bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure
Authors: Scarpignato Carmelo , Leifke Eckhard , Smith Neila , Mulford Darcy J. , Lahu Gezim , Facius Axel , Howden Colin W. 
Published: December 2021

AbstractVonoprazan, a potassium‐competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed‐effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non‐Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non‐Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non‐Asian populations.
Chiral resolution of DL‐glutamic acid by a chiral additive
Authors: Zhou Xin‐hui , Liu Qing , Wang Hai‐shui 
Published: December 2021

AbstractBACKGROUNDEnantiomerically pure compounds occupy an important position in industrial production of pharmaceuticals, food, chemical engineering, etc. The separation of d and l molecules is an important and challenging task. The ‘tailor‐made’ additive method is a simple and efficient crystallization separation technology. However, according to reports, there is a poor crystal yield when obtaining a relatively ideal enantiopurity and vice versa. Furthermore, the crystallization time always needs to be controlled strictly.RESULTSIn this paper, we studied the effect of the amount and kinds of additives, crystal seeds and crystallization time on the purity and yields of crystals. Two strategies involving a chiral additive for the selective crystallization of only d‐glutamic acid from a solution of racemic dl‐glutamic acid (dl‐Glu) are presented. One strategy is based on the addition of sufficient additive (l‐arginine or l‐phenylalanine with a mole fraction of 40%) and β‐d‐Glu crystal seeds, the crystal yield reaching 23–25%. The other relies on carrying out the crystallization twice in the presence of the additive (5 mol%) and the crystal seeds, the yield reaching 30–34%.CONCLUSIONSTwo separation methods with a relatively high crystal yield and optical purity were established. The proposed strategies could meet the requirements of both crystal purity and yield on chiral separation, and the separation of d‐ and l‐Glu is nearly perfect. Furthermore, the methods are very easy to operate, and require no hand picking. Most importantly, our methods are barely influenced by the crystallization time. © 2021 Society of Chemical Industry (SCI).
Adult‐onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage‐gated potassium channel downregulation in male mice
Authors: Suda Machiko , Takatsuru Yusuke , Amano Izuki , Haraguchi Shogo , Koibuchi Noriyuki 
Published: December 2021

AbstractThyroid hormones play an important role in the central and peripheral nervous system functions. Approximately 50% of adult‐onset hypothyroid patients have sensory symptoms including pain, possibly caused by peripheral neuropathy. However, the mechanism causing the pain has not been clarified. We generated an adult‐onset hypothyroid model animal by administering 50 ppm propylthiouracil (PTU) for 5 weeks to male mice. Female mice were not tested in this study. Mechanical hypersensitivity, determined by the von Frey hair test, was observed during the PTU exposure and recovered after the exposure termination. The sciatic nerve compound action potential was also analyzed. Under single‐pulse stimulation, no significant change in the threshold and conduction velocity was observed in the PTU‐administered group. On the other hand, under train‐pulse stimulation, the latency delay in the Aδ‐fiber component was less in the PTU‐administered group in Week 4 of PTU exposure, indicating relative hyperexcitability. Fluticasone, which is the anti‐inflammatory agent with an ability to activate the voltage‐gated potassium channel subfamily A (Kv1), restored the decrease in the latency change ratio by PTU exposure under the train‐pulse stimulation supporting our hypothesis that Kv1 may be involved in the conductivity change. Kv1.1 protein level decreased significantly in the sciatic nerve of the PTU‐administered group. These results indicate that adult‐onset hypothyroidism causes mechanical hypersensitivity owing to hyperexcitability of the peripheral nerve and that reduction of Kv1.1 level may be involved in such alteration.
Musculoskeletal modeling‐based definition of load cases and worst‐case fracture orientation for the design of clavicle fixation plates
Authors: Vancleef Sanne , Wesseling Mariska , Vander Sloten Jos , Jonkers Ilse 
Published: December 2021

AbstractMechanical performance of clavicle fracture fixation plates is often evaluated using finite element (FE) analysis. Typically, these studies use simplified loading conditions and assume a transversal fracture orientation. However, the loading conditions and fracture orientation influence how the fracture site and thus fixation plate is loaded. In this study, a musculoskeletal model that included the clavicle muscles and scapulohumeral rhythm was defined based on previously published models. The standard OpenSim workflow (inverse kinematics, inverse dynamics, static optimization, and joint reaction analysis) was used to calculate muscle and joint contact forces based on 3D marker data collected in three subjects during seven activities of daily living (ADL). These loading conditions were then applied to a 3D clavicle model with three different fracture orientations and the mean resulting moments on both fragments were calculated to assess fracture stability. Magnitude of glenohumeral contact forces showed good agreement with instrumented shoulder prosthesis data, whereas simulated muscle activations were comparable to experimental EMG data. An oblique fracture orienting from superomedial to inferolateral was the least self‐stabilizing. The loading to which the clavicle is exposed during ADL tasks is more complex than the simplified loading conditions typically used as boundary conditions in FE analyses of clavicle fracture fixation plates. Additionally, transversal fractures did not represent the least self‐stabilizing fracture orientation, and thus calculated stresses in the plate could be underestimated. Therefore, more complex loading conditions and evaluation of a midshaft fracture running from superomedial to inferolateral is more relevant in FE analyses of midshaft clavicle fracture fixation plates.
Methotrexate treatment suppresses osteoblastic differentiation by inducing Notch2 signaling and blockade of Notch2 rescues osteogenesis by preserving Wnt/β‐catenin signaling
Authors: Peymanfar Yaser , Su Yu‐Wen , Hassanshahi Mohammadhossein , Xian Cory J. 
Published: December 2021

AbstractMethotrexate (MTX) is a commonly used antimetabolite in cancer treatment. Its intensive use is linked with skeletal adverse effects such as reduced bone formation and bone loss, and yet little information is available on molecular mechanisms underlying MTX‐induced impaired bone formation. This study investigated the effects of MTX treatment at a clinical chemotherapy relevant dose on osteogenic differentiation in MC3T3E1 osteoblastic cells. To investigate the potential mechanisms, the expression of 87 genes regulating osteoblast differentiation and bone homeostasis was screened in MTX‐treated versus untreated cells by polymerase chain reaction (PCR) arrays and results illustrated significant upregulation of Notch2 and Notch target genes at both early and late stages of MC3T3E1 differentiation following MTX treatment. To confirm the roles of Notch2 pathway and its potential action mechanisms, MC3T3E1 cells were treated with MTX with an anti‐Notch2 neutralizing antibody or control IgG and effects were examined on osteogenesis and activation of the Wnt/β‐catenin pathway. Our results demonstrated that induction of Notch2 activity is associated with MTX adverse effects on osteogenic differentiation and blocking Notch2 rescues osteoblast differentiation by preserving activation of the Wnt/β‐catenin pathway.
Umbilical Vein Pulse Wave Spectral Analysis: A Possible Method for Placental Assessment Through Evaluation of Maternal and Fetal Flow Components
Authors: Rubin Jonathan M. , Fowlkes J. Brian , Pinter Stephen Z. , Treadwell Marjorie C. , Kripfgans Oliver D. 
Published: December 2021

ObjectivesPlacental blood flow analysis is complicated by having both maternal and fetal flow components. Using the Fast Fourier Transform (FFT) of the umbilical venous pulse wave spectra (PW) envelope, we could simultaneously assess maternal/fetal blood flow in the placenta and investigate if normal and intrauterine growth restriction (IUGR)/pre‐eclamptic pregnancies could be distinguished.MethodsThis retrospective study included normal gestations (N = 11) and gestations with IUGR, pre‐eclampsia, or both (N = 13). Umbilical vein PW were acquired and spectral envelopes were identified as a function of time and analyzed by FFT. Base‐10 logarithms of the ratios of the maternal/fetal spectral peaks (LRSP) were compared in normal and IUGR/pre‐eclamptic populations (two‐tailed t‐test). Body mass index (BMI), gestational age at scan time, placental position, and weight‐normalized umbilical vein blood volume flow (two‐tailed t‐test, analysis of variance [ANOVA] analysis) were tested. P < .05 was considered significant.ResultsThe LRSP for normal and IUGR/pre‐eclamptic pregnancies were 0.141 ± 0.180 and −0.072 ± 0.262 (mean ± standard deviation), respectively (P = .033). We detected differences between normal gestations and combinations of LRSP and weight‐normalized umbilical venous blood flows. Placental effects based on LRSPs and blood flow may act synergistically in cases with both pre‐eclampsia and IUGR (P = .014). No other significant associations were seen.ConclusionsIn this preliminary study, we showed that umbilical venous flow contains markers related to placental maternal/fetal blood flow, which can be used to assess IUGR and pre‐eclampsia. When coupled with umbilical cord blood flow, this new marker may potentially identify the primary causes of the two conditions.
Multiplexed Generation of Generalized Vortex Beams with On‐Demand Intensity Profiles Based on Metasurfaces
Authors: Zhang Xue , Huang Lingling , Zhao Ruizhe , Wei Qunshuo , Li Xin , Geng Guangzhou , Li Junjie , Li Xiaowei , Wang Yongtian , Zhang Shuang 
Published: December 2021

AbstractOptical vortex beams (VB) have provided a new degree of freedom for carrying optical information due to the unbounded number of orthogonal orbital angular momentum (OAM) channels. Due to the presence of phase singularity, VBs possess a dark zone in the center surrounded by a bright ring whose radius is directly related to the OAM carried by the beam. Here multiplexed generalized vortex beams (GVB) are demonstrated with various custom‐defined closed‐loop beam profiles, including polygons, star and windmill, by tailoring the local phase gradient along the azimuthal direction. By utilizing different polarization channels of metasurfaces, multiple GVBs with independent intensity profiles are generated. This approach provides a playground for realizing various optical modulating capabilities, such as precise particle manipulation, optical source, and OAM encryption.
Broad‐Bandwidth Micro‐Diffractive Optical Elements
Authors: Hu Zhi‐Yong , Jiang Tong , Tian Zhen‐Nan , Niu Li‐Gang , Mao Jiang‐Wei , Chen Qi‐Dai , Sun Hong‐Bo 
Published: December 2021

AbstractThin, lightweight micro‐diffractive optical elements (M‐DOEs) are of great significance to integrated optics. However, the narrow working bandwidth of M‐DOEs allows them to operate only at specific wavelengths. Existing solutions require multiple components assembly, which is difficult to implement in an integrated system. Here, a general designing and processing scheme of an optofluidic‐integrated broad‐bandwidth M‐DOE is reported, achieving an average diffraction efficiency of over 84% across the entire visible band (406–824 nm). As a proof‐of‐concept, a wideband operating micro‐diffractive lens and orbital angular momentum beam micro‐generator are demonstrated. This strategy provides a common protocol for various broad‐bandwidth M‐DOEs operating in integrated optical systems.
The Myelin‐Weighted Connectome in Parkinson's Disease
Authors: Boshkovski Tommy , Cohen‐Adad Julien , Misic Bratislav , Arnulf Isabelle , Corvol Jean‐Christophe , Vidailhet Marie , Lehéricy Stéphane , Stikov Nikola , Mancini Matteo 
Published: December 2021

AbstractBackgroundEven though Parkinson's disease (PD) is typically viewed as largely affecting gray matter, there is growing evidence that there are also structural changes in the white matter. Traditional connectomics methods that study PD may not be specific to underlying microstructural changes, such as myelin loss.ObjectiveThe primary objective of this study is to investigate the PD‐induced changes in myelin content in the connections emerging from the basal ganglia and the brainstem. For the weighting of the connectome, we used the longitudinal relaxation rate as a biologically grounded myelin‐sensitive metric.MethodsWe computed the myelin‐weighted connectome in 35 healthy control subjects and 81 patients with PD. We used partial least squares to highlight the differences between patients with PD and healthy control subjects. Then, a ring analysis was performed on selected brainstem and subcortical regions to evaluate each node's potential role as an epicenter for disease propagation. Then, we used behavioral partial least squares to relate the myelin alterations with clinical scores.ResultsMost connections (~80%) emerging from the basal ganglia showed a reduced myelin content. The connections emerging from potential epicentral nodes (substantia nigra, nucleus basalis of Meynert, amygdala, hippocampus, and midbrain) showed significant decrease in the longitudinal relaxation rate (P < 0.05). This effect was not seen for the medulla and the pons.ConclusionsThe myelin‐weighted connectome was able to identify alteration of the myelin content in PD in basal ganglia connections. This could provide a different view on the importance of myelination in neurodegeneration and disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Cervical paraspinal skeletal muscle index outperforms frailty indices to predict postoperative adverse events in operable head and neck cancer with microvascular reconstruction
Authors: Mascarella Marco A. , Gardiner Lauren , Patel Terral , Vendra Varun , Khan Nayel , Kergoat Marie‐Jeanne , Kubik Mark W. , Solari Mario G. , Snyderman Carl H. , Traylor Katie S. , Sridharan Shaum S. 
Published: December 2021

AbstractObjectiveSarcopenia is increasingly being recognized as a negative prognostic factor in patients with head and neck cancer (HNC). We associate a sarcopenia biomarker measured radiographically from computed tomography (CT) of the neck to postoperative adverse events in patients with operable HNC.Patients and methodsA prospective cohort of treatment‐naïve HNC patients undergoing surgery with microvascular reconstruction was performed. Cervical paraspinal skeletal muscle index (CPSMI) was calculated using preoperative CT neck imaging and adjusted for height and sex. Postoperative adverse events, including Clavien‐Dindo Grade 3+ complications and fistula, were recorded within 30‐days of the index surgery. Multivariate logistic regression was used to evaluate the association between CPSMI and postoperative complications. The modified frailty index (mFI) and Risk Assessment Index (RAI) were compared with CPSMI outcomes.ResultsA total of 127 patients with mucosal HNC were included in the study. The mean age was 60.5 years, and 87 (68.5%) patients were male. Sixty Clavien‐Dindo grade 3+ events occurred; 17 patients developed an oro/pharyngocutaneous fistula. Low CPSMI was independently associated with Clavien‐Dindo Grade 3+ events (OR 2.80, 95% CI of 1.18–6.99) and fistula (OR of 6.10, 95% CI of 1.53–24.3) when adjusted for multiple factors. CPSMI outperformed the mFI and RAI frailty indices to predict postoperative adverse events (p < .05).ConclusionLow CPSMI is independently associated with postoperative adverse events and outperforms current frailty indices inoperable HNC with microvascular reconstruction.
DIRECT‐Net: A unified mutual‐domain material decomposition network for quantitative dual‐energy CT imaging
Authors: Su Ting , Sun Xindong , Yang Jiecheng , Mi Donghua , Zhang Yikun , Wu Haodi , Fang Shibo , Chen Yang , Zheng Hairong , Liang Dong , Ge Yongshuai 
Published: December 2021

AbstractPurposeThe purpose of this paper is to present an end‐to‐end deep convolutional neural network to improve the dual‐energy CT (DECT) material decomposition performance.MethodsIn this study, we proposes a unified mutual‐domain (sinogram domain and CT domain) material decomposition network (DIRECT‐Net) for DECT imaging. By design, the DIRECT‐Net has immediate access to mutual‐domain data, and utilizes stacked convolution neural network layers for noise reduction and material decomposition. The training data are numerically generated following the fundamental DECT imaging physics. Numerical simulation of the XCAT digital phantom, experiments of a biological specimen, a calcium chloride phantom and an iodine solution phantom are carried out to evaluate the performance of DIRECT‐Net. Comparisons are performed with different DECT decomposition algorithms.ResultsResults demonstrate that the proposed DIRECT‐Net can generate water and bone basis images with less artifacts compared to the other decomposition methods. Additionally, the quantification errors of the calcium chloride (75‐375 mg/cm3) and the iodine (2‐20 mg/cm3) are less than 4%.ConclusionsAn end‐to‐end material decomposition network is proposed for quantitative DECT imaging. The qualitative and quantitative results demonstrate that this new DIRECT‐Net has promising benefits in improving the DECT image quality.
Estimation of Postrelease Longline Mortality in Pacific Halibut Using Acceleration-Logging Tags
Authors: Loher Timothy , Dykstra Claude L. , Hicks Allan C. , Stewart Ian J. , Wolf Nathan , Harris Bradley P. , Planas Josep V. 
Published: December 2021

Abstract
Pacific Halibut Hippoglossus stenolepis captured in directed commercial longline fisheries in Canada and the USA that are below the legal minimum size for retention must be returned to the sea without incurring additional injury. Estimates of mortality caused by discarding sublegal-sized fish are included in annual estimates of total mortality from all sources and affect the results of stock assessment and the yield available to fisheries. Currently, an average discard mortality rate (DMR) of 16% is applied to all sublegal-sized longline discards. These discards consist of fish that suffer injuries ranging from minor to severe. The 16% DMR that is currently applied was derived by averaging injury-specific DMRs that in turn assume 3.5% mortality of Pacific Halibut that are released to the sea with only minor injuries. The latter has been derived experimentally but only in captivity. Here, we used acceleration-logging pop-up archival transmitting tags to infer individual survival outcomes for Pacific Halibut that were released in situ following capture on longline gear. Postrelease behavioral data were evaluated for 75 fish that were at liberty for 2–96 d. Three fish were confidently inferred to have died after periods at liberty of 41–80 d, and another three fish may have died 96 d after release, resulting in minimum and maximum estimated 96-d postrelease DMRs of 4.2% (range = 0.0–8.7%) and 8.4% (range = 1.7–14.6%), respectively. These ranges are consistent with the currently applied value of 3.5%. However, the observation that no mortalities occurred until after 40 d postrelease departs from the findings of captive studies, in which the majority of capture-induced mortality occurred within 20 d of release.
Effects of a Shallow Lake Condition Shift on Habitat, Zooplankton, and Yellow Perch Dynamics
Authors: Skolte Alicia , Schoenebeck Casey W. , Hafs Andrew W. 
Published: December 2021

Abstract
Aquatic ecosystems around the world exist on a continuum between turbid, algal-dominated conditions and clear, macrophyte-dominated conditions, which may influence population dynamics of fish in these systems (such as Yellow Perch Perca flavescens). Since turbidity influences the amount of light penetration and occurrence of vegetation, spawning and nursery habitat, as well as food availability, may change depending on lake condition. For example, a decrease in turbidity encourages a shift in the prevalent zooplankton taxa from Bosmina spp. to Daphnia spp. We hypothesized that many factors associated with a condition shift may combine to influence Yellow Perch, including increased abundance and therefore increased intraspecific competition, resulting in a reduced length and body condition. We used long-term monitoring data from Lake Shaokatan, Minnesota, to examine whether a rarely documented condition shift from a turbid, algal-dominated condition to a clear, macrophyte-dominated condition occurred in 2014 and whether that shift influenced population dynamics of Yellow Perch, including relative abundance (gill-net CPUE), mean total length, and mean relative weight. A condition shift from turbid to clear was determined in 2014 using mixed-effects models that showed significant decreases in phosphorous and chlorophyll a concentration, as well as an increase from a mean of 22% to over 90% vegetation occurrence. The zooplankton community qualitatively showed a prevalence of Daphnia spp. and cyclopoids over small cladocerans during the clear condition period until 2018. Mixed-effect models were also used to determine that the shift to a clear condition resulted in a significant decrease in Yellow Perch mean total length and relative weight. Therefore, the condition shift and resulting habitat changes that occurred in 2014 and later influenced the size and condition of Yellow Perch. Continued monitoring may overcome variability in relative abundance and help elucidate emerging trends.