bluuebunny/crossref_metadata_2025_split huggingface dataset:
Which decentralised trial activities are reported in clinical trial protocols of drug trials initiated in 2019–2020? A cross-sectional study in ClinicalTrials.gov
Authors: de Jong Amos J , Grupstra Renske J , Santa-Ana-Tellez Yared , Zuidgeest Mira G P , de Boer Anthonius , Gardarsdottir Helga 
Published: August 2022

ObjectivesDecentralised clinical trial activities—such as participant recruitment via social media, data collection through wearables and direct-to-participant investigational medicinal product (IMP) supply—have the potential to change the way clinical trials (CTs) are conducted and with that to reduce the participation burden and improve generalisability. In this study, we investigated the decentralised and on-site conduct of trial activities as reported in CT protocols with a trial start date in 2019 or 2020.DesignWe ascertained the decentralised and on-site conduct for the following operational trial activities: participant outreach, prescreening, screening, obtaining informed consent, asynchronous communication, participant training, IMP supply, IMP adherence monitoring, CT monitoring, staff training and data collection. Results were compared for the public versus private sponsors, regions involved, trial phases and four time periods (the first and second half of 2019 and 2020, respectively).SettingPhases 2, 3 and 4 clinical drug trial protocols with a trial start date in 2019 or 2020 available from ClinicalTrials.gov.Outcome measuresThe occurrence of decentralised and on-site conduct of the predefined trial activities reported in CT protocols.ResultsFor all trial activities, on-site conduct was more frequently reported than decentralised conduct. Decentralised conduct of the individual trial activities was reported in less than 25.6% of the 254 included protocols, except for decentralised data collection, which was reported in 68.9% of the protocols. More specifically, 81.9% of the phase 3 protocols reported decentralised data collection, compared with 73.3% and 47.0% of the phase 2 and 4 protocols, respectively. For several activities, including prescreening, screening and consenting, upward trends in reporting decentralised conduct were visible over time.ConclusionsDecentralised methods are used in CTs, mainly for data collection, but less frequently for other activities. Sharing best practices and a detailed description in protocols can drive the adoption of decentralised methods.
Lived experiences of parents providing care to young people who self-harm: a protocol for a meta-aggregative synthesis of qualitative studies
Authors: Zhao Yanli , D Dela Rosa Ronnell , Zhang Qiushi , Zhao Wei , Xu Hui , Wang Rui , Ma Ling 
Published: August 2022

IntroductionThe self-harm of young people can cause tremendous distress to their parents/carers and impair parents’ ability to provide care. At the same time, parents play an essential role in supporting their child during the management and treatment of self-harm. The synthesis of evidence about parental experiences and needs can inform mental health practice and the development of interventions to provide better care to young people who self-harm and their parents.Methods and analysisA comprehensive search will be conducted across several information sources, including multiple electronic databases (eg, PubMed, Embase, CINAHL, PsycINFO, ProQuest, CNKI, Wanfang, VIP and SinoMed), grey literature, the websites of specific organisations and hand-searched reference lists of all the relevant studies. Qualitative studies published in English or Chinese and focusing on the lived experiences of parents whose child self-harms will be included. Two reviewers will independently screen all the retrieved articles according to the flow diagram proposed by PRISMA (the Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Two independent reviewers will then appraise the methodological quality of all the included articles using the JBI (Joanna Briggs Institute) critical appraisal checklist for qualitative research. The meta-aggregation approach will be used to synthesise the findings of the included qualitative studies, and the level of confidence in the synthesised findings will be assessed using the Confidence in the Qualitative synthesised finding approach.Ethics and disseminationNo additional ethical clearance is required since this review is a secondary analysis of published primary studies. The findings will be disseminated through publication in a peer-reviewed journal and conference presentations.PROSPERO registration numberCRD42021265525.
Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants inSMAD4:a nationwide study
Authors: Jelsig Anne Marie , Kjeldsen Anette , Christensen Lise Lotte , Bertelsen Birgitte , Karstensen John Gásdal , Brusgaard Klaus , Torring Pernille M 
Published: August 2022

Background and aimsHereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by recurrent epistaxis, telangiectatic lesions in the skin and mucosal membranes, and arteriovenous malformations (AVMs) in various organs. In 3%–5% of patients, HHT is caused by pathogenic germline variants (PVs) inSMAD4, and these patients often have additional symptoms of juvenile polyposis syndrome and thoracic aneurysms. The phenotypic spectrum ofSMAD4-associated HHT is less known, including the penetrance and severity of HHT. We aimed to investigate the phenotypic spectrum of HHT manifestations in Danish patients with PVs inSMAD4and compare the findings with current literature.MethodsThe study is a retrospective nationwide study with all known Danish patients with PVs inSMAD4. In total, 35 patients were included. The patients were identified by collecting data from genetic laboratories, various databases and clinical genetic departments across the country. Clinical information was mainly collected from the Danish HHT-Centre at Odense University Hospital.ResultsTwenty-nine patients with PVs inSMAD4(83%) were seen at the HHT-Centre. Seventy-six per cent of these fulfilled the Curaçao criteria, 86% experienced recurrent epistaxis and 83% presented with telangiectatic lesions at different anatomical localisations. Almost 60% had AVMs, mainly pulmonary and hepatic, while none was found to have cerebral AVMs. Fifteen per cent had thoracic aortic abnormalities.ConclusionWe present a nationwide study of one of the largest populations of patients with PVs inSMAD4that has systematically been examined for HHT manifestations. The patients presented the full spectrum of HHT-related manifestations and the majority fulfilled the Curaçao criteria.
Perceived exertion and dyspnea while cycling during a hypoxic and hyperoxic placebo
Authors: Kipp Shalaya , Leahy Michael G. , Hanna Jacob A. , Sheel A. William 
Published: August 2022

Rating of perceived exertion (RPE) is used to subjectively quantify the perception of physical activity, breathlessness or dyspnea, and leg discomfort (RPElegs) during exercise. However, it is unknown how dyspnea or RPElegs can be influenced by expectations. Thirty healthy, active participants (19 males, 11 females) completed five, 5-minute submaximal cycling trials at 60% peak work rate. We deceived participants by telling them they were inspiring different hypoxic and hyperoxic gases, when in fact they breathed room air. Cardiorespiratory variables were similar between the trials, however, dyspnea and RPElegs evaluated with a Borg scale changed in a dose–response manner. When participants believed they were breathing 15% O2, they significantly increased dyspnea +0.70 ± 0.2 units ( p = 0.03) compared to room air, whereas RPElegs was unchanged +0.35 ± 0.1 units ( p = 0.70). When participants believed they were breathing 15% O2, they significantly increased dyspnea +1.05 ± 0.4 units ( p = 0.003) compared to 23% hyperoxic condition, whereas RPElegs was unchanged +0.35 ± 0.1 units ( p = 0.70). We found that dyspnea during exercise is susceptible to expectancy, without any accompanying physiological changes. Given coaches and clinicians use perceived exertion to prescribe exercise intensity and evaluate treatments, our findings show that the effect of expectations must be considered when interpreting sensations of breathlessness.
Effects of dam-induced delays on system-wide survival of Atlantic salmon smolts during high-flow, high-survival years in the Penobscot River, Maine, USA
Authors: Molina-Moctezuma Alejandro , Stich Daniel S. , Zydlewski Joseph D. 
Published: August 2022

System-wide survival of hatchery-reared Atlantic salmon ( Salmo salar) smolts was evaluated (2017–2019) in the Penobscot River and compared to survival estimates from previous years that spanned major changes (2005–2016). This system was transformed through two dam removals in 2012 and construction of a nature-like passage structure at a third. The main stem had three dams (five prior to 2012), while the main tributary had four dams (one with the new nature-like passage). We estimated survival using acoustic telemetry mark–recapture ( n = 1482) from 2017 to 2019. Six release sites and two release dates were included to assess system-wide survival. Survival from 2017 to 2019 was higher than previous years, with total cumulative survival > 0.75, independently of year and release sites, compared to survival < 0.5 in previous years. These years coincided with exceptional high flows not seen previously. We found an effect of delays on survival, longer delays associated with lower survival. Overall, survival in these years increased in all reaches relative to previous years except for one dam, Weldon Dam, which was a site of sustained high mortality.
Quantification of Phenolic and Flavonoid Content, Antioxidant Activity, and Proximate Composition of Some Legume Seeds Grown in Nepal
Authors: Sharma Khaga Raj , Giri Govinda 
Published: August 2022

This study was carried out to evaluate some legume seeds growing in Nepal for their proximate composition, quantification of total phenolic (TPC) and flavonoid (TFC) contents, and in vitro, antioxidant and antidiabetic activities. These included legume grains such as chickpeas (Cicer arietinum), pea (Pisum sativum), mung bean (Vigna mungo), lima bean (Phaseolus lunatus), broad bean (Vicia faba), lentil (Lens culinaris), soybean (Glycine max), and common bean (Phaseolus vulgaris). The legume seeds were ground to make the flour which was extracted with methanol. The phenolic and flavonoid content was estimated by Folin-Ciocalteu’s phenol and aluminum chloride colorimetric methods. The in vitro antioxidant and antidiabetic activity was evaluated by using DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical scavenging and α-amylase enzyme inhibition assay. The different legumes showed considerable variations in their phenolic contents (

30.64
±
1.50

mg·GAE/g to

46.65
±
1.25

mg·GAE/g legume seeds). Similarly, the total flavonoid contents showed

135.5
±
10.88

mg·QE/g to

191.7
±
8.73

mg·QE/g legume seeds. The in vitro antioxidant activity was evaluated in IC50 which ranged from

31.60
±
0.06

μg/mL to

69.74
±
0.89

μg/mL. The α-amylase inhibition was evaluated in IC50 which ranged from 217.38 μg/mL to 425.75 μg/mL as compared to the standard acarbose of 52.76 μg/mL. This study suggested that legumes are good sources of proteins, carbohydrates, and fats mainly for vegetarian people. The selection of the right legume species could be a good source of natural antioxidants and antidiabetics for nutraceutical uses and the beneficial effects of legumes from human health perspectives. Legume seeds growing in Nepal could be used as a sustainable and cheap meat alternative and are considered the most important food source.
Effect of Ultrasonic Osteotome on Therapeutic Efficacy and Safety of Spinal Surgery: A System Review and Meta-Analysis
Authors: Wu Leilei , Wang Sheng 
Published: August 2022

Background. A meta-analysis was performed to evaluate the effectiveness and safety of ultrasonic osteotomes in spine surgery to standard spinal surgery procedures. Methods. Using the search keywords “bone curette”, “cutter”, “scalpel”, “bone shaver”, “aspirator”, “osteotome”, “ultrasonic”, “piezosurgery”, and “

dent

∗

” in the databases of PubMed (1966-2021.12), Cochrane Library, Embase (1986-2018.12), Web of Science (1978-2021.12), and China Academic Journals Full-Text Database (CNKI, 1979-2021.12). Two researchers reviewed the literature, extracted and extensively assessed the data, and included information on the study quality. RevMan v5.3.5.0 was used for the meta-analysis. Results. A total of 10 trials with a total of 911 patients were included. The meta-analysis findings revealed that, when compared to traditional methods, ultrasonic osteotomes could save operation time (

OR
=
−
18.83

, 95 percent CI (-22.76, -14.99),

P
=
0.03

) and reduce intraoperative bleeding (

OR
=
−
66.73

, 95 percent CI (-75.70, -57.76),

P
=
0.04

) and postoperative complications (

OR
=
0.38

, 95 percent CI (0.21, 0.69),

P
=
0.001

). There was, however, no significant difference in the hospital stay (

OR
=
−
1.34

, 95 percent CI (-1.90, -0.77),

P
=
0.23

) and symptom improvement rate (

OR
=
1.03

, 95 percent CI (0.73, 1.45),

P
=
0.86

). Conclusion. There is evidence that using an ultrasonic osteotome in spine surgery is safe and effective and may minimize intraoperative bleeding and save time. However, there is no significant difference in symptom improvement rate, hospital stay length, or postoperative complications compared to standard surgical equipment. Therefore, more high-quality investigations are needed to corroborate the initial results.
Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity Against Glioblastoma
Authors: Meister Hanna , Look Thomas , Roth Patrick , Pascolo Steve , Sahin Ugur , Lee Sohyon , Hale Benjamin D. , Snijder Berend , Regli Luca , Ravi Vidhya M. , Heiland Dieter Henrik , Sentman Charles L. , Weller Michael , Weiss Tobias 
Published: August 2022

Abstract

Purpose:
Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma.

Experimental Design:
We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo.

Results:
Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without signs of toxicity. Mechanistically, the coexpression of IL12 and IFNα2 in addition to the CAR promoted a proinflammatory tumor microenvironment and reduced T-cell exhaustion as demonstrated by ex vivo immune phenotyping, cytokine profiling, and RNA sequencing. The translational potential was demonstrated by image-based single-cell analyses of mRNA-modified T cells in patient glioblastoma samples with a complex cellular microenvironment. This revealed strong antiglioma activity of human mRNA-based multifunctional NKG2D CAR T cells coexpressing IL12 and IFNα2 whereas T cells that expressed either the CAR or cytokines alone did not demonstrate comparable antiglioma activity.

Conclusions:
These data provide a robust rationale for future clinical studies with mRNA-based multifunctional CAR T cells to treat malignant brain tumors.
A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer
Authors: Han Kathy , Fyles Anthony , Shek Tina , Croke Jennifer , Dhani Neesha , D'Souza David , Lee Ting-Yim , Chaudary Naz , Bruce Jeffrey , Pintilie Melania , Cairns Rob , Vines Douglass , Pakbaz Sara , Jaffray David , Metser Ur , Rouzbahman Marjan , Milosevic Michael , Koritzinsky Marianne 
Published: August 2022

Abstract

Purpose:
Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT.

Patients and Methods:
A window-of-opportunity, phase II randomized trial was performed in stage IB–IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic.

Results:
Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%–34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%–33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09).

Conclusions:
Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor.
See related commentary by Lyng et al., p. 5233
Systemic Checkpoint Blockade by PD-L1 Single-Chain Antibody Confers Potent Antitumor Immunity and Long-term Survival
Authors: Wang Hong , Khattar Vinayak , Hensel Jonathan A. , Ashton Reading , Lu Yun , Sorace Anna G. , Wang Yong , Deshane Jessy S. , Mieher Joshua L. , Deivanayagam Champion , Ponnazhagan Selvarangan 
Published: August 2022

Abstract
Immune checkpoint inhibitors (ICI) are promising in adjuvant settings for solid tumors and hematologic malignancies. They are currently used in the treatment as mAbs in high concentrations, raising concerns of toxicity and adverse side effects. Among various checkpoint molecules, targeting the programmed cell death protein-1 (PD-1)–programmed death-ligand 1 (PD-L1) axis has garnered more clinical utility than others have. To develop a physiologically relevant and systemically stable level of ICIs from a one-time application by genetic antibody engineering, we endeavored using a nonpathogenic, replication-deficient recombinant adeno-associated vector (rAAV) expressing single-chain variable fragments (scFv) of PD-L1 antibody and tested in syngeneic mouse therapy models of MC38 colorectal and EMT6 breast tumors. Results of this study indicated a significant protection against PD-L1–mediated inhibition of CD8+ T-cell function, against the growth of primary and secondary tumors, and durable antitumor CTLs activity by adoptive CD8+ T-cell transfer. Stable maintenance of PD-L1 scFv in vivo resulted in an increase in PD-1− CD8+ T cells and a concomitant decrease in regulatory T cells, M2 macrophages, and myeloid-derived suppressor cells in the tumor microenvironment. Overall, these data demonstrate the potential of rAAV-PD-L1-scFv as an alternative to mAb targeting of PD-L1 for tumor therapy.
ECG T‐Wave Morphologic Variations Predict Ventricular Arrhythmic Risk in Low‐ and Moderate‐Risk Populations
Authors: Ramírez Julia , Kiviniemi Antti , van Duijvenboden Stefan , Tinker Andrew , Lambiase Pier D. , Junttila Juhani , Perkiömäki Juha S. , Huikuri Heikki V. , Orini Michele , Munroe Patricia B. 
Published: August 2022

Background
Early identification of individuals at risk of sudden cardiac death (SCD) remains a major challenge. The ECG is a simple, common test, with potential for large‐scale application. We developed and tested the predictive value of a novel index quantifying T‐wave morphologic variations with respect to a normal reference (TMV), which only requires one beat and a single‐lead ECG.

Methods and Results

We obtained reference T‐wave morphologies from 23 962 participants in the UK Biobank study. With Cox models, we determined the association between TMV and life‐threatening ventricular arrhythmia in an independent data set from UK Biobank study without a history of cardiovascular events (N=51 794; median follow‐up of 122 months) and SCD in patients with coronary artery disease from ARTEMIS (N=1872; median follow‐up of 60 months). In UK Biobank study, 220 (0.4%) individuals developed life‐threatening ventricular arrhythmias. TMV was significantly associated with life‐threatening ventricular arrhythmias (hazard ratio [HR] of 1.13 per SD increase [95% CI, 1.03–1.24];
P
=0.009). In ARTEMIS, 34 (1.8%) individuals reached the primary end point. Patients with TMV ≥5 had an HR for SCD of 2.86 (95% CI, 1.40–5.84;
P
=0.004) with respect to those with TMV <5, independently from QRS duration, corrected QT interval, and left ventricular ejection fraction. TMV was not significantly associated with death from a cause other than SCD.

Conclusions
TMV identifies individuals at life‐threatening ventricular arrhythmia and SCD risk using a single‐beat single‐lead ECG, enabling inexpensive, quick, and safe risk assessment in large populations.
Probing the Explainability of Neural Network Cloud-Top Pressure Models for LEO and GEO Imagers
Authors: White Charles H. , Heidinger Andrew K. , Ackerman Steven A. 
Published: August 2022

Abstract
Satellite low-Earth-orbiting (LEO) and geostationary (GEO) imager estimates of cloud-top pressure (CTP) have many applications in both operations and in studying long-term variations in cloud properties. Recently, machine learning (ML) approaches have shown improvement upon physically based algorithms. However, ML approaches, and especially neural networks, can suffer from a lack of interpretability, making it difficult to understand what information is most useful for accurate predictions of cloud properties. We trained several neural networks to estimate CTP from the infrared channels of the Visible Infrared Imaging Radiometer Suite (VIIRS) and the Advanced Baseline Imager (ABI). The main focus of this work is assessing the relative importance of each instrument’s infrared channels in neural networks trained to estimate CTP. We use several ML explainability methods to offer different perspectives on feature importance. These methods show many differences in the relative feature importance depending on the exact method used, but most agree on a few points. Overall, the 8.4- and 8.6-μm channels appear to be the most useful for CTP estimation on ABI and VIIRS, respectively, with other native infrared window channels and the 13.3-μm channel playing a moderate role. Furthermore, we find that the neural networks learn relationships that may account for properties of clouds such as opacity and cloud-top phase that otherwise complicate the estimation of CTP.

Significance Statement
Model interpretability is an important consideration for transitioning machine learning models to operations. This work applies several explainability methods in an attempt to understand what information is most important for estimating the pressure level at the top of a cloud from satellite imagers in a neural network model. We observe much disagreement between approaches, which motivates further work in this area but find agreement on the importance of channels in the infrared window region around 8.6 and 10–12 μm, informing future cloud property algorithm development. We also find some evidence suggesting that these neural networks are able to learn physically relevant variability in radiation measurements related to key cloud properties.