COPD Subtypes Are Differentially Associated with Cardiovascular Events and COPD Exacerbations.

BACKGROUND: The coronary artery calcium score (CACS) and ratio of the pulmonary artery to aorta diameters (PA:A ratio) measured from chest CT scans have been established as predictors of cardiovascular events and chronic obstructive pulmonary disease (COPD) exacerbations, respectively. However, little is known about the reciprocal relationship between these predictors and outcomes. Furthermore, the prognostic implications of COPD subtypes on clinical outcomes remain insufficiently characterized. RESEARCH QUESTION: How can these two chest CT-derived parameters predict subsequent cardiovascular events and COPD exacerbations in different COPD subtypes? STUDY DESIGN AND METHODS: Using COPDGene study data, we assessed prospective cardiovascular disease (CVD) and COPD exacerbation risk in COPD subjects (Global Initiative for Chronic Obstructive Lung Disease spirometric grades 2-4), focusing on CACS and PA:A ratio at study enrollment, with logistic regression models. These outcomes were analyzed in three COPD subtypes: 1,042 Non-emphysema-predominant COPD (NEPD; low attenuation area at -950 Hounsfield units [LAA-950]<5%), 1,324 Emphysema-predominant COPD (EPD; LAA-950≥10%), and 465 Intermediate Emphysema COPD (IE; 5≤LAA-950<10%). RESULTS: Our study indicated significantly higher overall risk for cardiovascular events in subjects with higher CACS (≥median; Odds Ratio (OR): 1.61, 95% Confidence Interval (CI)=1.30-2.00) and increased COPD exacerbations in those with higher PA:A ratios (≥1; OR: 1.80, 95% CI=1.46-2.23). Notably, NEPD subjects showed a stronger association between these indicators and clinical events compared to EPD (with CACS/CVD, NEPD vs. EPD, OR 2.02 vs. 1.41; with PA:A ratio/COPD exacerbation, NEPD vs. EPD, OR 2.50 vs. 1.65); the difference in odds ratios between COPD subtypes was statistically significant for CACS/CVD. INTERPRETATION: Two chest CT parameters, CACS and PA:A ratio, hold distinct predictive values for cardiovascular events and COPD exacerbations that are influenced by specific COPD subtypes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00608764.

Clinical predictors and outcomes of ST-elevation myocardial infarction related cardiogenic shock in the Asian population.

Background: Cardiogenic shock (CS) complicating myocardial infarction is associated with poor outcomes. Data among Asian populations are scarce. We aimed to investigate the long-term outcomes, prognostic factors, and predictors of CS among Asian ST elevation myocardial infarction (STEMI) patients. Methods: This was a retrospective cohort study of consecutive patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI within our regional STEMI network between 2015 and 2019. The long-term outcomes of those with and without CS were compared. Clinical predictors of outcomes and development of CS were investigated. Results: A total of 1791 patients who underwent PPCI were included. Patients completed at least 2 years' follow-up with a median follow-up period of 2.6 years (IQR 1.0, 3,9). Overall, 208/1791 (11.6 %) STEMI patients developed CS. These patients were older (61.1 ± 12.5 vs 57.8 ± 12.2, P < 0.001) and mostly men (87.0 %). All-cause mortality (59.9 % vs 4.7 % P < 0.001), cardiac mortality (43.8 % vs 2.2 %, P < 0.001) and major adverse cardiovascular events (MACE) was significantly higher in the CS group (59.1 % vs 14.0 %, P < 0.001). Independent predictors of survival were higher index LVEF (adjusted hazards ratio [aHR] 0.967, 95 %CI 0.951-0.984, p < 0.001) and higher arterial pH at onset of shock (aHR 0.750, 0.626-0.897, p = 0.002). Increased serum lactate concentration independently predicts poor prognosis (aHR 1.084, 95 % CI 1.046-1.124, p < 0.001). Conclusion: In Asian STEMI patients who underwent PPCI, CS was associated with poor outcomes. Higher LVEF on index admission was associated with better outcomes; while lactic acidosis independently predicted mortality.

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.

Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.

The Princeton IV Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease.

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative symposium dedicated to optimizing sexual function and preserving cardiovascular health. The Fourth Princeton Consensus Conference was convened on March 10-11, 2023, at the Huntington Medical Research Institutes in Pasadena, California. Princeton panels I to III addressed the clinical management of men with erectile dysfunction (ED) who also had cardiovascular disease. Thirteen years since Princeton III, Princeton IV builds on previous foundations in several key areas. Mounting evidence supports the need for providers to treat men with ED as being at risk for cardiac events until proven otherwise. Algorithms for the diagnosis and treatment of ED are updated with new recommendations for coronary artery calcium scoring for advanced cardiovascular risk stratification. Optimization of oral phosphodiesterase type 5 inhibitors in the treatment of men with ED and cardiovascular disease is thoroughly explored, including recent evidence of potential cardioprotective effects of these drugs.

rTMS for Poststroke Pusher Syndrome: A Randomized, Patient-Blinded Controlled Clinical Trial.

BACKGROUND: Patients with poststroke pusher syndrome (PS) require longer duration of rehabilitation and more supplemental care after discharge. Effective treatment of PS remains a challenge. The role of repetitive transcranial magnetic stimulation (rTMS) for PS has not been examined. OBJECTIVE: Assess the efficacy of rTMS for patients with poststroke PS in reducing pushing behavior, enhancing motor recovery and improving mobility. METHODS: A randomized, patient- and assessor-blinded sham-controlled trial with intention-to-treat analysis was conducted. Thirty-four eligible patients with poststroke PS were randomly allocated to receive either rTMS or sham rTMS for 2 weeks. Pushing behavior on the Burke lateropulsion scale and scale for contraversive pushing, motor function on Fugl-Meyer assessment scale-motor domain (FMA-m) and mobility on modified Rivermead mobility index were measured at baseline, 1 and 2 weeks after intervention. Repeated-measures analysis of covariance was used for data analysis. RESULTS: There was no significant interaction between intervention and time on Burke lateropulsion scale (F = 2.747, P = .076), scale for contraversive pushing (F = 1.583, P = .214), or change of modified Rivermead mobility index (F = 1.183, P = .297). However, a significant interaction between intervention and time was observed for FMA-m (F = 5.464, P = .019). Post hoc comparisons of FMA-m show better improvement in rTMS group with mean differences of 12.7 (95% CI -7.3 to 32.7) and 15.7 (95% CI -4.6 to 36.0) at post-treatment week 1 and week 2 respectively. CONCLUSIONS: rTMS did not demonstrate significant efficacy in improving pushing behavior and mobility in patients with PS. However, rTMS might have potential effect in enhancing motor function for patients with PS. REGISTRATION: The study was registered in the Chinese Clinical Trial Registry (registration No. ChiCTR2200058015 at http://www.chictr.org.cn/searchprojen.aspx) on March 26, 2022.

Anaemia and quality of life in chronic kidney disease: a consensus document from the European Anaemia of CKD Alliance.

Anaemia is common in chronic kidney disease (CKD) and has a significant impact on quality of life (QoL), work productivity and outcomes. Current management includes oral or intravenous iron and erythropoiesis-stimulating agents (ESAs), to which hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been recently added, increasing the available therapeutic options. In randomised controlled trials, only intravenous iron improved cardiovascular outcome, while some ESAs were associated with increased adverse cardiovascular events. Despite therapeutic advances, several challenges and unmet needs remain in the current management of anaemia of CKD. In particular, clinical practice does not include an assessment of QoL, which prompted a group of European nephrologists and representatives of patient advocacy groups to revisit the current approach. In this consensus document, the authors propose a move towards a more holistic, personalised and long-term approach, based on existing evidence. The focus of treatment should be on improving QoL without increasing the risk of adverse cardiovascular events, and tailoring management strategies to the needs of the individual. In addition, the authors discuss the suitability of a currently available anaemia of CKD-specific health-related QoL measure for inclusion in the routine clinical management of anaemia of CKD. The authors also outline the logistics and challenges of incorporating such a measure into electronic health records and how it may be used to improve QoL for people with anaemia of CKD.

Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Efficacy of powered air-purifying respirators (PAPRs) for source control of simulated respiratory aerosols.

BACKGROUND: Loose-fitting powered air-purifying respirators (PAPRs) are a popular alternative to the use of filtering facepiece respirators for health care workers. Although PAPRs protect the wearer from aerosol particles, their ability to block infectious aerosol particles exhaled by the wearer from being released into the environment (called source control) is unclear. METHODS: The source control performance of 4 PAPRs with loose-fitting facepieces were tested using a manikin that exhales aerosol particles. The PAPRs were tested by themselves and in combination with a face-worn product intended to provide source control (either a surgical mask or an N95 filtering facepiece respirator). RESULTS: Two PAPR facepieces with filtration panels significantly reduced the release of exhaled aerosols into the environment, while 3 facepieces without such panels did not. Wearing a surgical mask or respirator under the facepiece significantly improved the source control performance. CONCLUSIONS: Most PAPR facepieces do not block aerosols exhaled by the wearer. Facepieces designed to filter exhaled particles can prevent aerosols from being released into the environment. Wearing a surgical mask or a filtering facepiece respirator under the facepiece can also provide source control, but PAPRs are not typically certified for use with masks and respirators.

Heart failure risk assessment in patients with hypertrophic cardiomyopathy based on the H2FPEF score.

AIMS: The aim of this study was to investigate whether the H2FPEF score, which was developed to improve the diagnosis of heart failure (HF) with preserved ejection fraction, is associated with HF outcomes in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Patients with HCM and preserved left ventricular ejection fraction (LVEF ≥50%) were included from a multicentre registry and the H2FPEF score was calculated. Patients were divided into three groups: low (0-1), intermediate (2-5) and high (6-9) H2FPEF score. The primary combined endpoint was a composite of all-cause death and HF admissions, while the secondary endpoints were all-cause death and HF admissions separately. A total of 955 patients were included (age 51 ± 17 years, 310 [32.5%] female). Patients with a high H2FPEF score (n = 105) were more often female, and presented with more symptoms and comorbidities. On echocardiography, patients with a high H2FPEF score had lower LVEF, more impaired diastolic function and more frequently left ventricular outflow tract obstruction. During follow-up (median 90 months [interquartile range 49-176]), 103 (11%) patients died and 57 (6%) patients had a first HF hospitalization. Event-free survival rate for the primary combined and secondary endpoints was lower for patients with an intermediate and high H2FPEF score. On multivariate Cox regression analysis, female sex (hazard ratio [HR] 1.670, 95% confidence interval [CI] 1.157-2.410; p = 0.006), Asian ethnicity (HR 6.711, 95% CI 4.076-11.048; p < 0.001), ischaemic heart disease (HR 1.732, 95% CI 1.133-2.650; p = 0.011), left atrial diameter (HR 1.028, 95% CI 1.005-1.051; p = 0.016) and intermediate (HR 2.757, 95% CI 1.612-4.713; p < 0.001) or high H2FPEF score (HR 3.689, 95% CI 1.908-7.134; p < 0.001) were independently associated with the primary combined endpoint. CONCLUSION: The H2FPEF score is independently associated with HF outcome in patients with HCM and may be considered for risk stratification.

A Transdiagnostic Network Analysis of Childhood Trauma and Psychopathology.

BACKGROUND AND HYPOTHESIS: Psychiatric comorbidities suggest that symptoms overlap across different diagnoses; the transdiagnostic network approach is valuable for studying psychopathology. Childhood trauma is a common transdiagnostic risk factor for psychiatric disorders, but the complex relationship between childhood trauma and psychopathology has seldom been investigated using a large cross-sectional transdiagnostic sample. STUDY DESIGN: This study recruited 869 patients with different diagnoses, including 418 schizophrenia, 215 bipolar disorder, and 236 major depressive disorder. Participants completed psychiatric interviews and self-report questionnaires. We constructed dimension- and item-level Least Absolute Shrinkage and Selection Operator-based (LASSO) networks to explore the relationship between childhood trauma, psychopathology, and duration of illness. Moreover, we constructed directed acyclic graphs (DAGs) to tentatively clarify the potential directions of associations among these variables. Network Comparison Tests (NCTs) were conducted for different diagnostic groups and gender-stratified groups. STUDY RESULTS: The transdiagnostic LASSO networks showed that different types of childhood trauma exerted distinct impacts on various psychopathological dimensions. Emotional abuse was linked to depressive symptoms, physical abuse to excited symptoms, sexual abuse to positive and disorganized symptoms, emotional neglect to depressive symptoms and motivation and pleasure (MAP) deficits factor of negative symptoms, and physical neglect to MAP factor. The DAG findings generally concurred with the LASSO network. The NCT showed comparable networks. CONCLUSIONS: Our findings suggest that childhood trauma is significantly associated with the development of psychopathology across different diagnostic groups. The affective pathway model suggests that early identification and tailored interventions would be needed for people with a history of childhood trauma.

Benefits of dapagliflozin in chronic kidney disease for US commercial payers: A cost-offset analysis.

BACKGROUND: One in 7 adults have chronic kidney disease (CKD), which is associated with high morbidity and mortality and substantial health care costs, especially in more advanced disease. Our data from a US commercial payer show rising per-member-per-year costs for renal and cardiac complications associated with CKD. OBJECTIVE: To predict the clinical and economic impact of treatment with or without dapagliflozin from the perspective of a US commercial payer using a cost-offset model (COM). METHODS: The COM used real-world cost and member count data from a US employer-sponsored commercial payer and results of the double-blind, randomized, phase 3 Dapagliflozin and Prevention of Adverse Outcomes in CKD clinical trial (NCT03036150) to predict the incidence of clinical events, including a greater than or equal to 50% decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, and hospitalization for heart failure, and their associated costs over a 3-year period. The COM compared a hypothetical scenario of the experience with or without dapagliflozin in members with CKD stages 2-4, aged younger than 65 years. RESULTS: In the simulated populations of 130 members, the COM projected 9 events of a greater than or equal to 50% decline in estimated glomerular filtration rate for the experience with dapagliflozin vs 15 events for the experience without dapagliflozin (6 fewer events; number needed to treat [NNT] = 20, amounting to estimated cumulative cost offsets of $0.57 million [M] over a 3-year period). The COM projected similar results for end-stage kidney disease (8 events with dapagliflozin vs 14 events without dapagliflozin; NNT = 24, amounting to $1.92 M in cumulative cost offsets) and for hospitalization for heart failure (13 events with dapagliflozin vs 33 events without dapagliflozin; NNT = 7, amounting to $0.79 M in cumulative cost offsets). These projections translated to total mean, cumulative cost offsets of $3.89 M for all clinical events evaluated over the 3-year period (36.6% reduction with dapagliflozin vs without dapagliflozin), and net mean, cumulative cost offsets of $2.58 M over the 3-year period (24.2% reduction with dapagliflozin vs without dapagliflozin) after factoring in a discounted wholesale acquisition cost for dapagliflozin expenditure ($1.31 M over 3 years). Thus, the net mean, cumulative cost offsets were $19,843 per member over 3 years, representing a 197% return on investment for dapagliflozin expenditure. CONCLUSIONS: Results of our COM suggest that dapagliflozin can reduce clinical events and their associated costs over a 3-year period when compared with a scenario without dapagliflozin. Cost offsets increased with each year, indicating that US commercial payers can substantially reduce costs associated with CKD morbidity and mortality.

Differential manifestations of anhedonia in people with social anhedonia and subsyndromal depression.

Empirical findings suggested that anhedonia, a reduced capability to access pleasure and a core symptom in both schizophrenia and the major depressive disorder, can be present in people with high levels of social anhedonia and people with subsyndromal depression. Few studies have adopted a multidimensional framework to investigate anhedonia in these subclinical samples. We recruited 35 participants with high social anhedonia (SA), 53 participants with subsyndromal depression (SD), 20 participants with co-occurrence of both traits (CO), and 47 participants with low levels of both traits (CN) to complete a self-report questionnaire capturing the pleasure experience, and the Monetary Incentives Delay (MID) Task and the Social Incentives Delay (SID) Task capturing the motivation of reward. Results indicated that people with SA, SD and CO exhibited lower abstract anticipatory pleasure compared to CN. Moreover, people with SD and CO exhibited specific impairment in response to social incentives. Together, our findings characterized the multidimensional features of anhedonia performances of subclinical samples with SA, SD and CO, which may contribute to the formulation of early identification of at-risk groups.

Cost Offset of Dapagliflozin in the US Medicare Population with Cardio-Kidney Metabolic Syndrome.

INTRODUCTION: Cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent in the US Medicare population and is projected to increase further. Sodium-glucose co-transporter 2 inhibitors have indications in chronic kidney disease (CKD), heart failure (HF), and type 2 diabetes (T2D), providing protective efficacy across conditions within CKM syndrome. The objective of this study was to develop a model to extrapolate key outcomes observed in pivotal clinical trials to the US Medicare population, and to assess the potential direct cost offsets associated with dapagliflozin therapy. METHODS: All US 2022 Medicare beneficiaries (≥ 65 years of age) eligible to receive dapagliflozin were estimated according to drug label indication and Medicare enrollment and claims data. Incidence of key outcomes from the dapagliflozin clinical program were modelled over a 4-year time horizon based on patient-level data with CKD, HF, and T2D. Published cost data of relevant clinical outcomes were used to calculate direct medical care cost-offset associated with treatment with dapagliflozin. RESULTS: In a population of 13.1 million patients with CKM syndrome, treatment with dapagliflozin in addition to historical standard of care (hSoC) versus hSoC alone led to fewer incidents of HF-related events (hospitalization for HF, 613,545; urgent HF visit, 98,896), renal events (kidney failure, 285,041; ≥ 50% sustained decline in kidney function, 375,137), and 450,355 fewer deaths (of which 225,346 and 13,206 incidences of cardiovascular and renal death were avoided). In total this led to medical care cost offsets of $99.3 billion versus treatment with hSoC only (dapagliflozin plus hSoC, $310.3 billion; hSoC, $211.0 billion). CONCLUSION: By extrapolating data from trials across multiple indications within CKM syndrome, this broader perspective shows that considerable medical care cost offsets may result through attenuated incidence of clinical events in CKD, T2D, and HF populations if treated with dapagliflozin in addition to hSoC over a 4-year time horizon. Graphical abstract available for this article.

Association of diastolic blood pressure with coronary perfusion pressure during resuscitation in pediatric swine.

BACKGROUND: Diastolic blood pressure (DBP) is suggested as a surrogate for coronary perfusion pressure (CPP) during cardiopulmonary resuscitation. We examined the correlation between DBP and CPP and hypothesized that both would be associated with survival in a pediatric swine model of asphyxial cardiac arrest. METHODS: We performed a retrospective, secondary analysis of 102 pediatric swine resuscitations. DBP and CPP were recorded every 30 s during resuscitation. Values were compared between survivors and non-survivors. RESULTS: DBP mirrored CPP in survivors and non-survivors throughout resuscitation and both were associated with survival. Improvements in DBP and CPP after the first epinephrine administration were greater in survivors (DBP: 25.1 ± 3.0 vs. 5.4 ± 0.8 mmHg, p < 0.01; CPP: 24.9 ± 3.2 vs. 4.8 ± 0.9 mmHg, p < 0.01). DBP and CPP after epinephrine administration were highly predictive of survival, with an area under the curve of 0.95 (0.89-1.00) for DBP and 0.90 (0.81-0.99) for CPP. The optimal threshold for DBP was 22.5 mmHg, whereas that for CPP was 14.5 mmHg. CONCLUSIONS: DBP and CPP were associated with survival throughout resuscitation, and the response of both to the first epinephrine administration was highly predictive of survival in this model. Clinically, the availability of DBP makes it useful as a target for physiologic feedback during resuscitation. IMPACT: Diastolic blood pressure (DBP) mirrored coronary perfusion pressure (CPP) throughout prolonged resuscitation in a pediatric model of asphyxial cardiac arrest. Mean DBP and CPP were significantly greater in survivors than in non-survivors both before and after administration of epinephrine. The response of both DBP and CPP to the first dose of epinephrine was highly predictive of return of spontaneous circulation. Given the clinical availability of DBP, these findings support its use as a surrogate for CPP to guide high-quality cardiopulmonary resuscitation in this pediatric swine model.

Natural history of initially asymptomatic severe aortic stenosis: a one-stage meta-analysis.

BACKGROUND: Current guidelines on the management strategy for patients with asymptomatic severe aortic stenosis (AS) remain unclear. This uncertainty stems from the lack of data regarding the natural history of these patients. To address this gap, we performed a systematic review and meta-analysis examining the natural history of asymptomatic severe AS patients receiving conservative treatment. METHODS: The PubMed, Cochrane, and Embase databases were searched from inception to 24 January 2024 using the keywords "asymptomatic" AND "aortic" AND "stenosis". We included studies examining patients with asymptomatic severe AS. In interventional trials, only data from conservatively managed arms were collected. A one-stage meta-analysis was conducted using individual patient data reconstructed from published Kaplan-Meier curves. Sensitivity analysis was performed for major adverse cardiovascular outcomes in patients who remained asymptomatic throughout follow-up. RESULTS: A total of 46 studies were included (n = 9545). The median time to the development of symptoms was 1.11 years (95% CI 0.90-1.53). 49.36% (40.85-58.59) of patients who were asymptomatic had suffered a major adverse cardiovascular event by 5 years. The median event-free time for heart failure hospitalization (HFH) was 5.50 years (95% CI 5.14-5.91) with 36.34% (95% CI 33.34-39.41) of patients experiencing an HFH by year 5. By 5 years, 79.81% (95% CI 69.26-88.58) of patients developed symptoms (angina, dyspnoea, syncope and others) and 12.36% (95% CI 10.01-15.22) of patients died of cardiovascular causes. For all-cause mortality, the median survival time was 9.15 years (95% CI 8.50-9.96) with 39.43% (CI 33.41-36.40) of patients dying by 5 years. The median time to AVR was 4.77 years (95% CI 4.39-5.17), with 52.64% (95% CI 49.85-55.48) of patients requiring an AVR by 5 years. CONCLUSION: Our results reveal poor cardiovascular outcomes for patients with asymptomatic severe AS on conservative treatment. A significant proportion eventually requires an AVR. Further research is needed to determine if early intervention with AVR is more effective than conservative treatment.

Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.

BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo. METHODS: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes. RESULTS: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes. CONCLUSIONS: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders.

Contemporary Incidence of Cognitive Impairment or Dementia in Patients Undergoing Coronary Artery Bypass Grafting: A Systematic Review and Meta-Analysis.

INTRODUCTION: Despite the high prevalence of cognitive impairment or dementia post-coronary artery bypass grafting (CABG), the incidence of cognitive impairment or dementia post-CABG in contemporary practice is currently unclear. Therefore, this paper aims to investigate the incidence and associated risk factors of cognitive impairment or dementia in patients' post-CABG. METHODS: A systematic search across three databases (PubMed, SCOPUS, and Embase) was conducted for studies published in or after 2013 that reported cognitive impairment or dementia post-CABG. Subgroup analyses and meta-regression by risk factors were performed to determine their influence on the results. RESULTS: This analysis included 23 studies with a total of 2,620 patients. The incidence of cognitive impairment or dementia less than 1 month, 2 to 6 months, and more than 12 months post-CABG was 35.96% (95% confidence interval [CI]: 28.22-44.51, I2 = 87%), 21.33% (95% CI: 13.44-32.15, I2 = 88%), and 39.13% (95% CI: 21.72-58.84, I2 = 84%), respectively. Meta-regression revealed that studies with more than 80% of the cohort diagnosed with hypertension were significantly associated with incidence of cognitive impairment or dementia less than 1 month post-CABG. CONCLUSION: This meta-analysis demonstrates a high incidence of cognitive impairment or dementia in patients' post-CABG in contemporary practice, particularly less than 1 month post-CABG and more than 12 months post-CABG. We found that hypertension was a significant risk factor in the short-term (less than 1 month) follow-up period for cognitive impairment or dementia post-CABG. Future research should be done to assess strategies to reduce cognitive impairment post-CABG.

NMNAT2 is a druggable target to drive neuronal NAD production.

Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.