Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy: The ARCADIA Randomized Clinical Trial.

Importance: Atrial cardiopathy is associated with stroke in the absence of clinically apparent atrial fibrillation. It is unknown whether anticoagulation, which has proven benefit in atrial fibrillation, prevents stroke in patients with atrial cardiopathy and no atrial fibrillation. Objective: To compare anticoagulation vs antiplatelet therapy for secondary stroke prevention in patients with cryptogenic stroke and evidence of atrial cardiopathy. Design, Setting, and Participants: Multicenter, double-blind, phase 3 randomized clinical trial of 1015 participants with cryptogenic stroke and evidence of atrial cardiopathy, defined as P-wave terminal force greater than 5000 µV × ms in electrocardiogram lead V1, serum N-terminal pro-B-type natriuretic peptide level greater than 250 pg/mL, or left atrial diameter index of 3 cm/m2 or greater on echocardiogram. Participants had no evidence of atrial fibrillation at the time of randomization. Enrollment and follow-up occurred from February 1, 2018, through February 28, 2023, at 185 sites in the National Institutes of Health StrokeNet and the Canadian Stroke Consortium. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily (n = 507) vs aspirin, 81 mg, once daily (n = 508). Main Outcomes and Measures: The primary efficacy outcome in a time-to-event analysis was recurrent stroke. All participants, including those diagnosed with atrial fibrillation after randomization, were analyzed according to the groups to which they were randomized. The primary safety outcomes were symptomatic intracranial hemorrhage and other major hemorrhage. Results: With 1015 of the target 1100 participants enrolled and mean follow-up of 1.8 years, the trial was stopped for futility after a planned interim analysis. The mean (SD) age of participants was 68.0 (11.0) years, 54.3% were female, and 87.5% completed the full duration of follow-up. Recurrent stroke occurred in 40 patients in the apixaban group (annualized rate, 4.4%) and 40 patients in the aspirin group (annualized rate, 4.4%) (hazard ratio, 1.00 [95% CI, 0.64-1.55]). Symptomatic intracranial hemorrhage occurred in 0 patients taking apixaban and 7 patients taking aspirin (annualized rate, 1.1%). Other major hemorrhages occurred in 5 patients taking apixaban (annualized rate, 0.7%) and 5 patients taking aspirin (annualized rate, 0.8%) (hazard ratio, 1.02 [95% CI, 0.29-3.52]). Conclusions and Relevance: In patients with cryptogenic stroke and evidence of atrial cardiopathy without atrial fibrillation, apixaban did not significantly reduce recurrent stroke risk compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Age and 17ß-Estradiol (E2) Facilitate Nuclear Export and Argonaute Loading of microRNAs in the Female Brain.

Aging in women is accompanied by a dramatic change in circulating sex steroid hormones. Specifically, the primary circulating estrogen, 17ß-estradiol (E2), is nearly undetectable in post-menopausal women. This decline is associated with a variety of cognitive and mood disorders, yet hormone replacement therapy is only effective within a narrow window of time surrounding the menopausal transition. Our previous work identified microRNAs as a potential molecular substrate underlying the change in E2 efficacy associated with menopause in advanced age. Specifically, we showed that E2 regulated a small subset of mature miRNAs in the aging female brain. In this study, we hypothesized that E2 regulates the stability of mature miRNAs by altering their subcellular localization and their association with argonaute proteins. We also tested the hypothesis that the RNA binding protein, hnRNP A1, was an important regulator of mature miR-9-5p expression in neuronal cells. Our results demonstrated that E2 treatment affected miRNA subcellular localization and its association with argonaute proteins differently, depending on the length of time following E2 deprivation (i.e., ovariectomy). We also provide strong evidence that hnRNP A1 regulates the transcription of pri-miR-9 and likely plays a posttranscriptional role in mature miR-9-5p turnover. Taken together, these data have important implications for considering the optimal timing for hormone replacement therapy, which might be less dependent on age and more related to how long treatment is delayed following menopause.

International implementation of a care review process for mortality reviews: improving quality and safety virtually across the world.

Mortality reviews are intended to produce transparent, non-punitive personal and organisational learning that leads to systematic improvement in care. Mayo Clinic has a well-established care review process that has accomplished that objective within our system. The establishment of a new hospital, a joint venture between Mayo Clinic and Sheikh Shakhbout Medical City (SSMC) in Abu Dhabi, provided a unique opportunity to share this care review process internationally.During a baseline measurement period, only 78.3% of mortality reviews at SSMC were completed within 45 days, 16.7 percentage points below the target of 95%. A collaboration between SSMC and Mayo Clinic aimed to accelerate the design and implementation of a care review process system. Collaboration was constrained by travel restrictions imposed by COVID-19, language barriers, legal privacy concerns, and differing electronic health records.Mayo Clinic facilitated a 12-week virtual engagement with SSMC using weekly video meetings, education and training regarding Mayo Clinic's care review process.The engagement led to implementation of weekly mortality review huddles, restructuring of the mortality review committee to be multidisciplinary, use of a standardised taxonomy to characterise opportunities to improve care and creation of an education/communication plan regarding identified improvement opportunities using change management strategies.After the care review process for mortality reviews was instituted, SSMC achieved and sustained a target of 100% of mortality reviews completed within 45 days. The new process resulted in improved mortality review indicators and provided quality feedback to staff with engagement in performance improvement efforts.A virtual collaboration led to successful implementation of a care review process and substantial gains in the effectiveness of the quality programme at SSMC. This could serve as a model to assist other organisations, even if in-person engagement is hindered.

The Pittman Scholar Program for junior faculty recognition at the University of Alabama at Birmingham Heersink School of Medicine.

The University of Alabama at Birmingham Heersink School of Medicine established the Pittman Scholars Program in 2015 to elevate scientific impact and to support the recruitment and retention of highly competitive junior faculty. The authors examined the impact of this program on research productivity and on faculty retention. The authors evaluated publications and extramural grant awards and available demographic data for the Pittman Scholars compared to all junior faculty in the Heersink School of Medicine. From 2015 to 2021, the program awarded a diverse group of 41 junior faculty members across the institution. For this cohort, ninety-four new extramural grants were awarded and 146 grant applications were submitted since the inception of the scholar award. Pittman Scholars published a total of 411 papers during the term of the award. The faculty retention rate of the scholars was 95%, comparable to that of all Heersink junior faculty, with 2 recipients being recruited to other institutions. The implementation of the Pittman Scholars Program has been an effective strategy to celebrate scientific impact and acknowledge junior faculty members as outstanding scientists at our institution. The Pittman Scholars award allows junior faculty to use funds for their research program, publications, collaborations, and career advancement. The Pittman Scholars are recognized at local, regional, and national levels for the work they are contributing to academic medicine. The program has served as an important pipeline faculty development program and an avenue for individual recognition for research-intensive faculty.

Association between caffeine use disorder and socio-demographic characteristics (sex, employment and smoking status) of Quezon City residents: An analytical cross-sectional study / The Health Sciences Journal

Introduction@#Caffeine use disorder (CUD), a problematic caffeine use pattern, is yet to be recognized under DSM-5 and is under consideration for further research. This study aimed to determine if the sex, employment status, and smoking status of Quezon City residents aged 18 years old and above are associated with CUD, and to determine the mean daily caffeine consumption (MDCC) of caffeinated products and the proportion of individuals meeting the CUD criteria.@*Methods@#A total of 334 respondents accomplished the online survey that collected socio-demographic information and evaluated CUD using an 8-point Caffeine Consumption Questionnaire (CCQ). @*Results@#The study population was mostly composed of females, unemployed, and non-smokers. Results showed that 17% of respondents have CUD, that brewed coffee was most consumed daily, the MDCC of the study population was 158.31 mg; and females were at an increased risk for CUD, while nonsmokers and unemployed individuals were at reduced risk. @*Conclusion@#The proportion of Quezon city residents that have CUD is at 17%, consuming an average of 158.31 mg of coffee daily, with brewed coffee being consumed most. Female residents are at an increased risk of having CUD, while nonsmokers and unemployed individuals are at a decreased risk.

17ß-Estradiol Regulates miR-9-5p and miR-9-3p Stability and Function in the Aged Female Rat Brain.

Clinical studies demonstrated that the ovarian hormone 17ß-estradiol (E2) is neuroprotective within a narrow window of time following menopause, suggesting that there is a biological switch in E2 action that is temporally dependent. However, the molecular mechanisms mediating this temporal switch have not been determined. Our previous studies focused on microRNAs (miRNA) as one potential molecular mediator and showed that E2 differentially regulated a subset of mature miRNAs which was dependent on age and the length of time following E2 deprivation. Notably, E2 significantly increased both strands of the miR-9 duplex (miR-9-5p and miR-9-3p) in the hypothalamus, raising the possibility that E2 could regulate miRNA stability/degradation. We tested this hypothesis using a biochemical approach to measure miRNA decay in a hypothalamic neuronal cell line and in hypothalamic brain tissue from a rat model of surgical menopause. Notably, we found that E2 treatment stabilized both miRNAs in neuronal cells and in the rat hypothalamus. We also used polysome profiling as a proxy for miR-9-5p and miR-9-3p function and found that E2 was able to shift polysome loading of the miRNAs, which repressed the translation of a predicted miR-9-3p target. Moreover, miR-9-5p and miR-9-3p transcripts appeared to occupy different fractions of the polysome profile, indicating differential subcellular. localization. Together, these studies reveal a novel role for E2 in modulating mature miRNA behavior, independent of its effects at regulating the primary and/or precursor form of miRNAs.

Electrical Pumping of Perovskite Diodes: Toward Stimulated Emission.

The success of metal halide perovskites in photovoltaic and light-emitting diodes (LEDs) motivates their application as a solid-state thin-film laser. Various perovskites have shown optically pumped stimulated emission of lasing and amplified spontaneous emission (ASE), yet the ultimate goal of electrically pumped stimulated emission has not been achieved. As an essential step toward this goal, here, a perovskite diode structure that simultaneously exhibits stable operation at high current density (≈1 kA cm-2 ) and optically excited ASE (with a threshold of 180 µJ cm-2 ) is reported. This diode structure achieves an electroluminescence quantum efficiency of 0.8% at 850 A cm-2 , which is estimated to be ≈3% of the charge carrier population required to reach ASE in the same device. It is shown that the formation of a large angle waveguide mode and the reduction of parasitic absorption losses are two major design principles for diodes to obtain a positive gain for stimulated emission. In addition to its prospect as a perovskite laser, a new application of electrically pumped ASE is proposed as an ideal perovskite LED architecture allowing 100% external radiation efficiency.

Absolute Quantification of Phosphorylated ERß Amino Acids in the Hippocampus of Women and in A Rat Model of Menopause.

The rapid decline of circulating 17ß-estradiol (E2) at menopause leads to negative neurological consequences, although hormone therapy paradoxically has both harmful and positive effects depending on the age at which it is delivered. The inconsistent response to E2 suggests unappreciated regulatory mechanisms for estrogen receptors (ERs), and we predicted it could be due to age-related differences in ERß phosphorylation. We assessed ERß phosphorylation using a sensitive mass spectrometry approach that provides absolute quantification (AQUA-MS) of individually phosphorylated residues. Specifically, we quantified phosphorylated ERß in the hippocampus of women (aged 21-83 years) and in a rat model of menopause at 4 residues with conserved sequence homology between the 2 species: S105, S176, S200, and Y488. Phosphorylation at these sites, which spanned all domains of ERß, were remarkably consistent between the 2 species, showing high levels of S105 phosphorylation (80%-100%) and low levels of S200 (20%-40%). Further, S200 phosphorylation decreased with aging in humans and loss of E2 in rats. Surprisingly, Y488 phosphorylation, which has been linked to ERß ligand-independent actions, exhibited approximately 70% phosphorylation, unaltered by species, age, or E2, suggesting ERß's primary mode of action may not require E2 binding. We further show phosphorylation at 2 sites directly altered ERß DNA-binding efficiency, and thus could affect its transcription factor activity. These findings provide the first absolute quantification of ERß phosphorylation in the human and rat brain, novel insights into ERß regulation, and a critical foundation for providing more targeted therapeutic options for menopause in the future.

BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease.

Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere Z-disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1.NEW & NOTEWORTHY Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.

Returning to Growth: One Academic Medical Center's Successful Five-Step Approach to Change Management.

The University of Alabama at Birmingham academic medical center (UAB AMC) had achieved great success and growth during the 50 years since its founding. However, the challenging and more competitive environment of the 2000s left the UAB AMC on a downward trajectory. The UAB AMC had to overcome difficult internal cultural and structural barriers that stood in the way of the transformational change needed to remain competitive. Competition rather than collaborative and strategic financial investment were the primary cultural barriers for the UAB AMC, while people were the primary structural barrier. Leadership identified 5 steps that were critical for the transformation that occurred between 2013 and 2018: alignment of leadership; creating a compelling and credible shared vision; identifying cultural and structural barriers; creating a thoughtful, data-driven intervention; and improved communication and accountability. Following these steps enabled the UAB AMC to transform its institutional structure and culture. As a result, the UAB AMC thrived, returning to substantial growth in research and clinical care. UAB AMC School of Medicine grew by $100 million in National Institutes of Health funding and moved up 10 spots in ranking. In 2018, UAB Hospital had 10 specialties ranked by U.S. News & World Report, 7 more than in 2013. This article outlines the approach taken and provides a conceptual framework for other AMCs eager to transform their structure and culture and position themselves for growth.

Marianismo Beliefs, Intimate Partner Violence, and Psychological Distress Among Recently Immigrated, Young Adult Latinas.

Marianismo is a Latino cultural value that describes both positive and negative aspects of traditional Latina femininity. Marianismo emphasizes culturally valued qualities such as interpersonal harmony, inner strength, self-sacrifice, and morality. Endorsement of marianismo is hypothesized to correlate with individual economic, educational, and personal variables. Marianismo also is theorized to potentially influence attitudes about, experiences of, and responses to intimate partner violence (IPV) among Latina women. The present study examined whether endorsement of marianismo beliefs mitigated or exacerbated psychological distress after experiences of IPV in a sample of 205 recently immigrated Latina women, aged 18 to 23 years. Latina women experiencing higher levels of IPV and endorsing greater marianismo beliefs were hypothesized to indicate greater psychological distress. Unexpectedly, women who endorsed more Subordinate to Others/Self-Silencing to Maintain Harmony marianismo beliefs indicated more psychological distress (p = .05), greater symptoms of psychological distress (p = .01), and greater average distress (p = .03) when they also reported less IPV than peers. Implications for understanding Latinas' responses to and reporting of IPV, as well as for culturally tailored counseling interventions for this underserved and understudied population, are discussed.

Attendance for diagnostic colposcopy among high-risk human papillomavirus positive women in a Brazilian feasibility study.

OBJECTIVE: To investigate factors associated with colposcopy attendance in HPV-positive women in São Paulo, Brazil. METHODS: We analyzed data from a prospective cohort of women positive for high-risk HPV (hr-HPV) undergoing cervical cancer screening in primary care services in São Paulo, Brazil. Non-pregnant women attending routine screening between December 2014 and March 2016 were offered an hr-HPV test, and those testing positive and aged 25 years or older were invited for colposcopy. Sociodemographic information was recorded at study enrollment. We compared variables between women who did and did not attend colposcopy within a logistic regression framework. RESULTS: Of 1537 hr-HPV-positive women, 1235 (80.4%) attended for colposcopy, with a median time from primary test to colposcopy of 132 days. Younger age (P<0.001) and concurrent negative cytology results (P=0.025) were associated with lower attendance. Women registered at units providing both the primary test and colposcopy were more likely to attend than those at units making external referrals (788/862 [91.4%] versus 447/675 [66.2%], P<0.001). CONCLUSION: Non-attendance for colposcopy may limit the success of future screening programs based on hr-HPV testing in Brazil. Transfer of colposcopy services to primary care is a simple and effective facilitator of attendance.

miRNA degradation in the mammalian brain.

MicroRNAs (miRNAs) are short, noncoding RNAs that are evolutionarily conserved across many different species. miRNA regulation of gene expression, specifically in the context of the mammalian brain, has been well characterized; however, the regulation of miRNA degradation is still a focus of ongoing research. This review focuses on recent findings concerning the cellular mechanisms that govern miRNA degradation, with an emphasis on target-mediated miRNA degradation and how this phenomenon is uniquely poised to maintain homeostasis in neuronal systems.

Binge Alcohol Exposure in Adolescence Impairs Normal Heart Growth.

Background Approximately 1 in 6 adolescents report regular binge alcohol consumption, and we hypothesize it affects heart growth during this period. Methods and Results Adolescent, genetically diverse, male Wistar rats were gavaged with water or ethanol once per day for 6 days. In vivo structure and function were assessed before and after exposure. Binge alcohol exposure in adolescence significantly impaired normal cardiac growth but did not affect whole-body growth during adolescence, therefore this pathology was specific to the heart. Binge rats also exhibited signs of accelerated pathological growth (concentric cellular hypertrophy and thickening of the myocardial wall), suggesting a global reorientation from physiologic to pathologic growth. Binge rats compensated for their smaller filling volumes by increasing systolic function and sympathetic stimulation. Consequently, binge alcohol exposure increased PKA (protein kinase A) phosphorylation of troponin I, inducing myofilament calcium desensitization. Binge alcohol also impaired in vivo relaxation and increased titin-based cellular stiffness due to titin phosphorylation by PKCα (protein kinase C α). Mechanistically, alcohol inhibited extracellular signal-related kinase activity, a nodal signaling kinase activating physiology hypertrophy. Thus, binge alcohol exposure depressed genes involved in growth. These cardiac structural alterations from binge alcohol exposure persisted through adolescence even after cessation of ethanol exposure. Conclusions Alcohol negatively impacts function in the adult heart, but the adolescent heart is substantially more sensitive to its effects. This difference is likely because adolescent binge alcohol impedes the normal rapid physiological growth and reorients it towards pathological hypertrophy. Many adolescents regularly binge alcohol, and here we report a novel pathological consequence as well as mechanisms involved.

microRNA Expression Profiles in the Ventral Hippocampus during Pubertal Development and the Impact of Peri-Pubertal Binge Alcohol Exposure.

Adolescence is hallmarked by two parallel processes of sexual maturation and adult patterning of the brain. Therefore, adolescence represents a vulnerable postnatal period for neurodevelopment where exogenous factors can negatively impact adult brain function. For example, alcohol exposure during pubertal development can lead to long-term and widespread neurobiological dysfunction and these effects have been shown to persist even in the absence of future alcohol exposure. However, the molecular mechanisms mediating the persistent effects of alcohol are unclear. We propose that dysregulation of microRNAs (miR) could be a unifying epigenetic mechanism underlying these widespread long-term changes. We tested the hypothesis that repeated alcohol exposure during pubertal development would cause disruption of normal miR expression profiles during puberty and, subsequently, their downstream mRNA target genes in the ventral hippocampus using an established rat model of adolescent binge drinking. We found 6 alcohol-sensitive miRs that were all downregulated following alcohol exposure and we also investigated the normal age-dependent changes in those miRs throughout the pubertal period. Interestingly, these miRs were normally decreased throughout the process of puberty, but alcohol prematurely exacerbated the normal decline in miR expression levels. The work presented herein provides foundational knowledge about the expression patterns of miRs during this critical period of neurodevelopment. Further, this regulation of miR and mRNA expression by alcohol exposure presents a complex regulatory mechanism by which perturbation in this time-sensitive period could lead to long-term neurological consequences.

Binge Drinking and Intergenerational Implications: Parental Preconception Alcohol Impacts Offspring Development in Rats.

Preconception behaviors and experiences of mothers and fathers can affect future offspring. Recently, our laboratory showed that alcohol-naive offspring of parents who were exposed to repeated binge alcohol during adolescence showed altered DNA methylation patterns in the hypothalamus, a brain region involved in regulation of pubertal development, stress, and behavior. These observations have potentially far-reaching consequences for human health, as more than 4.6 million Americans under the age of 21 years report engaging in the rapid intoxication behavior of binge-pattern alcohol (EtOH) drinking. Therefore, we tested the hypothesis that offspring of binge EtOH‒exposed parents would have altered hypothalamic function manifested phenotypically as improper pubertal development, impaired socialization, and dysregulated stress response. In addition, we tested the hypothesis that parental EtOH exposure would confer adaptive protection from the negative effects of EtOH when offspring were themselves exposed to EtOH. Rats received EtOH via oral gavage once daily for 6 days at both early [postnatal day (PND) 37] and late puberty (PND 67). Animals were paired (EtOH-EtOH, vehicle-vehicle) for mating 24 hours after the last EtOH dose. After weaning, offspring were randomized to vehicle treatment to assess changes in normal development or to EtOH treatment to assess the effect of parental EtOH exposure on offspring response to this treatment. We found that offspring had smaller body weights and displayed fewer play behaviors when parents had been exposed to EtOH before conception. In addition, offspring showed a reduction in pubertal development markers that could indicate that parental preconception EtOH exposure confers maladaptive epigenetic traits in first-generation offspring.

The Survival Effect of Repeat Surgery at Glioblastoma Recurrence and its Trend: A Systematic Review and Meta-Analysis.

BACKGROUND: Glioblastoma (GBM) is a dismal disease managed in the first instance by surgical resection, temozolomide, and radiation. The role of repeat surgery at recurrence remains ill defined. This study aims to quantify the effect of repeat surgery in recurrent GBM on overall survival and determine if a trend in reported effect over time exists. METHODS: Searches of 7 electronic databases from inception to January 2018 were conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 2692 articles identified for screening. Prognostic hazard ratios (HRs) derived from multivariate regression analysis were extracted and analyzed using meta-analysis of proportions and linear regression. RESULTS: Eight observational studies reporting prognostic HRs in 10 cohorts were included. They described 1906 recurrent GBM diagnoses, managed by surgery at primary diagnosis, with 709 (37%) undergoing further repeat surgery at recurrence. Repeat surgery was shown to confer a statistically significant survival advantage compared with no surgery at recurrence in the pooled cohort (HR, 0.722; P < 0.001). Newer studies trended toward a more superior prognostic advantage of repeat surgery compared with earlier studies (effect coefficient, 0.856; P = 0.012). CONCLUSIONS: This meta-analysis of contemporary literature suggests that repeat surgery at GBM recurrence in select patients confers a significant, prognostic overall survival advantage independent of other prognostic factors. Furthermore, newer studies are significantly more likely to suggest greater benefit than are older studies. The main limitation is the selection bias inherent in the cohorts pooled for analysis. Larger prospective randomized controlled studies are needed to validate the findings of this study and provide stratification for such benefit justified by quality of life metrics.

Quantifying the prognostic significance in glioblastoma of seizure history at initial presentation: A systematic review and meta-analysis.

The role of prognostic factors in the management of glioblastoma (GBM) is very important given the stasis in improving its clinical outcomes. Patients who initially present with a positive seizure history at diagnosis have anecdotally experienced superior survival outcomes. The aim of this review was to perform a systematic review and meta-analysis to quantify the potential prognostic significance of positive seizure history in GBM patients. A search strategy was performed using the PRISMA guidelines for article identification, screening, eligibility and inclusion. Relevant articles were identified from six electronic databases from their inception to August 2017. These articles were screened against established criteria for inclusion into this study. Meta-analysis was conducted by pooling results with multivariate-adjusted hazard ratios (HRs). After screening, 6 relevant studies were included for analysis. There was a total cohort of 1836 GBM patients, of which 488 (27%) had a positive seizure history at initial presentation. There was a significant association found between positive seizure history in GBM patients and less mortality events, with an overall HR of 0.71 (95%CI=0.63-0.81, p<0.00001, I2=4%). Positive seizure history at initial presentation of GBM can be associated with improved prognosis. However, there are a number of variables that need to be considered further, including genetic profiling, lead time bias, and anti-epileptic drug (AED) therapy. This review represents the highest level of evidence to date, and its result will be validated by future, prospective study of larger cohorts.

17ß-estradiol regulates the RNA-binding protein Nova1, which then regulates the alternative splicing of estrogen receptor ß in the aging female rat brain.

Alternative RNA splicing results in the translation of diverse protein products arising from a common nucleotide sequence. These alternative protein products are often functional and can have widely divergent actions from the canonical protein. Studies in humans and other vertebrate animals have demonstrated that alternative splicing events increase with advanced age, sometimes resulting in pathological consequences. Menopause represents a critical transition for women, where the beneficial effects of estrogens are no longer evident; therefore, factors underlying increased pathological conditions in women are confounded by the dual factors of aging and declining estrogens. Estrogen receptors (ERs) are subject to alternative splicing, the spliced variants increase following menopause, and they fail to efficiently activate estrogen-dependent signaling pathways. However, the factors that regulate the alternative splicing of ERs remain unknown. We demonstrate novel evidence supporting a potential biological feedback loop where 17ß-estradiol regulates the RNA-binding protein Nova1, which, in turn, regulates the alternative splicing of ERß. These data increase our understanding of ER alternative splicing and could have potential implications for women taking hormone replacement therapy after menopause.