Examining the Role of Cerebral Embolic Protection Devices in Preventing Postoperative Stroke in Patients with a History of Stroke or Transient Ischemic: Insights from the National Inpatient Sample.

Cerebral embolic protection devices (CEPD) during transcatheter aortic valve replacement (TAVR) have been shown to lower the risk of stroke during the procedure. However, their long-term and clinical effects on neuro-cognition are unknown. Therefore, we hypothesized the benefit of CEPD in TAVR patients with a prior history of stroke or transient ischemic attack (TIA). National Inpatient Sample (2019) and International Classification of Diseases, 10th Revision codes were used to identify patients undergoing TAVR with prior stroke or TIA. Propensity-matched analysis was performed to adjust for baseline characteristics and comorbidities. Primary outcome measures were postoperative stroke and all-cause mortality. Length of stay and hospital cost were secondary outcomes. Of 8450 unmatched TAVR patients with prior stroke or TIA in 2019, 1095 (13%) utilized CEPD. After propensity matching previous myocardial infarction (MI), coronary artery bypass grafting, and drug abuse were higher in the TAVR-only cohort. Postoperative stroke rate (1.4% vs 2.2%; P = 0.081) and odds [adjusted odds ratio (aOR), 0.48; 95% confidence interval (CI), 0.11-2.17; P = 0.341] were lower in the CEPD group. There was no difference in all-cause in-hospital mortality between the 2 groups (0.9% vs 1.0%). Length of stay (3 vs 2 days, P <0.001) and hospital expenditure ($172,711 vs $162,284; P = 0.002) were higher for the TAVR-only cohort. CEPD in TAVR patients with prior stroke or TIA did not show statistically significant postoperative stroke benefits. However, further larger-scale prospective studies are needed to evaluate the long-term neurocognitive benefits of CEPD in these patients. As the use of TAVR continues to expand, optimizing peri-procedural strategies such as the use of CEPD remains a critical area of research to improve patient outcomes.

Impact of obstructive sleep apnoea on cardiovascular outcomes and mortality in young adults with congenital heart anomalies: insights from the national inpatient sample (2019).

BACKGROUND: Obstructive sleep apnoea is a common sleep disorder, and adult congenital heart disease (CHD) is also a significant burden on the population. Early diagnosis and treatment are important for improving quality of life and reducing the risk of health complications. The limited research on obstructive sleep apnoea and adult CHD highlights the need for further investigation into the relationship between these two conditions and the mechanisms underlying this relationship. METHOD: We used NIS 2019 database to identify adult CHD admissions aged 18-44 years and assess the impact of obstructive sleep apnoea on all-cause mortality, dysrhythmia, and stroke. A propensity-matched cohort of individuals with and without obstructive sleep apnoea was obtained, and the outcomes were assessed using multivariable analysis and compared in terms of resource utilisation. RESULTS: Of the 41,950 young adult CHD admissions, 6.3% (n = 2630) had obstructive sleep apnoea. The obstructive sleep apnoea+ (n = 2590) and obstructive sleep apnoea- (n = 2590) cohorts were comparable in terms of median age (35 years) and were predominantly male (63.1% versus 62.5%). The obstructive sleep apnoea+ cohort had a higher frequency of risk factors like chronic obstructive pulmonary disease, hypothyroidism, and prior venous thromboembolism than the obstructive sleep apnoea cohort. We found significant association of obstructive sleep apnoea with dysrhythmia (adjusted odds ratio 2.99, 95% confidence interval 2.13-4.19, p < 0.001), but no significant impact on the risk of all-cause mortality or stroke. The obstructive sleep apnoea+ cohort also had higher transfers to short-term facilities, prolonged stays, and higher charges (p < 0.001). CONCLUSION: Our study provides important insights into relationship between obstructive sleep apnoea and adult CHD and highlights the need for further investigation into the impact of obstructive sleep apnoea on individuals with adult CHD.

Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner.

Oncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress.

Knowledge and Attitude Toward Organ Donation Among Interns and Residents in a Tertiary Care Hospital in Gujarat, India.

Background The study aims to assess knowledge and attitudes toward organ donation among medical school interns and postgraduate residents in a tertiary care hospital in Anand, Gujarat, India. Methodology A cross-sectional study was conducted among 250 medical school interns and residents of Shree Krishna Hospital, a tertiary care hospital in Anand, Gujarat, India, between March 2021 and March 2022 using a paper questionnaire comprising questions regarding attitudes and beliefs toward organ donation. Results Among the 250 participants in this study, 124 (49.6%) were residents, and 126 (50.4%) were interns, with a mean age of 24.18 ± 2.02 years. Of all participants, 88.8% were willing to donate their organs; the main reason was to help people in need. However, the main reason for the refusal to donate organs was the fear of organs being misused/trafficked. Another finding was that 77.2% of the participants had no issue regarding who receives their organs. Only 25.2% of participants had correct knowledge and were aware of the Transplantation of Human Organs Act, 1994 of India, and 66% felt that the current curriculum does not provide sufficient learning experience related to organ donation. Conclusions There was less awareness regarding organ donation, despite the willingness to donate organs. Thus, it is essential to increase awareness through curriculum and various workshops to make the process of pledging organs more accessible among those willing to donate. This will play a significant role in addressing the problem and, in turn, help those in need.

The yeast RNA methylation complex consists of conserved yet reconfigured components with m6A-dependent and independent roles.

N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologues. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC's m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent, and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.

Epicardial Potential in the Left Atrium During Posterior Wall Isolation in Persistent Atrial Fibrillation.

Pulmonary vein isolation (PVI) is used for rhythm control in atrial fibrillation (AF). Posterior wall isolation (PWI) is often an adjunct to PVI. Successful PWI is limited by esophageal location, epicardial bridging signals, tissue thickness, and mapping catheter resolution. High-density grid mapping catheters can assist with PWI. Here, we report a case of a 71-year-old woman with persistent AF who underwent PVI and PWI with high-density grid mapping catheters, thus demonstrating the use of omnipolar technology in facilitating successful PWI.

Substance Use Disorders (SUDs) and Risk of Cardiovascular Disease (CVD) and Cerebrovascular Disease (CeVD): Analysis of the Nationwide Inpatient Sample (NIS) Database.

BACKGROUND:  Substance use continues to be on the rise in the United States and has been linked to new onset cardiovascular diseases (CVDs) and cerebrovascular disorders (CeVDs). We aimed to study the association between the types of substance use disorders (SUDs) with specific subtypes of CVDs and CeVDs among hospitalized patients using the National Inpatient Sample (NIS) Database. METHODS:  A retrospective study of the NIS database (2016-2017) using the ICD-10-CM codes was performed. The hospitalizations with a secondary diagnosis of SUDs were identified. Weighted univariate analysis using the Chi-square test and multivariate survey logistic regression analysis was performed to evaluate for the incidence, prevalence, and odds of association between vascular events and SUDs. RESULTS:  There were a total of 58,259,589 hospitalizations, out of which 21.42% had SUDs. SUDs were more common in the younger age group of 18-50, males, and the lower median household income group. We found a significant association of acute ischemic stroke (AIS) with amphetamine dependence (adjusted odds ratio, aOR 1.23, 95% confidence interval, CI 1.14-1.33), cocaine-related disorders (1.17, 1.12-1.23), and nicotine dependence (1.42, 1.40-1.43). There was a significant association between intracerebral hemorrhage with amphetamine dependence (2.58, 2.26-2.93), cocaine-related disorders (1.62, 1.46-1.79), and alcohol-related disorders (1.35, 1.01-1.82). The association of subarachnoid hemorrhage (SAH) was noted to be higher with amphetamine dependence (1.82, 1.48-2.24) and nicotine dependence (1.47, 1.39-1.55). The patients with nicotine dependence had greater odds of having a myocardial infarction (1.85, 1.83-1.87), those with cocaine-related disorders had higher odds of having angina pectoris (2.21, 1.86-2.62), and patients with alcohol-related disorders had higher odds of developing atrial fibrillation (1.14, 1.11-1.17) in comparison to non-SUDs. CONCLUSION:  Our study demonstrates the variability of CVD and CeVD in patients hospitalized for SUD. Findings from our study may help promote increased awareness and early management of these events. Further studies are needed to evaluate the specific effects of frequency and dose on the incidence and prevalence of CVD and CeVD in patients with SUD.

Patients prefer free drug disposal options delivered by pharmacists at the point of care: Results of a decision tree analysis of a national factorial vignette panel survey.

BACKGROUND: Unused opioid medication in the home increases risk of medication diversion, misuse, and unintended harm. The United States Federal Food and Drug Administration is currently considering the implementation of a risk evaluation and mitigation strategy (REMS) program that would require US pharmacists to provide drug disposal products with opioid prescriptions. Still, little is known about consumer preference for drug disposal method. The objective of this study was to identify product and program characteristics associated with consumer preference for at-home drug disposal products. METHODS: A 2x2x3x3 full-factorial design was employed to text-based vignettes representing opioid analgesic disposal scenarios. Each vignette varied on four characteristics: product cost (free vs paid), ease of use (a mail back envelope, bringing medication to a takeback site, and an at-home drug deactivation pouch), potential environmental impact (incineration), and point of access (pharmacy, community organization, and prescriber). Of the 36 possible vignettes, 12 were removed as they represented a non-realistic combination of vignette characteristics. The remaining 24 were administered to a panel of patients with controlled-substance use in the past six-months. Decision tree modeling and general linear mixed (GLM) models were used sequentially to identify product characteristics associated with patient drug preferences RESULTS: A total of 1,006 participants completed all vignette drug disposal scenarios. Regression tree analysis found that the most important predictor of use was cost followed by ease of access and product design. GLM showed that takeback programs offered at a pharmacy were the most preferred disposal option followed by at-home products (mailed envelope or deactivation system) dispensed with the prescription. CONCLUSION: Programs that provide disposal resources directly to the patient at no cost with their prescription are likely to optimize willingness to dispose. Findings support the FDA's plan for a REMS program requiring pharmacies to distribute mail-back envelopes to patients when dispensed opioids.

A new species of naked-toed gecko Cyrtopodion sensu lato (Squamata: Sauria: Gekkonidae) from Gujarat, India.

We describe a new species of naked-toed gecko of the genus Cyrtopodion Fitzinger, 1843, from the Dahod and Panchmahal districts of Gujarat state, India. The new species is diagnosable by the following suite of characters: a medium-sized Cyrtopodion (adult, snout to vent length up to 50 mm); dorsal scalation on trunk granular, intermixed with enlarged, regularly arranged transverse rows of 15 trihedral tubercles; 6 transverse rows of tubercles on the second segment of the tail; midbody scale rows across belly 20-22; midventral scales 89-97; males with a continuous series of 29-33 precloacal-femoral pores. The new species, Cyrtopodion vindhya sp. nov. is the fifth endemic species of reptile described in the last 15 years from the state of Gujarat that highlights the rich and unique diversity of this understudied region.

Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation.

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Improved left atrial appendage closure procedural efficiency using radiofrequency transseptal wire system.

OBJECTIVE: The radiofrequency (RF) needle has been shown to improve transseptal puncture efficiency and safety compared to mechanical needles. This study aimed to investigate the use of VersaCross RF transseptal wire system (Baylis Medical) to improve procedural efficiency of left atrial appendage closure (LAAC) compared to the standard RF needle-based workflow. METHODS: Eighty-one LAAC procedures using WATCHMAN FLX were retrospectively analyzed comparing the standard RF needle-based workflow to a RF wire-based workflow. Study primary endpoint was time to WATCHMAN device release, and secondary endpoints were transseptal puncture time, LAAC success, fluoroscopy use, and procedural complications. RESULTS: Twenty-five cases using standard RF needle-based workflow were compared to 56 cases using the RF wire-based workflow. Baseline patient characteristics were similar between both groups. LAAC was successful in all patients with no differences in intraprocedural complication rates (p = 0.40). Transseptal puncture time was 1.3 min faster using the RF wire-based workflow compared to the standard RF needle-based workflow (6.5 ± 2.3  vs. 7.8 ± 2.3 min, p = 0.02). Overall, time to final WATCHMAN device release was 4.5 min faster with the RF wire-based workflow compared to the RF needle-based workflow (24.6 ± 5.6 vs. 29.1 ± 9.6 min, p = 0.01). Fluoroscopy time was 21% lower using the RF wire-based workflow (7.6 ± 2.8 vs. 9.6 ± 4.4 min; p = 0.05) and fluoroscopy dose was 67% lower (47.1 ± 35.3 vs. 144.9 ± 156.9 mGy, p = 0.04) and more consistent (F-test, p ˂ 0.0001). CONCLUSIONS: The RF wire-based workflow streamlines LAAC procedures, improving LAAC efficiency and safety by reducing fluoroscopy, device exchanges, and delivery sheath manipulation.

Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia.

The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This "transcriptional numbness" lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.

Carotid Artery Stenting Versus Carotid Artery Endarterectomy in Asymptomatic Severe Carotid Stenosis: An Updated Meta-Analysis.

Carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) are revascularization options for the management of severe carotid disease in asymptomatic patients. We aimed to compare the peri-procedural outcomes of the two modalities. A systematic review of the databases PUBMED, EBSCO, and Cochrane Library was performed. All the studies that reported periprocedural outcomes (within 30 days) in asymptomatic carotid stenosis patients were included in the meta-analysis. Random effects models with inverse-variance weighting were used to estimate pooled risk ratios (RRs) to compare the outcomes. Fifteen studies (including seven randomized controlled trials) met the inclusion criteria. A total of 15251 patients were included, out of which 6419 (42%) underwent CAS and 8832 (57.9%) underwent CEA. There was no statistical difference in the primary composite outcome of death/stroke/myocardial infarction (MI) (RR 1.02, 95% CI [0.69-1.51], p 0.93). No difference was found in the secondary outcome of all-cause mortality. CAS was associated with a slightly lower risk of MI and cranial nerve palsy. CAS was associated with a slightly higher risk of stroke with no difference in the occurrence of disabling stroke or ipsilateral stroke. In general terms, the study confirms equipoise in the two treatment strategies with a higher risk of MI and cranial nerve palsy with CEA and a higher risk of non-disabling stroke with CAS.

Functional crosstalk between the cohesin loader and chromatin remodelers.

The cohesin complex participates in many structural and functional aspects of genome organization. Cohesin recruitment onto chromosomes requires nucleosome-free DNA and the Scc2-Scc4 cohesin loader complex that catalyzes topological cohesin loading. Additionally, the cohesin loader facilitates promoter nucleosome clearance in a yet unknown way, and it recognizes chromatin receptors such as the RSC chromatin remodeler. Here, we explore the cohesin loader-RSC interaction. Amongst multi-pronged contacts by Scc2 and Scc4, we find that Scc4 contacts a conserved patch on the RSC ATPase motor module. The cohesin loader directly stimulates in vitro nucleosome sliding by RSC, providing an explanation how it facilitates promoter nucleosome clearance. Furthermore, we observe cohesin loader interactions with a wide range of chromatin remodelers. Our results provide mechanistic insight into how the cohesin loader recognizes, as well as influences, the chromatin landscape, with implications for our understanding of human developmental disorders including Cornelia de Lange and Coffin-Siris syndromes.

ERK1/2 signalling dynamics promote neural differentiation by regulating chromatin accessibility and the polycomb repressive complex.

Fibroblast growth factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress, FGF signalling must decline. Why these signalling dynamics are required has not been determined. Here, we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos, and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs genome-wide across neural genes. Importantly, ERK1/2 inhibition induces precocious neural gene transcription, and this involves dissociation of the polycomb repressive complex from key gene loci. This takes place independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. Transient ERK1/2 inhibition is sufficient for the dissociation of the repressive complex, and this is not reversed on resumption of ERK1/2 signalling. Moreover, genomic footprinting of sites identified by ATAC-seq together with ChIP-seq for polycomb protein Ring1B revealed that ERK1/2 inhibition promotes the occupancy of neural transcription factors (TFs) at non-polycomb as well as polycomb associated sites. Together, these findings indicate that ERK1/2 signalling decline promotes global changes in chromatin accessibility and TF binding at neural genes by directing polycomb and other regulators and appears to serve as a gating mechanism that provides directionality to the process of differentiation.

N6-methyladenosine (m6A) reader Pho92 is recruited co-transcriptionally and couples translation to mRNA decay to promote meiotic fitness in yeast.

N6- methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here, we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3'end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate protein synthesis and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.

RSC and GRFs confer promoter directionality by restricting divergent noncoding transcription.

The directionality of gene promoters-the ratio of protein-coding over divergent noncoding transcription-is highly variable. How promoter directionality is controlled remains poorly understood. Here, we show that the chromatin remodelling complex RSC and general regulatory factors (GRFs) dictate promoter directionality by attenuating divergent transcription relative to protein-coding transcription. At gene promoters that are highly directional, depletion of RSC leads to a relative increase in divergent noncoding transcription and thus to a decrease in promoter directionality. We find that RSC has a modest effect on nucleosome positioning upstream in promoters at the sites of divergent transcription. These promoters are also enriched for the binding of GRFs such as Reb1 and Abf1. Ectopic targeting of divergent transcription initiation sites with GRFs or the dCas9 DNA-binding protein suppresses divergent transcription. Our data suggest that RSC and GRFs play a pervasive role in limiting divergent transcription relative to coding direction transcription. We propose that any DNA-binding factor, when stably associated with cryptic transcription start sites, forms a barrier which represses divergent transcription, thereby promoting promoter directionality.

Revisiting the type of Cyrtopodion aravallense (Gill, 1997): redescription of the species with comments on the genus.

Cyrtopodion aravallense (Gill, 1997) is a poorly known species, known only from the holotype and original description. I re-examined the holotype housed in the museum of Bombay Natural History Society, Mumbai and find some discrepancies between the original description and the holotype. Here, I redescribe the holotype of C. aravallense in greater detail and provide a revised diagnosis of the species. It is distinguished from all its congeners in having enlarged, regularly arranged transverse rows of 15 trihedral tubercles; 2526 midbody scale rows across belly; 102 midventral scales; males with 6 precloacal pores, 78 femoral pores on each side separated by 35 poreless scales between precloacal and femoral pores.

An Important Role for RPRD1B in the Heat Shock Response.

During the heat shock response (HSR), heat shock factor (HSF1 in mammals) binds to target gene promoters, resulting in increased expression of heat shock proteins that help maintain protein homeostasis and ensure cell survival. Besides HSF1, only a relatively few transcription factors with a specific role in ensuring correctly regulated gene expression during the HSR have been described. Here, we use proteomic and genomic (CRISPR) screening to identify a role for RPRD1B in the response to heat shock. Indeed, cells depleted for RPRD1B are heat shock sensitive and show decreased expression of key heat shock proteins (HSPs). These results add to our understanding of the connection between basic gene expression mechanisms and the HSR.