bluuebunny/crossref_metadata_2025_split huggingface dataset:
High versus low positive end-expiratory pressure setting in patients receiving veno-venous extracorporeal membrane oxygenation support for severe acute respiratory distress syndrome: study protocol for the multicentre, randomised ExPress SAVER Trial
Authors: Nishikimi Mitsuaki , Ohshimo Shinichiro , Hamaguchi Jun , Fujizuka Kenji , Hagiwara Yoshihiro , Anzai Tatsuhiko , Ishii Junki , Ogata Yoshitaka , Aokage Toshiyuki , Ikeda Tokuji , Yagi Tsukasa , Suzuki Ginga , Ishikura Ken , Katsuta Ken , Konno Daisuke , Hattori Noriyuki , Nakamura Tomoyuki , Matsumura Yosuke , Kasugai Daisuke , Kikuchi Hitoshi , Iino Tatsuhiko , Kai Shinichi , Hashimoto Haruka , Yoshida Takeshi , Igarashi Yumi , Ogura Takayuki , Matsumura Kazuki , Shimizu Keiki , Nakamura Mitsunobu , Ichiba Shingo , Takahashi Kunihiko , Shime Nobuaki 
Published: October 2023

IntroductionWhile limiting the tidal volume to 6 mL/kg during veno-venous extracorporeal membrane oxygenation (V-V ECMO) to ameliorate lung injury in patients with acute respiratory distress syndrome (ARDS) is widely accepted, the best setting for positive end-expiratory pressure (PEEP) is still controversial. This study is being conducted to investigate whether a higher PEEP setting (15 cmH2O) during V-V ECMO can decrease the duration of ECMO support needed in patients with severe ARDS, as compared with a lower PEEP setting.Methods and analysisThe study is an investigator-initiated, multicentre, open-label, two-arm, randomised controlled trial conducted with the participation of 20 intensive care units (ICUs) at academic as well as non-academic hospitals in Japan. The subjects of the study are patients with severe ARDS who require V-V ECMO support. Eligible patients will be randomised equally to the high PEEP group or low PEEP group. Recruitment to the study will continue until a total of 210 patients with ARDS requiring V-V ECMO support have been randomised. In the high PEEP group, PEEP will be set at 15 cmH2O from the start of V-V ECMO until the trials for liberation from V-V ECMO (or until day 28 after the allocation), while in the low PEEP group, the PEEP will be set at 5 cmH2O. Other treatments will be the same in the two groups. The primary endpoint of the study is the number of ECMO-free days until day 28, defined as the length of time (in days) from successful libration from V-V ECMO to day 28. The secondary endpoints are mortality on day 28, in-hospital mortality on day 60, ventilator-free days during the first 60 days and length of ICU stay.Ethics and disseminationEthics approval for the trial at all the participating hospitals was obtained on 27 September 2022, by central ethics approval (IRB at Hiroshima University Hospital, C2022-0006). The results of this study will be presented at domestic and international medical congresses, and also published in scientific journals.Trial registration numberThe Japan Registry of Clinical Trials jRCT1062220062. Registered on 28 September 2022.Protocol version28 March 2023, version 4.0.
Construction and validation of safe care theory for older inpatients from the perspective of socio-ecological model: a study protocol
Authors: Yan Lupei , Liu Li , Wang Fang , Hu Xiuying 
Published: October 2023

IntroductionIn an ageing society, older adults are the main users of healthcare services, and Chinese healthcare systems have been struggling to meet the care demand of older adults. Due to the illness, many older inpatients cannot finish daily activities independently and require healthcare from caregivers. Evaluating the care needs of older adults and exploring the factors affecting safe care at multiple levels are conducive to providing systematic care services for older inpatients. This study aims to examine which and how factors impact safe care for older inpatients and propose a safe care theory to provide directions on improving the safe care system in the hospital.Methods and analysisA mixed-methods study with three interrelated research streams will be designed. (1) A safe care concept model: we will conduct a scoping review to extract the facilitators and barriers influencing the safe care of older inpatients and construct a concept model based on the socio-ecological model and the Yorkshire Contributory Factors Framework. (2) A safe care theory model: we will conduct a qualitative study with thematic analysis (aimed at older inpatients, caregivers and nurses) to define the concept connotations and propose a theory model. (3) A safe care theory: we will use the scales related to the theory model to test the concepts and statements. We will revise the theory model and derive a safe care theory based on the mixed-methods study results. This study will start in October 2023 and end in October 2025.Ethics and disseminationThis study was approved by the ethics committee (No. 20221598). All participants will be provided with consent forms prior to data collection. The study will be disseminated via peer-reviewed manuscripts and conferences.Trial registration numberChiCTR2300067421.
Representation of ethnic and racial minority groups in European vaccine trials: a quantitative analysis of clinical trials registries
Authors: Puttick Natasha F , Vanderslott Samantha , Tanner Rachel 
Published: October 2023

ObjectivesThe representation of ethnic minority groups in European vaccine trials is an important and hitherto unaddressed gap in the literature. The objectives of this study were to determine the proportion of European vaccine trials that report data on the ethnic demographics of participants, to evaluate the distribution of ethnic minority groups among trial participants (where reported), and ascertain whether this is representative of the wider population of the country.DesignWe evaluated the representation of ethnic/racial minority groups in clinical research, conducting a quantitative analysis of clinical trials registry data from completed vaccine trials in Europe that commenced between 1 January 2010 and 31 December 2020.Data sourcesData were collected from four major clinical trial databases: ClinicalTrials.gov, the European Union Clinical Trials Register (EUCTR), the International Standard Randomised Controlled Trial Number (ISRCTN) and the International Clinical Trials Registry Platform (ICTRP).ResultsA majority of clinical trials failed to either record or report the race/ethnicity of their volunteers on the clinical trials registry databases. Reported participants in UK vaccine trials were not representative of the ethnic demographics of the wider population. Unavailability of population-level ethnicity data for many European countries was a significant barrier to determining the wider applicability of these findings.ConclusionsUnder-representation of ethnic minority groups in vaccine trials may have implications for the effectiveness of routine vaccinations, threatening the principles of justice and equity that are embedded in national medical research guidelines. Unavailability of population-level ethnicity data exacerbates the prevailing lack of understanding of the extent of this issue, despite literature indicating cause for concern.
Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer
Authors: Akce Mehmet , Farran Batoul , Switchenko Jeffrey M , Rupji Manali , Kang Sandra , Khalil Lana , Ruggieri-Joyce Amanda , Olson Brian , Shaib Walid L , Wu Christina , Alese Olatunji B , Diab Maria , Lesinski Gregory B , El-Rayes Bassel F 
Published: October 2023

BackgroundPreclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.MethodsNivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.ResultsA total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).ConclusionsNivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients.
Temporal progression of functional independence after mechanical thrombectomy in acute vertebrobasilar artery occlusions
Authors: Xu Yingjie , Zhang Pan , Li Wei , Wang Jinjing , Xiao Lulu , Huang Xianjun , Duan Zuowei , Li Yongkun , Peng Feng , Zhang Feng , Luo Genpei , Sun Wen 
Published: October 2023

BackgroundNeurological recovery after endovascular treatment (EVT) for large vessel occlusion stroke often has diverse timelines. Understanding the temporal progression of functional independence after EVT, especially delayed functional independence (DFI) and highly delayed functional independence (HDFI), in patients who do not improve early is essential for prognostication and rehabilitation. We aimed to analyze the prevalence and predictors of DFI and HDFI after EVT in acute vertebrobasilar artery occlusions (VBAO).MethodsPatients with VBAO who received EVT in China were retrospectively enrolled. Early functional independence (EFI) was defined as a modified Rankin Scale (mRS) score of 0–2 at discharge. The incidence and predictors of DFI (mRS score 0–2 at 90 days in non-EFI patients) and HDFI (mRS score 0–2 at 1 year in non-DFI patients) were analyzed.Results2422 patients met the study criteria. EFI was observed in 20% (483) of patients. Among non-EFI patients, DFI was observed in 21% (395/1880). HDFI was observed in 13% (191/1439) of non-DFI patients. Younger age (P=0.006), lower pre-EVT National Institutes of Health Stroke Scale (NIHSS) score (P<0.001), higher posterior circulation-Alberta Stroke Program Early CT Score (PC-ASPECTS) (P=0.012), and absence of symptomatic intracranial hemorrhage (sICH) (P<0.001) were predictors of DFI. Predictors of HDFI were younger age (P<0.001) and lower pre-EVT NIHSS score (P<0.001).ConclusionA considerable proportion of patients have DFI and HDFI. The independent predictors of DFI were younger age, lower pre-EVT NIHSS score, higher PC-ASPECTS, and absence of sICH. Predictors of HDFI included younger age and lower pre-EVT NIHSS score.
Massive scalar field perturbations in Weyl black holes
Authors: Bécar Ramón , González P. A. , Moncada Felipe , Vásquez Yerko 
Published: October 2023

AbstractIn this work we consider the propagation of massive scalar fields in the background of Weyl black holes, and we study the effect of the scalar field mass in the spectrum of the quasinormal frequencies (QNFs) via the Wentzel–Kramers–Brillouin (WKB) method and the pseudo-spectral Chebyshev method. The spectrum of QNFs is described by two families of modes: the photon sphere and the de Sitter modes. Essentially, we show via the WKB method that the photon sphere modes exhibit an anomalous behaviour of the decay rate of the QNFs; that is, the longest-lived modes are the ones with higher angular numbers, and there is a critical value of the scalar field mass beyond which the anomalous behaviour is inverted. We also analyse the effect of the scalar field mass on each family of modes and on their dominance, and we give an estimated value of the scalar field mass where the interchange in the dominant family occurs.
Exploring meandering river cutoffs
Authors: Gao Peng , Li Zhiwei 
Published: October 2023

Abstract

Cutoffs, which include neck and chute cutoffs, are the results of the fluvial processes that fundamentally influence evolution of meandering rivers. A neck cutoff happens when the two limbs of a highly sinuous bend touch, whereas a chute cutoff refers to the formation of a shortcut channel passing through a meander bend. In this review, we begin by distinguishing the morphological and hydrological conditions of the two cutoff types. Mechanisms driving the development of a neck cutoff are embodied in a variety of kinematical and hydrodynamic models simulating processes governing the long-term evolution of meandering rivers. These models adopt a morphological threshold for judging the occurrence of a neck cutoff,
b
=
αw
, where
α
is a constant ranging between 0 and 1,
b
is the bend neck width and
w
is the mean channel width. The potential underestimation of the evolutionary period during the late stage of bend evolution toward a neck cutoff when using this morphological threshold and the uncertainties in quantifying the migration–curvature relationship limit the abilities of existing models to predict the occurrence of neck cutoffs. We then suggest three possible directions for future research on meander neck cutoffs. Mechanisms controlling chute cutoffs are relevant to six key factors representing the meander hydrological regime, planform morphology, bed topography and floodplain characteristics. The combination of these factors gives rise to four distinguishable triggering mechanisms: headward-erosion, embayment, mid-channel bar and scroll–slough chute cutoffs, though the initiation of the chute cutoff may be caused by some combination of these. However, the hydraulic and morphological characteristics of meander bends under these triggering mechanisms are so complex that they are often site-specific, making it extremely challenging to generalize the known morphodynamic and hydrodynamic processes driving the formation of chute cutoffs in individual meander bends. We close the review by recommending three possible research directions on chute cutoffs for tackling the existing challenges in the future.
Computational Thinking and Notional Machines: The Missing Link
Authors: Munasinghe Bhagya , Bell Tim , Robins Anthony 
Published: October 2023

In learning to program and understanding how a programming language controls a computer, learners develop both insights and misconceptions whilst their mental models are gradually refined. It is important that the learner is able to distinguish the different elements and roles of a computer (compiler, interpreter, memory, etc.), which novice programmers may find difficult to comprehend. Forming accurate mental models is one of the potential sources of difficulty inextricably linked to mastering computing concepts and processes, and for learning computer programming.
It is common to use some form of representation (e.g., an abstract machine or a Computational Agent (CA)) to support technical or pedagogic explanations. The Notional Machine (NM) is a pedagogical device that entails one or more computational concepts, originally described as an idealised computer operating with the constructs of a particular programming language. It can be used to support specific or general learning goals and will typically have some concrete representation that can be referred to. Computational Thinking (CT), which is defined as a way of thinking that is used for [computational] problem solving, is often presented as using a CA to carry out information processing presented by a solution.
In CT, where the typical goal is to produce an algorithm or a computer program, the CA seemingly serves a purpose very similar to an NM. Although it changes through the different stages of development (of the learner and of the curriculum), the roles of CAs and NMs can be seen as versatile tools that connect a learner’s mental model with the conceptual model of a program. In this article, we look at this relationship between CAs and NMs, and indicate how they would look at different stages of learning. We traverse the range of definitions and usages of these concepts, and articulate models that clarify how these are viewed in the literature. This includes exploring the nature of machines and agents, and how historical views of these relate to modern pedagogy for computation. We argue that the CA can be seen as an abstract, simplified variant of an NM that provides a useful perspective to the learner to support them to form robust mental models of NMs more efficiently and effectively. We propose that teaching programming should make use of the idea of a CA at different stages of learning, as a link that connects a learner’s mental model to a full NM.
Unlocking the Mysteries of Chromatin Biology through Functional Epigenomics
Authors: Ye Ziyang , Soshnev Alexey A. , Soto-Feliciano Yadira 
Published: October 2023

Abstract
In the ever evolving field of functional genomics, CRISPR-based screening technologies have become pivotal tools for elucidating gene function across various cell types. A recent study by Gilan and colleagues advances this technological frontier by introducing CRISPR-ChIP, a platform designed to investigate the complex dynamics of epigenetic regulation of chromatin. In proof-of-concept experiments, the authors demonstrate the potential of this tool to identify key molecular regulators of two major histone modifications associated with active transcription, H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 79 dimethylation (H3K79me2). They further unveiled a previously unknown functional partitioning of the H3K79-specific methyltransferase DOT1L into an oncogenic complex with MLL-AF9 and a native complex with MLLT10, which cooperatively regulate mixed lineage leukemia fusion protein (MLL-FP) target gene expression. This novel epigenomic approach integrates high-throughput CRISPR screening with chromatin immunoprecipitation–based direct readout of chromatin modifications in situ, offering a powerful tool to investigate the epigenetic regulatory layers across a diverse spectrum of biological processes and disease states.
Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors
Authors: Hayashi Takahiro , Tateishi Kensuke , Matsuyama Shinichiro , Iwashita Hiromichi , Miyake Yohei , Oshima Akito , Honma Hirokuni , Sasame Jo , Takabayashi Katsuhiro , Sugino Kyoka , Hirata Emi , Udaka Naoko , Matsushita Yuko , Kato Ikuma , Hayashi Hiroaki , Nakamura Taishi , Ikegaya Naoki , Takayama Yutaro , Sonoda Masaki , Oka Chihiro , Sato Mitsuru , Isoda Masataka , Kato Miyui , Uchiyama Kaho , Tanaka Tamon , Muramatsu Toshiki , Miyake Shigeta , Suzuki Ryosuke , Takadera Mutsumi , Tatezuki Junya , Ayabe Junichi , Suenaga Jun , Matsunaga Shigeo , Miyahara Kosuke , Manaka Hiroshi , Murata Hidetoshi , Yokoyama Takaakira , Tanaka Yoshihide , Shuto Takashi , Ichimura Koichi , Kato Shingo , Yamanaka Shoji , Cahill Daniel P. , Fujii Satoshi , Shankar Ganesh M. , Yamamoto Tetsuya 
Published: October 2023

Abstract

Purpose:
The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay.

Experimental Design:
FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability.

Results:
After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL.

Conclusions:
The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.
Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer
Authors: Suehnholz Sarah P. , Nissan Moriah H. , Zhang Hongxin , Kundra Ritika , Nandakumar Subhiksha , Lu Calvin , Carrero Stephanie , Dhaneshwar Amanda , Fernandez Nicole , Xu Benjamin W. , Arcila Maria E. , Zehir Ahmet , Syed Aijazuddin , Brannon A. Rose , Rudolph Julia E. , Paraiso Eder , Sabbatini Paul J. , Levine Ross L. , Dogan Ahmet , Gao Jianjiong , Ladanyi Marc , Drilon Alexander , Berger Michael F. , Solit David B. , Schultz Nikolaus , Chakravarty Debyani 
Published: October 2023

Abstract

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes.

Significance:
Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers.
See related commentary by Horak and Fröhling, p. 18.
This article is featured in Selected Articles from This Issue, p. 5