bluuebunny/crossref_metadata_2025_split huggingface dataset:
De-imFAR phase II project: a study protocol for a cluster randomised implementation trial to evaluate the effectiveness of de-implementation strategies to reduce low-value statin prescribing in the primary prevention of cardiovascular disease
Authors: Sanchez Alvaro , Pijoan Jose Ignacio , Sainz de Rozas Rita , Lekue Itxasne , San Vicente Ricardo , Quindimil Jose Antonio , Rotaeche Rafael , Etxeberria Arritxu , Mozo Carmela , Martinez-Cengotitabengoa Monica , Monge Monica , Gómez-Ramírez Cristina , Samper Ricardo , Ogueta Lana Mikel , Celorrio Sara , Merino-Inda Nerea , Llarena Marta , Gonzalez Saenz de Tejada Marta , García-Alvarez Arturo , Grandes Gonzalo 
Published: April 2024

IntroductionThis study aims to reduce potentially inappropriate prescribing (PIP) of statins and foster healthy lifestyle promotion in cardiovascular disease (CVD) primary prevention in low-risk patients. To this end, we will compare the effectiveness and feasibility of several de-implementation strategies developed following the structured design process of the Behaviour Change Wheel targeting key determinants of the clinical decision-making process in CVD prevention.Methods and analysisA cluster randomised implementation trial, with an additional control group, will be launched, involving family physicians (FPs) from 13 Integrated Healthcare Organisations (IHOs) of Osakidetza-Basque Health Service with non-zero incidence rates of PIP of statins in 2021. All FPs will be exposed to a non-reflective decision assistance strategy based on reminders and decision support tools. Additionally, FPs from two of the IHOs will be randomly assigned to one of two increasingly intensive de-implementation strategies: adding a decision information strategy based on knowledge dissemination and a reflective decision structure strategy through audit/feedback. The target population comprises women aged 45–74 years and men aged 40–74 years with moderately elevated cholesterol levels but no diagnosed CVD and low cardiovascular risk (REGICOR<7.5%), who attend at least one appointment with any of the participating FPs (May 2022–May 2023), and will be followed until May 2024. We use the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework to evaluate outcomes. The main outcome will be the change in the incidence rate of PIP of statins and healthy lifestyle counselling in the study population 12 and 24 months after FPs’ exposure to the strategies. Moreover, FPs’ perception of their feasibility and acceptability, and patient experience regarding the quality of care received will be evaluated.Ethics and disseminationThe study was approved by the Basque Country Clinical Research Ethics Committee and was registered in ClinicalTrials.gov (NCT04022850). Results will be disseminated in scientific peer-reviewed journals.Trial registration numberNCT04022850.
Outcomes after cancer diagnosis in children and adult patients with congenital heart disease in Sweden: a registry-based cohort study
Authors: Karazisi Christina , Dellborg Mikael , Mellgren Karin , Giang Kok Wai , Skoglund Kristofer , Eriksson Peter , Mandalenakis Zacharias 
Published: April 2024

ObjectivePatients with congenital heart disease (CHD) have an increased cancer risk. The aim of this study was to determine cancer-related mortality in CHD patients compared with non-CHD controls, compare ages at cancer diagnosis and death, and explore the most fatal cancer diagnoses.DesignRegistry-based cohort study.Setting and participantsCHD patients born between 1970 and 2017 were identified using Swedish Health Registers. Each was matched by birth year and sex with 10 non-CHD controls. Included were those born in Sweden with a cancer diagnosis.ResultsCancer developed in 758 out of 67814 CHD patients (1.1%), with 139 deaths (18.3%)—of which 41 deaths occurred in patients with genetic syndromes. Cancer was the cause of death in 71.9% of cases. Across all CHD patients, cancer accounted for 1.8% of deaths. Excluding patients with genetic syndromes and transplant recipients, mortality risk between CHD patients with cancer and controls showed no significant difference (adjusted HR 1.17; 95% CI 0.93 to 1.49). CHD patients had a lower median age at cancer diagnosis—13.0 years (IQR 2.9–30.0) in CHD versus 24.6 years (IQR 8.6–35.1) in controls. Median age at death was 15.1 years (IQR 3.6–30.7) in CHD patients versus 18.5 years (IQR 6.1–32.7) in controls. The top three fatal cancer diagnoses were ill-defined, secondary and unspecified, eye and central nervous system tumours and haematological malignancies.ConclusionsCancer-related deaths constituted 1.8% of all mortalities across all CHD patients. Among CHD patients with cancer, 18.3% died, with cancer being the cause in 71.9% of cases. Although CHD patients have an increased cancer risk, their mortality risk post-diagnosis does not significantly differ from non-CHD patients after adjustements and exclusion of patients with genetic syndromes and transplant recipients. However, CHD patients with genetic syndromes and concurrent cancer appear to be a vulnerable group.
Building CapaCITY/É for sustainable transportation: protocol for an implementation science research program in healthy cities
Authors: Winters Meghan , Fuller Daniel , Cloutier Marie-Soleil , Harris M Anne , Howard Andrew , Kestens Yan , Kirk Sara , Macpherson Alison , Moore Sarah , Rothman Linda , Shareck Martine , Tomasone Jennifer R , Laberee Karen , Stephens Zoé Poirier , Sones Meridith , Ayton Darshini , Batomen Brice , Bell Scott , Collins Patricia , Diab Ehab , Giles Audrey R , Hagel Brent E , Harris Mike S , Harris Patrick , Lachapelle Ugo , Manaugh Kevin , Mitra Raktim , Muhajarine Nazeem , Myrdahl Tiffany Muller , Pettit Christopher J , Pike Ian , Skouteris Helen , Wachsmuth David , Whitehurst David , Beck Ben 
Published: April 2024

IntroductionImproving sustainable transportation options will help cities tackle growing challenges related to population health, congestion, climate change and inequity. Interventions supporting active transportation face many practical and political hurdles. Implementation science aims to understand how interventions or policies arise, how they can be translated to new contexts or scales and who benefits. Sustainable transportation interventions are complex, and existing implementation science frameworks may not be suitable. To apply and adapt implementation science for healthy cities, we have launched our mixed-methods research programme, CapaCITY/É. We aim to understand how, why and for whom sustainable transportation interventions are successful and when they are not.Methods and analysisAcross nine Canadian municipalities and the State of Victoria (Australia), our research will focus on two types of sustainable transportation interventions: all ages and abilities bicycle networks and motor vehicle speed management interventions. We will (1)documentthe implementation process and outcomes of both types of sustainable transportation interventions; (2)examineequity, health and mobility impacts of these interventions; (3)advanceimplementation science by developing a novel sustainable transportation implementation science framework and (4)developtools for scaling up and scaling out sustainable transportation interventions. Training activities will develop interdisciplinary scholars and practitioners able to work at the nexus of academia and sustainable cities.Ethics and disseminationThis study received approval from the Simon Fraser University Office of Ethics Research (H22-03469). A Knowledge Mobilization Hub will coordinate dissemination of findings via a website; presentations to academic, community organisations and practitioner audiences; and through peer-reviewed articles.
Achieving high inter-rater reliability in establishing data labels: a retrospective chart review study
Authors: Wu Guosong , Eastwood Cathy , Sapiro Natalie , Cheligeer Cheligeer , Southern Danielle A , Quan Hude , Xu Yuan 
Published: April 2024

BackgroundIn medical research, the effectiveness of machine learning algorithms depends heavily on the accuracy of labeled data. This study aimed to assess inter-rater reliability (IRR) in a retrospective electronic medical chart review to create high quality labeled data on comorbidities and adverse events (AEs).MethodsSix registered nurses with diverse clinical backgrounds reviewed patient charts, extracted data on 20 predefined comorbidities and 18 AEs. All reviewers underwent four iterative rounds of training aimed to enhance accuracy and foster consensus. Periodic monitoring was conducted at the beginning, middle, and end of the testing phase to ensure data quality. Weighted Kappa coefficients were calculated with their associated 95% confidence intervals (CIs).ResultsSeventy patient charts were reviewed. The overall agreement, measured by Conger's Kappa, was 0.80 (95% CI: 0.78-0.82). IRR scores remained consistently high (ranging from 0.70 to 0.87) throughout each phase.ConclusionOur study suggests the detailed manual for chart review and structured training regimen resulted in a consistently high level of agreement among our reviewers during the chart review process. This establishes a robust foundation for generating high-quality labeled data, thereby enhancing the potential for developing accurate machine learning algorithms.
Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma
Authors: Liu Wei , Liu Wei , Zou Hesong , Chen Lianting , Huang Wenyang , Lv Rui , Xu Yan , Liu Huimin , Shi Yin , Wang Kefei , Wang Yi , Xiong Wenjie , Deng Shuhui , Yi Shuhua , Sui Weiwei , Peng Guangxin , Ma Yueshen , Wang Huijun , Lv Lulu , Wang Jianxiang , Wei Jun , Qiu Lugui , Zheng Wenting , Zou Dehui 
Published: April 2024

BackgroundApproximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL.MethodsTransplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells.ResultsA total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy.ConclusionsThe combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile.Trial registration numbersChiCTR1900025419 andNCT04690192.
Acute performance fatigability following continuous versus intermittent cycling protocols is not proportional to total work done
Authors: MacDougall Keenan B. , Zhang Jenny , Grunau Micah , Anklovitch Eric , MacIntosh Brian R. , MacInnis Martin J. , Aboodarda Saied Jalal 
Published: April 2024

Classical training theory postulates that performance fatigability following a training session should be proportional to the total work done (TWD); however, this notion has been questioned. This study investigated indices of performance and perceived fatigability after primary sessions of high-intensity interval training (HIIT) and constant work rate (CWR) cycling, each followed by a cycling time-to-task failure (TTF) bout. On separate days, 16 participants completed an incremental cycling test, and, in a randomized order, (i) a TTF trial at 80% of peak power output (PPO), (ii) an HIIT session, and (iii) a CWR session, both of which were immediately followed by a TTF trial at 80% PPO. Central and peripheral aspects of performance fatigability were measured using interpolated twitch technique, and perceptual measures were assessed prior to and following the HIIT and CWR trials, and again following the TTF trial. Despite TWD being less following HIIT ( P = 0.029), subsequent TTF trial was an average of 125 s shorter following HIIT versus CWR ( P < 0.001), and this was accompanied by greater impairments in voluntary and electrically evoked forces ( P < 0.001), as well as exacerbated perceptual measures ( P < 0.001); however, there were no differences in any fatigue measure following the TTF trial ( P ≥ 0.149). There were strong correlations between the decline in TTF and indices of peripheral ( r = 0.70) and perceived fatigability ( r ≥ 0.80) measured at the end of HIIT and CWR. These results underscore the dissociation between TWD and performance fatigability and highlight the importance of peripheral components of fatigability in limiting endurance performance during high-intensity cycling exercise.
Timing of hydrocarbon charge in the Axial Zone of the Eastern Cordillera, Colombia
Authors: Pacheco-Mendoza Jael Yanine , Tesón-Del Hoyo Eliseo , García-González Mario , Mora Andrés , Ketcham Richard 
Published: April 2024

The petroleum potential of onshore basins in Colombia has been partly controlled by the Andean Orogeny since the end of the Cretaceous. Its Axial Zone has at least one understudied active petroleum system with a rather low petroleum potential and few commercial medium to heavy oil accumulations, raising questions about how the Andean deformation influenced the petroleum system and the possible undiscovered accumulations. We examine the timing of this petroleum system in the Axial Zone through oil–source correlations and two 2D petroleum system models across the Boyacá and Soápaga faults based on cross-sections.
Modelling reveals the direct control of deformation on generation–accumulation in the Axial Zone, where the Lower Cretaceous source rocks, due to high heat flows during the synrift phase, started generation so early (100 to 60 Ma) that no reservoirs or traps were yet available to allow hydrocarbon entrapment and accumulation. Equally, for the younger Upper Cretaceous source rocks, the tectonic inversion of the basin between 33 and 23 Ma along the Boyacá and Soápaga faults interrupted burial and the maturation in most parts of the basin, leaving only local pods of active source rocks where maturation continues today due to the tectonic overburden along the footwall of the Soápaga Fault. The latter is thus the major kitchen, contributing more than 50% of the liquid hydrocarbons trapped mainly in Upper Cretaceous and Paleocene sandstones. Hydrocarbons migrate upwards where biodegradation and water washing occurred in the near-surface, giving rise to the many tar sand occurrences in the Eocene sandstones.
The 1st Hanrahan Lecture: Geotechnical properties of Irish glacial and interglacial soils
Authors: Farrell Eric Raymond 
Published: April 2024

This paper reviews the current state of the art in relation to geotechnical design in unsorted till deposits, commonly called boulder clays by engineers or diamictons by geologists, generally taking the topics discussed by Professor Eamon Hanrahan in his seminal work of 1977 on Irish tills. These topics include the permeability, stiffness and consolidation characteristics of these deposits, together with their undrained and drained behaviour. The geological background to the deposition of these tills is discussed and the available information on the presence of interglacial soils around the country is presented. Where possible, practical experience from working with these deposits is compared with predictions made from field or laboratory test results: for example, in settlement assessment of foundations, slope stability and in earthworks.
Whilst most of Ireland is covered with stony boulder clays, which is the main topic of this paper, the geotechnical parameters of a fine-grained till encountered on the east coast, known as Irish Sea Till or colloquially as Macamore Clay, are discussed and the implications of this on slope stability is investigated.
Overcoming Osimertinib Resistance with AKT Inhibition in EGFRm-Driven Non–Small Cell Lung Cancer with PIK3CA/PTEN Alterations
Authors: Grazini Ursula , Markovets Aleksandra , Ireland Lucy , O’Neill Daniel , Phillips Benjamin , Xu Man , Pfeifer Matthias , Vaclova Tereza , Martin Matthew J. , Bigot Ludovic , Friboulet Luc , Hartmaier Ryan , Cuomo Maria E. , Barry Simon T. , Smith Paul D. , Floc’h Nicolas 
Published: April 2024

Abstract

Purpose:
Osimertinib is an EGFR tyrosine kinase inhibitor indicated for the treatment of EGFR-mutated (EGFRm)–driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line–treated patients with EGFRm advanced non–small cell lung cancer (NSCLC). Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression.

Experimental Design:
ctDNA profiling analysis of on-progression plasma samples from patients treated with osimertinib in both first- (phase III, FLAURA trial) and second-line trials (phase III, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR-engineered NSCLC cell lines and patient-derived xenograft (PDX) models supports a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance.

Results:
These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be resensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alterations, and in these double-mutant models, capivasertib and osimertinib combination elicits an improved antitumor effect versus osimertinib alone.

Conclusions:
Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC who have a suboptimal response or develop resistance to osimertinib through PIK3CA/AKT/PTEN alterations.
See related commentary by Vokes et al., p. 3968
Efficacy of Pembrolizumab and Biomarker Analysis in Patients with WGS-Based Intermediate to High Tumor Mutational Load: Results from the Drug Rediscovery Protocol
Authors: Geurts Birgit S. , Zeverijn Laurien J. , Leek Lindsay V.M. , van Berge Henegouwen Jade M. , Hoes Louisa R. , van der Wijngaart Hanneke , van der Noort Vincent , van de Haar Joris , van Ommen-Nijhof Annemiek , Kok Marleen , Roepman Paul , Jansen Anne M.L. , de Leng Wendy W.J. , de Jonge Maja J.A. , Hoeben Ann , van Herpen Carla M.L. , Westgeest Hans M. , Wessels Lodewyk F.A. , Verheul Henk M.W. , Gelderblom Hans , Voest Emile E. 
Published: April 2024

Abstract

Purpose:
To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing–based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).

Patients and Methods:
Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer cohort harboring a TML of 140 to 290, cohort B: tumor-agnostic cohort harboring a TML of 140 to 290, and cohort C: tumor-agnostic cohort harboring a TML &gt;290. Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint was clinical benefit [CB; objective response or stable disease (SD) ≥16 weeks]. Pretreatment tumor biopsies were obtained for whole-genome sequencing and RNA sequencing.

Results:
Seventy-two evaluable patients with 26 different histotypes were enrolled. The CB rate was 13% in cohort A [3/24 with partial response (PR)], 21% in cohort B (3/24 with SD; 2/24 with PR), and 42% in cohort C (4/24 with SD; 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohorts A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, whereas in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated.

Conclusions:
Although pembrolizumab lacked activity in cohort A, cohorts B and C met the study’s primary endpoint. Further research is warranted to refine the selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.
See related commentary by Hsu and Yen, p. 3652
Melanoma Clonal Heterogeneity Leads to Secondary Resistance after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes
Authors: König David , Sandholzer Michael T. , Uzun Sarp , Zingg Andreas , Ritschard Reto , Thut Helen , Glatz Katharina , Kappos Elisabeth A. , Schaefer Dirk J. , Kettelhack Christoph , Passweg Jakob R. , Holbro Andreas , Baur Katharina , Medinger Michael , Buser Andreas , Lardinois Didier , Jeker Lukas T. , Khanna Nina , Stenner Frank , Kasenda Benjamin , Homicsko Krisztian , Matter Matthias , Rodrigues Mantuano Natalia , Zippelius Alfred , Läubli Heinz 
Published: April 2024

Abstract
Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells. To the best our knowledge, this is the first case of clonal selection of a pre-existing nondominant tumor cell clone; this report demonstrates the mechanism involved in secondary resistance to TIL-ACT that can potentially change current clinical practice because it advocates for T-cell collection from multiple tumor sites and analysis of tumor heterogeneity before treatment with TIL-ACT.