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Introduction: Transcatheter aortic valve implantation (TAVI) has emerged as a common and effective treatment for patients with severe aortic stenosis. Changes in systemic blood pressure after TAVI have been described, yet their prognostic value is not established. Thus, we aimed to examine the association of the periprocedural changes in systolic blood pressure (SBP) and in pulse pressure on clinical outcomes after the procedure. Methods: A retrospective study of consecutive patients who underwent TAVI procedure in our medical center. We assessed the effect of the periprocedural changes in blood pressure measurements on mortality, acute myocardial infarction, stroke and hospitalizations at 1 year and on the combined outcome of death, myocardial infarction, and stroke 1 year following the procedure. Results: Our cohort included 455 patients (44% males). Of them, 343 patients (75.4%) had raised SBP immediately after the procedure. Patients with raised SBP had a significantly higher rate of the 1-year composite outcome, compared to patients who did not have a raise in SBP following the procedure (43 [13%] vs. 6 [5.4%], respectively, p = 0.033). After adjustment for age and sex, the postprocedural increase in SBP was significantly associated with the composite outcome, with a hazard ratio of 2.42, 95% CI: 1.03–5.7. Conclusion: An immediate increase in SBP after TAVI is associated with worse 1-year clinical cardiovascular outcomes.

UK Biobank is a biomedical database containing de-identified data for over 500,000 participants within the United Kingdom, made globally available to researchers for health-related research in the public interest. To obtain comprehensive health outcome data, UK Biobank links to participants’ electronic medical record (EHR) data from the National Health Service (NHS) amongst others. This currently involves fifteen data pipelines covering death and cancer registries, inpatient records, primary care records, and COVID-19 test and vaccination data, with numerous others planned. Integrating diverse “real-world” datasets into the resource necessitates a complex data infrastructure and thorough quality assurance. Challenges include file format changes, linkage problems, incomplete or invalid records, problems with encoding systems and discordances between different data sources. Various methods can be used to integrate data into the resource, including commercial software, internally developed tools, and custom-scripted pipelines for individual feeds. To streamline and standardize data processing, we are trialing a new data integration architecture and toolset. This aims to reduce manual input, and improve transparency, quality assurance and efficiency within and between data pipelines. The pilot is currently ongoing with results expected in mid-2024. We anticipate these new tools will help to streamline the end-to-end process, which will allow the data analysis and linkage teams to focus on further improving data quality and providing more ‘research-ready’ summary outputs on researchers’ health outcomes of interest. The findings of the pilot will be relevant to researchers and data scientists looking to employ cutting-edge approaches to linkage of any large-scale population data.

IntroductionThe Massachusetts Academic Health Department Consortium (AHD) established the Academic Public Health Volunteer Corps (APHVC) to support Local Health Departments (LHDs, n = 351) to meet rapidly emerging needs during the COVID-19 pandemic through engaging student volunteers. A program evaluation captured lessons learned and informed recommendations for sustainability and future replication.MethodsThe mixed-methods evaluation leveraged the Consolidated Framework for Implementation Research (CFIR). Data were stratified by LHD engagement with APHVC. Quantitative surveys informed probes for qualitative focus groups and interviews; findings were categorized into CFIR constructs using a deductive approach.ResultsOne-fifth of LHDs (n = 76, 27 used APHVC services, 45 did not) completed the survey. Eleven employees participated in follow-up focus groups or interviews. APHVC filled resource gaps, built capacity, and provided high-quality deliverables. LHDs experienced issues with reliability and communication of volunteers and lacked time to train volunteers.ConclusionsCFIR aided in evaluating APHVC in real time, producing actionable recommendations for best practices, dissemination, and future iterations of the program. Results are being used to enhance program effectiveness and sustainability, community health, and health equity across Massachusetts, and may help inform academic practice-based programs across the United States.

BackgroundRecent developments in CRISPR/Cas9 genome-editing tools have facilitated the introduction of precise alleles, including genetic intervals spanning several kilobases, directly into the embryo. However, the introduction of donor templates, via homology directed repair, can be erroneous or incomplete and these techniques often produce mosaic founder animals. Thus, newly generated alleles must be verified at the sequence level across the targeted locus. Screening for the presence of the desired mutant allele using traditional sequencing methods can be challenging due to the size of the interval to be sequenced, together with the mosaic nature of founders.Methodology/principal findingsIn order to help disentangle the genetic complexity of these animals, we tested the application of Oxford Nanopore Technologies long-read sequencing at the targeted locus and found that the achievable depth of sequencing is sufficient to offset the sequencing error rate associated with the technology used to validate targeted regions of interest. We have assembled an analysis workflow that facilitates interrogating the entire length of a targeted segment in a single read, to confirm that the intended mutant sequence is present in both heterozygous animals and mosaic founders. We used this workflow to compare the output of PCR-based and Cas9 capture-based targeted sequencing for validation of edited alleles.ConclusionTargeted long-read sequencing supports in-depth characterisation of all experimental models that aim to produce knock-in or conditional alleles, including those that contain a mix of genome-edited alleles. PCR- or Cas9 capture-based modalities bring different advantages to the analysis.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is thought to occur when the cellular prion protein (PrPC) spontaneously misfolds and assembles into prion fibrils, culminating in fatal neurodegeneration. In a genome-wide association study of sCJD, we recently identified risk variants in and around the gene STX6, with evidence to suggest a causal increase of STX6 expression in disease-relevant brain regions. STX6 encodes syntaxin-6, a SNARE protein primarily involved in early endosome to trans-Golgi network retrograde transport. Here we developed and characterised a mouse model with genetic depletion of Stx6 and investigated a causal role of Stx6 expression in mouse prion disease through a classical prion transmission study, assessing the impact of homozygous and heterozygous syntaxin-6 knockout on disease incubation periods and prion-related neuropathology. Following inoculation with RML prions, incubation periods in Stx6−/− and Stx6+/− mice differed by 12 days relative to wildtype. Similarly, in Stx6−/− mice, disease incubation periods following inoculation with ME7 prions also differed by 12 days. Histopathological analysis revealed a modest increase in astrogliosis in ME7-inoculated Stx6−/− animals and a variable effect of Stx6 expression on microglia activation, however no differences in neuronal loss, spongiform change or PrP deposition were observed at endpoint. Importantly, Stx6−/− mice are viable and fertile with no gross impairments on a range of neurological, biochemical, histological and skeletal structure tests. Our results provide some support for a pathological role of Stx6 expression in prion disease, which warrants further investigation in the context of prion disease but also other neurodegenerative diseases considering syntaxin-6 appears to have pleiotropic risk effects in progressive supranuclear palsy and Alzheimer's disease.

Acute ischemic stroke remains a serious complication of transcatheter aortic valve replacement (TAVR). Cerebral embolic protection devices (CEPD) were developed to mitigate the risk of acute ischemic stroke complicating TAVR (AISCT). However, the existing body of evidence does not clearly support CEPD efficacy in AISCT prevention. In a cohort of patients with AISCT, we aimed to compare the characteristics and outcomes of patients who have had unprotected TAVR (CEPD−) vs CEPD-protected TAVR (CEPD+). Data were derived from an international multicenter registry focusing on AISCT. We included all patients who experienced ischemic stroke within 72 hours of TAVR. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Primary outcomes were neurologic disability status according to the modified Rankin Score at 30 days, and 6-month all-cause death. Propensity score matched analysis was used to control for differences between groups. In 18,725 TAVR procedures, 416 AISCT (2.2%) within 72 hours were documented, of which 376 were in the CEPD− TAVR group and 40 in the CEPD+ TAVR group. Although the middle cerebral artery stroke rate was similar in both groups (29.7% CEPD− vs 33.3% CEPD+; P = 0.71), AISCT in the CEPD+ group was characterized by a lower rate of internal carotid artery occlusion (0% vs 4.7%) and higher rate of vertebrobasilar system strokes (15.4% vs 5.7%; P = 0.04). AISCT was severe (NIHSS ≥15) in 21.6% CEPD− and 23.3% CEPD+ AISCT (P = 0.20). Disabling stroke rates (modified Rankin Score >1 at 30 days) were 47.3% vs 42.5% (P = 0.62), and 6-month mortality was 31.3% vs 23.3% (P = 0.61), in the CEPD− and CEPD+ groups, respectively. In the propensity score matched cohort, disabling stroke rates were 56.5% vs 41.6% (P = 0.16), and 6-month mortality was 33% vs 19.5% (P = 0.35), in the CEPD− and CEPD+ groups, respectively. In a large cohort of patients with AISCT, the use of CEPD had little effect on stroke distribution, severity, and outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: We examined whether thickness of the basal muscular interventricular septum (IVS), as measured by pre-procedural computed tomography (CT), could be used to identify the risk of conduction disturbances following transcatheter aortic valve replacement (TAVR). The IVS is a pivotal region of the electrical conduction system of the heart where the atrioventricular conduction axis is located., Methods and Results: Included were 78 patients with severe aortic stenosis who underwent CT imaging prior to TAVR. The thickness of muscular IVS was measured in the coronal view, in systolic phases, at 1, 2, 5, and 10 mm below the membranous septum (MS). The primary endpoint was a composite of conduction disturbance following TAVR. Conduction disturbances occurred in 24 out of 78 patients (30.8%). Those with conduction disturbances were significantly more likely to have a thinner IVS than those without conduction disturbances at every measured IVS level (2.98 ± 0.52 mm vs. 3.38 ± 0.52 mm, 4.10 ± 1.02 mm vs. 4.65 ± 0.78 mm, 6.11 ± 1.12 mm vs. 6.88 ± 1.03 mm, and 9.72 ± 1.95 mm vs. 10.70 ± 1.55 mm for 1, 2, 5 and 10 mm below MS, respectively, P < 0.05 for all). Multivariable logistic regression analysis showed that pre-procedural IVS thickness (<4 mm at 2 mm below the MS) was a significant independent predictor of post-procedural conduction disturbance (adjOR 7.387, 95% CI: 2.003-27.244, P = 0.003)., Conclusion: Pre-procedural CT assessment of basal IVS thickness is a novel predictive marker for the risk of conduction disturbances following TAVR. The IVS thickness potentially acts as an anatomical barrier protecting the underlying conduction system from mechanical compression during TAVR., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)