bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ruxolitinib rechallenge in resistant or intolerant patients with myelofibrosis: Frequency, therapeutic effects, and impact on outcome
Authors: Palandri Francesca , Tiribelli Mario , Breccia Massimo , Bartoletti Daniela , Elli Elena M. , Benevolo Giulia , Martino Bruno , Cavazzini Francesco , Tieghi Alessia , Iurlo Alessandra , Abruzzese Elisabetta , Pugliese Novella , Binotto Gianni , Caocci Giovanni , Auteri Giuseppe , Cattaneo Daniele , Trawinska Malgorzata M. , Stella Rossella , Scaffidi Luigi , Polverelli Nicola , Micucci Giorgia , Masselli Elena , Crugnola Monica , Bosi Costanza , Heidel Florian H. , Latagliata Roberto , Pane Fabrizio , Cuneo Antonio , Krampera Mauro , Semenzato Gianpietro , Lemoli Roberto M. , Cavo Michele , Vianelli Nicola , Bonifacio Massimiliano , Palumbo Giuseppe A. 
Published: April 2021

BACKGROUNDAfter ruxolitinib discontinuation, the outcome of patients with myelofibrosis (MF) is poor with scarce therapeutic possibilities.METHODSThe authors performed a subanalysis of an observational, retrospective study (RUX‐MF) that included 703 MF patients treated with ruxolitinib to investigate 1) the frequency and reasons for ruxolitinib rechallenge, 2) its therapeutic effects, and 3) its impact on overall survival.RESULTSA total of 219 patients (31.2%) discontinued ruxolitinib for ≥14 days and survived for ≥30 days. In 60 patients (27.4%), ruxolitinib was rechallenged for ≥14 days (RUX‐again patients), whereas 159 patients (72.6%) discontinued it permanently (RUX‐stop patients). The baseline characteristics of the 2 cohorts were comparable, but discontinuation due to a lack/loss of spleen response was lower in RUX‐again patients (P = .004). In comparison with the disease status at the first ruxolitinib stop, at its restart, there was a significant increase in patients with large splenomegaly (P < .001) and a high Total Symptom Score (TSS; P < .001). During the rechallenge, 44.6% and 48.3% of the patients had spleen and symptom improvements, respectively, with a significant increase in the number of patients with a TSS reduction (P = .01). Although the use of a ruxolitinib dose > 10 mg twice daily predicted better spleen (P = .05) and symptom improvements (P = .02), the reasons for/duration of ruxolitinib discontinuation and the use of other therapies before rechallenge were not associated with rechallenge efficacy. At 1 and 2 years, 33.3% and 48.3% of RUX‐again patients, respectively, had permanently discontinued ruxolitinib. The median overall survival was 27.9 months, and it was significantly longer for RUX‐again patients (P = .004).CONCLUSIONSRuxolitinib rechallenge was mainly used in intolerant patients; there were clinical improvements and a possible survival advantage in many cases, but there was a substantial rate of permanent discontinuation. Ruxolitinib rechallenge should be balanced against newer therapeutic possibilities.
Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates
Authors: Jukić Marin M. , Smith Robert L. , Molden Espen , Ingelman‐Sundberg Magnus 
Published: April 2021

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf), and decreased function (CYP2D6Decr; i.e., CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n = 77–103) cotreated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; P < 0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9–10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9–10, 33.1% for CYP2D6*9‐10/*9–10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9–10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared with the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9–10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.
White matter microstructure disruption in early stage amyloid pathology
Authors: Collij Lyduine E. , Ingala Silvia , Top Herwin , Wottschel Viktor , Stickney Kristine E. , Tomassen Jori , Konijnenberg Elles , ten Kate Mara , Sudre Carole , Lopes Alves Isadora , Yaqub Maqsood M. , Wink Alle Meije , Van ‘t Ent Dennis , Scheltens Philip , van Berckel Bart N.M. , Visser Pieter Jelle , Barkhof Frederik , Braber Anouk Den 
Published: April 2021

AbstractIntroductionAmyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort.MethodsWe included 179 individuals from the European Medical Information Framework for AD (EMIF‐AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract‐level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden.ResultsRegression analyses showed a non‐linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC.DiscussionEarly amyloid deposition is associated with changes in WM microstructure. The non‐linear relationship might reflect multiple stages of axonal damage.
Regeneration in anamniotes was replaced by regengrow and scarring in amniotes after land colonization and the evolution of terrestrial biological cycles
Authors: Alibardi Lorenzo 
Published: April 2021

AbstractAn evolutionary hypothesis explaining failure of regeneration among vertebrates is presented. Regeneration derives from postembryonic processes present during the life cycles of fish and amphibians that include larval and metamorphic phases with broad organ reorganizations. Developmental programs imprinted in their genomes are re‐utilized with variations also in adults for regeneration. When vertebrates colonized land adopting the amniotic egg, some genes driving larval changes, and metamorphosis were lost and new genes evolved, further limiting regeneration. These included neural inhibitors for maintaining complex nervous systems, behavior and various levels of intelligence, and adaptive immune cells. The latter, that in anamniotes are executioners of metamorphic reorganization, became intolerant to embryonic‐oncofetal‐antigens impeding organ regeneration, a process that requires de‐differentiation of adult cells and/or expansion of stem cells where these early antigens are formed. The evolution of terrestrial lifecycles produced vertebrates with complex bodies but no longer capable to regenerate their organs, mainly repaired by regengrow. Efforts of regenerative medicine to improve healing in humans should determine the diverse developmental pathways evolved between anamniotes and amniotes before attempting genetic manipulations such as the introduction of “anamniote regenerative genes” in amniotes. This operation may determine alteration in amniote developmental programs leading to teratomes, cancer, or death.
How to make use of unlabeled observations in species distribution modeling using point process models
Authors: Guilbault Emy , Renner Ian , Mahony Michael , Beh Eric 
Published: April 2021

Abstract

Species distribution modeling, which allows users to predict the spatial distribution of species with the use of environmental covariates, has become increasingly popular, with many software platforms providing tools to fit such models. However, the species observations used can have varying levels of quality and can have incomplete information, such as uncertain or unknown species identity.

In this paper, we develop two algorithms to classify observations with unknown species identities which simultaneously predict several species distributions using spatial point processes. Through simulations, we compare the performance of these algorithms using 7 different initializations to the performance of models fitted using only the observations with known species identity.

We show that performance varies with differences in correlation among species distributions, species abundance, and the proportion of observations with unknown species identities. Additionally, some of the methods developed here outperformed the models that did not use the misspecified data. We applied the best‐performing methods to a dataset of three frog species (Mixophyes).

These models represent a helpful and promising tool for opportunistic surveys where misidentification is possible or for the distribution of species newly separated in their taxonomy.
Tree diversity and functional leaf traits drive herbivore‐associated microbiomes in subtropical China
Authors: Li Yi , Chesters Douglas , Wang Ming‐Qiang , Wubet Tesfaye , Schuldt Andreas , Anttonen Perttu , Guo Peng‐Fei , Chen Jing‐Ting , Zhou Qing‐Song , Zhang Nai‐Li , Ma Ke‐Ping , Bruelheide Helge , Wu Chun‐Sheng , Zhu Chao‐Dong 
Published: April 2021

AbstractHerbivorous insects acquire microorganisms from host plants or soil, but it remains unclear how the diversity and functional composition of host plants contribute to structuring herbivore microbiomes. Within a controlled tree diversity setting, we used DNA metabarcoding of 16S rRNA to assess the contribution of Lepidoptera species and their local environment (particularly, tree diversity, host tree species, and leaf traits) to the composition of associated bacterial communities. In total, we obtained 7,909 bacterial OTUs from 634 caterpillar individuals comprising 146 species. Tree diversity was found to drive the diversity of caterpillar‐associated bacteria both directly and indirectly via effects on caterpillar communities, and tree diversity was a stronger predictor of bacterial diversity than diversity of caterpillars. Leaf toughness and dry matter content were important traits of the host plant determining bacterial species composition, while leaf calcium and potassium concentration influenced bacterial richness. Our study reveals previously unknown linkages between trees and their characteristics, herbivore insects, and their associated microbes, which contributes to developing a more nuanced understanding of functional dependencies between herbivores and their environment, and has implications for the consequences of plant diversity loss for trophic interactions.
Impact of lifestyle Intervention on branched‐chain amino acid catabolism and insulin sensitivity in adolescents with obesity
Authors: Jachthuber Trub Catherine , Balikcioglu Metin , Freemark Michael , Bain James , Muehlbauer Michael , Ilkayeva Olga , White Phillip J. , Armstrong Sarah , Østbye Truls , Grambow Steven , Gumus Balikcioglu Pinar 
Published: April 2021

IntroductionInsulin resistance in adolescents with obesity associates with a sex‐dependent metabolic ‘signature’ comprising branched‐chain amino acids (BCAAs), glutamate and C3/C5 acylcarnitines (C3/C5), implicating altered flux through BCAA catabolic pathways. Here, we investigated the effects of lifestyle intervention on BCAA catabolism and insulin sensitivity. We hypothesized (1) weight reduction and improved insulin sensitivity associate with enhanced BCAA catabolism; (2) baseline BCAAs and their metabolic by‐products predict changes in weight and insulin sensitivity during lifestyle intervention.MethodsA 33 adolescents with obesity were studied before and after 6 months of lifestyle intervention. Principal component analysis and multiple linear regression models were used to correlate changes in metabolic factors with changes in weight and insulin sensitivity assessed by HOMA‐IR, adiponectin and ratio of triglyceride (TG) to HDL. Baseline metabolic factors were used as explanatory variables in prediction models.ResultsWeight reduction was associated with reductions in BCAA, glutamate, and C3/C5 (p = .002) and increases in urea cycle AA (p = .029), suggesting an increase in BCAA catabolism. Increases in urea cycle AA during weight reduction were associated with increases in adiponectin, a marker of insulin sensitivity. Markers of insulin resistance (high BCAA, glutamate, and C3/C5 and low urea cycle AA) at baseline predicted increases in metrics of insulin sensitivity (decreased TG/HDL and increased adiponectin) during lifestyle intervention.ConclusionsWeight reduction in adolescents is associated with increases in BCAA catabolism and improvements in insulin sensitivity. Our study underscores the therapeutic potential of manipulating BCAA catabolism to treat obesity‐associated insulin resistance in adolescents and prevent progression to T2D.
Numerical modelling shows an old check‐dam still attenuates flooding and sediment transport
Authors: Ran Qihua , Tang Honglei , Wang Feng , Gao Jihui 
Published: April 2021

AbstractCheck dams are an effective and widespread measure for soil and water conservation around the world (e.g., in the Chinese Loess Plateau). However, the quantitative impact of a heavy silted check dam with small remaining storage capacity and large deposition area on river flow and sediment transport during floods remained unclear. In this study, to investigate this impact, a physics‐based distributed hydrological model (the Integrated Hydrology Model, InHM) was employed to simulate runoff and sediment processes during floods in a small catchment with a check dam in the Loess Plateau, considering different heavy rainfalls and check‐dam remaining storages. The model was calibrated and validated against the observed hydrographs and sedigraphs in two flood events and obtained satisfactory modelling performance (the Nash–Sutcliffe efficiencies > 0.70). The scenario modelling results showed that a heavy silted check dam still remarkably reduced and delayed the peaks of river flow and sediment rate, due to the attenuated surface flow movement and sediment transport on the deposition area. The largest flow peak occurred around the 85% silting stage of the check dam rather than the fully silting stage (100%). Even in the fully silted stage, sediment deposition continually occurred on the deposition area with a maximum deposition of 11,700 t sediment in a heavy‐rainfall scenario and more sediment deposited on the tail‐end regions of the deposition area than other regions after a flood. Moreover, in heavy silted stage backwater on the tail‐end areas and gullies largely attenuated local erosion and promoted sediment deposition, indirectly reducing the total sediment yield of the catchment during flood. These results indicated that numerous ageing check dams built in the Loess Plateau and worldwide are still useful to attenuate flood risk and soil erosion, and sound maintenance and management of the check‐dam will be beneficial to flood and soil erosion control.
Lattice Boltzmann method for the simulation of White–Metzner fluid flows
Authors: Ouallal Firdaousse , Hakim Abdelilah , Raghay Said 
Published: April 2021

AbstractThe simulation of non‐Newtonian fluids is a challenging task from theoretical and numerical points of view. Different numerical methods has been used to study this class of fluids. In this article, a novel numerical scheme based on lattice Boltzmann method is presented for the simulation of White–Metzner (WM) fluid flows, where two types of distribution functions are defined for the evolution of momentum and stress, respectively. We study the accuracy, and the influence of different parameters on the flow on different benchmarks: we validate our model first for a two‐dimensional planar channel, and then we investigate in details the behavior of WM fluid flows in a square lid driven cavity. In the numerical results, we give a very detailed investigation to elaborate the effect over a large range of each parameter on the flow field.
A Close‐to‐Aromatize Approach for the Late‐Stage Functionalization through Ring Closing Metathesis
Authors: Lozhkin Boris , Ward Thomas R. 
Published: April 2021

AbstractAn efficient approach for the synthesis of monosubstituted aromatic compounds relying on a ring‐closing metathesis followed by spontaneous 1,2‐elimination is presented. The efficiency for late‐stage functionalization is highlighted in various solvents (up to 920 TON). This approach is compatible with strained cycles and other multiple bonds in the substrate.
Impact of National Health Mission on infant mortality in India: An interrupted time series analysis
Authors: Prinja Shankar , Sharma Atul , Nimesh Ruby , Sharma Vineeta , Madan Gopal K , Badgaiyan Nina , Lakshmi PVM , Gupta Madhu 
Published: April 2021

AbstractGovernment of India introduced National Rural Health Mission in 2005—now transformed into National Health Mission (NHM), to bring about architectural reforms in health sector. In this study, we evaluate the overall impact of NHM on infant mortality at national and state level. Annual data on infant mortality rate (IMR) from 1990 to 2016 were obtained from Sample Registration System bulletins. With reporting year 2009 considered as cut‐off point, a two‐step segmented time series regression analysis was conducted. Estimates of pre‐slope, post‐slope and change at the point of intervention were computed by applying auto‐regressive integrated moving average (1, 0, 0) while adjusting for trend and auto correlation. We found that while IMR reduced from around 80 to 34 per 1000 live births at the national level from 1990 to 2016, the annual rate of reduction increased from 1.6 per 1000 live births before NHM to 2.2 per 1000 live births after NHM. This is estimated to have averted 248,212 infant deaths in India, between 2005 and 2017. The rate of decline in IMR accelerated in 13 out of 17 larger states, most significantly in Andhra Pradesh, Gujarat, Assam, Haryana, Punjab and Uttar Pradesh. NHM has thus been successful in accelerating the overall rate of reduction in IMR in India. There is still a need to identify the determinants of variations at state level. We recommend strengthening of NHM in terms of funding and implementation.
A two‐layer model for studying 2D dissolved pollutant runoff over impermeable surfaces
Authors: Zhang Taotao , Xiao Yang , Liang Dongfang , Tang Hongwu , Xu Junzeng , Yuan Saiyu , Wang Nairu , Luan Bin 
Published: April 2021

AbstractDissolved pollutants in stormwater are a main contributor to water pollution in urban environments. However, many existing transport models are semi‐empirical and only consider one‐dimensional flows, which limit their predictive capacity. Combining the shallow water and the advection–diffusion equations, a two‐dimensional physically based model is developed for dissolved pollutant transport by adopting the concept of a ‘control layer’. A series of laboratory experiments has been conducted to validate the proposed model, taking into account the effects of buildings and intermittent rainfalls. The predictions are found to be in good agreement with experimental observations, which supports the assumption that the depth of the control layer is constant. Based on the validated model, a parametric study is conducted, focusing on the characteristics of the pollutant distribution and transport rate over the depth. The hyetograph, including the intensity, duration and intermittency, of rainfall event has a significant influence on the pollutant transport rates. The depth of the control layer, rainfall intensity, surface roughness and area length are dominant factors that affect the dissolved pollutant transport. Finally, several perspectives of the new pollutant transport model are discussed. This study contributes to an in‐depth understanding of the dissolved pollutant transport processes on impermeable surfaces and urban stormwater management.
End member and Bayesian mixing models consistently indicate near‐surface flowpath dominance in a pristine humid tropical rainforest
Authors: Birkel Christian , Correa Barahona Alicia , Duvert Clément , Granados Bolaños Sebastián , Chavarría Palma Andres , Durán Quesada Ana Maria , Sánchez Murillo Ricardo , Biester Harald 
Published: April 2021

AbstractThe impacts of forest conversion on runoff generation in the tropics have received much interest, but scientific progress is still hampered by challenging fieldwork conditions and limited knowledge about runoff mechanisms. Here, we assessed the runoff generation, flow paths and water source dynamics of a pristine rainforest catchment in Costa Rica using end member mixing analysis (EMMA) and a Bayesian mixing model (MixSIAR). Geochemical tracer data collected over a 4‐week field campaign were combined with tritium data used to assess potential deeper groundwater flow pathways to the perennial stream. The streamflow composition was best captured using three end‐members, namely throughfall, shallow (5–15 cm) and deeper (15–50 cm) soil water. We estimated the end‐member contributions to the main stream and two tributaries using the two mixing approaches and found good agreement between results obtained from EMMA and MixSIAR. The system was overwhelmingly dominated by near‐surface sources, with little evidence for deeper and older groundwater as tritium‐derived baseflow mean transit time was between 2.0 and 4.4 years. The shallow soil flow pathway dominated streamflow contributions in the main stream (median 39% and 49% based on EMMA and MixSIAR, respectively), followed by the deeper soil (32% and 31%) and throughfall (25% and 19%). The two tributaries had even greater shallow soil water contributions relative to the main stream (83% and 74% for tributary A and 42% and 63% for tributary B). Tributary B had no detectable deep soil water contribution, reflecting the morphology of the hillslope (steeper slopes, shallower soils and lower vegetation density compared to hillslope A). Despite the short sampling campaign and associated uncertainties, this study allowed to thoroughly assess runoff generation mechanisms in a humid tropical catchment. Our results also provide a first comparison of two increasingly used mixing models and suggest that EMMA and MixSIAR yield comparable estimates of water source partitioning in this tropical, volcanic rainforest environment.