the success and sustainability of an LHS., (©Marieke J Hollestelle, Rieke van der Graaf, Miriam C J M Sturkenboom, Marianne Cunnington, Johannes J M van Delden. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 08.02.2024.)

Introduction: Regulatory guidance encourages transparent reporting of information on the quality and validity of electronic health record data being used to generate real-world benefit-risk evidence for vaccines and therapeutics. We aimed to provide an overview of the availability of validated diagnostic algorithms for selected safety endpoints for Coronavirus disease 2019 (COVID-19) vaccines and therapeutics in the context of the emerging pandemic prior to December 2020., Methods: We reviewed the literature up to December 2020 to identify validation studies for various safety events of interest, including myocardial infarction, arrhythmia, myocarditis, acute cardiac injury, vasculitis/vasculopathy, venous thromboembolism, stroke, respiratory distress syndrome (RDS), pneumonitis, cytokine release syndrome (CRS), multiple organ dysfunction syndrome, and renal failure. We included studies published between 2015 and 2020 that were considered high quality assessed with QUADAS and that reported positive predictive values (PPVs)., Results: Out of 43 identified studies, we found that diagnostic algorithms for cardiovascular outcomes were supported by the highest number of validation studies (n=17). Accurate algorithms are available for myocardial infarction (median PPV 80%; IQR 22%), arrhythmia (PPV range >70%), venous thromboembolism (median PPV: 73%) and ischaemic stroke (PPV range ≥85%). We found a lack of validation studies for less common respiratory and cardiac safety outcomes of interest (eg, pneumonitis and myocarditis), as well as for COVID-specific complications (CRS, RDS)., Conclusion: There is a need for better understanding of barriers to conducting validation studies, including data governance restrictions. Regulatory guidance should promote embedding validation within real-world EHR research used for decision-making., Competing Interests: KA, MH-C, BP & NQ were full- or part-time employees of OXON. MC was an employee at GSK at the time the project was executed. MD is a full-time GSK employee and hold share in GSK. The authors report no other conflicts of interest in this work., (© 2024 Andresen et al.)

Purpose: Prevalent new user (PNU) designs extend the active comparator new user design by allowing for the inclusion of initiators of the study drug who were previously on a comparator treatment. We performed a literature review summarising current practice., Methods: PubMed was searched for studies applying the PNU design since its proposal in 2017. The review focused on three components. First, we extracted information on the overall study design, including the database used. We summarised information on implementation of the PNU design, including key decisions relating to exposure set definition and estimation of time-conditional propensity scores. Finally, we reviewed the analysis strategy of the matched cohort., Results: Nineteen studies met the criteria for inclusion. Most studies (73%) implemented the PNU design in electronic health record or registry databases, with the remaining using insurance claims databases. Of 15 studies including a class of prevalent users, 40% deviated from the original exposure set definition proposals in favour of a more complex definition. Four studies did not include prevalent new users but used other aspects of the PNU framework. Several studies lacked details on exposure set definition (n = 2), time-conditional propensity score model (n = 2) or integration of complex analytical techniques, such as the high-dimensional propensity score algorithm (n = 3)., Conclusion: PNU designs have been applied in a range of therapeutic and disease areas. However, to encourage more widespread use of this design and help shape best practice, there is a need for improved accessibility, specifically through the provision of analytical code alongside guidance to support implementation and transparent reporting., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: No detailed data on left bundle branch block (LBBB) and permanent pacemaker implantation (PPI) exist from randomised clinical trials comparing the ACURATE neo and CoreValve Evolut devices., Aims: Our aim was to assess the incidence and impact of new LBBB and PPI with self-expanding prostheses from a powered randomised comparison., Methods: From the SCOPE 2 trial, 648 patients with no previous pacemaker were analysed for PPI at 30 days, and 426 patients without previous LBBB were adopted for analysis of LBBB at 30 days.  Results: At 30 days, 16.5% of patients required PPI; rates were higher in CoreValve Evolut compared to ACURATE neo recipients (21.0% vs 12.3%; p=0.004). Previous right bundle branch block (odds ratio [OR] 6.11, 95% confidence interval [CI]: 3.19-11.73; p<0.001) was associated with an increased risk of PPI at 30 days, whereas the use of the ACURATE neo (OR 0.50, 95% CI: 0.31-0.81; p=0.005) was associated with a decreased risk. One-year mortality was similar in patients with and without new PPI. A total of 9.4% of patients developed persistent LBBB at 30 days, with higher incidences in CoreValve Evolut recipients (13.4% vs 5.5%; p=0.007). New LBBB at 30 days was associated with lower ejection fraction at 1 year (65.7%±11.0 vs 69.1%±7.6; p=0.041)., Conclusions: New LBBB and PPI rates were lower in ACURATE neo compared to CoreValve Evolut recipients. The ACURATE neo valve was associated with a lower risk of PPI at 30 days. No effect on 1-year mortality was determined for PPI at 30 days, while LBBB at 30 days was associated with reduced ejection fraction at 1 year.

Background: Despite the extensive use of real-world data for retrospective, observational clinical research, our understanding of how real-world data might increase the efficiency of data collection in patient-level randomized clinical trials is largely unknown. The structure of real-world data is inherently heterogeneous, with each source electronic health record and claims database different from the next. Their fitness-for-use as data sources for multisite trials in the United States has not been established., Methods: For a subset of participants in the HARMONY Outcomes Trial, we obtained electronic health record data from recruiting sites or Medicare claims data from the Centers for Medicare & Medicaid Services. For baseline characteristics and follow-up events, we assessed the level of agreement between these real-world data and data documented in the trial database., Results: Real-world data-derived demographic information tended to agree with trial-reported demographic information, although real-world data were less accurate in identifying medical history. The ability of real-world data to identify baseline medication usage differed by real-world data source, with claims data demonstrating substantially better performance than electronic health record data. The limited number of lab results in the collected electronic health record data matched closely with values in the trial database. There were not enough follow-up events in the ancillary study population to draw meaningful conclusions about the performance of real-world data for identification of events. Based on the conduct of this ancillary study, the challenges and opportunities of using real-world data within clinical trials are discussed., Conclusion: Based on a subset of participants from the HARMONY Outcomes Trial, our results suggest that electronic health record or claims data, as currently available, are unlikely to be a complete substitute for trial data collection of medical history or baseline lab results, but that Medicare claims were able to identify most medications. The limited size of the study population prevents us from drawing strong conclusions based on these results, and other studies are clearly needed to confirm or refute these findings.

Background: The Academic Research Consortium - High Bleeding Risk (ARC-HBR) initiative defined conditions associated with percutaneous coronary intervention (PCI)-related bleeding., Aims: We sought to further explore these HBR conditions in the setting of transcatheter aortic valve replacement (TAVR)., Methods: Patients from the SCOPE 2 trial were stratified by their bleeding risk status based on the ARC-HBR definitions. Baseline and procedural characteristics, as well as key clinical outcomes including Bleeding Academic Research Consortium (BARC) 3-5 bleeding, were compared in ARC-HBR positive (HBR+) and ARC-HBR negative (HBR-) patients., Results: Of 787 patients randomised in SCOPE 2 and included in this study, 633 were HBR+ (80.4%). Compared with HBR- patients, those HBR+ were older and more frequently presented with diabetes, a history of coronary artery disease, atrial fibrillation, prior cerebrovascular accident, and a Society of Thoracic Surgeons predicted risk of 30-day mortality (STS-PROM) (4.9±2.9% vs 3.3%±2.1%; p<0.0001). In addition, HBR+ patients were more frequently on oral anticoagulation therapy. At 1 year, HBR+ patients had higher rates of all-cause death (12.4% vs 4.3%, respectively, risk difference 8.09%; 95% confidence interval [CI]: 3.76-12.41; p=0.0002); the rates of BARC 3-5 type bleeding were relatively high but not statistically different compared with HBR- patients (7.7% vs 6.1%, risk difference 1.67%; 95% CI: -2.72 to 6.06; p=0.46). Subgroup analyses for bleeding events showed no significant interaction in terms of STS-PROM score, age, or medications., Conclusions: The ARC-HBR criteria failed to isolate a subgroup of patients at higher bleeding risk in TAVR patients from a randomised trial. These findings have potential implications, especially for the selection of post-TAVR antithrombotic regimens based on individual bleeding-risk profiles. Specific HBR criteria should be defined for TAVR patients.

Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of Na V 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNa V 1.5 channel and voltage clamp electrophysiology to quantify the potency (half-maximal inhibitory concentration) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late Na V 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak Na V 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder., (© 2022 GSK. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Existing individual-level human data cover large populations on many dimensions such as lifestyle, demography, laboratory measures, clinical parameters, etc. Recent years have seen large investments in data catalogues to FAIRify data descriptions to capitalise on this great promise, i.e. make catalogue contents more Findable, Accessible, Interoperable and Reusable. However, their valuable diversity also created heterogeneity, which poses challenges to optimally exploit their richness., Methods: In this opinion review, we analyse catalogues for human subject research ranging from cohort studies to surveillance, administrative and healthcare records., Results: We observe that while these catalogues are heterogeneous, have various scopes, and use different terminologies, still the underlying concepts seem potentially harmonizable. We propose a unified framework to enable catalogue data sharing, with catalogues of multi-center cohorts nested as a special case in catalogues of real-world data sources. Moreover, we list recommendations to create an integrated community of metadata catalogues and an open catalogue ecosystem to sustain these efforts and maximise impact., Conclusions: We propose to embrace the autonomy of motivated catalogue teams and invest in their collaboration via minimal standardisation efforts such as clear data licensing, persistent identifiers for linking same records between catalogues, minimal metadata 'common data elements' using shared ontologies, symmetric architectures for data sharing (push/pull) with clear provenance tracks to process updates and acknowledge original contributors. And most importantly, we encourage the creation of environments for collaboration and resource sharing between catalogue developers, building on international networks such as OpenAIRE and research data alliance, as well as domain specific ESFRIs such as BBMRI and ELIXIR., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (IMIA and Thieme. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial., Methods and Analysis: We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups., Ethics and Dissemination: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20&#95;012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences., Competing Interests: Competing interests: PJB is funded by a GSK PhD studentship. CC has received consultation, advisory board membership or research funding from the Ontario Ministry of Health, Sanofi, Pfizer, Leo Pharma, Astellas, Janssen, Amgen, Boehringer-Ingelheim and Baxter. In 2018 she co-chaired a KDIGO potassium controversies conference sponsored at arm’s length by Fresenius Medical Care, AstraZeneca, Vifor Fresenius Medical Care, relypsa, Bayer HealthCare and Boehringer Ingelheim. She co-chairs the cloth mask knowledge exchange, a stakeholder group that includes cloth mask manufacturers and fabric distributors. MC is an employee of, and own shares in, GSK., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The ACURATE neo™ is a novel, second-generation self-expanding supra-annular transcatheter heart valve (THV). The objective of this multi-centre registry is to assess the safety, clinical utility, and impact of 'learning-curve-experience' (LCE) on transcatheter aortic valve replacement outcomes in the United Kingdom (UK) and Ireland., Methods: We prospectively collected data from seven ACURATE neo™ THV implanting centres (n = 484) between February 2016 and November 2020. We compared mortality rates and outcomes in the LCE group (n = 120) compared to next successive 120 cases., Results: The mean age of the cohort was 81.9(SD: 6.1) years and the majority were in the moderate risk category (EuroSCORE-II):3.3(SD: 3). The 97.5% of cases were performed under local anesthetic. The valve was successfully deployed in 98.8% of cases. The survival rate at 30 days was 97.9%. The incidence of stroke was 2.5%. Life threatening bleeding occurred in 0.6% of cases and vascular access complications occurred in 21 (4.3%) patients. Implantation-related conduction abnormalities occurred in 8.3% but only 5.6% required a PPM. The successful valve deployment occurred in 96% of the patients in the LCE group compared to 100% in the other group (p = 0.04; OR-2[CI 1.7-2.3]). The mortality rates at 30 days (1.7% vs. 1.7%) and 1 year (1.9% vs. 2.7%) were comparable between the two groups., Conclusions: This study represents the largest published UK and Ireland real-world experience of the ACURATE neo™ valve. The procedural success rates and safety outcomes were excellent and endorse its utility in clinical practice. The LCE appears to have an impact on the successful valve deployment but without translating into short-term or long-term outcomes., (© 2021 Wiley Periodicals LLC.)

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project-Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation-with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To assess the use and safety of free combination therapy (dutasteride and tamsulosin), dutasteride monotherapy, or tamsulosin monotherapy in patients with benign prostatic hyperplasia (BPH)., Methods: This non-interventional retrospective cohort study used claims data from the Korea Health Insurance Review and Assessment-National Patient Sample database. Patients with BPH ≥ 40 years of age receiving combination therapy (dutasteride 0.5 mg and tamsulosin 0.4 mg daily) or dutasteride 0.5 mg, or tamsulosin 0.4 mg daily dose between 2012 and 2017 were included. The frequency, duration of treatment and risk of any adverse event (AE) or serious AE (SAE) was compared for combination therapy versus each monotherapy using non-inferiority testing., Results: Of 14,755 eligible patients, 1529 (10.4%) received combination therapy, 6660 (45.1%) dutasteride monotherapy, and 6566 (44.5%) tamsulosin monotherapy. The proportion of patients treated with combination therapy exceeded the pre-specified 3% threshold for 'frequent' use. Safety results indicated a similar risk of any AE and SAE irrespective of treatment group. The adjusted relative risk for any AE over the treatment observation period comparing combination therapy with dutasteride monotherapy was 1.07 (95% confidence interval [CI] 1.03, 1.12), and with tamsulosin monotherapy was 0.98 (95% CI 0.95, 1.02) demonstrating non-inferiority. The adjusted relative risk for any SAE was 1.07 (95% CI 0.66, 1.74) and 0.90 (95% CI 0.56, 1.45), compared with dutasteride and tamsulosin monotherapy, respectively. Although the SAE results did not statistically demonstrate non-inferiority of combination therapy based on pre-specified margins, the 95% CI for the risk ratio estimates included the null with a lower limit below the non-inferiority margins, indicating no meaningful differences in SAE risk between groups. Absolute SAE risks were low., Conclusion: Combination therapy with dutasteride and tamsulosin is frequently used in real-world practice in South Korea for treatment of BPH and demonstrates a safety profile similar to either monotherapy., (© 2021. The Author(s).)

Background: Few randomized trials have compared bioprostheses for transcatheter aortic valve replacement, and no trials have compared bioprostheses with supra-annular design. The SCOPE 2 trial (Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation 2) was designed to compare the clinical outcomes of the ACURATE neo and CoreValve Evolut bioprostheses for transcatheter aortic valve replacement., Methods: SCOPE 2 was a randomized trial performed at 23 centers in 6 countries between April 2017 and April 2019. Patients ≥75 years old with an indication for transfemoral transcatheter aortic valve replacement as agreed by the heart team were randomly assigned to receive treatment with either the ACURATE neo (n=398) or the CoreValve Evolut bioprostheses (n=398). The primary end point, powered for noninferiority of the ACURATE neo bioprosthesis, was all-cause death or stroke at 1 year. The key secondary end point, powered for superiority of the ACURATE neo bioprosthesis, was new permanent pacemaker implantation at 30 days., Results: Among 796 randomized patients (mean age, 83.2±4.3 years; mean Society of Thoracic Surgeons Predicted Risk of Mortality score, 4.6±2.9%), clinical follow-up information was available for 778 (98%) patients. Within 1 year, the primary end point occurred in 15.8% of patients in the ACURATE neo group and in 13.9% of patients in the CoreValve Evolut group (absolute risk difference, 1.8%, upper 1-sided 95% confidence limit, 6.1%; P =0.0549 for noninferiority). The 30-day rates of new permanent pacemaker implantation were 10.5% in the ACURATE neo group and 18.0% in the CoreValve Evolut group (absolute risk difference, -7.5% [95% CI, -12.4 to -2.60]; P =0.0027). No significant differences were observed in the components of the primary end point. Cardiac death at 30 days (2.8% versus 0.8%; P =0.03) and 1 year (8.4% versus 3.9%; P =0.01), and moderate or severe aortic regurgitation at 30 days (10% versus 3%; P =0.002) were significantly increased in the ACURATE neo group., Conclusions: Transfemoral transcatheter aortic valve replacement with the self-expanding ACURATE neo did not meet noninferiority compared with the self-expanding CoreValve Evolut in terms of all-cause death or stroke at 1 year, and it was associated with a lower incidence of new permanent pacemaker implantation. In secondary analyses, the ACURATE neo was associated with more moderate or severe aortic regurgitation at 30 days and cardiac death at 30 days and 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03192813.

Background: Integration of animal and human data to assess potential risks of the use of medications in pregnancy is important. A qualitative weight of evidence process enables all available evidence to be considered in a consistent, systematic manner., Methods: We aim to describe the weight of evidence methodology utilized by the authors, a summary of which was presented at the 59th Annual Meeting of the Teratology Society entitled "Integration of Human and Animal Data to Inform Medication Use in Pregnant Women." The qualitative weight of evidence process evaluates data that inform on a potential relationship between an adverse pregnancy outcome and a medication exposure. An interdisciplinary panel evaluates all available human and animal data related to the question of interest. Study quality assessments of both human and animal data are incorporated. The evaluation assesses gaps in the data from the following areas: (a) strength, (b) specificity, (c) consistency, (d) dose response relationship, (e) methodological considerations, and (f) biological plausibility for the potential association of interest., Results: The panel integrates all the information to arrive at an assessment of the evidence and provides recommendations, which may include obtaining more specific information. We provide examples of how the authors apply this process at a pharmaceutical company for evaluation of potential postmarketing safety issues regarding medications and pregnancy outcomes., Conclusions: This weight of evidence method improves the ability to integrate published literature and other data sources to assess the potential risks of medication use in pregnant women and inform future drug safety studies., (© 2020 Wiley Periodicals LLC.)

Introduction: No-reflow (NR) phenomenon is characterised by the failure of myocardial reperfusion despite the absence of mechanical coronary obstruction. NR negatively affects patient outcomes, emphasising the importance of prediction and management. The objective was to evaluate the incidence and independent predictors of NR in patients presenting with ST-elevation myocardial infarction (STEMI)., Methods: This was a single-centre prospective case-control study. Cases were subjects who suffered NR, and the control comparators were those who did not. Clinical outcomes were documented. Salient variables relating to the patients and their presentation, history and angiographical findings were compared using one-way analysis of variance or χ 2 test. Multiple regression determined the independent predictors, and a risk score was established based on the β coefficient., Results: Of 173 consecutive patients, 24 (13.9%) suffered from NR, with 46% occurring post stent implantation. Patients with NR had increased risk of in-hospital death (OR 7.0, 95% CI 1.3 to 36.7, p=0.022). From baseline variables available prior to percutaneous coronary intervention, the independent predictors of NR were increased lesion complexity, admission systolic hypertension, weight of <78 kg and history of hypertension. Continuous data were transformed into best-fit binary variables, and a risk score was defined. Significant difference was demonstrated between the risk score of patients with NR (4.1±1) compared with controls (2.6±1) (p<0.001), and the risk score was considered a good test (area under the curve=0.823). A score of ≥4 had 75% sensitivity and 76.5% specificity., Conclusion: Patients with NR have a higher rate of mortality following STEMI. Predictors of NR include lesion complexity, systolic hypertension and low weight. Further validation of this risk model is required., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Invasive group B Streptococcus (GBS) remains a leading cause of illness and death among infants globally. We conducted prospective and retrospective laboratory-based surveillance of GBS-positive cultures from infants <3 months of age in 18 hospitals across China during January 1, 2015-December 31, 2017. The overall incidence of GBS was 0.31 (95% CI 0.27-0.36) cases/1,000 live births; incidence was 0-0.76 cases/1,000 live births across participating hospitals. The case-fatality rate was 2.3%. We estimated 13,604 cases of GBS and 1,142 GBS-associated deaths in infants <90 days of age annually in China. GBS isolates were most commonly serotype III (61.5%) and clonal complex 17 (40.6%). Enhanced active surveillance and implementation of preventive strategies, such as maternal GBS vaccination, warrants further investigation in China to help prevent these infections.

Access site vascular complications remain relatively frequent following trans-femoral (TF) transcatheter aortic valve implantation (TAVI), and are associated with significant morbidity as well as increased mortality. Suture-based vascular closure devices (VCD) are widely used and have been demonstrated to reduce the rate of vascular complications. However, failure to achieve adequate hemostasis following their use occurs in some cases, and may necessitate surgical escalation. We report a case of a patient with complex ileo-femoral anatomy in whom the novel plug-based MANTA VCD was successfully used to achieve hemostasis post-TF TAVI following failed closure with ProGlides ® . A 79-year-old male underwent valve-in-valve TF TAVI for the treatment of severe degenerative disease of a Mitroflow prosthesis. Pre-procedural imaging demonstrated tortuous and calcific ileo-femoral arteries and torrential bleeding occurred following sheath removal and deployment of the pre-sited ProGlides ® . Consideration was given to surgical intervention but the decision was taken to attempt rescue closure using a 14F MANTA VCD. Hemostasis was successfully achieved and the patient recovered well. Early data assessing the efficacy of the MANTA VCD have been promising and this relatively novel technology appears to be a viable alternative to established VCDs. < Learning objective: Access site vascular complications remain relatively frequent following trans-femoral (TF) transcatheter aortic valve implantation (TAVI), and are associated with significant morbidity and mortality. The MANTA vascular closure device (VCD) appears to be a promising alternative to established VCDs. Early data from clinical trials suggests that the MANTA may be non-inferior to currently used suture-based VCDs. Furthermore, experience from our case demonstrates its utility as a rescue device for emergency hemostasis when more traditional measures have failed.>.

Trans-catheter aortic valve implantation (TAVI) has become an established treatment for inoperable and high-surgical risk patients with severe, symptomatic aortic stenosis (AS). Post-procedural acute kidney injury (AKI) is a frequent complication following TAVI and is associated with increased mortality. Patients with pre-existing chronic renal impairment are at particularly high risk. The etiology of post-TAVI AKI is multi-factorial, but the principal procedural issues are contrast-induced nephropathy, and renal hypoperfusion secondary to intra-procedural hypotension. We report a case of a TAVI in an 80-year-old patient with severe AS and significant chronic kidney disease (CKD), which was carried out without the use of contrast and with minimal procedural hypotension. Pre-procedural imaging was carried out using 3D trans-esophageal echocardiography (TEE) rather than computed tomography (CT) to avoid contrast administration. The Lotus valve (Boston Scientific, Marlborough, MA, USA) was chosen due to a number of design features which minimize both the need for contrast injection and procedural hypotension during valve positioning and deployment. The procedure was carried out successfully and produced an excellent result with no decline in renal function. We believe that the approach of using TEE and the mechanically-expanded Lotus valve illustrates an important therapeutic approach in patients with severe CKD. < Learning objective: Post-procedural acute kidney injury (AKI) is a frequent complication following trans-catheter aortic valve implantation (TAVI), and is associated with increased mortality. The principal procedural issues are contrast-induced nephropathy and intra-procedural hypotension. Our case report demonstrates how TAVI can be performed with zero contrast and minimization of procedural hypotension, facilitated by the use of trans-esophageal echocardiography and the mechanically-expanded Lotus valve. This approach should only be used in exceptional circumstances, but can be particularly relevant for patients with pre-existing chronic renal impairment, who are at increased risk of post-TAVI AKI.>.

Background: Meningococcal conjugate vaccination is recommended in the United States. This study evaluates the safety of quadrivalent meningococcal conjugate vaccine in a cohort aged 11 to 21 years., Methods: This cohort study with self-controlled case-series analysis was conducted at Kaiser Permanente Southern California. Individuals receiving MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, during September 30, 2011 to June 30, 2013, were included. Twenty-six prespecified events of interest (EOIs), including neurologic, rheumatologic, hematologic, endocrine, renal, pediatric, and pediatric infectious disease EOIs, were identified through electronic health records 1 year after vaccination. Of these, 16 were reviewed by case review committees. Specific risk and comparison windows after vaccination were predefined for each EOI. The relative incidence (RI) and 95% confidence intervals (CIs) were estimated through conditional Poisson regression models, adjusted for seasonality., Results: This study included 48 899 vaccinated individuals. No cases were observed in the risk window for 14 of 26 EOIs. The RI for Bell's palsy, a case review committee-reviewed EOI, was statistically significant (adjusted RI: 2.9, 95% CI: 1.1-7.5). Stratified analyses demonstrated an increased risk for Bell's palsy in subjects receiving concomitant vaccines (RI = 5.0, 95% CI = 1.4-17.8), and no increased risk for those without concomitant vaccine (RI = 1.1, 95% CI = 0.2-5.5)., Conclusions: We observed a temporal association between occurrence of Bell's palsy and receipt of MenACWY-CRM concomitantly with other vaccines. The association needs further investigation as it could be due to chance, concomitant vaccination, or underlying medical history predisposing to Bell's palsy., (Copyright © 2017 by the American Academy of Pediatrics.)

Aims: To compare all-cause and Alzheimer's disease (AD)-related healthcare resource utilization (HCRU) by cognitive stage., Methods and Materials: This retrospective study analyzed insurance claims data linked to electronic health records (01/01/2015-12/31/2021). Patients with ≥1 cognitive assessment (Mini-Mental State Examination or Montreal Cognitive Assessment) and ≥1 medical or pharmacy claim for an AD diagnosis or AD medications were included. Inverse probability of treatment weighting (IPTW) was used to address potential confounding. All-cause and AD-related HCRU were summarized per patient per year (PPPY) and compared between early AD and advanced AD cohorts (defined according to cognitive scores) using generalized linear regression models; adjusted incidence rate ratios (IRRs), and 95% confidence intervals (CI) were reported., Results: A total of 193 patients were included (median age: 82 years; 63.2% female), 108 with early AD and 85 with advanced AD, with similar mean follow up. All-cause HCRU, on average, was similar between early AD and advanced AD cohorts (37.4 PPPY and 38.9 encounters PPPY, respectively). For AD-related HCRU, patients with early AD had fewer encounters PPPY, on average, than patients with advanced AD (1.26 and 3.88 encounters, respectively). Following IPTW adjustment, the advanced AD cohort had significantly higher overall AD-related HCRU (IRR: 3.64 [95% CI: 1.96-6.75], p  < 0.001) and outpatient visits (IRR: 2.76 [95% CI: 1.68-4.54], p  < 0.001) compared to the early AD cohort., Limitations: The relatively small sample size of patients with linked claims and cognitive score data limited the ability to assess contribution of all encounter types to HCRU trends, as well as generalizability to the broader AD population., Conclusions: Although all-cause HCRU was similar, patients with advanced AD incurred higher AD-related HCRU compared to patients living with early AD. Further research is needed to determine whether interventions earlier in disease progression can mitigate the AD-related healthcare burden for patients with advanced AD.

Introduction: Infectious causes are a significant contributor to morbidity and mortality in neonates and young infants. Immunization of pregnant women to protect the mother and/or her infant is gaining momentum due to the benefits of this strategy demonstrated in numerous implemented strategies (Maternal and Neonatal Tetanus Elimination Initiative) and clinical trials. Reluctance by regulators, participants and healthcare providers to include pregnant women in clinical trials is considerable, but reducing. Infectious disease burden, and therefore need for interventions to reduce morbidity and mortality in mothers and infants, is highest in low-middle income countries (LMIC), however, reliable background data on adverse pregnancy outcomes and lack of experience in clinical trials and community opinions on immunization during pregnancy are not well documented., Methods: We used our experiences in conducting two clinical studies in pregnant women in South Africa to illustrate the challenges experienced and lessons learnt which may benefit others working in the maternal immunization field., Results: Accurate gestational age assessment, which is essential for clinical trials, is challenging in LMIC due to limited access to early ultrasound examinations, and unreliable assessment by history (last menstrual period date) and physical examination (symphyseal-fundal height). Concomitant administration of recommended vaccines has previously been avoided in clinical trials; however, this limitation could impact the potentially beneficial interventions that participants can access during antenatal care. Women in LMIC have a higher burden of concomitant illnesses (e.g. HIV infection, malaria and anaemia) and adverse pregnancy outcomes (e.g. stillbirth) than pregnant women in higher income countries. Availability of local data is essential for safety monitoring committees to identify vaccine-related adverse event triggers., Conclusion: Immunization of pregnant women to reduce disease burden in them and their infants is promising, and women in high-risk settings should be included in trials (Clinical trial registry number: 'Study A': NCT01193920, 'Study B': NCT01888471)., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Limited epidemiological data on the association between maternal rectovaginal group B Streptococcus (GBS) colonisation and stillbirth makes assessment of antenatal interventions for GBS stillbirth difficult., Objectives: To systematically review the existing literature and evaluate the incidence of GBS-related stillbirth by region up to March 2015., Search Strategy: A systematic review of the published literature was completed using PubMed/MEDLINE, EMBASE, LILACS, and Cochrane Library, with Medical Subject Headings (MeSH) and search terms based upon the Centers for Disease Control and Prevention's (CDC) Active Bacterial Core Surveillance (ABCs) GBS-related stillbirth definition and chorioamnionitis., Selection Criteria: Studies reporting original data on GBS-related stillbirth occurring ≥20 weeks of gestation, with GBS confirmed by autopsy or by culture from the placenta, amniotic fluid, or other normally sterile site samples from the stillborn., Data Collection and Analysis: Descriptive analyses were performed with the absolute GBS-related stillbirth rates and proportion of stillbirths attributed to GBS calculated per study where possible. Differences in stillbirth definitions did not allow for pooled estimates to be calculated., Main Results: Seventeen studies reported GBS-related stillbirth rates varying from 0.04 to 0.9 per 1000 births, with the proportion of stillbirths associated with GBS ranging from 0 to 12.1%. Most studies reported data from before the year 2000 and from high-income countries., Conclusions: The sparsely available epidemiological evidence was not reported consistently, emphasising the importance of standardised stillbirth definitions and diagnostic methods to optimally assess the effectiveness of any future antenatal interventions. Timing of stillbirth, GBS serotype, and global diversity were gaps in the current evidence., Tweetable Abstract: Systematic review finds Group B Streptococcus causes up to 12.1% of stillbirths, but more research is needed., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objectives: To estimate the incidence, case fatality ratio and serotypes associated with early-onset (EOD) and late-onset (LOD) invasive GBS disease in infants in southern mainland China., Methods: During the six-month study period, infants aged ≤ 90 days with culture-confirmed GBS disease born in the study hospitals or elsewhere, but presenting to a study hospital, were enrolled. GBS-positive cultures were genotyped, serotyped and sequence typed. The incidence rate was calculated for infants born in the study hospitals, and case fatality ratio and causative serotypes identified for all enrolled GBS cases., Results: Ten cases were enrolled: 2 EOD cases born in the study hospitals and 8 LOD cases born elsewhere. Incidence rate was 0.28 (95% confidence interval: 0.08-1.03, n = 2/7061 successfully followed-up consenting subjects); no cases resulted in fatality. In the 8 GBS isolates available for typing, 4 serotypes (Ia, Ib, III and V) and 5 multi-locus sequence types (1, 10, 12, 17 and 23) were identified., Conclusions: This is the first study specifically investigating the incidence of GBS invasive disease in infants in southern mainland China. Incidence and case fatality were low but further research is needed in larger, more diverse cohorts to estimate disease burden for the broader Chinese population.

Group B Streptococcus (GBS) is a leading cause of meningitis and sepsis in infancy, but burden of disease data are scarce for Asia. We performed two hospital-based, prospective, descriptive, observational studies using similar protocols in the Philippines and Thailand to evaluate neonatal GBS disease epidemiology. Infants aged <90 days with a GBS-positive culture from normally sterile sites using routine microbiological standards were eligible for inclusion. Awareness of GBS symptoms was raised by informing all women at delivery and follow-up for 90 days post-delivery. Infections were classified as early onset disease (EOD) if they occurred within 6 days of birth and late Onset disease (LOD) if they occurred 7-89 days after birth. Due to ethical requirements in Thailand, consent for study participation, including periodic post-discharge telephone calls, was obtained at delivery. Parents in the Philippines gave consent for study participation at case identification. The clinical outcomes of GBS infections were recorded. During the 6-month study period, two cases (one fatal) of EOD were identified among 8,409 live births at the study hospitals in Thailand and three cases (two fatal) of EOD were identified among 11,768 live births reported at the study hospitals in the Philippines. Incidence rates per 1,000 live births were 0.2 (95% CI: 0.0-0.8) and 0.3 (95% CI: 0.1-0.8) in Thailand and the Philippines, respectively. There were no cases of reported LOD. The low number of cases precluded analysis of serotype distribution and case fatality rates. Large epidemiological studies are needed to better understand the factors influencing GBS infection incidence in Asia.

Purpose: The International Lamotrigine Pregnancy Registry monitored for a signal of a substantial increase in the frequency of major congenital malformations associated with lamotrigine exposures in pregnancy over an 18-year period. Key methodological lessons are discussed., Methods: The strengths and weaknesses of the Registry were assessed using quantifiable methodological and operational parameters including enrollment, completeness of exposure and outcome data reporting, and lost to follow-up. The choice of comparator groups and stopping rules for registry closure were critically evaluated., Results: The reliance on voluntary reporting was associated with a clustered geographical distribution of registered pregnancies. The enrollment rate increased over time with new approvals and indications for lamotrigine and publication of interim data. Reporter burden was minimized through a streamlined data collection approach resulting in a high level of completeness of exposure and primary outcome data. Lost to follow-up rates were high (28.5% overall) representing a major limitation; incentives to increase the completeness of reporting failed to reduce rates. A lack of an internal comparator group complicated data interpretation; but external comparisons with multiple external groups allowed an assessment of consistency of outcome data across multiple data sources. A lack of a priori closure criteria prolonged the life of the Registry, and consideration of regulatory guidelines on this subject is encouraged at the time of conception of future registries., Conclusions: A successful pregnancy exposure registry requires ongoing flexibility and continuous re-assessment of enrollment, recruitment, and retention methods and the availability of comparison data, throughout its lifecycle., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose of Review: The aim is to describe and quantify the association between genitourinary tract infections and preterm birth., Recent Findings: Recent studies confirm the importance of identifying and treating both asymptomatic and symptomatic bacteriuria in pregnancy, which is reflected in current antenatal screening guidelines. These guidelines do not recommend routine screening for other asymptomatic lower genital infections (bacterial vaginosis, trichomonas and gonorrhoea) reflecting inconsistent study results, which may reflect differences in study design, size, diagnostics and the timing of screening in pregnancy. Screening for group B Streptococcus (GBS) late in pregnancy is recognized to reduce neonatal disease, but there is a striking lack of robust studies, specifically randomized controlled trials (RCTs), considering the effect of GBS screening earlier in pregnancy on adverse pregnancy outcomes., Summary: The potential for screening and treatment of genitourinary tract infections in pregnancy to reduce preterm birth rates has been demonstrated in some RCTs. Current guidelines do not reflect these data because of inconsistencies across the body of evidence. There is a need for robust RCTs to confirm or refute earlier data, to inform the optimal timing for screening in pregnancy and to better quantify the contribution of individual infections to the burden of preterm birth.

The authors explore the use of third generation echo contrast to define plaque in the ascending aorta and exclude more invasive procedures.

Entrapment of the rotablator burr within heavily calcified lesions is a recognized complication, which usually necessitates sternotomy and open surgical intervention to retrieve the trapped burr. In some cases, the trapped burr can be retrieved using simple traction, but this is potentially hazardous with possible trauma and perforation of the vessel. Passing a wire alongside the trapped burr with ballooning to free the burr can be attempted. We describe a novel technique to remove a trapped rotablator burr from a heavily calcified lesion using counter-traction with a GuideLiner, child-in-a-mother catheter, which successfully removed the entrapped burr without the need for surgery when simple traction alone had been ineffective., (Copyright © 2011 Wiley Periodicals, Inc.)

Objective: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure., Methods: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates., Results: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed., Discussion: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

Objectives: To monitor for a signal of major teratogenicity by determining the risk of all major defects following in utero exposure to sumatriptan and naratriptan. To monitor for unusual patterns of birth defects that might suggest teratogenicity., Background: The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to these drugs in pregnancy is likely. The Sumatriptan and Naratriptan Pregnancy Registry captures data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity., Methods: Healthcare professionals from anywhere in the world can enroll, on a voluntary basis, women exposed to sumatriptan or naratriptan during their pregnancies in this primarily prospective, observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure., Results: Data are available on pregnancy outcomes from 599 exposed women. Among 479 first-trimester exposures to sumatriptan, 20 outcomes with major birth defects were reported (4.6%, 95% confidence interval [CI] 2.9-7.2%). The risk of major birth defects following exposure to sumatriptan during any trimester was 4.7% (95% CI 3.1-7.0%). No distinctive pattern of major birth defects among exposed infants was noted. There were 50 first-trimester exposures to naratriptan with 1 reported birth defect in a fetus with exposure to both sumatriptan and naratriptan., Conclusions: The risk of all major birth defects following first-trimester exposure to sumatriptan was 4.6% (95% CI 2.9-7.2%). This coupled with a consistent failure of additional epidemiological studies to observe a signal for major teratogenicity gives a level of reassurance concerning the safety of sumatriptan in pregnancy. There are too few data on naratriptan to draw definitive conclusions, and the sample size for sumatriptan remains too small to detect any but very large increases in specific birth defects.

Background: A recent UK audit showed that a significant proportion of patients who received pacemakers had pacing indications previously overlooked, leading to significant delays to pacemaker implantation., Aim: To investigate the reasons for, and morbidity associated with, overlooked pacing indications., Design: Prospective observational study in a UK regional pacing centre and its referring district hospitals., Methods: Hospital records from referring and implanting centres were reviewed for 95 consecutive patients undergoing first pacemaker implant to determine symptoms, investigations and hospitalisations occurring after documentation of a pacing indication., Results: Thirty-three of ninety-five patients (35%) had a pacing indication overlooked, which was Class I in 14 patients and Class IIa in 19. Reasons for not making a pacing referral in these patients included: failure to recognize the indication in 14, making adjustments to potentially culprit medication in 15 and requesting additional 'confirmatory' tests in 4. Twenty-six patients (79%) with missed indications experienced adverse events after documentation of an indication, and before receiving a pacemaker: 23 had ongoing symptoms (including one cardiac arrest), three received temporary pacing wires and 18 were hospitalized with symptoms related to cardiac rhythm. Twenty-seven patients (82%) had a total of 38 additional specialist investigations after documentation of a pacing indication., Conclusion: Documentation of an indication for pacing failed to trigger referral for permanent pacing in 35% of patients. This failure led to significant delays, morbidity and use of health service resource, which may have been avoided if timely recognition of the pacing indication had prompted referral. Failure to recognize pacing indications and reassessing symptoms and repeating investigation after changes to medication, often required for the management of associated tachyarrhythmias or other medical conditions, contribute to these delays, perhaps unnecessarily.

Background: Regional variation in permanent pacemaker (PPM) implantation rates is well described, the reasons for which are unclear. Significant delays to PPM implantation in UK practice were described 20 years ago, but contemporary data are lacking., Aim: To investigate delays to PPM implantation and their causes., Design: Prospective observational study in a UK regional pacing centre and its referring district hospitals., Methods: A total of 95 consecutive patients receiving first PPM implant for bradycardia indications from 1 June 2006 to 31 August 2006 were included. Hospital records from the referring and implanting centres were reviewed to determine the timings of: symptom onset; first hospital contact; documented pacing indication (defined by 2002 ACC/AHA/NASPE guidelines); referral to implanter; and PPM implantation., Results: Forty-eight patients (51%) were referred for pacing urgently; median delay from symptoms to PPM 15 days (range 0-7332 days). Forty-seven patients (49%) were referred electively; median delay from symptoms to PPM 380 days (range 33-7505 days), P < 0.0001. Twenty-three of the 47 elective patients (49%) had previous hospitalization with symptoms suggestive of bradycardia. Thirty-three of the 95 patients (35%) had a Class I or IIa pacing indication which did not trigger a pacing referral., Conclusion: There are significant delays to PPM implantation in the United Kingdom, longer in those treated electively than those managed as emergencies. Some delays are due to 'process' problems including waiting lists, but a substantial proportion of patients had delays due to failure to refer for pacing once a pacing indication was documented.

Objectives: The primary objective was to investigate whether nonadherence to antiepileptic drugs (AEDs) is associated with increased mortality and the secondary objective to examine whether nonadherence increases the risk of serious clinical events, including emergency department (ED) visits, hospitalizations, motor vehicle accident (MVA) injuries, fractures, and head injuries., Methods: A retrospective open-cohort design was employed using Medicaid claims data from Florida, Iowa, and New Jersey from January 1997 through June 2006. Patients aged > or =18 years with > or =1 diagnosis of epilepsy by a neurologist and > or =2 AED pharmacy dispensings were selected. Medication possession ratio (MPR) was used to evaluate AED adherence on a quarterly basis with MPR > or =0.80 considered adherent and <0.80 nonadherent. The association of nonadherence with mortality was assessed using a time-varying Cox regression model adjusting for demographic and clinical confounders. Incidence rates for serious clinical events were compared between adherent and nonadherent quarters using incidence rate ratios (IRRs) with 95% CIs calculated based on the Poisson distribution., Results: The 33,658 study patients contributed 388,564 AED-treated quarters (26% nonadherent). Nonadherence was associated with an over threefold increased risk of mortality compared to adherence (hazard ratio = 3.32, 95% CI = 3.11-3.54) after multivariate adjustments. Time periods of nonadherence were also associated with a significantly higher incidence of ED visits (IRR = 1.50, 95% CI = 1.49-1.52), hospital admissions (IRR = 1.86, 95% CI = 1.84-1.88), MVA injuries (IRR = 2.08, 95% CI = 1.81-2.39), and fractures (IRR = 1.21, 95% CI = 1.18-1.23) than periods of adherence., Conclusion: These findings suggest that nonadherence to antiepileptic drugs can have serious or fatal consequences for patients with epilepsy.

Purpose: Most previous observational studies assessing cardiovascular risk associated with Cox-2 inhibitors (Cox-2is) used a case control approach, limiting the assessment of absolute risk by disease group and effect of duration of exposure. We conducted a retrospective cohort study in patients with osteoarthritis., Methods: Using the Life-link US claims database, all subjects had at least five years history in the database. Exposure was defined as the first chronic period of Cox-2i (celecoxib, rofecoxib or valdecoxib) or naproxen use. Non-users and non-chronic users of non-steroidal anti-inflammatory drug (NSAID)/Cox-2i within the osteoarthritis cohort served as the reference. The primary outcome was myocardial infarction and ischaemic stroke., Results: A cohort of 16,580 subjects were chronically exposed to celecoxib, 9800 received rofecoxib, 2907 received naproxen and 51,539 were non-chronically exposed controls. With a median follow up of 506 days, there were 2116 ischaemic events for the entire cohort. The strongest predictors of AMI/ ischaemic stroke risk were history of ischaemic stroke (HR 2.34, 2.12-2.59) and age 65+ years (HR 2.28, 2.07-2.52). For rofecoxib, (HR 1.25,1.04-1.50), the attributable risk varied from 3 per 1000 patients years in individuals aged under 65 years with no history of CVD to 19 per 1000 patients years in older individuals with a history of CVD. The hazard ratios did not change over time. Celecoxib and naproxen were not associated with increased risks., Conclusions: The attributable risk for rofecoxib varied substantially with the underlying cardiovascular risk profile, being lower in clinical trial than in clinical practice populations.

The chronic nature of epilepsy treatment, as well as the peak in incidence in children and adolescents, makes it likely that women of childbearing age will be exposed to antiepileptic drugs (AEDs). This has led to the establishment of several pregnancy registries to monitor the safety of anticonvulsants in terms of the risk of major birth defects following in utero exposure. Many registries are now approaching their second decade of data collection. With the release of substantial information on a range of AEDs (both older and newer generation drugs), it becomes increasingly important to understand how the methodological variations between cohorts may affect the risks of major birth defects being reported. This chapter explores the key methodological elements of these registries in terms of patient enrolment, the source of exposure and outcome information, outcome definition and ascertainment and comparator groups and how these elements may influence the reported risk estimates. With multiple registries collecting and releasing substantial data on AED safety in pregnancy, the chapter also reflects on how an increasing number of "signals" around increased risk of specific birth defects is likely. Possible methods for interpreting such signals, that the registries were not originally designed to detect and interpret, are also discussed.

Data from the International Lamotrigine Pregnancy Registry were analyzed to examine the effect of maximal first-trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (MBDs). Among 802 exposures, the frequency of MBDs was 2.7% (95% confidence interval [CI] 1.8-4.2%). The distribution of dose did not differ between infants with and those without MBDs (mean 248.3 milligrams per day [mg/day] and 278.9 mg/day, respectively, median 200 mg/day for both groups). A logistic regression analysis showed no difference in the risk of MBDs as a continuous function of dose (summary odds ratio [OR] per 100 mg increase =0.999, 95% CI 0.996-1.001). There was also no effect of dose, up to 400 mg/day, on the frequency of MBDs.

Background: It has been proposed that multiple sclerosis (MS) might be a sexually transmitted disorder. There is evidence that seropositivity to herpes simplex virus type 2 (HSV-2) correlates well with the number of sexual partners. Accordingly, a raised overall HSV-2 seroprevalence in MS would lend support to this theory., Materials and Methods: Serum from 497 UK subjects with clinically definite MS was tested for antibodies to HSV-2 and compared with matched historical controls from within and outside London, blood donors and genito-urinary medicine (GUM) clinics., Results: The unadjusted MS seropositivity rate was 14%. HSV-2 seroprevalence in MS patients aged 35-64 years was significantly higher overall compared with a non-London general population in an unadjusted comparison. HSV-2 seroprevalence in London MS patients compared with London blood donors was significantly greater irrespective of age, but the MS seropositive rate was lower than GUM clinic attenders. In a logistic regression analysis, increased age, female sex and MS diagnosis all independently increased the odds of seropositivity after adjustment for each other., Conclusion: It is concluded that there is increased likelihood of HSV-2 exposure in patients with MS and this may indicate a higher than average number of partners.

Objective: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry., Methods: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects., Results: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy., Conclusions: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects.

Seroprevalence data among ethnic minority groups within England and Wales are rare. An opportunistic approach was taken to test residual oral fluid, collected from pre-adolescent school children from an ethnically diverse region of northwest England, for anti-hepatitis A virus (HAV) IgG. Individual data on ethnicity and country of birth were also available. Of the 257 children who consented to participate, 62% were of South Asian ethnic origin. The overall seroprevalence was 18.8%, higher than 13.1% reported from a recent population-based survey in England and Wales among a mainly Caucasian population of the same age. The only factor significantly associated with HAV seropositivity in a multivariable logistic regression model was birth of the child abroad. Association with the place of birth of the child, but not that of the parent indicates that infection within this group occurs mainly abroad. Larger studies among ethnic minority groups are needed to investigate this claim further.

Population-based seroprevalence studies provide important data on susceptible groups and the potential for future outbreaks. However, the invasive nature of serum collection has limited studies. This paper describes the first postal population-based survey using noninvasive oral fluid technology to collect antibody prevalence data in conjunction with extensive risk factor data to assess the distribution of immunity to common viral infections in England and Wales. These results pertain to hepatitis A virus (HAV). Approximately 5,500 oral fluid samples were collected between August 2001 and May 2002, as well as individual risk factor data through a questionnaire, from persons aged less than 45 years randomly sampled from general practices countrywide. Samples were tested for immunoglobulin G-specific antibody marking a past infection or immunity to HAV using an antibody-capture enzyme-linked immunosorbent assay. The age-specific HAV seroprevalences indicated a low incidence of infection (overall seroprevalence of 18.9% (95% confidence interval: 17.0, 20.9) and of 9.2% (95% confidence interval: 7.1, 11.3) after the exclusion of vaccinees). Vaccination proved the most important determinant of seropositivity. Ethnic minority groups were underrepresented, and adjustment increased the overall prevalence to 20.1% and to 12.1% in unvaccinated individuals. The availability of comprehensive risk factor data allowed the description of two risk profiles related to natural infection and vaccination.

Objectives: There have been few recent population-based herpes simplex virus type 2 (HSV-2) seroprevalence studies in England, but reports from the United States have indicated a 30% rise in HSV-2 seroprevalence between 1976 and 1994. This study aimed to ascertain trends in HSV-2 infection in England between 1991 and 2000., Study Design: Anonymized serum residues collected through public health laboratories across England from individuals aged 16 to 64 years seeking health care through the National Health Service in 1991 (n = 2259) and 2000 (n = 3646) were tested for anti-HSV-2 IgG using the HerpeSelect 2 enzyme-linked immunosorbent assay IgG (Focus)., Results: In 9 sites across England, the age- and sex-standardized HSV-2 seroprevalence was 9.7% (95% confidence interval, 8.4-11.0%). Data from 4 sites common to both study years indicated no change in HSV-2 seroprevalence between 1991 and 2000., Conclusions: After adjustment for age, sex, and geographic location, there was no evidence of a change in seroprevalence between 1991 and 2000.

Serological surveys among representative population samples have proved rare given their reliance on invasive sample collection. We therefore completed the first population-based postal survey of immunity in England and Wales using new oral fluid technology. This paper examines the feasibility of this new methodological approach. Nearly 5500 oral fluid samples were collected, with individual demographic and social data via a questionnaire, from persons under 45 years of age recruited through general practices. Instructions were accurately followed with only 1% of samples returned without risk-factor data. The overall response rate was 40%. Response was independently associated with age, sex and location. Response was highest in children aged 5-14 years, adult females and in rural locations. This approach allowed the successful collection of comprehensive individual risk data, but response rates in adults must be improved if oral fluid surveys are to routinely complement serological surveillance.