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Abstract The International Mouse Phenotyping Consortium (IMPC) systematically produces and phenotypes mouse lines with presumptive null mutations to provide insight into gene function. The IMPC now uses the programmable RNA-guided nuclease Cas9 for its increased capacity and flexibility to efficiently generate null alleles in the C57BL/6N strain. In addition to being a valuable novel and accessible research resource, the production of 3313 knockout mouse lines using comparable protocols provides a rich dataset to analyze experimental and biological variables affecting in vivo gene engineering with Cas9. Mouse line production has two critical steps – generation of founders with the desired allele and germline transmission (GLT) of that allele from founders to offspring. A systematic evaluation of the variables impacting success rates identified gene essentiality as the primary factor influencing successful production of null alleles. Collectively, our findings provide best practice recommendations for using Cas9 to generate alleles in mouse essential genes, many of which are orthologs of genes linked to human disease.

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.

BACKGROUND: Coronary obstruction following transcatheter aortic valve replacement (TAVR) is a life-threatening complication. For patients at elevated risk, it is not known how valve choice is influenced by clinical and anatomic factors and how outcomes differ between valve platforms. For patients at high risk of coronary obstruction, we sought to describe the anatomical and clinical characteristics of patients treated with both balloon-expandable (BE) and self-expanding (SE) valves. METHODS: This was a multicenter international registry of patients undergoing TAVR who are considered to be at high risk of coronary obstruction and receiving pre-emptive coronary protection. RESULTS: A total of 236 patients were included. Patients receiving SE valves were more likely to undergo valve-in-valve procedures and also had smaller sinuses of Valsalva and valve-to-coronary distance. Three-year cardiac mortality was 21.6% with SE vs 3.7% with BE valves. This was primarily driven by increased rates of definite or probable coronary occlusion, which occurred in 12.1% of patients with SE valves vs 2.1% in patients with BE valves. CONCLUSIONS: In patients undergoing TAVR with coronary protection, those treated with SE valves had increased rates of clinical and anatomic features that increase the risk of coronary obstruction. These include an increased frequency of valve-in-valve procedures, smaller sinuses of Valsalva, and smaller valve-to-coronary distances. These patients were observed to have increased cardiac mortality compared with patients treated with BE valves, but this is likely due to their higher risk clinical and anatomic phenotypes rather than as a function of the valve type itself.

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.

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes, including 2,850 novel null, 2,987 novel conditional- ready, and 4,433 novel reporter alleles.

This study assessed relationship between adverse economic events (AEE) and hunger level (i.e., little to no, moderate, severe). A cross-sectional survey was conducted from June to August 2018 in 10 food pantries with 616 food pantry users. Hunger level was assessed by the Household Hunger Scale. AEE were evaluated over the past 3 months. Participants (60.55%) experienced unexpected or increased medical expenses (17.69%), job loss (13.64%), pay reduction (11.85%), and death of a family member (9.09%). Pay reduction (OR = 1.87, 95% CI: 1.12, 3.14) and increased debt (OR = 2.71, 95% CI: 1.92, 3.84) were associated with moderate hunger; death of a family member (OR = 2.43, 95% CI: 1.21, 4.90), pay reduction (OR = 2.95, 95% CI: 1.24, 7.04), and increased debt (OR = 3.46, 95% CI: 1.98, 6.04) were associated with severe hunger. Awareness of AEE can inform public health programs and policies for people in need of additional resources, which is essential in times of increased economic instability.

The American Association for the Surgery of Trauma Critical Care Committee has developed clinical consensus guides to help with practical answers based on the best evidence available. These are focused in areas in which the levels of evidence may not be that strong and are based on a combination of expert consensus and research. Overall, quality of the research is mixed, with many studies suffering from small numbers and issues with bias. The first two of these focus on the use of extracorporeal membrane oxygenation in trauma patients and nutrition for the critically ill surgical/trauma patient.

Background Various hemodynamic changes occur following transcatheter aortic valve implantation (TAVI) that may impact therapeutic decisions. NICaS is a noninvasive bioimpedance monitoring system aimed at hemodynamic assessment. We used the NICaS system in patients with severe aortic stenosis (AS) to evaluate short‐term hemodynamic changes after TAVI. Methods and Results We performed hemodynamic analysis using NICaS on 97 patients with severe AS who underwent TAVI using either self‐expandable (68%) or balloon‐expandable (32%) valves. Patients were more often women (54%) and had multiple comorbidities including hypertension (83%), coronary artery disease (46%), and diabetes (37%). NICaS was performed at several time points—before TAVI, soon after TAVI, at hospital discharge, and during follow‐up. Compared with baseline NICaS measurements, we observed a significant increase in systolic blood pressure and total peripheral resistance (systolic blood pressure 132±21 mm Hg at baseline versus 147±23 mm Hg after TAVI, P

To assess the determinants of hunger among food pantry users, the present study used a cross-sectional survey that included a modified Household Hunger Scale to quantify hunger. Mixed-effects logistic regression models were used to assess the relationship between hunger categories and various household socio-demographic and economic characteristics, such as age, race, household size, marital status and experience of any economic hardship. The survey was administered to food pantry users from June 2018 to August 2018 at various food pantries across Eastern Massachusetts with 611 food pantry users completing the questionnaire at any of the 10 food pantry sites. One-fifth (20⋅13 %) of food pantry users experienced moderate hunger and 19⋅14 % experienced severe hunger. Food pantry users who were single, divorced or separated; had less than a high school education; working part-time, unemployed or retired; or, who earned incomes less than $1000 per month were most likely to experience severe or moderate hunger. Pantry users who experienced any economic hardship had 4⋅78 the adjusted odds of severe hunger (95 % CI 2⋅49, 9⋅19), which was much larger than the odds of moderate hunger (AOR 1⋅95; 95 % CI 1⋅10, 3⋅48). Younger age and participation in WIC (AOR 0⋅20; 95 % CI 0⋅05–0⋅78) and SNAP (AOR 0⋅53; 95 % CI 0⋅32–0⋅88) were protective against severe hunger. The present study illustrates factors affecting hunger in food pantry users, which can help inform public health programmes and policies for people in need of additional resources. This is essential particularly in times of increasing economic hardships recently exacerbated by the COVID-19 pandemic.

BackgroundThe link between thyroid dysfunction and cardiovascular disease is well established. Hypothyroidism has been significantly associated with increased risk of dyslipidemia, atherosclerosis and heart failure. However, little is known regarding its effect on patients undergoing percutaneous coronary intervention (PCI).AimThe aim of study was to examine the impact of concomitant hypothyroidism on mortality and major adverse cardiac event (MACE) in patients undergoing PCI.MethodsThe Rabin Medical Center PCI registry includes all consecutive patients who have undergone PCI between 2004 and 2020. We identified patients with prior diagnosis of hypothyroidism, and compared rates of mortality and MACE (comprising death, myocardial infarction, target vessel revascularization and/or coronary bypass surgery).ResultsAmong 28,274 patients, 1,922 (6.8%) were found to have hypothryoidism. These patients were older (70.3 ± 10.4 vs. 66.0 ± 11.8 y.o, P < 0.001) and more likely to be women (34.2% vs. 26.1%, P < 0.001). They had a higher prevalence of atrial fibrillation (10.8% vs. 7.7%, P < 0.001), chronic renal dysfunction (25.1% vs. 18.7%, P = 0.04) and dementia (2.9% vs. 1.8%, P = 0.004). PCI was performed on ACS setting in 52–54% of patients in both groups (p = 0.569). Unadjusted 5-year rates of all-cause mortality (26.9% vs. 20.3%, P < 0.001) and MACE (40.3% vs. 29.4%, P < 0.001) were higher for hypothyroid patients. A propensity match score was able to form 672 matched pairs of HT and control patients, showing similar results. Moreover, following multivariate analysis, TSH as a continuous parameter was associated with a higher risk of mortality and MACE (HR, 1.06 per additional 1 mIU/L; CI, 1.02–1.11; P < 0.001 and HR, 1.07; CI, 1.02–1.12; P < 0.001, respectively) at 5-year follow up.ConclusionIn our study, hypothyroidism confers worse outcomes in patients undergoing PCI. Further research is needed to establish effective ways to mitigate this augmented risk.

Although next-generation sequencing has revolutionized the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by a lack of knowledge of the functions and pathobiological mechanisms of most genes. To address this challenge, the International Mouse Phenotyping Consortium is creating a genome- and phenome-wide catalog of gene function by characterizing new knockout-mouse strains across diverse biological systems through a broad set of standardized phenotyping tests. All mice will be readily available to the biomedical community. Analyzing the first 3,328 genes identified models for 360 diseases, including the first models, to our knowledge, for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations were novel, providing functional evidence for 1,092 genes and candidates in genetically uncharacterized diseases including arrhythmogenic right ventricular dysplasia 3. Finally, we describe our role in variant functional validation with The 100,000 Genomes Project and others.

This paper examines risk factors influencing food insecurity during the first year of the COVID-19 pandemic in a state in the U.S. heavily impacted by it and offers recommendations for multi-sector intervention.The U.S. Census Bureau Household Pulse Survey was analyzed to evaluate the impacts of COVID-19 on food security in Massachusetts from April 2020 through March 2021 using a study sample of 57,678 participants. Food security was defined as a categorical variable (food security, marginal food security, low food security, very low food security) and binary variable (food security and food insecurity). Known or suspected factors that contribute to it, such as childcare, education, employment, housing, and transportation were examined in multivariate logistic regression models. Data imputation methods accounted for missing data.Sociodemographic characteristics, including lower education level and living in a household with children, were determinants of food insecurity. Another factor that influenced food insecurity was economic hardships, such as unemployment, being laid off due to COVID-19, not working due to concerns about contracting or spreading COVID-19, or not having enough money to buy food. A third factor influencing food insecurity was food environment, such as lack of geographic access to healthy foods. Some of these factors have been exacerbated by the pandemic and will continue to impact food security. These should be addressed through a comprehensive approach with public health efforts considering all levels of the social ecological model and the context created by the pandemic.

BackgroundAccumulated experience combined with technological advancements in percutaneous coronary interventions (PCI) over the past four decades, has led to a gradual increase in PCI utilization and complexity. We aimed to investigate the temporal trends in PCI complexity and the outcomes of complex PCI (C-PCI) in our institution.MethodsWe analyzed 20,301 consecutive PCI procedures performed over a 12-year period. C-PCI was defined as a procedure involving at least one of the following: Chronic total occlusion (CTO), left main (LM), bifurcation or saphenous vein graft (SVG) PCI. Four periods of 3-year time intervals were defined (2008–10, 2011–2013, 2014–2016, 2017–2019), and temporal trends in the rate and outcomes of C-PCI within these intervals were studied. Endpoints included mortality and major adverse cardiac events [MACE: death, acute myocardial infarction (MI), and target vessel revascularization (TVR)] at 1 year.ResultsA total of 5,647 (27.8%) C-PCI procedures were performed. The rate of C-PCI has risen significantly since 2,017 (31.2%, p < 0.01), driven mainly by bifurcation and LM interventions (p < 0.01). At 1-year, rates of death, acute MI, TVR and MACE, were all significantly higher in the C-PCI group (8.8 vs. 5.1%, 5.6 vs. 4.5%, 5.5 vs. 4.0%, 17.2 vs. 12.2%, p < 0.001 for all, respectively), as compared to the non-complex group. C-PCI preformed in the latter half of the study period (2014–2019) were associated with improved 1-year TVR (4.4% and 4.8% vs. 6.7% and 7.1%, p = 0.01, respectively) and MACE (13.8% and 13.5% vs. 17.3% and 18.2%, p = 0.001, respectively) rates compared to the earlier period (2007–2013). Death rate had not significantly declined with time.ConclusionIn the current cohort, we have detected a temporal increase in PCI complexity coupled with improved 1-year clinical outcomes in C-PCI.

Abstract Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.

Este artículo analiza el rol de las Oficinas de Transferencia Tecnológica (OTT) en las Universidades Nacionales de gestión pública de Argentina. Se describe el contexto histórico en el que a nivel mundial la extensión y la transferencia de conocimiento por parte de las universidades se articula como vinculación y transferencia de tecnología, surgiendo las OTT como dispositivos institucionales encargados de realizar esta función. Por otro lado, se presentan los resultados de un estudio basado en encuestas realizadas a encargados de OTT de las Universidades Nacionales. Se concluye, entre otros aspectos, que la relación de las OTT con la industria y la producción es más una dimensión aspiracional que real; que existen tensiones entre la cultura cientificista y la posibilidad de generar resultados de impacto productivo o social; que existe una enorme diversidad entre las OTT vinculadas a las Universidades Nacionales y que la profesionalización de las actividades de la OTT exige la formación especializada de gestores.

The Valve-in-Valve (ViV) technique is an emerging alternative for the treatment of bioprosthetic structural valve deterioration (SVD) in the mitral position. We report on intermediate-term outcomes of patients with symptomatic SVD in the mitral position who were treated by transcatheter mitral valve-in-valve (TM-ViV) implantation during the years 2010–2019 in our center. Three main outcomes were examined during the follow-up period: NYHA functional class, TM-ViV hemodynamic data per echocardiography, and mortality. Our cohort consisted of 49 patients (mean age 77.4 ± 10.5 years, 65.3% female). The indications for TM-ViV were mainly for regurgitant pathology (77.6%). All 49 patients were treated with a balloon-expandable device. The procedure was performed via transapical access in 17 cases (34.7%) and transfemoral vein/trans-atrial septal puncture in 32 cases (65.3%). Mean follow-up was 4.4 ± 2.0 years. 98% and 91% of patients were in NYHA I/II at 1 and 5 years, respectively. Mitral regurgitation was ≥moderate in 86.3% of patients prior to the procedure and this decreased to 0% (p < 0.001) following the procedure and was maintained over 2 years follow-up. The mean trans-mitral valve gradients decreased from pre-procedural values of 10.1 ± 5.1 mmHg to 7.0 ± 2.4 mmHg at 1 month following the procedure (p = 0.03). Mortality at 1 year was 16% (95%, CI 5–26) and 35% (95%, CI 18–49) at 5 years. ViV in the mitral position offers an effective and durable treatment option for patients with SVD at high surgical risk.

BackgroundTranscatheter heart valve (THV) selection for transcatheter aortic valve implantation (TAVI) is crucial to achieve procedural success. Borderline aortic annulus size (BAAS), which allows a choice between two consecutive valve sizes, is a common challenge during device selection. In the present study, we evaluated TAVI outcomes in patients with BAAS according to THV size selection.MethodsWe performed a retrospective study including patients with severe aortic stenosis (AS) and BAAS, measured by multi-detector computed tomography (MDCT), undergoing TAVI with self-expandable (SE) or balloon-expandable (BE) THV from the Israeli multi-center TAVI registry. The aim was to evaluate outcomes of TAVI, mainly paravalvular leak (PVL) and valve hemodynamics, in patients with BAAS (based on MDCT) according to THV sizing selection in between 2 valve sizes. In addition, to investigate the benefit of shifting between different THV types (BE and SE) to avoid valve size selection in BAAS.ResultsOut of 2,352 patients with MDCT measurements, 598 patients with BAAS as defined for at least one THV type were included in the study. In BAAS patients treated with SE-THV, larger THV selection was associated with lower rate of PVL, compared to smaller THV (45.3 vs. 64.5%; pv = 0.0038). Regarding BE-THV, larger valve selection was associated with lower post-procedural transvalvular gradients compared to smaller THV (mean gradient: 9.9 ± 3.7 vs. 12.5 ± 7.2 mmHg; p = 0.019). Of note, rates of mortality, left bundle branch block, permanent pacemaker implantation, stroke, annular rupture, and/or coronary occlusion did not differ between groups.ConclusionBAAS is common among patients undergoing TAVI. Selection of a larger THV in these patients is associated with lower rates of PVL and optimized THV hemodynamics with no effect on procedural complications. Additionally, shift from borderline THV to non-borderline THV modified both THV hemodynamics and post-dilatation rates.

A novel approach to the design and fabrication of field-emission tips with self-aligned gates intended for electric propulsion micro-thruster applications is presented. Their micro-electromechanical systems fabrication process is derived from the recent proliferation of research toward developing field emitter arrays, which are used primarily for field-emission flat-panel display applications. An array of micronsized tips for electric field enhancement via wet isotropic etching of silicon, using silicon nitride as a hard mask is fabricated. The wet etching is accomplished using a combination of hydrofluoric, nitric, and acetic acids. The tips were then coated with a metal layer to enhance wetting by indium, the proposed propellant. Next, a layer of SU-8 photoresist was applied by spin coating and patterned to serve as a dielectric spacer. A second layer of metal was then applied to serve as a gate electrode. In addition, the results of electrostatic simulations of the prototype is described.

Background: Ischemic mitral regurgitation (IMR) is a common complication of acute ST-elevation myocardial infarction (STEMI). Little is known regarding the impact of IMR over a long period of follow up.Methods: Of 3,208 consecutive STEMI patients from a prospective registry, full echocardiographic information was available for 2,985 patients between the years 2000 and 2020. We compared the two decades- 2001 to 2010 and 2011 to 2020, and assessed for the presence of IMR at baseline, 3 (range 2–6) months and 12 (range 10–14) months after the index event.Results: One thousand six hundred and sixty six patients were included in the first decade, 1,319 in the second. Mean patient age was 61.3 ± 12.3 years, 21.1% female patients in the first decade vs. 60.9 ± 12.0 years and 22.2% female in the second (p = 0.40 and p = 0.212, respectively). Rates of moderate IMR or above during the index admission were 17.2% in the first period and 9.3% in the second one (p < 0.001). After 3 months, the rate of IMR was 48.5% for those who suffered from IMR at baseline, vs. 9.5% for those without IMR at baseline (HR- 4.2, p < 0.001). Death rates for those with moderate IMR or above were 14.7% and 17.8% after 1 and 2 years, respectively, vs. 7.3 and 9.6% for those without (p < 0.001 for both). IMR was associated with 1 year mortality in multivariate analysis (HR-1.37; 1.09–2.20, p = 0.009), as well as in propensity score matched analysis (HR 1.29; CI: 1.07–1.91; p < 0.001).Conclusions: IMR is a common complication following acute STEMI, impacting prognosis. Rates of IMR have declined significantly over the years.

Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing.

Summary: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.

The Valve-in-Valve (ViV) technique is an established alternative for the treatment of structural bioprosthetic valve deterioration (SVD). Data describing the intermediate term follow up of patients treated with this approach is scarce. We report on our intermediate-term outcomes of patients with SVD in the Aortic position treated with ViV. Included were patients with symptomatic SVD in the aortic position valve who were treated by Valve in valve transcatheter aortic valve implantation (ViV-TAVI) during the years 2010-2019 in our center. Three main outcomes were examined during the follow up period: NYHA functional class, ViV-TAVI hemodynamic per echocardiography, and mortality. Our cohort consisted of 85 patients (mean age 78.8 ± 8.9 years). The indications for aortic ViV were: SVD isolated aortic stenosis in 37.6%, SVD isolated aortic regurgitation in 42.2% and combined valve pathology in 20.0%. Self-expandable and balloon-expandable devices were used in 73 (85.9%) and 12 (14.1%), respectively. Average follow up was 3.7 ± 2.4 years. 95 and 91% of patients were in NYHA functional class I/II at 1 and 5 year follow up respectively. At one year, the mean trans-aortic valve pressure was 15 ± 9 mmHg and rates of ≥ moderate aortic regurgitation were 3.7%. Mortality at one year was 8.6% (95% CI 2.3–14.4) and 31% (95% CI 16.5–42.5) at 5 years. ViV in the aortic position offers an effective and durable treatment option for patient with SVD, with low rates of all-cause mortality, excellent hemodynamic and improved functional capacity at intermediate follow up.

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., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: The use of drug-eluting balloons (DEBs) remains clinically relevant in the contemporary era of drug-eluting stent percutaneous coronary interventions (DES-PCI), especially in the setting of in-stent restenosis (ISR). Our goal was to assess the outcomes of ISR patients in a large prospective registry., Methods: A total of 2329 consecutive patients with ISR-PCI (675 using DEB and 1654 with DES) were treated in our medical centre from 2010 to 2021. Clinical end points included mortality and major adverse cardiac events (MACE) at 1 year. Clinical outcomes were adjusted for multiple confounders., Results: Mean ages (65.9 ± 11.0 vs 66.1 ± 10.5; P = 0.73) and percentages of female patients (16.6% vs 18.2%; P = 0.353) were similar between both ISR groups. Patients treated with DEB for ISR suffered more from diabetes, hypertension, and previous myocardial infarction (P < 0.01 for all) and presented more frequently with acute coronary syndrome (40.0% vs 34.4%; P = 0.01) compared with patients treated with DES for ISR. One-year MACE was significantly higher in the DEB ISR-PCI group (23.4% vs 19.6%; P = 0.002) compared to the DES ISR-PCI group, but no significant differences in mortality were observed at 1 year between the groups. After adjustment for multiple confounders, DEB ISR-PCI was not associated with increased MACE at 1 year (P = 0.55)., Conclusions: In our large experience, patients treated with DEB for ISR-PCI have higher baseline risk and sustained increased MACE rates compared with DES ISR-PCI patients. After adjustment for confounding variables, clinical outcomes are similar between the groups at 1 year after PCI., (Copyright © 2024 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

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]

Abstract Hearing relies on mechanically gated ion channels present in the actin‐rich stereocilia bundles at the apical surface of cochlear hair cells. Our knowledge of the mechanisms underlying the formation and maintenance of the sound‐receptive structure is limited. Utilizing a large‐scale forward genetic screen in mice, genome mapping and gene complementation tests, we identified Clrn2 as a new deafness gene. The Clrn2clarinet/clarinet mice (p.Trp4* mutation) exhibit a progressive, early‐onset hearing loss, with no overt retinal deficits. Utilizing data from the UK Biobank study, we could show that CLRN2 is involved in human non‐syndromic progressive hearing loss. Our in‐depth morphological, molecular and functional investigations establish that while it is not required for initial formation of cochlear sensory hair cell stereocilia bundles, clarin‐2 is critical for maintaining normal bundle integrity and functioning. In the differentiating hair bundles, lack of clarin‐2 leads to loss of mechano‐electrical transduction, followed by selective progressive loss of the transducing stereocilia. Together, our findings demonstrate a key role for clarin‐2 in mammalian hearing, providing insights into the interplay between mechano‐electrical transduction and stereocilia maintenance.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine conditions in women. PCOS may be more challenging to diagnose during adolescence due to an overlap with the physiological events of puberty, which are part of the diagnostic criteria in adult women. This review focuses on the evidence available in relation to PCOS diagnostic criteria for adolescents. Adolescent PCOS should be diagnosed using two main criteria irregular -menstrual cycles (relative to number of years post-menarche) and hyperandrogenism (clinical and/or biochemical); after excluding other conditions that mimic PCOS. Accurate definitions of the two main criteria will decrease challenges/controversies with the diagnosis and provide timely diagnosis during adolescence to establish early management. Despite the attempts to create accurate diagnostic criteria and definitions, this review highlights the limited research in this area, especially in the follow up of adolescents presenting with one diagnostic feature that are called “at risk of PCOS”. Studies in adolescents continue to use the Rotterdam diagnostic criteria that uses pelvic ultrasound. This is inappropriate, because previous and emerging data that show many healthy adolescents have polycystic ovarian morphology in the early years post-menarche. In the future, anti-Müllerian hormone levels might help support PCOS diagnosis if adolescents meet two main criteria.

This article, on hemodynamic monitoring, fluid responsiveness, volume assessment, and endpoints of resuscitation, is part of a compendium of guidelines provided by the AAST (American Association for the Surgery of Trauma) critical care committee. The intention of these guidelines is to inform practitioners with practical clinical guidance. To do this effectively and contemporarily, expert consensus via the critical care committee was obtained. Strict guideline methodology such a GRADE (Grading of Recommendations Assessment, Development and Evaluation) was purposefully NOT used so as not to limit the possible clinical guidance. The critical care committee foresees this methodology as practically valuable to the bedside clinician.

Background Peripheral artery disease (PAD) is a known risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention. However, in some studies PAD is not an independent risk factor. We sought to examine the independent impact of PAD on a large prospective percutaneous coronary intervention registry. Methods and Results From our single‐center prospective percutaneous coronary intervention registry, we have retrospectively analyzed 25 690 patients (years 2004–2018). We examined the influence of PAD on short‐ and long‐term outcomes using both regression and propensity‐matched analyses. Patients with documented PAD (n=1610, 6.3% of total) were older (66.7±10.8 versus 65.4±12.1, P