bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta-blockers effects according to sex: does selectivity and dose equally matter?
Authors: Salvioni E , Paolillo S , Galotta A , Mapelli M , Mattavelli I , Basile C , Vignati C , Moscucci F , Piepoli M , Agostoni P 
Published: November 2023

Abstract

Background
β-blockers are one of the four recommended disease-modifying classes of drugs for the treatment of heart failure with reduced ejection fraction (HFrEF). Although their efficacy and prognostic role is unquestionable in the general population of HFrEF patients, the differences in their effect in relation to sex have not been yet investigated in detail. The present study analyzed a large, real-world, Italian population of HFrEF patients aiming to highlight any prognostic difference between males and females in relation to dose and β-selectivity of the ongoing β-blocker treatment.

Methods
Out of the 7900 HFrEF patients included in the MECKI score registry, we retrospectively analyzed those treated with β-blockers. We investigated the prognostic role of β-selectivity, dividing the population in assuming β1/β2-receptor blockers (carvedilol) vs. β1-selective blockers (bisoprolol, nebivolol or metoprolol), according to sex, and the prognostic role of daily carvedilol-equivalent β-blocker dose in relation to sex. The primary outcome of the study was the composite of all cause mortality, urgent heart transplant and LVAD implant analyzed at 5 years, both as raw data and after correction of potential confounders.

Results
6784 HFrEF patients treated with β-blockers were analyzed (1215 females, 5569 males). Patients median follow-up was 4.05 years [1.72-7.47]: 4.37 [1.6-8.13] for females and 3.99 [1.75-7.3] for males (p=ns). According to β-selectivity no prognostic differences were found in the general population, as in female or males (Fig. 1 right panel). Stratification of patients according to β-blockers equivalent dose showed significant difference among groups: mortality decreases with increasing β-blockers dose in both males and females (Fig. 1, left panel), both at baseline and after adjustment for the main confounders (LVEF, age, peakVO2, systolic pressure, hemoglobin, rest heart rate; VE/VCO2 slope, etiology. ICD, MDRD).

Conclusions
In a large, real-life population of chronic HFrEF patients analyzed according to sex, no prognostic differences were found between stratifying for β-selectivity. A better outcome was observed in subjects receiving a high daily dose, independently from sex.Fig 1Table 1
Evaluation of disease progression in patients with ATTR amyloidosis with cardiomyopathy following treatment with patisiran: post-hoc analysis of the APOLLO-B study
Authors: Damy T , Shah Z , Drachman B , Schwartzmann P , Tinoco Mesquita C , Polydefkis M , Obici L , Jay P , Bender S , Capocelli K , Hanna M 
Published: November 2023

Abstract

Introduction
Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which cardiac deposition of transthyretin (TTR) amyloid commonly manifests as cardiomyopathy. Patisiran, an RNA interference therapeutic that reduces TTR synthesis, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The Phase 3 APOLLO-B study (NCT03997383) evaluated the clinical efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy (CM).

Purpose
This post-hoc analysis evaluated disease progression in APOLLO-B patients following treatment with patisiran vs placebo, based on the European Society of Cardiology (ESC) expert consensus on monitoring patients with ATTR amyloidosis with CM every 6–12 months using three domains: Clinical/Functional, Laboratory Biomarker, and Imaging/Electrocardiography (ECG).

Methods
Patients with ATTR amyloidosis with CM were randomised (1:1) to intravenous patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. Disease progression was defined at Month 12 (M12) relative to baseline using Clinical/Functional criteria (≥1 heart failure-related hospitalisation, increased New York Heart Association class ≥1, decline in Kansas City Cardiomyopathy Questionnaire ≥5, or decline in 6-minute walk test ≥30 metres), Laboratory Biomarker criteria (increased N-terminal prohormone B-type natriuretic peptide ≥30% and absolute change ≥300 ng/L, troponin I ≥30%, or ATTR disease stage ≥1), and Imaging/ECG criteria (conduction disturbances or change in left ventricular wall thickness ≥2 mm, change in diastolic dysfunction grade ≥1, or change in systolic function measurements). One marker from each domain provides the minimum criteria for disease progression.

Results
At M12, the patisiran group (N = 180) had improved odds of no disease progression compared with the placebo group (N = 178; odds ratio [OR] 1.4; 95% confidence interval [CI] 0.77, 2.55) (Figure). The patisiran group had benefits in Clinical and Functional markers vs placebo at M12 (OR 1.58; 95% CI 1.03, 2.42). Patisiran also showed favourable changes in Laboratory Biomarkers vs placebo at M12 (OR 2.14; 95% CI 1.33, 3.43) and a favourable trend in Imaging assessments/ECG vs placebo at M12 (OR 1.31; 95% CI 0.80, 2.15).

Conclusion
In this post-hoc analysis of APOLLO-B, fewer patisiran-treated patients had disease progression with respect to clinical, functional, and biomarker parameters vs placebo. The risk of disease progression was lower by Clinical/Functional and Laboratory Biomarker composite criteria, and trended lower by individual criterion from the ESC consensus statement among patisiran-treated patients at 12 months vs placebo patients. Long-term follow-up will further assess the impact of patisiran in patients with ATTR amyloidosis with CM.Figure 1
Survival analysis of tafamidis use in patients with ATTR cardiac amyloidosis
Authors: Starr N , Razvi Y , Bolhuis R E , Hague O , Petrie A , Fontana M , Gillmore J 
Published: November 2023

Abstract

Introduction
Transthyretin cardiac amyloidosis (ATTR-CM) is a condition in which amyloid fibrils are deposited within the myocardium causing a restrictive cardiomyopathy & resulting heart failure condition. With increasing recognition, a challenge posed, surrounds decisions on optimal treatment strategies. For patients with predominant cardiac amyloidosis, without peripheral/autonomic nervous system involvement, targeted treatments are limited, although the medication tafamidis – a TTR stabiliser, is available since approval by the FDA in 2019 & the European commission in 2020.

Aim
This study aims to analyse the real-world benefit of tafamidis use in patients with ATTR-CM attending the National Amyloidosis Centre (NAC), UK with regards overall survival from diagnosis when compared to those not on targeted treatment.

Methods
This was a retrospective study using data taken from a database at the NAC, as all patients included attend the NAC, UK. Patients on tafamidis were matched to control patients (not on targeted treatment) for age, ATTR NAC stage at diagnosis and type of ATTR (i.e. variant or wild-type). Outcome and survival analysis were determined using cox regression analysis and Kaplan-Meier curve using SPSS (V9.0).

Results
The demographics of patients in both groups are detailed in figure 1. There were 75 patients in both the treatment & control groups. The median follow-up time from diagnosis to data acquisition in the control group was 3.7 years [IQR1.8-5.8] compared to 4.3 years [IQR 3.6-5.4] in the treatment group (p = 0.03). Of note the median duration from diagnosis to starting tafamidis was 2.1 years [1.2-3.2]. Using cox regression analysis, tafamidis use was predictive of a reduced likelihood of death (R = -1.4, p&lt;0.001) [OR 0.24 95%CI 0.12-0.47]. Increasing NAC stage at diagnosis (R = 0.42, P = 0.03), [OR1.5, 95%CI 1.04-2.22] was predictive of increased likelihood of death. Increasing age (R = 0.03, p = 0.07) [OR 1.03, 95%CI 0.98-1.07] was non-significantly associated with increased likelihood of death. There was similarly a significant increase in mortality within the control/non-treatment group of patients (P&lt;0.001) which was reflected in the Kaplan-Meier survival curve (p&lt;0.001).

Conclusions
In this retrospective analysis, tafamidis use in 75 patients with ATTR-CM, initiated after a median of 2.2 year [IQR1.2-3.2] following diagnosis, was associated with significantly reduced mortality when compared to an untreated matched control group. Survival from diagnosis was similarly improved in the tafamidis group as depicted by the Kaplan-Meier curve. This real-world data suggests support for the use of tafamidis in treating those with ATTR-CM.
Non-adherence to prescribed medications in ambulatory patients with heart failure assessed using liquid chromatography tandem mass spectrometry
Authors: Sze S , Lane D , Krishnan S , Clark A L , Gupta P , Squire I B 
Published: November 2023

Abstract

Background
Reported rates of medication non-adherence in patients with heart failure (HF) vary widely, ranging between 5-60%, depending on the method of assessment. Very few studies have assessed non-adherence objectively by measuring the plasma level of medications or metabolites; the true prevalence of medication non-adherence in HF patients is unknown.

Objectives
To report prevalence and clinical associates of medication non-adherence in a cohort of ambulatory HF patients assessed using liquid chromatography–tandem mass spectrometry analysis of plasma levels of prescribed, evidence-based treatments.

Methods
We assessed adherence in 172 consecutive patients with HF attending a routine clinic follow-up visit. We used liquid chromatography-tandem mass spectrometry to measure the presence of prescribed medications (angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blocker (ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), diuretics and digoxin) in plasma samples collected during the visit. No patient knew in advance that the blood test would be used to assess adherence.

Results
69% were male; median (IQR) age 76 (67-82) years; median NTproBNP 1036 (433-2340) ng/L; 62% HF with reduced ejection fraction (HFrEF, LVEF &lt;40%). 1 in 5 patients had severe symptoms (NYHA III/IV) and 38% patients had Clinical Frailty Scale ≥ 5.
120 (70%) had all prescribed medications of interest detectable in plasma; in 52 (30%) patients, at least one prescribed medication was not detected. In none of the patients were no prescribed medications detected (Figure 1).
Among the 125 patients prescribed diuretics, 18 (14%) were non-adherent. Among the 106 patients with HFrEF, 25 (24%) were at least partially non-adherent to a disease modifying medication (ACEi/ ARB/BB/MRA). Amongst medication groups studied, the highest non-adherence rate was with ACEi/ARB and diuretics (14% for each) (Figure 2).
Comparing non-adherent patients to those who were adherent, there was no significant difference in age, sex or number of medications prescribed. Frailty was more common in the non-adherent compared to adherent group (46% vs 34%). Systolic/ diastolic blood pressure and heart rate were higher in non-adherent patients [median (IQR) SBP: 150 (137-174) vs 140 (125-164) mmHg; median (IQR) DBP 80 (69-89) vs 75 (64-83) mmHg; median (IQR) HR 76 (67-85) vs 69 (60-77) mmHg, each p&lt;0.05]. NTproBNP tended to be higher in those who were non-adherent [median (IQR): 1309 (673-2302) vs 891 (353-2391) ng/L].

Conclusion
Medication non-adherence, assessed using a single spot plasma measurement of medication levels, appears to be common in ambulatory patients with HF. 1 in 3 patients were at least partially non adherent to prescribed medications. Our observations have implications for the assessment and management of patients with HF.
Balloon surface temperature–controlled ablation using a second-generation radiofrequency HotBalloon: an in vivo feasibility study
Authors: Shinoda Yasutoshi , Yamasaki Hiro , Murakoshi Nobuyuki , Kohno Tsunesuke , Yamane Teiichi , Aonuma Kazutaka , Ishizu Tomoko 
Published: November 2023

Abstract

Aims
The first-generation radiofrequency HotBalloon (RHB) is a size-adjustable single-shot device used in atrial fibrillation. The energy output is determined by its central temperature and not by its balloon surface temperature (BST), thus limiting its efficacy and safety. Therefore, a second-generation RHB was developed to monitor BST and enable BST-controlled ablation. This animal study aims to evaluate the accuracy of a newly developed BST-monitoring system and validate the optimal BST for ablation.

Methods and results
In Protocol 1, thermocapsules were attached to the superior vena cava (SVC) epicardium. The accuracy of BST monitoring was examined during SVC isolation. In Protocol 2, the efficacy and safety of different BST-controlled ablations were examined. In the acute model, electrophysiological and pathological findings were assessed after energy applications with BST at 51, 54, 57, and 60°C. In the chronic model, the lesion durability and pathological findings were assessed 8 weeks after BST-controlled ablation (57 and 60°C). A significant positive correlation was found between the epicardial temperature and the BST-monitoring value (r = 0.98). In the acute model, all target veins were electrically isolated with BST-controlled ablation at ≥57°C (18/18, 100%). In the chronic model, durable lesions were observed in all veins at 60°C, while 44% of the veins showed reconnection at 57°C. In both pathological analyses, significantly greater lesions were observed at 60°C than at 57°C. There were no significant differences in adverse events between the two groups.

Conclusion
Balloon surface temperature–controlled ablation at 60°C using the second-generation RHB may be optimal for creating durable lesions without compromising safety.
Massive contractions of myotonic dystrophy type 2-associated CCTG tetranucleotide repeats occur via double-strand break repair with distinct requirements for DNA helicases
Authors: Papp David , Hernandez Luis A , Mai Theresa A , Haanen Terrance J , O’Donnell Meghan A , Duran Ariel T , Hernandez Sophia M , Narvanto Jenni E , Arguello Berenice , Onwukwe Marvin O , Mirkin Sergei M , Kim Jane C 
Published: November 2023

Abstract
Myotonic dystrophy type 2 (DM2) is a genetic disease caused by expanded CCTG DNA repeats in the first intron of CNBP. The number of CCTG repeats in DM2 patients ranges from 75 to 11,000, yet little is known about the molecular mechanisms responsible for repeat expansions or contractions. We developed an experimental system in Saccharomyces cerevisiae that enables the selection of large-scale contractions of (CCTG)100 within the intron of a reporter gene and subsequent genetic analysis. Contractions exceeded 80 repeat units, causing the final repetitive tract to be well below the threshold for disease. We found that Rad51 and Rad52 are involved in these massive contractions, indicating a mechanism that uses homologous recombination. Srs2 helicase was shown previously to stabilize CTG, CAG, and CGG repeats. Loss of Srs2 did not significantly affect CCTG contraction rates in unperturbed conditions. In contrast, loss of the RecQ helicase Sgs1 resulted in a 6-fold decrease in contraction rate with specific evidence that helicase activity is required for large-scale contractions. Using a genetic assay to evaluate chromosome arm loss, we determined that CCTG and reverse complementary CAGG repeats elevate the rate of chromosomal fragility compared to a short-track control. Overall, our results demonstrate that the genetic control of CCTG repeat contractions is notably distinct among disease-causing microsatellite repeat sequences.
Whole Genome Assembly and Annotation of Blackstripe Livebearer Poeciliopsis prolifica
Authors: Zhang Ying , Reynoso Yuridia , Reznick David , Wang Xu 
Published: November 2023

Abstract
The blackstripe livebearer Poeciliopsis prolifica is a live-bearing fish belonging to the family Poeciliidae with high level of postfertilization maternal investment (matrotrophy). This viviparous matrotrophic species has evolved a structure similarly to the mammalian placenta. Placentas have independently evolved multiple times in Poeciliidae from nonplacental ancestors, which provide an opportunity to study the placental evolution. However, there is a lack of high-quality reference genomes for the placental species in Poeciliidae. In this study, we present a 674 Mb assembly of P. prolifica in 504 contigs with excellent continuity (contig N50 7.7 Mb) and completeness (97.2% Benchmarking Universal Single-Copy Orthologs [BUSCO] completeness score, including 92.6% single-copy and 4.6% duplicated BUSCO score). A total of 27,227 protein-coding genes were annotated from the merged datasets based on bioinformatic prediction, RNA sequencing and homology evidence. Phylogenomic analyses revealed that P. prolifica diverged from the guppy (Poecilia reticulata) ∼19 Ma. Our research provides the necessary resources and the genomic toolkit for investigating the genetic underpinning of placentation.
The SWI/SNF nucleosome remodeler constrains enhancer activity during Drosophila wing development
Authors: Niederhuber Matthew J , Leatham-Jensen Mary , McKay Daniel J 
Published: November 2023

Abstract
Chromatin remodeling is central to the dynamic changes in gene expression that drive cell fate determination. During development, the sets of enhancers that are accessible for use change globally as cells transition between stages. While transcription factors and nucleosome remodelers are known to work together to control enhancer accessibility, it is unclear how the short stretches of DNA that they individually unmask yield the kilobase-sized accessible regions characteristic of active enhancers. Here, we performed a genetic screen to investigate the role of nucleosome remodelers in control of dynamic enhancer activity. We find that the Drosophila Switch/Sucrose Non-Fermenting complex, BAP, is required for repression of a temporally dynamic enhancer, brdisc. Contrary to expectations, we find that the BAP-specific subunit Osa is dispensable for mediating changes in chromatin accessibility between the early and late stages of wing development. Instead, we find that Osa is required to constrain the levels of brdisc activity when the enhancer is normally active. Genome-wide profiling reveals that Osa directly binds brdisc as well as thousands of other developmentally dynamic regulatory sites, including multiple genes encoding components and targets of the Notch signaling pathway. Transgenic reporter analyses demonstrate that Osa is required for activation and for constraint of different sets of target enhancers in the same cells. Moreover, Osa loss results in hyperactivation of the Notch ligand Delta and development of ectopic sensory structures patterned by Notch signaling early in development. Together, these findings indicate that proper constraint of enhancer activity is necessary for regulation of dose-dependent developmental events.
Lewis a−b− histo-blood group antigen phenotype is predictive of severe COVID-19 in the black South African population group
Authors: Magwira Cliff A , Nndwamato Ndivho P , Selabe Gloria , Seheri Mapaseka L 
Published: November 2023

Abstract
Several risk factors have been associated with SARS-CoV-2 infections and severity of COVID-19 disease it causes. This study investigated whether variations in histo-blood group antigen (HBGA) expression can predispose individuals to SARS-CoV-2 infections and severity of the disease. Nasopharyngeal swabs, randomly selected from SARS-CoV-2 positive and SARS-CoV-2 negative individuals, were tested for Lewis and H-type 1 HBGA phenotypes by ELISA using monoclonal antibodies specific to Lewis a, Lewis b and H type 1 antigens. The most common Lewis HBGA phenotype among all study participants was Lewis a−b+ (46%), followed by Lewis a−b− (24%), Lewis a+b− and Lewis a+b+ (15% each), while 55% of the study participants were H-type 1. Although SARS-CoV-2 negative individuals had a lower likelihood of having a Lewis a−b− phenotype compared to their SARS-CoV-2 positives counterparts (OR: 0.53, 95% C.I: 0.255–1.113), it did not reach statistical significance (P = 0.055). The frequency of Lewis a+b+, Lewis a+B−, Lewis a−b+, H type 1 positive and H type 1 negative were consistent between SARS-CoV-2 positive and SARS-CoV-2 negative individuals. When stratified according to severity of the disease, individuals with Lewis a+b− phenotype had a higher likelihood of developing mild COVID-19 symptoms (OR: 3.27, 95% CI; 0.9604–11.1), but was not statistically significant (P = 0.055), while Lewis a−b− phenotype was predictive of severe COVID-19 symptoms (OR: 4.3, 95% CI: 1.274–14.81), P = 0.016. In conclusion, individuals with Lewis a−b− phenotype were less likely to be infected by SARS-CoV-2, but when infected, they were at risk of severe COVID-19.
Exclusive Enteral Nutrition Mediates Beneficial Gut Microbiome Enrichment in Acute Severe Colitis
Authors: Bajaj Aditya , Markandey Manasvini , Singh Mukesh , Sahu Pabitra , Vuyyuru Sudheer K , Kante Bhaskar , Kumar Peeyush , Verma Mahak , Makharia Govind , Kedia Saurabh , Travis Simon P L , Ahuja Vineet 
Published: November 2023

Abstract

Background
Exclusive enteral nutrition (EEN) supplementation of the standard of care (SOC) augments steroid responsiveness in patients with acute severe ulcerative colitis (ASUC). EEN is known to alter gut microbial composition. The present study investigates EEN-driven gut microbial alterations in patients with ASUC and examines their correlations with clinical parameters.

Methods
Stool samples from patients with ASUC (n = 44) who received either EEN-supplemented SOC (EEN group; n = 20) or SOC alone (SOC group; n = 24) for 7 days were collected at baseline (day 0) and postintervention (day 7). Microbiome analysis was carried out using 16S ribosomal RNA gene sequencing followed by data processing using QIIME2 and R packages.

Results
Seven-day EEN-conjugated corticosteroid therapy in patients with ASUC enhanced the abundances of beneficial bacterial genera Faecalibacterium and Veillonella and reduced the abundance of Sphingomonas (generalized linear model fitted with Lasso regularization with robustness of 100%), while no such improvements in gut microbiota were observed in the SOC group. The EEN-associated taxa correlated with the patient’s clinical parameters (serum albumin and C-reactive protein levels). Unlike the SOC group, which retained its preintervention core microbiota, EEN contributed Faecalibacterium prausnitzii, a beneficial gut bacterial taxon, to the gut microbial core. EEN responders showed enhancement of Ligilactobacillus and Veillonella and reduction in Prevotella and Granulicatella. Analysis of baseline gut microbiota showed relative enhancement of certain microbial genera being associated with corticosteroid response and baseline clinical parameters and that this signature could conceivably be used as a predictive tool.

Conclusions
Augmentation of clinical response by EEN-conjugated corticosteroid therapy is accompanied by beneficial gut microbial changes in patients with ASUC.