bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advances in Targeting RET-Dependent Cancers
Authors: Subbiah Vivek , Cote Gilbert J. 
Published: February 2020

AbstractRET alterations have been characterized as oncogenic drivers in multiple cancers. The clinical validation of highly selective RET inhibitors demonstrates the utility of specific targeting of aberrantly activated RET in patients with cancers such as medullary thyroid cancer or non–small cell lung cancer. The remarkable responses observed have opened the field of RET-targeted inhibitors. In this review, we seek to focus on the impact of therapeutic RET targeting in cancers.Significance:Successful clinical translation of selective RET inhibitors is poised to alter the therapeutic landscape of altered cancers. Questions that clearly need to be addressed relate to the ability to maintain long-term inhibition of tumor cell growth, how to prepare for the potential mechanisms of acquired resistance, and the development of next-generation selective RET inhibitors.
Microbial Colonization of Germ‐Free Mice Restores Neointimal Hyperplasia Development After Arterial Injury
Authors: Chen Edmund B. , Shapiro Katherine E. , Wun Kelly , Kuntz Thomas , Theriault Betty R. , Nooromid Michael J. , Leone Vanessa A. , Harris Katharine G. , Jiang Qun , Spedale Melanie , Xiong Liqun , Gilbert Jack A. , Chang Eugene B. , Ho Karen J. 
Published: February 2020

Background
The potential role of the gut microbiome in cardiovascular diseases is increasingly evident. Arterial restenosis attributable to neointimal hyperplasia after cardiovascular procedures such as balloon angioplasty, stenting, and bypass surgery is a common cause of treatment failure, yet whether gut microbiota participate in the development of neointimal hyperplasia remains largely unknown.

Methods and Results
We performed fecal microbial transplantation from conventionally raised male C57BL/6 mice to age‐, sex‐, and strain‐matched germ‐free mice. Five weeks after inoculation, all mice underwent unilateral carotid ligation. Neointimal hyperplasia development was quantified after 4 weeks. Conventionally raised and germ‐free cohorts served as comparison groups.

Conclusions
Germ‐free mice have significantly attenuated neointimal hyperplasia development compared with conventionally raised mice. The arterial remodeling response is restored by fecal transplantation. Our results describe a causative role of gut microbiota in contributing to the pathogenesis of neointimal hyperplasia.
Right for the Wrong Reason?: A New Look at the 6 June 1944 D-Day Forecast by a Neutral Swede
Authors: Persson Anders 
Published: February 2020

AbstractThere are at least three popular perceptions surrounding the weather forecast for the D-day landing in Normandy, 6 June 1994: 1) that the Allied weather forecasters predicted a crucial break or “window of opportunity” in the unsettled weather prevailing at the time; 2) that the German meteorologists, lacking observations from the North Atlantic, failed to see this break coming and thus the invasion took the Wehrmacht by surprise; and 3) that the American forecasters, guided by a skillful analog system, predicted the favorable conditions several days ahead but got no support from their pessimistic British colleagues. This article will present evidence taken mostly from hitherto rather neglected sources of information, transcripts of the telephone discussions between the Allied forecasters and archived German weather analyses. They show that 1) the synoptic development for the invasion was not particularly well predicted and, if there was a break in the weather, it occurred for reasons other than those predicted; 2) the German forecasters were fairly well informed about the large-scale synoptic situation over most of the North Atlantic, probably thanks to decoded American analyses; and 3) from the viewpoint of a “neutral Swede,” the impression is that the American analog method might not have performed as splendidly as its adherents have claimed, but also not as badly as its critics have alleged. Finally, the D-day forecast, the discussions among the forecasters, and their briefings with the Allied command are interesting not only from a historical perspective, but also as an early and well-documented example of decision-making under meteorological uncertainty.
Cell Function and Viability in Glucose Polymer Peritoneal Dialysis Fluids
Authors: Liberek Tomasz , Topley Nicholas , Mistry Chandra D. , Coles Gerald A. , Morgan Tracy , Quirk Rosalie A. , Williams John D. 
Published: February 2020

Objective To investigate the biocompatibility profile of a new peritoneal dialysis fluid containing glucose polymer (GPF). Design Viability and function of peripheral neutrophils (PMN) from healthy donors and cultured human peritoneal mesothelial cells were assessed in vitro after exposure to dialysis fluids. Phagocytosis, leukotriene B4 synthesis, and respiratory burst activation were measured following stimulation with serum-treated zymosan (STZ) or opsonized Staphylococcus epidermidis (S. epidermidis). Bacterial growth in the fluids was also investigated. In vivo pH equilibration of GPF and subsequent respiratory burst activation following incubation in spent dialysate were studied. Results For all the host defense parameters measured, commercial dialysis fluids (Dianeal; 1.36% and 3.86% glucose) and GPF (pH 5.2) were significantly more inhibitory than the control buffer (pH 7.3). Mesothelial cell viability was reduced by all the fluids tested irrespective of pH. Glucose polymer fluid was significantly more inhibitory than DianeaI 1.36% for STZ phagocytosis and respiratory burst activation. In contrast, it was less suppressive than DianeaI3.86% for L TB4 synthesis. For all parameters tested, except LTB4 generation, there was a marked effect of pH, with GPF being significantly more inhibitory at pH 5.2 than at pH 7.3. None of the fluids tested supported the growth of S. epidermidis, although the viable counts in GPF were significantly higher than in Dianeal. Fluid inhibition of PMN respiratory burst activation and cytotoxicity were reduced in a time-dependent manner following increasing dwell time in vivo. Conclusions GPF does not appear to be significantly different from Dianeal as far as host defense parameters are concerned. However, the cell viability and bacterial survival data suggest some possibly negative aspects of this fluid formation.
A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers
Authors: Lu Genmin , Conley Pamela B. , Leeds Janet M. , Karbarz Mark J. , Levy Gallia G. , Mathur Vandana S. , Castillo Janice , Crowther Mark , Curnutte John T. 
Published: February 2020

AbstractAs with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor–induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P &lt; .05) and ≈82% (P &lt; .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).
Trajectory of migraine-related disability following long-term treatment with lasmiditan: results of the GLADIATOR study
Authors: Lipton Richard B. , Lombard Louise , Ruff Dustin D. , Krege John H. , Loo Li Shen , Buchanan Andrew , Melby Thomas E. , Buse Dawn C. 
Published: February 2020

Abstract
Background
Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT1F receptor agonist developed for acute treatment of migraine. Here we analyzed effects of lasmiditan on migraine disability assessed with the Migraine Disability Assessment (MIDAS) scale for interim data from a long-term safety study.

Methods
Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis.

Results
The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were − 12.5 and − 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks.

Conclusions
Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months.

Trial registration
clinicaltrials.govNCT02565186; first posted October 1, 2015.
The effects of vitamin D supplementation on interictal serum levels of calcitonin gene-related peptide (CGRP) in episodic migraine patients: post hoc analysis of a randomized double-blind placebo-controlled trial
Authors: Ghorbani Zeinab , Rafiee Pegah , Fotouhi Akbar , Haghighi Samane , Rasekh Magham Reyhaneh , Ahmadi Zeynab Sadat , Djalali Mahmoud , Zareei Mahnaz , Razeghi Jahromi Soodeh , Shahemi Sahar , Mahmoudi Maryam , Togha Mansoureh 
Published: February 2020

Abstract
Background
Emerging evidence showed promising effects of vitamin D on headaches characteristics. Thus, it seems there is still a need for more researches to clarify the mechanisms by which this vitamin exerts anti-migraine effects.

Methods
The present study was conducted as a 16-week randomized double-blind placebo-controlled trial on 80 episodic migraine patients allocated in 2 parallel groups each consisted of 40 patients who received vitamin D 2000 IU/d or placebo. At baseline and after the intervention completion, headache diaries and migraine disability assessment questionnaire (MIDAS) were used to assess migraine related variables in patients. Also, interictal serum concentration of calcitonin gene-related peptide (CGRP) (as the dominant mediator of migraine pain pathogenesis) was evaluated using ELISA method.

Results
The mean (SD) of age in the vitamin D and placebo groups was 37 (8) and 38 (12) years, respectively. ANCOVA test adjusted for baseline values, and confounders showed vitamin D supplementation resulted in a significant improvement in MIDAS score after 12 weeks in the intervention group (21.49 (16.22–26.77)) compared to placebo (31.16 (25.51–36.82) P value: 0.016). Moreover, after controlling for baseline levels, and other variables using ANCOVA, CGRP level was appeared to be significantly lower following vitamin D supplementation (153.26 (133.03–173.49) ng/L) than the patients in the placebo arm (188.35 (167.15–209.54) ng/L) (P value = 0.022).

Conclusion
According to the current findings, vitamin D supplementation in episodic migraineurs, particularly in those with migraine with aura, may potentially improve migraine headache characteristics and disability probably through attenuating CGRP levels. Therefore, these results could provide a new insight into anti-nociceptive effects of vitamin D; however, more studies are required to confirm our findings.

Trial registration
The trial is registered in the Iranian registry of clinical trials (IRCT) at 11 July 2018, with IRCT code: IRCT20151128025267N6.
Deep learning versus parametric and ensemble methods for genomic prediction of complex phenotypes
Authors: Abdollahi-Arpanahi Rostam , Gianola Daniel , Peñagaricano Francisco 
Published: February 2020

AbstractBackgroundTransforming large amounts of genomic data into valuable knowledge for predicting complex traits has been an important challenge for animal and plant breeders. Prediction of complex traits has not escaped the current excitement on machine-learning, including interest indeep learningalgorithms such as multilayer perceptrons (MLP) and convolutional neural networks (CNN). The aim of this study was to compare the predictive performance of two deep learning methods (MLP and CNN), two ensemble learning methods [random forests (RF) and gradient boosting (GB)], and two parametric methods [genomic best linear unbiased prediction (GBLUP) and Bayes B] using real and simulated datasets.MethodsThe real dataset consisted of 11,790 Holstein bulls with sire conception rate (SCR) records and genotyped for 58k single nucleotide polymorphisms (SNPs). To support the evaluation of deep learning methods, various simulation studies were conducted using the observed genotype data as template, assuming a heritability of 0.30 with either additive or non-additive gene effects, and two different numbers of quantitative trait nucleotides (100 and 1000).ResultsIn the bull dataset, the best predictive correlation was obtained with GB (0.36), followed by Bayes B (0.34), GBLUP (0.33), RF (0.32), CNN (0.29) and MLP (0.26). The same trend was observed when using mean squared error of prediction. The simulation indicated that when gene action was purely additive, parametric methods outperformed other methods. When the gene action was a combination of additive, dominance and of two-locus epistasis, the best predictive ability was obtained with gradient boosting, and the superiority of deep learning over the parametric methods depended on the number of loci controlling the trait and on sample size. In fact, with a large dataset including 80k individuals, the predictive performance of deep learning methods was similar or slightly better than that of parametric methods for traits with non-additive gene action.ConclusionsFor prediction of traits with non-additive gene action, gradient boosting was a robust method. Deep learning approaches were not better for genomic prediction unless non-additive variance was sizable.
An eQTL in the cystathionine beta synthase gene is linked to osteoporosis in laying hens
Authors: De Koning Dirk-Jan , Dominguez-Gasca Nazaret , Fleming Robert H. , Gill Andrew , Kurian Dominic , Law Andrew , McCormack Heather A. , Morrice David , Sanchez-Rodriguez Estefania , Rodriguez-Navarro Alejandro B. , Preisinger Rudolf , Schmutz Matthias , Šmídová Veronica , Turner Frances , Wilson Peter W. , Zhou Rongyan , Dunn Ian C. 
Published: February 2020

AbstractBackgroundSkeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology.ResultsSeveral single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene,cystathionine beta synthase(CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism wascis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype.ConclusionsValidated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.
Late viral or bacterial respiratory infections in lung transplanted patients: impact on respiratory function
Authors: Dubert Marie , Visseaux Benoit , Birgy André , Mordant Pierre , Metivier Anne-Cécile , Dauriat Gaelle , Fidouh Nadhira , Yazdanpanah Yazdan , Grall Nathalie , Castier Yves , Mal Hervé , Thabut Gabriel , Lescure François-Xavier 
Published: February 2020

Abstract
Background
Respiratory infections are a major threat for lung recipients. We aimed to compare with a monocentric study the impact of late viral and bacterial respiratory infections on the graft function.

Methods
Patients, who survived 6 months or more following lung transplantation that took place between 2009 and 2014, were classified into three groups: a viral infection group (VIG) (without any respiratory bacteria), a bacterial infection group (BIG) (with or without any respiratory viruses), and a control group (CG) (no documented infection). Chronic lung allograft dysfunction (CLAD) and acute rejection were analysed 6 months after the inclusion in the study.

Results
Among 99 included lung recipients, 57 (58%) had at least one positive virological respiratory sample during the study period. Patients were classified as follows: 38 in the VIG, 25 in the BIG (among which 19 co-infections with a virus) and 36 in the CG. The BIG presented a higher initial deterioration in lung function (p = 0.05) than the VIG. But 6 months after the infection, only the VIG presented a median decrease of forced expiratory volume in 1 s; − 35 mL (IQR; − 340; + 80) in the VIG, + 140 mL (+ 60;+ 330) in the BIG and + 10 (− 84;+ 160) in the CG, p < 0.01. Acute rejection was more frequent in the VIG (n = 12 (32%)), than the BIG (n = 6 (24%)) and CG (n = 3 (8%)), p < 0.05, despite presenting no more CLAD (p = 0.21).

Conclusions
Despite a less severe initial presentation, single viral respiratory infections seem to lead to a greater deterioration in lung function, and to more acute rejection, than bacterial infections.
How shoulder immobilization influences daily physical activity – an accelerometer based preliminary study
Authors: Rickert Carolin , Grabowski Monika , Gosheger Georg , Schorn Dominik , Schneider Kristian Nikolaus , Klingebiel Sebastian , Liem Dennis 
Published: February 2020

Abstract
Background
To investigate the influence of shoulder immobilization on daily physical activity.

Introduction
The harmful effect of sedentary behavior does not receive much attention in orthopedic surgery even though immobilization, especially of the lower extremity, has been associated with reduced physical activity. Immobilization of the shoulder is common after reconstructive shoulder surgery and could also potentially lead to reduced physical activity and have a negative effect on a patient’s general health.

Method
Twenty-one healthy volunteers were immobilized in an orthosis (DJO Ultrasling III) for 10 h on two consecutive days. In the following week, activity was measured on the same days without the orthosis. Activity including gait cycles per minute and total gait cycles per day was measured by accelerometer based step count StepWatchTMActivity Monitor. Average age was 26 +/− 3 years. A questionnaire was administered to evaluate subjective activity.

Results
Participants wearing the shoulder orthosis were significantly less active than without immobilization by 2227.5 gait cycles/day (5501.2 with SO, 7728.7 without SO). Also, significantly more time in sedentary behavior occurred (< 400 steps/h) when the shoulder was immobilized. Patients were significantly more active without shoulder orthosis in medium level activities (800–999 steps/h). Differences for low (400–799 steps/h) and high activity levels (> 1000 steps/h) were not statistically significant. Subjective limitations while wearing the orthosis were graded at 2.343 on a scale of 0–4.

Conclusion
Results of this study show that even in young, healthy volunteers immobilization of the shoulder in an orthosis for 2 days leads to significantly reduced activity levels. A negative influence on general health, especially in older patients who are immobilized for up to 6 weeks, can potentially occur. Promoting physical activity during the immobilization period should be part of rehabilitation after injuries/surgery of the shoulder.

Trial registration
Retrospectively registered in DRKS (DRKS00017636).