bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro fertilisation (IVF) versus intracytoplasmic sperm injection (ICSI) in patients without severe male factor infertility: study protocol for the randomised, controlled, multicentre trial INVICSI
Authors: Berntsen Sine , Nøhr Bugge , Grøndahl Marie Louise , Petersen Morten Rønn , Andersen Lars Franch , Englund Anne Lis , Knudsen Ulla Breth , Prætorius Lisbeth , Zedeler Anne , Nielsen Henriette Svarre , Pinborg Anja , Freiesleben Nina La Cour 
Published: June 2021

IntroductionOver the last decades, the use of intracytoplasmic sperm injection (ICSI) has increased, even among patients without male factor infertility. The increase has happened even though there is no evidence to support that ICSI results in higher live birth rates compared with conventional in vitro fertilisation (IVF) in cases with nonmale factor infertility. The lack of robust evidence on an advantage of using ICSI over conventional IVF in these patients is problematic since ICSI is more invasive, complex and requires additional resources, time and effort. Therefore, the primary objective of the IVF versus ICSI (INVICSI) study is to determine whether ICSI is superior to standard IVF in patients without severe male factor infertility. The primary outcome measure is first live birth from fresh and frozen-thawed transfers after one stimulated cycle. Secondary outcomes include fertilisation rate, ongoing pregnancy rate, birth weight and congenital anomalies.Methods and analysisThis is a two-armed, multicentre, randomised, controlled trial. In total, 824 couples/women with infertility without severe male factor will be recruited and allocated randomly into two groups (IVF or ICSI) in a 1:1 ratio. Participants will be randomised in variable block sizes and stratified by trial site and age. The main inclusion criteria are (1) no prior IVF/ICSI treatment, (2) male partner sperm with an expected count of minimum 2 million progressive motile spermatozoa following density gradient purification on the day of oocyte pick up and (3) age of the woman between 18 and 42 years.Ethics and disseminationThe study will be performed in accordance with the ethical principles in the Helsinki Declaration. The study is approved by the Scientific Ethical Committee of the Capital Region of Denmark. Study findings will be presented, irrespectively of results at international conferences and submitted for publication in peer-reviewed journals.Trial registration numberNCT04128904. Pre-results.
Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma
Authors: Deng Haijing , Kan Anna , Lyu Ning , He Meng , Huang Xin , Qiao Shuang , Li Shaolong , Lu Wenhua , Xie Qiankun , Chen Huiming , Lai Jinfa , Chen Qifeng , Jiang Xiongying , Liu Shousheng , Zhang Zhenfeng , Zhao Ming 
Published: June 2021

BackgroundNeutrophils play a controversial role in tumor development. The function of programmed cell death-1 ligand (PD-L1+) neutrophils, however, may inhibit the cytotoxicity of anti-tumor immunity. In this study, we elucidate the stimulators of PD-L1+neutrophils in tumor microenvironment (TME) and explore the optimal combination to enhance the effect of lenvatinib by inhibiting PD-L1+neutrophils in hepatocellular carcinoma.MethodsNeutrophil infiltration after lenvatinib treatment was examined with RNA sequencing and multicolor flow cytometry analysis in patient samples, subcutaneous and orthotopic mouse models. Neutrophils and T cells were isolated from peripheral blood and tumor tissues and purified with magnetic beads for cytotoxicity assay. Metabolites and cytokines were detected by a biochemical analyzer manufactured by Yellow Springs Instrument (YSI) and proteome profiler cytokines array. In vitro screening of pathway inhibitors was used to identify possible candidates that could reduce PD-L1+neutrophil infiltration. Further in vivo assays were used for verification.ResultsLenvatinib increased neutrophil recruitment by inducing CXCL2 and CXCL5 secretion in TME. After entering TME, neutrophils polarized toward N2 phenotype. PD-L1 expression was simultaneously upregulated. Thus, lenvatinib efficacy on tumor cells hindered. The increasing PD-L1+neutrophils positively corelated with a suppressive T cell phenotype. Further investigation indicated that JAK/STAT1 pathway activated by immune-cell-derived interferon γ and MCT1/NF-kB/COX-2 pathway activated by high concentrations of tumor-derived lactate could induce PD-L1+neutrophils. The latter could be significantly inhibited by COX-2 inhibitor celecoxib. Further in vivo assays verified that Celecoxib decreased the survival of lactate-stimulated PD-L1+neutrophil and promoted the antitumor effect of lenvatinib.ConclusionsPD-L1+neutrophils decrease T cell cytotoxicity. Tumor-derived lactate induces PD-L1 expression on neutrophils via MCT1/NF-κB/COX-2 pathway. Thus, COX-2 inhibitor could reduce PD-L1+neutrophil and restore T cell cytotoxicity. This may provide a potent addition to lenvatinib.
Body composition and risk of heart failure: protocol for a systematic review and meta-analysis
Authors: Oguntade Ayodipupo S. , Jin Danyao , Islam Nazrul , Malouf Reem , Taylor Hannah , Caleyachetty Rishi , Lewington Sarah , Lacey Ben 
Published: June 2021

IntroductionAlthough there is strong evidence of an association between general adiposity and incidence of heart failure, previous systematic reviews and meta-analyses have not reliably assessed the association of heart failure risk with other aspects of body composition (such as body fat distribution or lean mass), or between body composition and risk of heart failure subtypes. We aim to conduct a systematic review and meta-analysis of prospective studies to address these uncertainties, and inform efforts to prevent and treat heart failure.Methods and analysisThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols statement was used as a template for this protocol. A systematic search of Medline, Embase and Global Health from database inception to present will be conducted to identify prospective studies reporting on the associations between major measures of body composition (body mass index, waist circumference, waist–hip ratio, total body fat, visceral adiposity tissue and lean mass) and risk of heart failure. Article screening and selection will be performed by two reviewers independently, and disagreements will be adjudicated by consensus or by a third reviewer. Data from eligible articles will be extracted, and article quality will be assessed using the Newcastle-Ottawa Scale. Relative risks (and 95% CIs) will be pooled in a fixed effect meta-analysis, if there is no prohibitive heterogeneity of studies as assessed using the Cochrane Q statistic and I2statistic. Subgroup analyses will be by age, sex, ethnicity and heart failure subtypes. Publication bias in the meta-analysis will be assessed using Egger’s test and funnel plots.Ethics and disseminationThis work is secondary analyses on published data and ethical approval is not required. We plan to publish results in an open-access peer-reviewed journal, present it at international and national conferences, and share the findings on social media.PROSPERO registration numberCRD42020224584.
Electron irradiation and thermal chemistry studies of interstellar and planetary ice analogues at the ICA astrochemistry facility
Authors: Mifsud Duncan V. , Juhász Zoltán , Herczku Péter , Kovács Sándor T. S. , Ioppolo Sergio , Kaňuchová Zuzana , Czentye Máté , Hailey Perry A. , Muiña Alejandra Traspas , Mason Nigel J. , McCullough Robert W. , Paripás Béla , Sulik Béla 
Published: June 2021

Abstract
The modelling of molecular excitation and dissociation processes relevant to astrochemistry requires the validation of theories by comparison with data generated from laboratory experimentation. The newly commissioned Ice Chamber for Astrophysics-Astrochemistry (ICA) allows for the study of astrophysical ice analogues and their evolution when subjected to energetic processing, thus simulating the processes and alterations interstellar icy grain mantles and icy outer Solar System bodies undergo. ICA is an ultra-high vacuum compatible chamber containing a series of IR-transparent substrates upon which the ice analogues may be deposited at temperatures of down to 20 K. Processing of the ices may be performed in one of three ways: (i) ion impacts with projectiles delivered by a 2 MV Tandetron-type accelerator, (ii) electron irradiation from a gun fitted directly to the chamber, and (iii) thermal processing across a temperature range of 20–300 K. The physico-chemical evolution of the ices is studied in situ using FTIR absorbance spectroscopy and quadrupole mass spectrometry. In this paper, we present an overview of the ICA facility with a focus on characterising the electron beams used for electron impact studies, as well as reporting the preliminary results obtained during electron irradiation and thermal processing of selected ices.

Graphic Abstract
Spatio-temporal patterns of extreme fires in Amazonian forests
Authors: Cano-Crespo Ana , Traxl Dominik , Thonicke Kirsten 
Published: June 2021

AbstractFires are a fundamental part of the Earth System. In the last decades, they have been altering ecosystem structure, biogeochemical cycles and atmospheric composition with unprecedented rapidity. In this study, we implement a complex networks-based methodology to track individual fires over space and time. We focus on extreme fires—the 5% most intense fires—in the tropical forests of the Brazilian Legal Amazon over the period 2002–2019. We analyse the interannual variability in the number and spatial patterns of extreme forest fires in years with diverse climatic conditions and anthropogenic pressure to examine potential synergies between climate and anthropogenic drivers. We observe that major droughts, that increase forest flammability, co-occur with high extreme fire years but also that it is fundamental to consider anthropogenic activities to understand the distribution of extreme fires. Deforestation fires, fires escaping from managed lands, and other types of forest degradation and fragmentation provide the ignition sources for fires to ignite in the forests. We find that all extreme forest fires identified are located within a 0.5-km distance from forest edges, and up to 56% of them are within a 1-km distance from roads (which increases to 73% within 5 km), showing a strong correlation that defines spatial patterns of extreme fires.
Diversity of supergene gold expressions and implications for gold targetting in an equatorial regolith (AMG's Couriège Exploration Prospect, French Guiana)
Authors: Combes Vincent , Teitler Yoram , Eglinger Aurélien , André-Mayer Anne-Sylvie , Heuret Arnauld , Pochon Anthony , Cathelineau Michel , Gibert Pierre 
Published: June 2021

Abstract
The Couriège prospect (French Guiana) provides key examples of the diversity of gold distribution related to supergene processes. The nature of gold in two contrasted weathering profiles is examined as a function of the weathering lithofacies. The autochthonous profile hosts weathered Au-bearing quartz veins whereas the pediment profile is enriched in free gold issued from dismantled gold-bearing quartz veins. The gold distribution is controlled by: (1) the preservation of primary gold as free gold in both transported and autochthonous horizons and as electrum inclusions in detrital pyrite; and (2) the formation of secondary gold through dissolution/precipitation processes, expressed as gold spherulites on the free gold grain surface, an Ag-depleted rim around transported free gold grains and Ag-depleted gold micro-inclusions hosted by oxidized autochthonous pyrite. Gold enrichment through supergene chemical processes remains limited within the truncated autochthonous profile. A new conceptual model is proposed for the area, defining the role of chemical and physical processes in gold endowment and accounting for the geomorphological context. The overall evolution includes (1) deep weathering and peneplenation, (2) dismantlement and transport of lateritic material and (3) the development of a latosol cover. This study highlights that gold exploration in tropical environments must consider the residual v. transported nature and the inheritance of targeted pedogenic horizons.
IriTrack
Authors: Shen Meng , Wei Yaqian , Liao Zelin , Zhu Liehuang 
Published: June 2021

With a growing adoption of face authentication systems in various application scenarios, face Presentation Attack Detection (PAD) has become of great importance to withstand artefacts. Existing methods of face PAD generally focus on designing intelligent classifiers or customized hardware to differentiate between the image or video samples of a real legitimate user and the imitated ones. Although effective, they can be resource-consuming and suffer from performance degradation due to environmental changes.
In this paper, we propose IriTrack, which is a simple and efficient PAD system that takes iris movement as a significant evidence to identify face artefacts. More concretely, users are required to move their eyes along with a randomly generated poly-line, where the resulting trajectories of their irises are used as an evidence for PAD i.e., a presentation attack will be identified if the deviation of one's actual iris trajectory from the given poly-line exceeds a threshold. The threshold is carefully selected to balance the latency and accuracy of PAD. We have implemented a prototype and conducted extensive experiments to evaluate the performance of the proposed system. The results show that IriTrack can defend against artefacts with moderate time and memory overheads.
Intratumor CMS Heterogeneity Impacts Patient Prognosis in Localized Colon Cancer
Authors: Marisa Laetitia , Blum Yuna , Taieb Julien , Ayadi Mira , Pilati Camilla , Le Malicot Karine , Lepage Côme , Salazar Ramon , Aust Daniela , Duval Alex , Blons Hélène , Taly Valérie , Gentien David , Rapinat Audrey , Selves Janick , Mouillet-Richard Sophie , Boige Valérie , Emile Jean-François , de Reyniès Aurélien , Laurent-Puig Pierre 
Published: June 2021

Abstract

Purpose:
The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications.

Experimental Design:
We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%.

Results:
Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% confidence interval (CI; 1.12–1.59), 1.40, 95% CI (1.14–1.71), respectively]. Moreover, we uncovered specific combinations of CMS associated with dismal prognosis. In multivariate analysis, ITH represents the third parameter explaining DFS variance, after T and N stages. At a cellular level, combined WISP and single-cell transcriptomic analysis revealed that most colon cancer cell lines are a mixture of cells falling into different CMSs, indicating that ITH may correspond to distinct functional statuses of colon cancer cells.

Conclusions:
This study shows that CMS-based transcriptomic ITH is frequent in colon cancer and impacts its prognosis. CMS-based transcriptomic ITH may correspond to distinct functional statuses of colon cancer cells, suggesting plasticity between CMS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors
Authors: Foster Corey C. , Fleming Gini F. , Karrison Theodore G. , Liao Chih-Yi , Desai Ami V. , Moroney John W. , Ratain Mark J. , Nanda Rita , Polite Blase N. , Hahn Olwen M. , O'Donnell Peter H. , Vokes Everett E. , Kindler Hedy L. , Hseu Robyn , Janisch Linda A. , Dai Julia , Hoffman Mark D. , Weichselbaum Ralph R. , Pitroda Sean P. , Chmura Steven J. , Luke Jason J. 
Published: June 2021

Abstract

Purpose:
CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor).

Patients and Methods:
This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1–4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose-limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if ≤33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.

Results:
Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n = 3 grade 3, n = 4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months [95% confidence interval (CI), 2.9–4.8] and 17.0 months (95% CI, 6.8–undetermined), respectively. No patients with elevated pre-SBRT serum IL8 experienced a response.

Conclusions:
SBRT to ≤4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest antitumor activity.
See related commentary by Rodriguez-Ruiz et al., p. 5443
Safer Stroke-Dx Instrument: Identifying Stroke Misdiagnosis in the Emergency Department
Authors: Saleh Velez Faddi G. , Alvarado-Dyer Ronald , Pinto Camila Bonin , Ortiz García Jorge G. , Mchugh Daryl , Lu Jenny , Otlivanchik Oleg , Flusty Brent L. , Liberman Ava L. , Prabhakaran Shyam 
Published: June 2021

Background:
Missed or delayed diagnosis of acute stroke, or false-negative stroke (FNS), at initial emergency department (ED) presentation occurs in ≈9% of confirmed stroke patients. Failure to rapidly diagnose stroke can preclude time-sensitive treatments, resulting in higher risks of severe sequelae and disability. In this study, we developed and tested a modified version of a structured medical record review tool, the Safer Dx Instrument, to identify FNS in a subgroup of hospitalized patients with stroke to gain insight into sources of ED stroke misdiagnosis.

Methods:
We conducted a retrospective cohort study at 2 unaffiliated comprehensive stroke centers. In the development and confirmatory cohorts, we applied the Safer Stroke-Dx Instrument to report the prevalence and documented sources of ED diagnostic error in FNS cases among confirmed stroke patients upon whom an acute stroke was suspected by the inpatient team, as evidenced by stroke code activation or urgent neurological consultation, but not by the ED team. Inter-rater reliability and agreement were assessed using interclass coefficient and kappa values (κ).

Results:
Among 183 cases in the development cohort, the prevalence of FNS was 20.2% (95% CI, 15.0–26.7). Too narrow a differential diagnosis and limited neurological examination were common potential sources of error. The interclass coefficient for the Safer Stroke-Dx Instrument items ranged from 0.42 to 0.91, and items were highly correlated with each other. The κ for diagnostic error identification was 0.90 (95% CI, 0.821–0.978) using the Safer Stroke-Dx Instrument. In the confirmatory cohort of 99 cases, the prevalence of FNS was 21.2% (95% CI, 14.2–30.3) with similar sources of diagnostic error identified.

Conclusions:
Hospitalized patients identified by stroke codes and requests for urgent neurological consultation represent an enriched population for the study of diagnostic error in the ED. The Safer Stroke-Dx Instrument is a reliable tool for identifying FNS and sources of diagnostic error.
Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging
Authors: Czibik Gabor , Mezdari Zaineb , Murat Altintas Dogus , Bréhat Juliette , Pini Maria , d’Humières Thomas , Delmont Thaïs , Radu Costin , Breau Marielle , Liang Hao , Martel Cecile , Abatan Azania , Sarwar Rizwan , Marion Ophélie , Naushad Suzain , Zhang Yanyan , Halfaoui Maissa , Suffee Nadine , Morin Didier , Adnot Serge , Hatem Stéphane , Yavari Arash , Sawaki Daigo , Derumeaux Geneviève 
Published: June 2021

Background:
Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine and how it may promote age-related cardiac dysfunction.

Methods:

We studied cardiac structure and function, together with phenylalanine catabolism in wild-type (WT) and p21
−/−
mice (male; 2–24 months), with the latter known to be protected from cellular senescence. To explore phenylalanine’s effects on cellular senescence and ectopic phenylalanine catabolism, we treated cardiomyocytes (primary adult rat or human AC-16) with phenylalanine. To establish a role for phenylalanine in driving cardiac aging, WT male mice were treated twice a day with phenylalanine (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (10 mg/kg), the essential cofactor for the phenylalanine-degrading enzyme PAH (phenylalanine hydroxylase), or restricted dietary phenylalanine intake. The impact of senescence on hepatic phenylalanine catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting small interfering RNA or tetrahydrobiopterin, with quantification of PAH and tyrosine levels.

Results:
Natural aging is associated with a progressive increase in plasma phenylalanine levels concomitant with cardiac dysfunction, whereas p21 deletion delayed these changes. Phenylalanine treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, while triggering cellular senescence, redox, and epigenetic changes. Pharmacological restoration of phenylalanine catabolism with tetrahydrobiopterin administration or dietary phenylalanine restriction abrogated the rise in plasma phenylalanine and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic phenylalanine catabolism as a key driver of elevated plasma phenylalanine levels and showed increased myocardial PAH-mediated phenylalanine catabolism, a novel signature of cardiac aging.

Conclusions:
Our findings establish a pathogenic role for increased phenylalanine levels in cardiac aging, linking plasma phenylalanine levels to cardiac senescence via dysregulated phenylalanine catabolism along a hepatic-cardiac axis. They highlight phenylalanine/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.