bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel method to select meaningful outcomes for evaluation in clinical trials
Authors: McLeod Charlie , Norman Richard , Wood Jamie , Mulrennan Siobhain , Morey Sue , Schultz André , Messer Mitch , Spaapen Kate , Stoneham Matthew , Wu Yue , Smyth Alan , Blyth Christopher , Webb Steve , Mascaro Steven , Woodberry Owen , Snelling Tom 
Published: October 2021

BackgroundA standardised framework for selecting outcomes for evaluation in trials has been proposed by the Core Outcome Measures in Effectiveness Trials working group. However, this method does not specify how to ensure that the outcomes that are selected are causally related to the disease and the health intervention being studied. Causal network diagrams may help researchers identify outcomes that are both clinically meaningful and likely to be causally dependent on the intervention, and endpoints that are, in turn, causally dependent on those outcomes. We aimed to (1) develop a generalisable method for selecting outcomes and endpoints in trials and (2) apply this method to select outcomes for evaluation in a trial investigating treatment strategies for pulmonary exacerbations of cystic fibrosis (CF).MethodsWe conducted a series of online surveys and workshops among people affected by CF. We used a modified Delphi approach to develop a consensus list of important outcomes. A workshop involving domain experts elicited how these outcomes were causally related to the underlying pathophysiological processes. Meaningful outcomes were prioritised based on the extent to which each outcome captured separate rather than common aspects of the underlying pathophysiological process.ResultsThe 10 prioritised outcomes were: breathing difficulty/pain, sputum production/clearance, fatigue, appetite, pain (not related to breathing), motivation/demoralisation, fevers/night sweats, treatment burden, inability to meet personal goals and avoidance of gastrointestinal symptoms.ConclusionsThis proposed method for selecting meaningful outcomes for evaluation in clinical trials may improve the value of research as a basis for clinical decisions.
Diet-dependent acid load is associated with mean arterial pressure in a cohort of non-obese, non-black, postmenopausal women
Authors: Banerjee Tanushree , Sebastian Anthony , Frassetto Lynda 
Published: October 2021

Higher sodium (Na+) intake is associated with higher blood pressure (BP). Whether this relationship is stronger with diet-dependent acid load (DAL) and in patients diagnosed with hypertension or normal BP is not well determined. We studied 170 postmenopausal women randomized to receive potassium bicarbonate or placebo for 36 months, after which 24-hour urine and arterialized blood samples were collected. We investigated the association between DAL estimated as urinary potential renal acid load (UPRAL) and mean arterial pressure (MAP) using a mixed-effects model, adjusting for age, anthropometrics, creatinine clearance, and treatment. Adjusted regression estimates for changes in Na+ and UPRAL on MAP after 12 months of follow-up were calculated, and further adjustments were made for changes in potassium (K+) and body mass index (BMI). MAP was inversely associated with UPRAL (β [95% confidence interval]: –0.11 [–0.25, –0.001]). There was an effect modification by hypertension (p-interaction = 0.04); MAP decreased significantly in normotensives, but the association was not significant in hypertensives. A decrease of 0.70 mm Hg in MAP [0.13, 1.69] per 50 mmol/24 hour reduction in Na+ was noted when the model was adjusted for change in K+. Our results with UPRAL exhibited a stronger dose–response for MAP, which remained significant after adjusting for BMI. UPRAL was independently associated with MAP even after adjusting for potential confounders, and the data showed that this association was more pronounced in normotensive patients. Novelty: First longitudinal study on the association of UPRAL and MAP. Association was a more robust relationship than that between U [Na+/K+] ratio and MAP. UPRAL may play a significant role in the pathogenesis of primary hypertension.
Challenges in modelling diffusiophoretic transport
Authors: Ramírez-Hinestrosa Simón , Frenkel Daan 
Published: October 2021

Abstract
The methodology to simulate transport phenomena in bulk systems is well-established. In contrast, there is no clear consensus about the choice of techniques to model cross-transport phenomena and phoretic transport, mainly because some of the hydrodynamic descriptions are incomplete from a thermodynamic point of view. In the present paper, we use a unified framework to describe diffusio-osmosis(phoresis), and we report non-equilibrium molecular dynamics (NEMD) on such systems. We explore different simulation methods to highlight some of the technical problems that arise in the calculations. For diffusiophoresis, we use two NEMD methods: boundary-driven and field-driven. Although the two methods should be equivalent in the limit of very weak gradients, we find that finite Peclet-number effects are much stronger in boundary-driven flows than in the case where we apply fictitious color forces.

Graphic abstract
A study of traversable wormhole solutions in extended teleparallel theory of gravity with matter coupling
Authors: Ditta Allah , Hussain Ibrar , Mustafa G. , Errehymy Abdelghani , Daoud Mohammed 
Published: October 2021

AbstractThis study is devoted to explore the physical aspects of wormhole geometry under embedded class-1 spacetime in $$f(T,\tau )$$

f
(
T
,
τ
)

gravity, where $$\tau $$
τ
denotes the trace of the energy-momentum tensor and T is the torsion. We derive the embedded class-1 solutions by considering spherically symmetric static spacetime. The shape function is calculated in the framework of embedded class-1 spacetime. It is necessary to mention here that the calculated shape function can be used in other modified theories of gravity. To complete this study, we take diagonal and off-diagonal tetrad, and try to build a comparison by considering the validity region of energy conditions in embedded class-1 spacetime. The embedded surface diagram is given to understand the connection between the two different regions of spacetime. The validity regions of all the energy conditions are calculated. A detailed graphical analysis is provided for validity regions of all the energy conditions. The presence of exotic matter is confirmed in both the cases as the null energy condition is violated.
High harmonic generation in crystalline silicon irradiated by an intense ultrashort laser pulse
Authors: Apostolova Tzveta , Obreshkov Boyan 
Published: October 2021

Abstract
We investigate the high harmonic generation in bulk silicon irradiated by intense near-infrared laser pulses with pulse duration $$\le $$
≤
100 fs. For peak field strength of the applied laser is below 1 V/Å, the spectral intensity of the emitted harmonics follows the prediction of perturbative nonlinear optics—the frequency comb consists of a series of discrete peaks at odd harmonic orders. For a pulse duration longer than 30 fs and peak laser field strength exceeding 1 V/Å, non-perturbative effects and generation of even order harmonics occur. The appearance of even harmonics is due to optical rectification of the transmitted pulse, which includes weak quasi-DC component with electric field as low as 3 V/$$\upmu $$
μ
m. In the strong coupling regime, when the peak field strength inside vacuum exceeds 1.5 V/Å, the laser creates dense breakdown plasma of electron–hole pairs, which in turn results in severe spectral broadening of the transmitted pulse. The harmonic spectrum superimposes onto a continuous background, the spectral width of individual harmonics is substantially broadened, and their central wavelength undergoes a blue shift that covers the spacing between adjacent harmonic orders.

Graphic abstract
Carboniferous biostratigraphy of rugose corals
Authors: Wang Xiang-Dong , Yang Sun-Rong , Yao Le , Sugiyama Tetsuo , Hu Ke-yi 
Published: October 2021

Abstract
Rugose corals are one of the major fossil groups in shallow-water environments. They played an important role in dividing and correlating Carboniferous strata during the last century, when regional biostratigraphic schemes were established, and may be useful for long-distance correlation. Carboniferous rugose corals document two evolutionary events. One is the Tournaisian recovery event, with abundant occurrences of typical Carboniferous rugose corals such as columellate taxa and a significant diversification of large, dissepimented corals. The other is the changeover of rugose coral composition at the mid-Carboniferous boundary, which is represented by the disappearance of many large dissepimented taxa with complex axial structures and the appearance of typical Pennsylvanian taxa characterized by compound rugose taxa. The biostratigraphic scales for rugose corals show a finer temporal resolution in the Mississippian than in the Pennsylvanian, which was probably caused by the Late Paleozoic Ice Age that resulted in glacial–eustatic changes and a lack of continuous Pennsylvanian carbonate strata. The Pennsylvanian rugose corals are totally missing in the Cimmerian Continent. High-resolution biostratigraphy of rugose corals has so far only been achieved in few regions for the Mississippian timescale. In most regions, more detailed taxonomic work and precise correlations between different fossil groups are needed.
When saying the wrong thing doesn't really matter
Authors: Yaffe Philip 
Published: October 2021

Each "Communication Corner" essay is self-contained; however, they build on each other. For best results, before reading this essay and doing the exercise, go to the first essay "How an Ugly Duckling Became a Swan," then read each succeeding essay.
Getting one's tongue tangled is an ever-present fear for most public speakers. But it shouldn't be. Occasionally saying the wrong thing seldom does any serious damage, or any damage at all, to the effectiveness of a presentation. Here's why.
Phase I/IIa Trial of BMS-986148, an Anti-mesothelin Antibody–drug Conjugate, Alone or in Combination with Nivolumab in Patients with Advanced Solid Tumors
Authors: Rottey Sylvie , Clarke Jeffrey , Aung Kyaw , Machiels Jean-Pascal , Markman Ben , Heinhuis Kimberley M. , Millward Michael , Lolkema Martijn , Patel Sandip Pravin , de Souza Paul , Duca Matteo , Curigliano Giuseppe , Santoro Armando , Koyama Takafumi , Brown Michelle , Vezina Heather , He Chunsheng , Chu Quincy Siu-Chung 
Published: October 2021

Abstract

Purpose:
To assess the safety and tolerability of BMS-986148, a mesothelin-directed antibody–drug conjugate (ADC) ± nivolumab, in patients with selected tumors.

Patients and Methods:
In an international phase I/IIa study [NCT02341625 (CA008-002)], patients received BMS-986148 monotherapy (0.1–1.6 mg/kg intravenously (i.v.) every 3 weeks or 0.4 or 0.6 mg/kg i.v. once weekly; n = 96) or BMS-986148 0.8 mg/kg + nivolumab 360 mg i.v. every 3 weeks (n = 30). The primary endpoint was safety and tolerability.

Results:
In CA008-002, the most common (≥ 10%) treatment-related adverse events (TRAEs) included increased aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Grade 3/4 TRAEs occurred in 42 patients (49%) receiving BMS-986148 every 3 weeks monotherapy, three (25%) receiving BMS-986148 once-weekly monotherapy, and 10 (33%) receiving BMS-986148 + nivolumab every 3 weeks. Overall, 17 of 126 patients (13%) discontinued because of a TRAE. The MTD of BMS-986148 was 1.2 mg/kg i.v. every 3 weeks. The safety profile of BMS-986148 + nivolumab was similar to that of BMS-986148 monotherapy (0.8 mg/kg). Active ADC exposures increased in a dose-proportional manner with both dosing regimens (every 3 weeks and once weekly). Preliminary clinical activity was observed with BMS-986148 ± nivolumab. No association between mesothelin expression and response was detected.

Conclusions:
BMS-986148 ± nivolumab demonstrated a clinically manageable safety profile and preliminary evidence of clinical activity, supporting additional studies combining directed cytotoxic therapies with checkpoint inhibitors as potential multimodal therapeutic strategies in patients with advanced solid tumors.
18F-FMISO PET Imaging Identifies Hypoxia and Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy in Tumors Refractory to PD-1 and CTLA-4 Inhibition
Authors: Reeves Kirsten M. , Song Patrick N. , Angermeier Allyson , Manna Deborah Della , Li Yufeng , Wang Jianbo , Yang Eddy S. , Sorace Anna G. , Larimer Benjamin M. 
Published: October 2021

Abstract

Purpose:
Hypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.

Experimental Design:
In this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.

Results:
Longitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.

Conclusions:
The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
Platelet Heterogeneity in Myeloproliferative Neoplasms
Authors: Thomas Sally , Krishnan Anandi 
Published: October 2021

Myeloproliferative neoplasms (MPNs) are a group of malignant disorders of the bone marrow where a dysregulated balance between proliferation and differentiation gives rise to abnormal numbers of mature blood cells. MPNs encompass a spectrum of disease entities with progressively more severe clinical features, including complications with thrombosis and hemostasis and an increased propensity for transformation to acute myeloid leukemia. There is an unmet clinical need for markers of disease progression. Our understanding of the precise mechanisms that influence pathogenesis and disease progression has been limited by access to disease-specific cells as biosources. Here, we review the landscape of MPN pathology and present blood platelets as potential candidates for disease-specific understanding. We conclude with our recent work discovering progressive platelet heterogeneity by subtype in a large clinical cohort of patients with MPN.

Graphic Abstract:
A graphic abstract is available for this article.
Sacubitril/Valsartan Initiation Among Veterans Who Are Renin‐Angiotensin‐Aldosterone System Inhibitor Naïve With Heart Failure and Reduced Ejection Fraction
Authors: Mohanty April F. , Levitan Emily B. , King Jordan B. , Dodson John A. , Vardeny Orly , Cook James , Herrick Jennifer S. , He Tao , Patterson Olga V. , Alba Patrick R. , Russo Patricia A. , Obi Engels N. , Choi Michelle E. , Fang James C. , Bress Adam P. 
Published: October 2021

Background
Sacubitril/valsartan, a first‐in‐class angiotensin receptor neprilysin inhibitor, received US Food and Drug Administration approval in 2015 for heart failure with reduced ejection fraction (HFrEF). Our objective was to describe the sacubitril/valsartan initiation rate, associated characteristics, and 6‐month follow‐up dosing among veterans with HFrEF who are renin‐angiotensin‐aldosterone system inhibitor (RAASi) naïve.

Methods and Results
Retrospective cohort study of veterans with HFrEF who are RAASi naïve defined as left ventricular ejection fraction (LVEF) ≤40%; ≥1 in/outpatient heart failure visit, first RAASi (sacubitril/valsartan, angiotensin‐converting enzyme inhibitor [ACEI]), or angiotensin‐II receptor blocker [ARB]) fill from July 2015 to June 2019. Characteristics associated with sacubitril/valsartan initiation were identified using Poisson regression models. From July 2015 to June 2019, we identified 3458 sacubitril/valsartan and 29 367 ACEI or ARB initiators among veterans with HFrEF who are RAASi naïve. Sacubitril/valsartan initiation increased from 0% to 26.5%. Sacubitril/valsartan (versus ACEI or ARB) initiators were less likely to have histories of stroke, myocardial infarction, or hypertension and more likely to be older and have diabetes mellitus and lower LVEF. At 6‐month follow‐up, the prevalence of ≥50% target daily dose for sacubitril/valsartan, ACEI, and ARB initiators was 23.5%, 43.2%, and 47.1%, respectively.

Conclusions
Sacubitril/valsartan initiation for HFrEF in the Veterans Administration increased in the 4 years immediately following Food and Drug Administration approval. Sacubitril/valsartan (versus ACEI or ARB) initiators had fewer baseline cardiovascular comorbidities and the lowest proportion on ≥50% target daily dose at 6‐month follow‐up. Identifying the reasons for lower follow‐up dosing of sacubitril/valsartan could support guideline recommendations and quality improvement strategies for patients with HFrEF.
Conversion of the Knutson et al. (2020) Tropical Cyclone Climate Change Projections to Risk Model Baselines
Authors: Jewson Stephen 
Published: October 2021

AbstractKnutson et al. (2020) recently published a meta-study that gives multi-model projections for changes in various properties of tropical cyclones under climate change. They considered frequency of tropical cyclones, frequency of very intense tropical cyclones, intensity of tropical cyclones, and total rainfall rate of tropical cyclones. For each of these properties, they reported changes globally and by basin for the six major tropical cylone basins. The changes were presented as the change that would occur with 2 °C warming of global mean surface temperature. These projections are potentially of great use to the tropical cyclone risk modeling community. However, most risk models use temporal baselines, such as the period from 1950 to 2019, and the Knutson et al. results can only be applied to risk models after some steps of adjustment involving past and future global mean surface temperature values. We derive the necessary adjustments and present and discuss some of the resulting projections, for different properties, basins, RCPs and baselines. We find that the results are sensitive to the baseline being used, which implies that users of tropical cyclone risk models need to make sure they clearly understand what baseline their model represents before they adjust the model for climate change. One part of our analysis derives estimates of the implied impact of climate change so far on TC properties, relative to a representative baseline. The computer code we use to calculate the adjustments is available online.
Hemochromatosis classification: update and recommendations by the BIOIRON Society
Authors: Girelli Domenico , Busti Fabiana , Brissot Pierre , Cabantchik Ioav , Muckenthaler Martina U. , Porto Graça 
Published: October 2021

Abstract
Hemochromatosis (HC) is a genetically heterogeneous disorder in which uncontrolled intestinal iron absorption may lead to progressive iron overload (IO) responsible for disabling and life-threatening complications such as arthritis, diabetes, heart failure, hepatic cirrhosis, and hepatocellular carcinoma. The recent advances in the knowledge of pathophysiology and molecular basis of iron metabolism have highlighted that HC is caused by mutations in at least 5 genes, resulting in insufficient hepcidin production or, rarely, resistance to hepcidin action. This has led to an HC classification based on different molecular subtypes, mainly reflecting successive gene discovery. This scheme was difficult to adopt in clinical practice and therefore needs revision. Here we present recommendations for unambiguous HC classification developed by a working group of the International Society for the Study of Iron in Biology and Medicine (BIOIRON Society), including both clinicians and basic scientists during a meeting in Heidelberg, Germany. We propose to deemphasize the use of the molecular subtype criteria in favor of a classification addressing both clinical issues and molecular complexity. Ferroportin disease (former type 4a) has been excluded because of its distinct phenotype. The novel classification aims to be of practical help whenever a detailed molecular characterization of HC is not readily available.
Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2
Authors: Mill Christopher P. , Fiskus Warren , DiNardo Courtney D. , Birdwell Christine , Davis John A. , Kadia Tapan M. , Takahashi Koichi , Short Nicholas , Daver Naval , Ohanian Maro , Borthakur Gautam , Kornblau Steven M. , Green Michael R. , Qi Yuan , Su Xiaoping , Khoury Joseph D. , Bhalla Kapil N. 
Published: October 2021

Abstract
The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.