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This randomized clinical trial assesses the effect of a liberal vs a restrictive hemoglobin threshold for red blood cell transfusion on unfavorable neurological outcome in patients with acute brain injury.
This randomized clinical trial examines whether 3 cycles of carboplatin, etoposide, and vincristine chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features.
To the Editor We read with interest the recent study that compared the fecal immunochemical test (FIT) positivity threshold vs multitarget stool RNA (mt-sRNA) testing for colorectal cancer screening. However, we have concerns regarding the study methodology and the capability of FIT to fully replace the mt-sRNA panel.
In Reply Our study adjusted the FIT cutoff to yield the same overall positivity rate as reported for the mt-sRNA test (17%) to enhance comparability of diagnostic performance of both tests. Below we address each of the 3 points made by Drs Yang and Ma.
This randomized trial showed no difference in local or systemic side effects in patients receiving their vaccines on either schedule.
Objective
To investigate the effects of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) on the clinical outcomes of non-male factor patients aged >35 with three or fewer oocytes retrieved.
Design
Retrospective cohort study.
Setting
Reproductive centre of a university-affiliated hospital in China.
Participants
547 women with non-male factor infertility who underwent assisted reproductive technology (ART) treatment with three or fewer oocytes retrieved were identified from June 2019 to May 2022. Of these 547 patients, 334 were treated with IVF and 213 with ICSI.
Outcome measures
The primary outcomes were normal fertilisation rate, live birth rate per transfer and cumulative live birth rate per retrieval.
Results
The baseline characteristics were comparable between the two groups, except for the proportion of primary infertility, which was higher in the ICSI group (17.66% vs 32.86%, p=0.000). Compared with the IVF group, the ICSI group showed higher normal fertilisation rate and lower cycle cancellation rate (65.99% vs 76.56%, p=0.002; 33.53% vs 24.41%, p=0.023). However, no significant differences were found in clinical pregnancy rate per transfer (23.86% vs 18.92%, p=0.545), miscarriage rate per fresh embryo transfer (19.05% vs 28.57%, p=0.595), live birth rate per transfer (17.05% vs 13.51%, p=0.623), cumulative clinical pregnancy rate per retrieval (12.87% vs 11.27%, p=0.576) and cumulative live birth rate per retrieval (9.28% vs 6.57%, p=0.261) between the two groups (p >0.05).
Conclusions
In non-male factor ART cycles, ICSI was not associated with improved pregnancy outcomes in older women with a low number of oocytes retrieved. Routine use of ICSI is not recommended in older women who are infertile due to non-male factors.
A strategy of early AVR was superior to clinical surveillance due to a reduction in hospitalizations.
Circulation, Volume 150, Issue Suppl_1, Page ASa1107-ASa1107, November 12, 2024. Introduction:Lung donation after uncontrolled circulatory death (uDCD) following a witnessed cardiac arrest is feasible after resuscitation and assessment with ex vivo lung perfusion (EVLP). This bench study explores the efficacy of expiratory flow modulation in minimizing damage caused by mechanical power during volume-controlled ventilation within the EVLP procedure.Methods:Donor lungs were simulated using the ASL 5000 lung simulator (IngMar Medical) and ventilated in volume-controlled mode using the ViX-ventilator (KU Leuven), set at 7 breaths per minute with a positive end-expiratory pressure of 5 cmH2O. (Figure 1) Baseline measurements were obtained to deliver tidal volumes (VT) of 300, 400, and 500 mL. These measurements were then compared to an intervention where expiratory flow was modulated using an in-house designed device, the flow modulator. Mechanical power (J/min) was calculated using the pressure-volume curve. Differences in power between the baseline and various levels of flow modulation were assessed using a one-sided t-test.Results:No clinically relevant differences were observed in VT delivery between baseline settings and during expiratory flow modulation. (Table 1) However, significant differences in mechanical power were noted between baseline and flow modulation across the three VT settings (p
Circulation, Volume 150, Issue Suppl_1, Page A4145834-A4145834, November 12, 2024. Introduction:Managing severe aortic stenosis in patients with a history of coronary artery bypass grafting (CABG) is challenging. Traditionally, surgical aortic valve replacement (SAVR) was the standard treatment, but transcatheter aortic valve replacement (TAVR) offers a less invasive alternative. This meta-analysis compares the 30-day outcomes of TAVR versus SAVR in patients with prior CABG.Methods:A systematic review and meta-analysis were conducted according to PRISMA guidelines. Studies comparing TAVR and SAVR in patients with prior CABG were included. The primary outcomes were 30-day (cardiovascular) CV mortality, all-cause mortality, stroke, and myocardial infarction. Heterogeneity was assessed using the Chi-squared test and I-squared statistic. P value
Circulation, Volume 150, Issue Suppl_1, Page A4146303-A4146303, November 12, 2024. Background:Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism that inhibits the catabolism and clearance of triglyceride (TG)-rich lipoproteins in the blood. Loss-of-function APOC3 variants are associated with significantly lower TG levels and a reduced risk of heart disease, underscoring the potential of APOC3 inactivation as a therapeutic strategy for patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG). Here, we developed STX-1400 lead molecules as a novel investigational gene editing treatment using a highly engineered CRISPR-CasX mRNA and a guide RNA (gRNA) encapsulated into lipid nanoparticles (LNPs) to edit the APOC3 gene and knock out its hepatic expression.Methods:STX-1400 lead molecules were evaluated for editing potency and resulting functional effects on APOC3 reduction in vitro in primary human hepatocytes (PHHs) and primary cynomolgus hepatocytes (PCHs). In vivo studies were conducted in PXB mice, a humanized liver mouse model. Liver biopsies and serum samples were collected at two weeks post-dose. Human APOC3 mRNA and APOC3 protein levels were measured in liver biopsies and serum samples, respectively. Lipid profile evaluation, which included measuring TGs and total cholesterol (TC) levels, was also performed.Results:Treatment of PHHs with LNPs containing STX-1400 lead molecules showed a dose-dependent increase in editing activity; up to 90% editing at the APOC3 locus was associated with >70% reduction in secreted APOC3 protein levels. Potency was also observed in PCHs, with up to 70% editing. A single dose of LNPs encapsulating STX-1400 lead molecules delivered into PXB humanized mice resulted in >60% editing at the APOC3 locus in the liver, which was associated with >90% reduction of serum hAPOC3 protein levels, accompanied by reduction in TG and TC levels.Conclusions:These data demonstrate that the STX-1400 lead molecules efficiently knock down hepatic expression of APOC3 in preclinical models. This work suggests that the CRISPR-CasX-based editor approach could be developed as a single dose therapy for the treatment of hypertriglyceridemia.
Circulation, Volume 150, Issue Suppl_1, Page A4144508-A4144508, November 12, 2024. Background:Hypertension in pregnancy affects around 15% of all pregnant women and is one of the leading causes of maternal and fetal, mortality and morbidity. Hydralazine and labetalol are administered intravenously to control hypertension in pregnant women. However, data regarding their comparative efficacy and safety is limited. Considering the paucity of data, we conducted a systematic review and meta-analysis to pool all the studies published on this subject and provide robust evidence.Methods:We followed PRISMA guidelines for conducting this systematic review and meta-analysis. Two investigators searched PubMed/MEDLINE, Scopus, the Cochrane Library, and Google Scholar from inception until May 2024. The randomized controlled trials (RCTs) which compared the effects of intravenous labetalol versus hydralazine in pregnant women with hypertensive disorder of pregnancy were included in our pooled analysis. A random-effects model was used to calculate the weighted mean differences (MD) for continuous outcomes and odds ratio (OR) for the discrete outcomes along with the corresponding 95% confidence intervals (CIs). We considered a p-value of less than 0.05 statistically significant in all cases.Results:A total of 8 RCTs with total population of 1138 patients were pooled. The pooled analysis showed that the final systolic blood pressure (MD = -4.74, 95% CI: -12.09 to 2.62, p = 0.21) and diastolic pressure (MD = -0.86, 95% CI: -9.22 to 7.49, p = 0.84) remained comparable. The incidence of maternal hypotension (OR = 0.13, 95% CI: 0.06 to 0.29, p
Circulation, Volume 150, Issue Suppl_1, Page A4145840-A4145840, November 12, 2024. Introduction:High levels of blood pressure (BP) are responsible for 7.6 million deaths each year worldwide, more than any other risk factor. The diagnosis of hypertension is associated with a significant increase in the risk of kidney or cardiovascular events, with no prior history of these events. Our study aims to analyze trends in hypertensive heart disease and hypertensive heart and kidney disease-related mortality in the United States, focusing on different races.Method:We retrieved death certificate data from the CDC-WONDER database for adults aged ≥25 years. Crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated. Temporal trends were examined using the average annual percent change (AAPC) determined by joinpoint regression.Result:From 1999 to 2020, a total of 100,705 people died from hypertensive heart and renal disease in the USA. The overall AAMR of 1.4 per 100,000 displayed a trend during this period (AAPC: 4.8, 95% CI [3.3–6.2]). Total deaths from hypertensive heart disease and renal disease associated with heart failure were 5,274, showing an increasing trend from 1999 to 2020. The AAMR for hypertensive heart and renal disease with heart failure was 0.1 (AAPC: 5.2, 95% CI [3.8–6.7]). Black or African Americans have the highest AAMR (0.1, 95% CI [0.1–0.1]). Total deaths from hypertensive heart disease and renal disease associated with renal failure were 34,519, showing an increasing trend from 1999 to 2020. The AAMR for hypertensive heart and renal disease with renal failure was 0.4 (AAPC: 3.9, 95% CI [2.6–5.1]). Black or African American has the highest AAMR (1.6, 95% CI [1.5–1.6]), followed by American Indian or Alaska Native (0.5, 95% CI [0.4–0.5]), Asians and Pacific Islanders (0.4, 95% CI [0.4–0.4]), and White (0.4, 95% CI [0.3–0.4]).Conclusion:African Americans and other identified high-risk races should get targeted therapies to reduce the burden of hypertensive-related morbidity and mortality; those with renal impairment should receive special attention. The goals of these interventions ought to be to increase access to healthcare, raise public knowledge of hypertension, and support lifestyle changes.
Circulation, Volume 150, Issue Suppl_1, Page A4142798-A4142798, November 12, 2024. Background:Spontaneous coronary artery dissection (SCAD) refers to the nontraumatic, non-iatrogenic, and nonatherosclerotic separation of the coronary artery wall leading to acute coronary syndrome. This condition predominantly affects women with minimal or no traditional cardiac risk factors. We aimed to determine the differences in clinical presentation between SCAD and Type 1 myocardial infarction (MI) in the Aurora Health Care community.Methods:A retrospective, matched cohort, multicenter community study was carried out on adult patients aged >18 years admitted to all Aurora Hospitals from January 2012 to December 2022. A total of 57 patients were diagnosed with SCAD during that period. SCAD group and Type 1 MI group were matched by age and gender at a 1:5 ratio using a propensity score-based matching. Outcomes between the SCAD and the Type 1 MI groups were compared using chi-squared tests or Fisher’s exact tests, and t-tests or nonparametric equivalents (Wilcoxon).Results:A higher percentage of Type 1 MI patients presented as NSTEMI compared to SCAD patients (70% vs. 59.6%, p=0.028). Although not statistically significant, SCAD patients had a higher occurrence of STEMI than Type 1 MI patients (42.1% vs. 32.6%, p=0.169).On admission, SCAD patients had a higher maximum troponin (12,000 vs. 3,550, p=0.012). Type 1 MI patients had higher HgbA1C (6 vs. 5.4, p=0.0008). Both patients had similar LDL levels, but Type 1 MI had lower HDL levels (44 vs. 48, p=0.024). ESR, CRP, and D-dimer levels showed no significant difference. LV ejection fraction was 53% in both groups, and the LV global longitudinal strain was similar. The Type 1 MI group exhibited higher grades of diastolic dysfunction (Grade 2 and Grade 3) and mitral valve disease. E/e was higher in Type 1 MI compared to SCAD (11.5 vs 8.8, p
Circulation, Volume 150, Issue Suppl_1, Page A4139206-A4139206, November 12, 2024. Introduction:Maintaining LDL-C at goal levels is critical in populations at high risk for cardiovascular events, including people with heterozygous familial hypercholesterolemia (HeFH) and/or premature coronary artery disease (CAD). Despite multiple approved LDL-C lowering therapies for these populations, most patients are not at guideline-directed treatment goal.In vivobase editing to inactivate hepaticPCSK9has the potential to provide lifelong LDL-C lowering after a single course of treatment. Success of the base editing approach is contingent on safe and effective hepatocyte delivery and precise, consistentPCSK9editing.Aim:We set out to develop a base editing medicine to inactivatePCSK9with broad utility across diverse genetic backgrounds. Here we describe the investigational therapy, VERVE-102, and the design of the ongoing, phase 1b Heart-2 trial.Approach:VERVE-102 consists of an mRNA encoding an adenine base editor and guide RNA (gRNA) targetingPCSK9packaged in a novel, proprietary GalNAc lipid nanoparticle (LNP). VERVE-102 creates a precise A-to-G DNA edit to introduce a premature stop codon and thereby inactivatePCSK9in hepatocytes. In a DNA sequence analysis of 784,318 individuals from diverse ancestries, the 20 base-pair sequence targeted by the gRNA was identical in 99.97% of individuals. LNP delivery to hepatocytesin vivooccurs through either endogenous LDL receptor (LDLR) uptake or GalNAc-mediated endocytosis via the asialoglycoprotein receptor (ASGPR) and as such, may address the LDLR deficiency seen in a fraction of patients with HeFH. Heart-2 is a single ascending dose trial of VERVE-102 in males and females aged 18–65 with HeFH and/or premature CAD who require additional LDL-C lowering despite maximally tolerated oral lipid-lowering therapies. Participants receive a single intravenous infusion of VERVE-102 with 3 to 9 participants per dose cohort. The primary endpoint is safety and tolerability. Secondary endpoints include pharmacokinetics of VERVE-102 and changes from baseline in blood PCSK9 and LDL-C.Discussion:VERVE-102 was designed to access hepatocytes via either LDLR- or ASGPR-mediated uptake to enable robust LNP delivery and subsequentPCSK9editing. Consistency of the gRNA target site suggests that potential therapeutic benefits should apply broadly across ancestries. The ongoing Heart-2 clinical trial is intended to support selection of a safe and effective dose for future clinical investigation of VERVE-102.
Circulation, Volume 150, Issue Suppl_1, Page A4143363-A4143363, November 12, 2024. Background:Various temporary mechanical circulatory support device (t-MCS) options are available for supporting patients in cardiogenic shock. While each device has a different physiological impact on the heart, limited studies compare genetic changes in the heart t-MCS. Here, we compare the impact of a percutaneous left ventricular assist device (pVAD) vs an Intra-aortic balloon pump (IABP) on miRNA expression of the left ventricle in patients being bridged to cardiac replacement.Hypothesis:Difference in genetic signature exists between patients treated with pVAD vs IABPMethods:Myocardial tissue was collected at the time of cardiac surgery from 4 patients bridged with a pVAD (Impella 5.5) and 4 bridged with IABP. Samples from each strategy of support were combined. Bulk sequencing was performed on an Illumina Hiseq 4000. Raw data was processed to identify unique sequences with lengths of 18-26 nucleotides and were mapped to miRBase to identify known and novel microRNAs (miRs).Results:The top upregulated (Fig. 1A) and downregulated (Fig. 1B) miRs had functionality related to endothelial pathology and cell transitions (miR 422,378 &92a, miR-653, miR-144). For example, miR 21 has been shown to represent a pathogenic state in cancer and cardiac disease and was found to be significantly lower in heart failure patients supported with pVAD when compared to patients supported with IABP. Gene set enrichment analysis of all the downregulated miRs was performed using miRNA enrichment analysis and annotation tool (miEAA). UpSet plots (Fig. 1C) of the downregulated miRs exhibited a regulatory role in inflammatory and cancer-based genes. KEGG enrichment analysis oftarget genesof the differentially expressed miRs exhibited that 1000 genes were associated with metabolic pathways (hsa01100), followed by 500 genes in cancer pathways (hsa05200) (Fig. 1D).Conclusion:Our results suggest that direct cardiac unloading using a p-VAD might have a better improvement of the pathological milieu of heart failure when compared to counter-pulsation unloading. The choice of t-MCS to support myocardial recovery might be important. Our future work will include a prospective study with temporal evaluation of patient’s blood for miRNA profiling.
Circulation, Volume 150, Issue Suppl_1, Page A4139940-A4139940, November 12, 2024. Background:There are two approved methods for transcatheter aortic valve replacement (TAVR) namely balloon-expandable valves (BEV) and self-expanding valves (SEV). While several randomized controlled trials (RCTs) have compared the efficacy of SEV and BEV, the generalizability of their findings is questioned. Therefore, to generate concrete evidence regarding the superiority between the two, we conducted this real-world meta-analysis to compare the clinical efficacy and safety outcomes of SEV vs BEV in patients undergoing TAVR for aortic stenosis (AS).Methods:MEDLINE, EMBASE, and Scopus were queried to shortlist studies including AS patients undergoing TAVR. Primary outcomes included 30-day and 1-year all-cause and cardiac mortality. Secondary outcomes were permanent pacemaker implantation (PPI), paravalvular leak (PVL), aortic regurgitation (AR), stroke, major vascular complications (MVC), major bleeding (MB), acute kidney injury (AKI), myocardial infarction (MI), length of stay (LOS), patient prosthesis mismatch (PPM), and atrial fibrillation (AF). A random effects meta-analysis was conducted to derive risk ratios and mean differences with corresponding 95% confidence intervals (CI).Results:Our meta-analysis included 38 real-world studies. No significant association was seen in 30-day (RR=1.13, P=0.15) and 1-year all-cause mortality (RR=1.04, P=0.55), and cardiac mortality (RR=1.28, P=0.12). SEV was associated with a higher risk of 30-day PPI (RR=1.61, 95% CI 1.28-2.02, I2 = 88%, P
