bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II multicentre study of plasminogen activator inhibitor-1 inhibitor (TM5614) plus nivolumab for treating anti-programmed cell death 1 antibody-refractory malignant melanoma: TM5614-MM trial
Authors: Fujimura Taku , Yoshino Koji , Kato Hiroshi , Fukushima Satoshi , Ishizuki Shoichiro , Otsuka Atsushi , Matsushita Shigeto , Amagai Ryo , Muto Yusuke , Yamazaki Emi , Kambayashi Yumi , Yahata Takashi , Miyata Toshio , Fujisawa Yasuhiro , Asano Yoshihide 
Published: June 2024

Abstract

Background
Anti-programmed cell death 1 antibodies (PD-1 Abs) are widely used for advanced melanoma, but information on the efficacy of anti-PD-1 Abs is limited in the Asian population. There remains an unmet need to improve the therapeutic effects of anti-PD-1 Ab-treatment, particularly in patients with melanoma who are refractory to anti-PD-1 Abs. The aim of this study was to evaluate anti-PD-1 Ab-treatment in combination with TM5614 (a plasminogen activator inhibitor-1 inhibitor) in patients with unresectable melanoma.

Methods
The TM5614-MM study was a multicentre, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of nivolumab in combination with TM5614 in patients with advanced, unresectable malignant melanoma recruited at seven Japanese institutes between 13 September 2021 and 31 March 2023. Patients with metastatic or unresectable melanoma previously treated with anti-PD-1 Abs were enrolled. Nivolumab 480 mg was administered intravenously every 4 weeks for 8 weeks, while TM5614 was administered orally at a dose of 120 mg (0–4 weeks) and 180 mg once daily (5–8 weeks). The primary endpoint was the overall response rate after 8 weeks of concomitant use of TM5614.

Results
Thirty-nine patients were enrolled, and 34 patients were included in the anti-PD-1 Ab-refractory cohort. The overall response rate at 8 weeks was 25.9% (95% confidence interval 12.9–44.9%, P = 0.027) in 27 patients who were anti-PD-1 Ab-refractory based on investigator assessment in the protocol per set cohort. Seven patients discontinued treatment owing to progressive disease or adverse events. Treatment-related grade 3 or higher adverse events occurred in 3 of 39 patients (7.7%) in the intention-to-treat cohort.

Conclusions
TM5614 in combination with nivolumab is well tolerated and effective in anti-PD-1 Ab-refractory unresectable melanoma.
Brain lesions causing parkinsonism versus seizures map to opposite brain networks
Authors: Schaper Frederic L W V J , Morton-Dutton Mae , Pacheco-Barrios Niels , Turner Joseph I , Drew William , Khosravani Sanaz , Joutsa Juho , Fox Michael D 
Published: June 2024

Abstract
Recent epidemiological studies propose an association between parkinsonism and seizures, but the direction of this association is unclear. Focal brain lesions causing new-onset parkinsonism versus seizures may provide a unique perspective on the causal relationship between the two symptoms and involved brain networks. We studied lesions causing parkinsonism versus lesions causing seizures and used the human connectome to identify their connected brain networks. Brain networks for parkinsonism and seizures were compared using spatial correlations on a group and individual lesion level. Lesions not associated with either symptom were used as controls. Lesion locations from 29 patients with parkinsonism were connected to a brain network with the opposite spatial topography (spatial r = −0.85) compared to 347 patients with lesions causing seizures. A similar inverse relationship was found when comparing the connections that were most specific on a group level (spatial r = −0.51) and on an individual lesion level (average spatial r = −0.042; P &lt; 0.001). The substantia nigra was found to be most positively correlated to the parkinsonism network but most negatively correlated to the seizure network (spatial r &gt; 0.8). Brain lesions causing parkinsonism versus seizures map to opposite brain networks, providing neuroanatomical insight into conflicting epidemiological evidence.
Population dynamics is a cancer driver
Authors: dos Santos Oliveira Mariana , de C Griebeler Marcelo , Henz Bernardo , dos Santos Filipe Ferreira , Guardia Gabriela D A , Conceição Helena B , Galante Pedro A F , Minussi Darlan C , Oliveira Manuel M , Lenz Guido 
Published: June 2024

Abstract
Most tissues are continuously renovated through the division of stem cells and the death of old or damaged cells, which is known as the cell turnover rate (CTOR). Despite being in a steady state, tissues have different population dynamics thus producing diverse clonality levels. Here, we propose and test that cell population dynamics can be a cancer driver. We employed the evolutionary software esiCancer to show that CTOR, within a range comparable to what is observed in human tissues, can amplify the risk of a mutation due to ancestral selection (ANSEL). In a high CTOR tissue, a mutated ancestral cell is likely to be selected and persist over generations, which leads to a scenario of elevated ANSEL profile, characterized by few niches of large clones, which does not occur in low CTOR. We found that CTOR is significantly associated with the risk of developing cancer, even when correcting for mutation load, indicating that population dynamics per se is a cancer driver. This concept is central to understanding cancer risk and for the design of new therapeutic interventions that minimizes the contribution of ANSEL in cancer growth.
Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types
Authors: Maleyeff Lara , Park Hannah J , Khazal Zahra S H , Wypij David , Rollins Caitlin K , Yun Hyuk Jin , Bellinger David C , Watson Christopher G , Roberts Amy E , Newburger Jane W , Grant P Ellen , Im Kiho , Morton Sarah U 
Published: June 2024

Abstract
Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change β = 0.7, false discovery rate P = 0.004; β = 4.1, false discovery rate P = 0.03; and β = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.
The cytoarchitectonic landscape revealed by deep learning method facilitated precise positioning in mouse neocortex
Authors: Liu Zhixiang , Li Anan , Gong Hui , Yang Xiaoquan , Luo Qingming , Feng Zhao , Li Xiangning 
Published: June 2024

Abstract
Neocortex is a complex structure with different cortical sublayers and regions. However, the precise positioning of cortical regions can be challenging due to the absence of distinct landmarks without special preparation. To address this challenge, we developed a cytoarchitectonic landmark identification pipeline. The fluorescence micro-optical sectioning tomography method was employed to image the whole mouse brain stained by general fluorescent nucleotide dye. A fast 3D convolution network was subsequently utilized to segment neuronal somas in entire neocortex. By approach, the cortical cytoarchitectonic profile and the neuronal morphology were analyzed in 3D, eliminating the influence of section angle. And the distribution maps were generated that visualized the number of neurons across diverse morphological types, revealing the cytoarchitectonic landscape which characterizes the landmarks of cortical regions, especially the typical signal pattern of barrel cortex. Furthermore, the cortical regions of various ages were aligned using the generated cytoarchitectonic landmarks suggesting the structural changes of barrel cortex during the aging process. Moreover, we observed the spatiotemporally gradient distributions of spindly neurons, concentrated in the deep layer of primary visual area, with their proportion decreased over time. These findings could improve structural understanding of neocortex, paving the way for further exploration with this method.
The integrated care model: facilitating initiation of or transition to home dialysis
Authors: Poinen Krishna , Mitra Sandip , Quinn Robert R 
Published: June 2024

ABSTRACT
A proportion of end-stage kidney disease (ESKD) patients require kidney replacement therapy to maintain clinical stability. Home dialysis therapies offer convenience, autonomy and potential quality of life improvements, all of which were heightened during the COVID-19 pandemic. While the superiority of specific modalities remains uncertain, patient choice and informed decision-making remain crucial. Missed opportunities for home therapies arise from systemic, programmatic and patient-level barriers. This paper introduces the integrated care model which prioritizes the safe and effective uptake of home therapies while also emphasizing patient-centered care, informed decision-making, and comprehensive support. The integrated care framework addresses challenges in patient identification, assessment, eligibility determination, education and modality transitions. Special considerations for urgent dialysis starts are discussed, acknowledging the unique barriers faced by this population. Continuous quality improvement is emphasized, with the understanding that local challenges may require tailored solutions. Overall, the integrated care model aims to create a seamless and beneficial transition to home dialysis therapies, promoting flexibility and improved quality of life for ESKD patients globally.
Integrated home dialysis model: facilitating home-to-home transition
Authors: Desbiens Louis-Charles , Bargman Joanne M , Chan Christopher T , Nadeau-Fredette Annie-Claire 
Published: June 2024

ABSTRACTPeritoneal dialysis (PD) and home hemodialysis (HHD) are the two home dialysis modalities offered to patients. They promote patient autonomy, enhance independence, and are generally associated with better quality of life compared to facility hemodialysis. PD offers some advantages (enhanced flexibility, ability to travel, preservation of residual kidney function, and vascular access sites) but few patients remain on PD indefinitely due to peritonitis and other complications. By contrast, HHD incurs longer and more intensive training combined with increased upfront health costs compared to PD, but is easier to sustain in the long term. As a result, the integrated home dialysis model was proposed to combine the advantages of both home-based dialysis modalities. In this paradigm, patients are encouraged to initiate dialysis on PD and transfer to HHD after PD termination. Available evidence demonstrates the feasibility and safety of this approach and some observational studies have shown that patients who undergo the PD-to-HHD transition have clinical outcomes comparable to patients who initiate dialysis directly on HHD. Nevertheless, the prevalence of PD-to-HHD transfers remains low, reflecting the multiple barriers that prevent the full uptake of home-to-home transitions, notably a lack of awareness about the model, home-care “burnout,” clinical inertia after a transfer to facility HD, suboptimal integration of PD and HHD centers, and insufficient funding for home dialysis programs. In this review, we will examine the conceptual advantages and disadvantages of integrated home dialysis, present the evidence that underlies it, identify challenges that prevent its success and finally, propose solutions to increase its adoption.
Towards a better uptake of home dialysis in Europe: understanding the present and looking to the future
Authors: Brown Edwina A , Brivio Giulia Boni , Van Biesen Wim 
Published: June 2024

ABSTRACT
Use of peritoneal dialysis and home haemodialysis remains low in Europe, with the highest use in Scandinavian countries and the lowest in Eastern and Central Europe despite the advantages for people on dialysis and economic advantages for healthcare systems. This is partly due to the impact of the haemodialysis industry resulting in proliferation of haemodialysis units and nephrologist reimbursement related to use of haemodialysis. Equally important is the bias against home dialysis at both clinician and healthcare system levels. The underlying causes of this bias are discussed in relation to a mechanistic view of the human body, lack of compassion, failure to adjust dialysis provision for older age and frailty, proliferation of small dialysis centres, and complexity of decision-making and clinical care. For home dialysis to flourish, we need to foster a change in attitude to and vision of the aims of healthcare so that enabling meaningful activities of people requiring dialysis, as explored in the Standardized Outcomes in Nephrology initiative, rather than achieving biological numbers become the focus of care delivery.
Monitoring the stress physiology of free-ranging mugger crocodiles (Crocodylus palustris) across diverse habitats within Central Gujarat, India
Authors: Desai Brinky , Bhowmik Tathagata , Srinivasan Rohith , Whitaker Nikhil , Ghosal Ratna 
Published: June 2024

Abstract
Animals face several challenges in their natural environment, and to cope with such conditions, they may exhibit contrasting physiological responses that directly affect their overall well-being and survival. In this study, we assessed physiological responses via faecal glucocorticoid metabolite (fGCM) measurements in free-ranging mugger crocodiles inhabiting diverse habitats in Gujarat, India. We sampled muggers within Charotar, a rural area (Zone A) with local people having high tolerance towards the presence of muggers, and Vadodara, a region having both urban (Zone B) and rural (Zone C) areas with high levels of human–mugger conflict (HMC). Further, muggers in Vadodara live in water bodies that are mostly polluted due to sewage disposal from adjoining chemical industries. To measure fGCM (mean ± SEM, ng/g dry faeces) levels in muggers, scats were collected during both breeding (N = 107 scats) and non-breeding (N = 22 scats) seasons from all three zones. We used captive muggers (a focal enclosure) to biologically validate (via capture and restraint) the selected fGCM assay (11-oxoetiocholanolone assay). We showed a significant (P &lt; 0.05) 11-fold increase in fGCM levels between pre-capture (540.9 ± 149.2, N = 11) and post-capture (6259.7 ± 1150.5, N = 11) samples. The validated assay was applied to free-ranging muggers during the breeding season, and Zone A showed significantly (P &lt; 0.05) lower fGCM levels (542.03 ± 71.3) compared to muggers of Zone B (1699.9 ± 180.8) and Zone C (1806.4 ± 243.2), both zones having high levels of HMC with polluted water bodies. A similar contrast in fGCM levels was also observed during the non-breeding season. Overall, the study demonstrated that fGCM levels in muggers varied across habitats, and such variation could be due to a multitude of ecological factors that the species experience in their immediate local environment. Moreover, high fGCM levels in muggers of Vadodara during both breeding and non-breeding seasons may indicate a condition of chronic stress, which could be maladaptive for the species.
Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo
Authors: Bolesani Emiliano , Bornhorst Dorothee , Iyer Lavanya M , Zawada Dorota , Friese Nina , Morgan Michael , Lange Lucas , Gonzalez David M , Schrode Nadine , Leffler Andreas , Wunder Julian , Franke Annika , Drakhlis Lika , Sebra Robert , Schambach Axel , Goedel Alexander , Dubois Nicole C , Dobreva Gergana , Moretti Alessandra , Zelaráyan Laura C , Abdelilah-Seyfried Salim , Zweigerdt Robert 
Published: June 2024

Abstract

Aims
Understanding the molecular identity of human pluripotent stem cell (hPSC)-derived cardiac progenitors and mechanisms controlling their proliferation and differentiation is valuable for developmental biology and regenerative medicine.

Methods and results
Here, we show that chemical modulation of histone acetyl transferases (by IQ-1) and WNT (by CHIR99021) synergistically enables the transient and reversible block of directed cardiac differentiation progression on hPSCs. The resulting stabilized cardiovascular progenitors (SCPs) are characterized by ISL1pos/KI-67pos/NKX2-5neg expression. In the presence of the chemical inhibitors, SCPs maintain a proliferation quiescent state. Upon small molecules, removal SCPs resume proliferation and concomitant NKX2-5 up-regulation triggers cell-autonomous differentiation into cardiomyocytes. Directed differentiation of SCPs into the endothelial and smooth muscle lineages confirms their full developmental potential typical of bona fide cardiovascular progenitors. Single-cell RNA-sequencing-based transcriptional profiling of our in vitro generated human SCPs notably reflects the dynamic cellular composition of E8.25-E9.25 posterior second heart field of mouse hearts, hallmarked by nuclear receptor sub-family 2 group F member 2 expression. Investigating molecular mechanisms of SCP stabilization, we found that the cell-autonomously regulated retinoic acid and BMP signalling is governing SCP transition from quiescence towards proliferation and cell-autonomous differentiation, reminiscent of a niche-like behaviour.

Conclusion
The chemically defined and reversible nature of our stabilization approach provides an unprecedented opportunity to dissect mechanisms of cardiovascular progenitors’ specification and reveal their cellular and molecular properties.
Killip scale reclassification according to lung ultrasound: Killip pLUS
Authors: Carreras-Mora José , Vidal-Burdeus María , Rodríguez-González Clara , Simón-Ramón Clara , Rodríguez-Sotelo Laura , Sionis Alessandro , Giralt-Borrell Teresa , Martínez-Membrive María José , Izquierdo-Marquisá Andrea , Cainzos-Achirica Miguel , Vaquerizo-Montilla Beatriz , Rivas-Lasarte Mercedes , Ribas-Barquet Núria 
Published: June 2024

Abstract

Aims
The Killip scale remains a fundamental tool for prognostic assessment in ST-segment elevation myocardial infarction (STEMI) due to its simplicity and predictive value. Lung ultrasound (LUS) has emerged as a valuable adjunct for diagnosing and predicting outcomes in heart failure (HF) and STEMI patients, even those with subclinical congestion. We created a new classification (Killip pLUS), which reclassifies Killip I and II patients into an intermediate category (Killip I pLUS) based on LUS results. This category included Killip I patients and ≥1 positive zone (≥3 B-lines) and Killip II with 0 positive zones. We aimed to evaluate this new classification by comparing it with the Killip scale and a previous LUS-based reclassification scale (LUCK scale).

Methods and results
Lung ultrasound was performed within 24 h of admission in a multicentre cohort of 373 patients admitted for STEMI. In-hospital mortality and major adverse cardiovascular events within one year after admission, comprising mortality or readmission for HF, acute coronary syndrome, or stroke, were analysed. When predicting in-hospital mortality, the global comparison of these three classifications was statistically significant: Killip pLUS area under the curve (AUC) 0.90 (95% CI 0.85–0.95) vs. Killip AUC 0.85 (95% CI 0.73–0.96) vs. LUCK 0.83 (95% CI 0.70–0.95), P = 0.024. To predict events during follow-up, the comparison between scales was also significant: Killip pLUS 0.77 (95% CI 0.71–0.85) vs. Killip 0.72 (95% CI 0.65–0.79) vs. LUCK 0.73 (95% CI 0.66–0.81), P = 0.033.

Conclusion
The Killip pLUS scale provides enhanced risk stratification compared to the Killip and LUCK scales while preserving simplicity.
Severe multifocal coronary artery spasms after cessation of vasodilators in a patient with a spontaneous coronary artery dissection: a case report
Authors: Steffek Zdenek , Kurz David J , Bernheim Alain M , Meyer Matthias R 
Published: June 2024

Abstract

Background
Vasospastic angina (VSA) and spontaneous coronary artery dissection (SCAD) are challenging causes of non-atherosclerotic acute coronary syndromes (ACS). Here, we report a unique ACS case with coexisting VSA and SCAD, highlighting specific strategies in diagnosis and management of these poorly studied conditions.

Case summary
A woman in her mid-60s with a history of suspected microvascular angina and no atherosclerosis in a previously performed coronary computed tomography angiography presented with worsening chest pain. Invasive coronary angiography revealed a focal SCAD with a resulting high-degree stenosis of the right coronary artery. Shortly after successful percutaneous coronary intervention with stent implantation and stopping her previous vasodilator therapy with nitroglycerine and molsidomine, the patient developed recurrent anterior non-ST-segment elevation myocardial infarction. Surprisingly, repeat coronary angiography revealed severe multifocal coronary artery spasms that were successfully treated with intracoronary nitroglycerine. Vasospastic angina was subsequently managed with diltiazem, molsidomine, and nitrates.

Discussion
Our report underscores the challenges in diagnosing and managing SCAD and VSA in ACS. The possible interplay between SCAD and VSA highlights the need for careful vasodilator therapy management, as seen in our patient, where therapy discontinuation led to severe multifocal VSA. This emphasizes the need for a comprehensive approach for optimal outcomes in complex ACS cases.