bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of the Lifetime Quality-Adjusted Life Years (QALYs) Lost Due to Syphilis Acquired in the United States in 2018
Authors: Lee Kyueun , You Shiying , Li Yunfei , Chesson Harrell , Gift Thomas L , Berruti Andrés A , Hsu Katherine , Yaesoubi Reza , Salomon Joshua A , Rönn Minttu 
Published: June 2022

Abstract

Background
The purpose of this study was to estimate the health impact of syphilis in the United States in terms of the number of quality-adjusted life years (QALYs) lost attributable to infections in 2018.

Methods
We developed a Markov model that simulates the natural history and management of syphilis. The model was parameterized by sex and sexual orientation (women who have sex with men, men who have sex with women [MSW], and men who have sex with men [MSM]), and by age at primary infection. We developed a separate decision tree model to quantify health losses due to congenital syphilis. We estimated the average lifetime number of QALYs lost per infection, and the total expected lifetime number of QALYs lost due to syphilis acquired in 2018.

Results
We estimated the average number of discounted lifetime QALYs lost per infection as 0.09 (95% uncertainty interval [UI] .03–.19). The total expected number of QALYs lost due to syphilis acquired in 2018 was 13 349 (5071–31 360). Although per-case loss was the lowest among MSM (0.06), MSM accounted for 47.7% of the overall burden. For each case of congenital syphilis, we estimated 1.79 (1.43–2.16) and 0.06 (.01–.14) QALYs lost in the child and the mother, respectively. We projected 2332 (1871–28 250) and 79 (17–177) QALYs lost for children and mothers, respectively, due to congenital syphilis in 2018.

Conclusions
Syphilis causes substantial health losses in adults and children. Quantifying these health losses in terms of QALYs can inform cost-effectiveness analyses and can facilitate comparisons of the burden of syphilis to that of other diseases.
Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection
Authors: Chan Phillip , Yoon Bohyung , Colby Donn , Kroon Eugène , Sacdalan Carlo , Sriplienchan Somchai , Pinyakorn Suteeraporn , Ananworanich Jintanat , Valcour Victor , Vasan Sandhya , Hsu Denise , Phanuphak Nittaya , Paul Robert , Spudich Serena 
Published: June 2022

Abstract

Background
Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human immunodeficiency virus type 1 (HIV-1). Whether they impact the immunological and neuropsychiatric profile differentially remains unclear.

Methods
This retrospective analysis included 258 participants enrolled during acute HIV-1 infection (AHI). Participants initiated 1 of 3 ART regimens during AHI: EFV-based (n = 131), DTG-based (n = 92), or DTG intensified with maraviroc (DTG/MVC, n = 35). All regimens included 2 nucleoside reverse-transcriptase inhibitors and were maintained for 96 weeks. CD4+ and CD8+ T-cell counts, mood symptoms, and composite score on a 4-test neuropsychological battery (NPZ-4) were compared.

Results
At baseline, the median age was 26 years, 99% were male, and 36% were enrolled during Fiebig stage I–II. Plasma viral suppression at weeks 24 and 96 was similar between the groups. Compared with the EFV group, the DTG group showed greater increments of CD4+ (P &lt; .001) and CD8+ (P = .015) T-cell counts but a similar increment of CD4/CD8 ratio at week 96. NPZ-4 improvement was similar between the 2 groups at week 24 but greater in the DTG group at week 96 (P = .005). Depressive mood and distress symptoms based on the Patient Health Questionnaire and distress thermometer were similar between the 2 groups at follow-up. Findings for the DTG/MVC group were comparable to those for the DTG group vs the EFV group.

Conclusions
Among individuals with AHI, 96 weeks of DTG-based ART was associated with greater increments of CD4+ and CD8+ T-cell counts and improvement in cognitive performance.
Continued Increase of Erythromycin Nonsusceptibility and Clindamycin Nonsusceptibility Among Invasive Group A Streptococci Driven by Genomic Clusters, United States, 2018–2019
Authors: Li Yuan , Rivers Joy , Mathis Saundra , Li Zhongya , McGee Lesley , Chochua Sopio , Metcalf Benjamin J , Fleming-Dutra Katherine E , Nanduri Srinivas A , Beall Bernard 
Published: June 2022

Abstract
We analyzed 9630 invasive GAS surveillance isolates in the USA. From 2015–2017 to 2018–2019, significant increases in erythromycin-nonsusceptibility (18% vs 25%) and clindamycin-nonsusceptibility (17% vs 24%) occurred, driven by rapid expansions of genomic subclones. Prevention and control of clustered infections appear key to containing antimicrobial resistance.
A fast parameter estimator for large complex networks
Authors: Guzman Grover E C , Takahashi Daniel Yasumasa , Fujita André 
Published: June 2022

Abstract
Many natural phenomena are the results of interactions of different components. For example, an organism’s phenotype results from interactions of genes, proteins and the environment. The characteristics of our society are shaped by how people relate to each other. The internet is the product of billions of interconnected computers, electronic devices and users. To understand systems, we represent them using networks, that is, random graphs. A critical inferential step is to estimate the parameters of these networks. Often analytical likelihood estimators for random graph parameters are unknown. In these cases, non-parametric approximations for likelihood estimators can be used. However, known non-parametric estimators for complex network models are computationally inefficient. Here, we present a linear time and space non-parametric estimator for massive networks ($\mathcal{O}(n)$). We show that our method precisely estimates the parameters of networks composed of five million nodes in a few hours. In contrast, a usual approach would need 900 years.
A single cell transcriptional roadmap of human pacemaker cell differentiation
Authors: Wiesinger A , Li J , Fokkert L , Bakker P , Verkerk A , Christoffels V , Boink G , Devalla H 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research council starting grant 714866 and associated proof-of-concept grant 899422
Dutch Heart Foundation Dekker fellowship 2020T023
The sinoatrial node (SAN), the primary pacemaker of the heart generates electrical impulses that set the rhythm of the heartbeat. It is a multicomponent structure composed of "head", "tail" and "transitional" cardiomyocytes as well as proepicardium-derived mesenchymal cells. Previous studies have shown that pacemaker cells of the SAN originate from a common progenitor that also gives rise to the proepicardium. However, little is known of the molecular mechanisms that are implicated in 1) the divergence of pacemaker and proepicardial cells and, 2) the diversification of pacemaker cells into head, tail and transitional cells. Here, we performed single cell RNA sequencing (scRNA-seq) and trajectory inference analysis on human induced pluripotent stem cells (hiPSCs) differentiating to SAN-like cardiomyocytes (SANCM) to construct a roadmap of transcriptional changes and lineage decisions that guide these processes.
scRNA-seq of differentiated cells revealed transcriptionally distinct cardiomyocyte populations that closely resemble different subpopulations of the in vivo SAN, such as "head", "tail" and "transitional" cells. Moreover, we identified a side population of proepicardial cells suggesting their shared ontogeny with SANCM, as also reported in vivo. Reconstruction of transcriptional trajectories revealed that the SANCM and proepicardial lineages diverge early on and that this lineage decision is determined by WNT signaling. Furthermore, we uncovered a role for TGFβ and WNT signaling in differentiation towards transitional and head SANCM subtypes, respectively. Manipulation of the identified signaling pathways enhanced gene expression patterns of the corresponding cell type, confirming their involvement in diversification towards SANCM subtypes.
Our findings provide new insights into the molecular processes involved in human pacemaker cell differentiation, opening new avenues for complex disease modeling in vitro and inform approaches for cell-therapy based regeneration of the SAN.
Small molecule-mediated rapid maturation of human induced pluripotent stem cell derived cardiomyocytes
Authors: Chirico N , Kessler E L , Maas RGC , Fang J , Qin J , Dokter I , Ciccone S , Saric T , Buikema JW , Lei Z , Doevendans P , Sluijter JPG , Van Mil A 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Other. Main funding source(s): Gravitation Program “Materials Driven Regeneration” by the Netherlands Organization for Scientific Research (RegmedXB #024.003.013) and the Marie Skłodowska-Curie Actions (Grant agreement RESCUE #801540). The EU-funded project BRAV3 (H2020, ID:874827)

Background
Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) do not display all hallmarks of mature human primary cardiomyocytes: the ability to use fatty acids as an energy source, high mitochondrial mass, increased nuclei polyploidism, synchronized electrical conduction, and forceful contractions. Instead, their phenotype is similar to immature cardiomyocytes in the late fetal stage. This immaturity represents a bottleneck to their application in 1) disease modeling – as most cardiac (genetic) diseases have a middle-age onset – and 2) clinical use, where integration and functional coupling are key. So far, the mainly used methods to enhance iPSC-CM maturation include prolonged time-in-culture, 3D culture, cyclic mechanical stretch, and electrical stimulation with specialized media. However, these protocols are laborious, costly, and not easily scalable.

Methods
In this study, we developed a simple, low cost, and rapid protocol using two peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A/PGC-1α) activating small molecules: Asiatic Acid (AA) and GW501516 (GW) to promote cardiomyocyte maturity by inducing a metabolic switch to fatty acid utilization and increased mitochondrial biogenesis.

Results
Monolayers of iPSC-CMs were incubated with AA and GW every other day for 10 days resulting in increased expression of fatty acid-metabolism-related genes (5 and 10-fold increase in CPT1B gene expression, respectively), mitochondria biogenesis (protein expression of ATP5A) and fusion (50 and 100-fold increase in OPA1 gene expression, respectively). In addition, AA treated iPSC-CMs responded in the seahorse mitochondria stress test more rapidly to an artificial increase in mitochondrial activity and showed a higher flexibility in substrate utilization in the seahorse stress test. A more mature electrophysiological functionality was shown by increased ion channel gene expression (KCNA4, SCN5A, GJA1, CACNA1C, and SCN1B) and enhanced synchronous contraction in treated samples. Moreover, maturation was further shown by increased sarcomeric gene expression (5 and 7-fold increase in TNNI3 in AA and GW respectively) and nuclear polyploidism (&gt;4N fold 2.16 and 1.48-fold increase in AA and GW respectively).

Conclusions
Collectively, these findings show that AA and GW trigger a metabolic switch and induce extensive maturation of iPSC-CMs, providing a rapid and cost-effective method to obtain iPSC-CMs that more closely resemble their adult counterparts.
Determining the role of uremic toxins on cardiac electrophysiology and pro-arrhythmia during chronic kidney disease
Authors: Van Ham WB , Bossu A , Houtman MJC , Cornelissen CM , Vos MA , Van Veen TAB 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Young Talent Programme, CVON RECONNECT

Introduction
Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are one of the CKD-related factors already linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients is cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible still remain poorly understood.

Purpose
To assess the potentially increased pro-arrhythmic risk of pre-identified UTs at clinically relevant concentrations: 1) acutely in isolated adult dog ventricular cardiomyocytes (ADCMs) and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), 2) chronically in iPSC-CMs and 3) both conditions in human embryonic kidney (HEK) cells transfected with constructs that generate different ion channels, using optical and manual electrophysiological in vitro approaches.

Methods and results
Using the voltage sensitive membrane dye FluoVolt and manual patch clamp, action potential duration (APD) prolongation, considered as a pro-arrhythmic parameter, was assessed in ADCMs and iPSC-CMs. Acute exposure of indoxyl sulfate (IS), kynurenine (KYN) or kynurenic acid (KYNA) induced no alterations in APD in ADCMs and iPSC-CMs. iPSC-CMs, although having rather immature electrophysiological characteristics, showed significant APD prolongation when exposed chronically (48h) to those UTs.
Manual patch clamp on HEK293 cells was performed to investigate individual ion currents to reveal underlying mechanisms. The repolarizing current IKr, often most sensitive and responsible for APD alterations, was not acutely affected by IS, KYN, or KYNA. However, chronic exposure (48h) to IS or KYNA significantly decreased IKr at clinically relevant concentrations.
Finally, the protein level of the ion channel conducting IKr was determined in HEK293 cells, to further unveil the mechanism behind the effects of UTs on channels conducting IKr. Chronic exposure (48-72h) of the three UTs decreased total ion channel expression at pathological concentrations, which could be responsible for the decreased IKr and prolonged APD.

Conclusion
The results show the proof of concept to identify potentially pro-arrhythmogenic UTs and their mode of action, allowing the provision of a clinically relevant overview of (patho)physiological concentrations of UTs in both acute and chronic exposure.
Functional remodeling of perinuclear mitochondria alters nucleoplasmic Ca2+ signaling in heart failure
Authors: Voglhuber J , Holzer M , Radulovic S , Thai PN , Djalinac N , Matzer I , Wallner M , Bugger H , Zirlik A , Leitinger G , Dedkova EN , Bers DM , Ljubojevic-Holzer S 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): BioTechMed-Graz
Mitochondrial dysfunction in cardiomyocytes is a hallmark of heart failure (HF) development. Although initial studies recognized the importance of different mitochondrial subpopulations, there is a striking lack of direct comparison of intrafibrillar (IF) vs. perinuclear (PN) mitochondria during the development of HF.
Here, we use multiple approaches to examine the morphology and functional properties of IF vs. PN mitochondria in pressure overload-induced cardiac remodeling in mice, and in non-failing and failing human cardiomyocytes. We could demonstrate that PN mitochondria from failing cardiomyocytes are more susceptible to changes in mitochondrial membrane potential (ΔΨm), ROS generation and impairment in Ca2+ uptake compared to IF mitochondria at baseline and under physiological stress protocol. We also demonstrated, for the first time, that under normal conditions PN mitochondrial Ca2+ uptake shapes nucleoplasmic Ca2+ transients (CaTs) and prevents nucleoplasmic Ca2+ overload. Loss of PN mitochondria Ca2+ buffering capacity translates into increased nucleoplasmic CaTs and may explain disproportionate rise in nucleoplasmic [Ca2+] in failing cardiomyocytes at increased stimulation frequencies. Therefore, a previously unidentified benefit of restoring the mitochondrial Ca2+ uptake may be normalization of nuclear Ca2+ signaling and alleviation of altered excitation-transcription, which could be an important therapeutic approach to prevent adverse cardiac remodeling.
Cardiomyocytes (CM) derived small Extracellular Vesicles (sEV) plays an important role in heart development
Authors: Balbi C , Ceresa D , Schiano C , Malatesta P , Barile L , Vassalli G 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Schweizerische Herzstiftung - FF21017
Fondazione Leonardo

Introduction
Neonatal rats have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. Cardiac maturation lays the foundation for postnatal heart development and disease, yet little is known about the contributions of the microenvironment to cardiomyocyte maturation.
Extracellular vesicles (EV) are bilayer-membrane nanoparticles released by all cell types, carrying proteins, lipids, and nucleic acids, which reflect the activation state of parental cells. Secreted small extracellular vesicles (sEV), prominently figure among extracellular signals that regulate cell function.

Purpose
We aim to determine whether cardiomyocyte (CM) derived sEV carried miRNA that has a role in heart development with specific regards to cardiomyocyte maturation.

Methods
sEV were isolated from rat cardiomyocyte at day 0 and 7 after birth by serial ultracentrifugation. sEV were characterized by NTA and analyzed by Western blot for the presence of classical EV markers (TSG101, Syntenin-1). The role of sEV in cardiomyocyte proliferation was assesed by analysis of EdU incorporation on neoantal rat CM treated with sEV_p0 or sEV_p7. miRNA content on sEV was assesed using a rat-miRNome MicroRNA Profiling Kit and the identified miRNA's targets confirmed by RealTime-PCR and Western Blot.

Results
NTA and Western Blot analysis confirmed the presence of sEV in both the extracellular vesicles preparation. sEV_p0 showed to be able to sligtly increase EdU incorporation in treated cardiomyocyte (1.15-Fold) while sEV_p7 significantly inihibit CM proliferation (0.78-Fold) toghether with a change in cardiomyocyte citoscheletal architecture. Data from miRNome analysis showed in sEV_p7 a significan increase in miRNA with cyclines as tagets. Downregulation of Cdk1 ; Cdk4 ; Cdk2 ; CcnB1 and CcnD1 was confirmed on CM trated with sEV_p7 compared to Ctrl. Downregulation of CCND1 was aslo confrmed at the protein level by Western Blot analysis.

Conclusions
These preliminary resultes showed an important role in heart develompent of cardiomyocyte derived-sEV. A deeper investigation of the pathaway activated by sEV may have a potential interest for the identification of possible regulators for stimulating heart regeneration.
Re-activation of HIF signalling pathway in the epicardium improves heart regeneration after myocardial infarction
Authors: Gamen E , Price EL , Pezzolla D , De Villiers C , Gunadasa-Rohling M , Salama R , Mole DR , Bishop T , Pugh CW , Choudhury RP , Carr CA , Vieira JM , Riley PR 
Published: June 2022

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

Background
In mouse, cardiac regenerative capacity is maintained for the first week after birth but lost thereafter. Reactivation of this process holds great therapeutic potential, however, the molecular pathways that might be targeted to extend neonatal regeneration remain elusive. Here, we explore a role for hypoxia inducible factor (HIF) family of transcription factors on the regulation of epicardial activity which is essential for cardiac response to injury.

Purpose
HIF signalling might be involved in the quiescence of the epicardium observed in the first week of life. Thus, HIF stabilisation may induce epicardial re-activation and extend the 7-day regenerative window in a neonate mouse model of myocardial infarction (MI).

Methods
We analysed epicardial expression of HIF signalling during embryonic development, and in a regenerative post-natal day 1 (P1) versus non-regenerative (P7) mouse model by single cell RNA-sequencing. Next, we established in vitro epicardial explants to confirm the role of HIF signalling in epicardial activation, and finally we induced MI by permanent ligation of the proximal left anterior descending (LAD) coronary artery in P7 mice to test weather HIF signalling re-activation improved heart regeneration in a non-regenerative model.

Results
Expression of both HIF-1α and HIF-2α is very pronounced at early stages of heart development and gradually decreases throughout gestation. The epicardium preferentially expresses HIF-1α by embryonic day (E) 16.5. Postnatally, GO term analysis showed an enrichment of hypoxia-related pathways in P1 compared to P7 hearts, largely in the epicardial cell population. Accordingly, expression of Phd2, encoding for the main suppressor of HIF signalling, was enriched in P7 derived epicardial cells. Notably, the increase in Phd2 levels coincided with a clear reduction in the expression of Wilms’ tumour 1 (Wt1) in P7 versus P1 hearts, a key player in the epicardial activation. In vitro studies on epicardial explants confirmed regulation of WT1 expression and migration capacity following genetical and pharmacological modulation of HIF signalling. Finally, in vivo targeting of PHD enzymes through pharmacological inhibition with clinically approved drugs in a neonatal mouse model of MI led to prolonged epicardial activation, increased vascularisation, augmented infarct resolution and preserved cardiac function up to 3 weeks after injury.

Conclusions
Together, these findings show that modulation of HIF signalling can regulate epicardial activity and improve heart regeneration capacity beyond the 7-day regenerative window and may represent a viable therapeutic strategy for treating ischaemic heart disease.