bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure–response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose‐ranging phase 2 trial
Authors: Mukherjee Arnab , Hazra Anasuya , Smith Mike K. , Martin Steven W. , Mould Diane R. , Su Chinyu , Niezychowski Wojciech 
Published: January 2018

AimsTofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose‐ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.MethodsOne‐ and two‐compartment pharmacokinetic models, with first‐order absorption and elimination, were evaluated to describe plasma tofacitinib concentration‐time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss] and trough plasma concentration at steady state [Ctrough,ss]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates.ResultsPlasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ≤8 were 39% (95% CI: 7–70) and 21% (–2–50), respectively.ConclusionsExposure–response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.
Potassium channel dysfunction in neurons and astrocytes in Huntington's disease
Authors: Zhang Xiao , Wan Jie‐Qing , Tong Xiao‐Ping 
Published: January 2018

SummaryHuntington's disease (HD) is a late‐onset fatal neurodegenerative disease, characterized by progressive movement disorders, psychiatric symptoms, and cognitive impairment. The cytosine‐adenine‐guanine (CAG) triplet expansion encoding glutamine present in the protein huntingtin (Htt), produces widespread neuronal and glial pathology. Mutant huntingtin (mHtt) nuclear aggregates are the primary cause of cortical and striatal neuron degeneration, neuronal inflammation, apoptosis and eventual cell loss. The precise mechanisms underlying the pathogenesis of neurodegeneration in HD remain poorly understood and HD patients have no current cure. Potassium channels are widely expressed in most cell types. In neurons, they play a crucial role in setting the resting membrane potential, mediating the rapid repolarization phase of the action potential and controlling sub‐threshold oscillations of membrane potentials. In glial cells, their major contributions are maintaining the resting membrane potential and buffering extracellular K+. Thus, potassium channels have an essential function in both physiological and pathological brain conditions. This review summarizes recent progress on potassium channels involved in the pathology of HD by using different HD mouse models. Exploring the dysfunction of potassium channels in the brain illustrates new approaches for targeting this channel for the treatment of HD.
Conserving biodiversity and Indigenous bush tucker: Practical application of the strategic foresight framework to invasive alien species management planning
Authors: Adams Vanessa M. , Douglas Michael M. , Jackson Sue E. , Scheepers Kelly , Kool Johnathan T. , Setterfield Samantha A. 
Published: January 2018

AbstractInvasive alien species are a major driver of global biodiversity loss. Constrained conservation budgets demand that threat abatement strategies take into account the heterogeneity of areas in need of protection, such as significant ecological and cultural sites, as well as the competing values, preferences, and objectives of stakeholders. We used strategic foresight to assess the threat that invasive alien grasses pose to environmental and Indigenous cultural values on the floodplains of a comanaged, World Heritage‐inscribed national park. We found strategic foresight to be a useful framework to set management priorities that simultaneously conserve biological and cultural diversity. However, it required the development and application of novel ecological and participatory tools and significant time, financial, and human resources. This was the first study to apply strategic foresight to weed management planning in a realistic, culturally complex setting and our work provides an exemplar for the application of the strategic foresight framework and our tools to other contexts.
Increasing kidney donor profile index sequence does not adversely affect medium‐term health‐related quality of life after kidney transplantation
Authors: Forbes Rachel C. , Feurer Irene D. , LaNeve David , Concepcion Beatrice P. , Gamble Christianna , Rega Scott A. , Pinson C. Wright , Shaffer David 
Published: January 2018

AbstractBackgroundThe United Network for Organ Sharing system allocates deceased donor kidneys based on the kidney donor profile index (KDPI), stratified as sequences (A ≤ 20%, B > 20‐<35%, C ≥ 35‐≤85%, and D > 85%), with increasing KDPI associated with decreased graft survival. While health‐related quality of life (HRQOL) may improve after transplantation, the effect of donor kidney quality, reflected by KDPI sequence, on post‐transplant HRQOL has not been reported.MethodsHealth‐related quality of life was measured using the eight scales and physical and mental component summaries (PCS, MCS) of the SF‐36® Health Survey. Multivariable mixed effects models that adjusted for age, gender, rejection, and previous transplant and analysis of variance methods tested the effects of time and KDPI sequence on post‐transplant HRQOL.ResultsA total of 141 waitlisted adults and 505 recipients (>1700 observations) were included. Pretransplant PCS and MCS averaged, respectively, slightly below and within general population norms (GPN; 40‐60). At 31 ± 26 months post‐transplant, average PCS (41 ± 11) and MCS (51 ± 11), overall and within each KDPI sequence, were within GPN. KDPI sequence was not related to post‐transplant HRQOL (P > .134) or its trajectory (interaction P > .163).ConclusionIncreasing KDPI does not adversely affect the medium‐term values and trajectories of HRQOL after kidney transplantation. This may reassure patients and centers when considering using high KDPI kidneys.
Ivory as Cultural Document: The Crushing Burden of Conservation
Authors: Curnow Kathy 
Published: January 2018

AbstractEfforts to stop the international ivory trade and save the affected elephants have increasingly emphasized public ivory crushes of confiscated tusks and carved works. While this and other efforts to involve the public in conservation are commendable, they have a burdensome side. First, African cultural ivories, the artists who made them, and the people who used them may be scapegoated in a misplaced desire to identify perpetrators and hold them responsible for elephant loss. Second, simpler but authentic cultural ivories may remain unidentified and accidentally destroyed. Last, even seemingly negligible tourist art and fakes hold cultural information and deserve individual photographic records for future research. This paper examines the cultural value encoded in select African ivory objects made for small‐scale societies, major kingdoms, and foreign markets to demonstrate the value African societies have for the elephant and its products in the hope that institutions and federal agencies can work together to preserve these cultural documents.
Assessing the economic value of maintained improvements in Type 1 diabetes management, in terms of HbA1c, weight and hypoglycaemic event incidence
Authors: McEwan P. , Bennett H. , Bolin K. , Evans M. , Bergenheim K. 
Published: January 2018

AbstractAimsInsulin therapy is indicated for people with Type 1 diabetes mellitus; however, treatment‐related weight gain and hypoglycaemia represent barriers to optimal glycaemic management. This study assessed the health economic value of maintained reductions in HbA1c, BMI and hypoglycaemia incidence among the UK Type 1 diabetes population.MethodsThe Cardiff Type 1 Diabetes Model was used to estimate lifetime costs, life‐years and quality‐adjusted life‐years (QALYs) for individuals with Type 1 diabetes at different baseline HbA1c, BMI and hypoglycaemic event rates. Results were discounted at 3.5%, and the net monetary benefit associated with improving Type 1 diabetes management was derived at £20 000/QALY gained. Per‐person outputs were inflated to national levels using UK Type 1 diabetes prevalence estimates.ResultsModelled subjects with an HbA1c of 86 mmol/mol (10.0%) were associated with discounted lifetime per‐person costs of £23 795; £12 649 of which may be avoided by maintaining an HbA1c of 42 mmol/mol (6.0%). Combined with estimated QALY gains of 2.80, an HbA1c of 42 mmol/mol (6.0%) vs. 86 mmol/mol (10.0%) was associated with a £68 621 per‐person net monetary benefit. Over 1 year, unit reductions in BMI produced £120 per‐person net monetary benefit, and up to £197 for the avoidance of one non‐severe hypoglyceamic event.ConclusionsMaintained reductions in HbA1c significantly alleviate the burden associated with Type 1 diabetes in the UK. Given the influence of weight and hypoglycaemia on health economic outcomes, they must also be key considerations when assessing the value of Type 1 diabetes technologies in clinical practice.
Chantey Castings: A Hands‐On Simulation to Teach Constraint Management and Demand‐Driven Supply Chain Approaches
Authors: Grandzol Christian J. , Grandzol John R. 
Published: January 2018

ABSTRACTSupply chain design and constraint management are widely‐adopted techniques in industry, necessitating that operations and supply chain educators teach these topics in ways that enhance student learning and retention, optimize resource utilization (especially time), and maximize student interest. The Chantey Castings Simulation provides a platform to accomplish all three criteria. In a fun, collaborative environment, students learn important concepts related to these techniques by identifying obstacles to matching customer demand with sourcing, production, and logistics for a variety of products made from Play‐Doh. Assessment data indicate the simulation is a highly‐effective experiential learning activity.
A System's View of E‐Learning Success Model
Authors: Eom Sean B. , Ashill Nicholas J. 
Published: January 2018

ABSTRACTThe past several decades of e‐learning empirical research have advanced our understanding of the effective management of critical success factors (CSFs) of e‐learning. Meanwhile, the proliferation of measures of dependent and independent variables has been overelaborated. We argue that a significant reduction in dependent and independent variables and their measures is necessary for building an e‐learning success model, and such a model should incorporate the interdependent (not independent) process nature of e‐learning success. We applied structural equation modeling to empirically validate a comprehensive model of e‐learning success at the university level. Our research advances existing literature on CSFs of e‐learning and provides a basis for comparing existing research results as well as guiding future empirical research to build robust e‐learning theories. A total of 372 valid unduplicated responses from students who have completed at least one online course at a university in the Midwestern United States were used to examine the structural model. Findings indicated that the e‐learning success model satisfactorily explains and predicts the interdependency of six CSFs of e‐learning systems (course design quality, instructor, motivation, student‐student dialog, student‐instructor dialog, and self‐regulated learning) and perceived learning outcomes.
Can there be a moral obligation to participate in biomedical research?
Authors: Seiler Christian 
Published: January 2018

AbstractIn clinical medicine, the moral obligation to care for the individual patient is absolute. Patient care means at least and by negative terms to minimize any risk of treatment. In this context, the question arises about the compatibility of clinical ethics and human biomedical research ethics. Or conversely, is there a common ground between the two? At the opposite end of the field between clinical ethics and biomedical research ethics is the proposal of an obligation to participate in biomedical research, which is argued for on the basis of biomedical knowledge being a public good available to the community as a whole. While patient accrual during a clinical investigation would certainly be facilitated by obligatory research participation, and the data obtained would be—at first sight—more representative for the population studied, the still feasible refusal to participate would be stigmatizing and as such detrimental for the patient‐physician relation. This essay seeks to provide a reply to the titled question by focusing on aspects such as individual vs common medical claims, shared grounds between the two and an important document of medical research ethics, that is the Nuremberg code.
Delayed myelination and neurodevelopment in male seizure‐prone versus seizure‐resistant rats
Authors: Sharma Pragati , Powell Kim L. , Wlodek Mary E. , O'Brien Terence J. , Gilby Krista L. 
Published: January 2018

SummaryObjectiveAberrant myelination and developmental delay have been reported in epilepsy. However, it is unclear whether these are linked to intrinsic mechanisms that support a predisposition toward seizures and the development of epilepsy. Thus, we compared rates of myelination and neurodevelopment in male rats selectively bred for enhanced susceptibility to kindling epileptogenesis (FAST) with male rats bred for resistance (SLOW).MethodsMyelin‐specific gene expression was compared in the brainstem, cerebellum, and cerebral hemisphere of FAST and SLOW rats on postnatal days (PNDs) 5, 11, 17, 23, and 90 to determine strain‐specific myelination rates. Myelin protein levels were also compared at PNDs 5 and 23 in the brainstem. Relative rates of neurodevelopment were evaluated between PNDs 5 and 21 using physical growth landmarks and neuromotor tests including righting reflex, cliff avoidance, negative geotaxis, and locomotor activity.ResultsMyelin‐specific mRNA expression was significantly down‐regulated in FAST rats on PNDs 5 and 11 in all 3 brain structures, indicating relatively delayed myelination. Likewise, corresponding protein levels were significantly lower in FAST brainstem on PND 5. Developmental delay was evident in the FAST strain such that only 9% of FAST pups, compared to 81% of SLOW, had open eyes by PND 13, locomotor activity was significantly reduced between PNDs 12 and 16, and neuromotor task acquisition was delayed between PNDs 5 and 10.SignificanceRelative delays in myelination and neurodevelopment co‐occurred in the seizure‐prone FAST strain in the absence of seizures. These findings suggest these symptoms are not seizure‐induced and may be mechanistically linked to an underlying pathophysiology supporting a predisposition toward developing epilepsy.
Native or not? Ancient DNA rejects persistence of New Zealand's endemic black swan: A reply to Montano et al.
Authors: Rawlence Nicolas J. , Kardamaki Afroditi , Easton Luke J. , Tennyson Alan J. D. , Scofield Richard P. , Waters Jonathan M. 
Published: January 2018

AbstractMontano et al.'s (Evolutionary Applications, 2017) recent coalescent analysis of modern black swan (Cygnus atratus) genotypes concluded that New Zealand's native black swan survived prehistoric hunting, to later hybridize with introduced black swans from Australia. However, this persistence scenario conflicts with new ancient DNA, morphometric and archaeological analyses of prehistoric New Zealand swan (C. sumnerensis) remains, which instead support a wholesale extinction‐replacement scenario. Multiple lines of evidence indicate that C. sumnerensis did not survive beyond the earliest phase of Polynesian settlement in New Zealand and thus question the reliability of coalescent inferences derived from small numbers of microsatellite loci.
Occupational risks of working with horses: A questionnaire survey of equine veterinary surgeons
Authors: Parkin T. D. H. , Brown J. , Macdonald E. B. 
Published: January 2018

SummaryLimited scientific evidence from other countries and plenty of anecdotal evidence suggest that the risk of personal injury in equine veterinary practice is high. However, a comprehensive description of the types of risks to which equine veterinary surgeons expose themselves has not previously been available. The aim of this study was to quantify the number, types and causes of personal injury sustained by equine veterinary practitioners in the UK. An interview (and online) questionnaire‐based survey was conducted with a large number of equine veterinary practitioners. Questions were designed to identify the number of injuries sustained during the respondent's career to date and to acquire details of the worst injury sustained including cause, treatment and short‐ and long‐term outcomes. A total of 2292 injuries were reported by 620 respondents, equating to one injury every 3 years 7 months in those respondents. Most ‘worst’ injuries occurred while the veterinary surgeon was conducting most common reasons for equine examination. The most frequent sites of this ‘worst’ injury were the leg and the head with the main cause of injury being a kick with hindlimb. Of all reports, 33% of injuries resulted in a hospital admission of which 43% required hospital admission for longer than 24 h and 7% of reports resulted in a loss of consciousness. The main limitation of this work is the descriptive nature of the survey. It would be unwise to assume that the procedures identified as being most commonly associated with injury in the study are more risky than other less commonly conducted procedures. In conclusion, equine veterinary practice is a risky profession. Greater emphasis on and awareness of methods to avoid or mitigate risk should be a priority for anyone working with horses and their employers.
Atypical myopathy in the South‐East of England: Clinicopathological data and outcome in hospitalised horses
Authors: Dunkel B. , Ryan A. , Haggett E. , Knowles E. J. 
Published: January 2018

SummaryThis retrospective case series describes clinicopathological data and outcome of hospitalised atypical myopathy (AM) cases in the South‐East of England. The study aimed to describe the frequency of metabolic abnormalities (hyperglycaemia, hyperlactataemia, hypertriglyceridaemia) and outcome in AM cases in the South‐East of England and test the hypothesis that serum creatine kinase (CK) activity and blood glucose, lactate and triglyceride concentrations are associated with outcome. Medical records (2011–2017) from three referral hospitals were reviewed for cases with a clinical diagnosis of AM. A previously described algorithm was applied and cases were included if a diagnosis of AM was considered highly likely. In cases admitted after 2013 known or possible exposure to sycamore trees was also required for inclusion. Sixty‐four animals were included, 44% (28/64) survived. Hyperglycaemia, hyperlactataemia and hypertriglyceridaemia were present in 76%, 89% and 92% of horses on admission, respectively. Survivors had lower blood lactate concentrations (survivors: median 3.5 mmol/L; range 0.5–10.4 mmol/L vs. nonsurvivors: median 7.3 mmol/L; range 2.5–16.5 mmol/L; P = 0.011) and serum CK activities (survivors: median 38,369 U/L; range 7024–570,498 U/L vs. nonsurvivors: median 172,687 U/L; range 2036–570,953 U/L; P = 0.027) on admission when compared to nonsurvivors. Increasing CK activity (P = 0.008) and triglyceride concentrations (P = 0.038) during hospitalisation were associated with nonsurvival. More nonsurvivors required sedation (18/29; 62.1% vs. 4/22; 18.2%; P = 0.002). The prognosis for hospitalised horses with AM is guarded and outcome in this population was associated with admission CK activity and lactate concentrations, and increasing CK activity and triglyceride concentrations and need for sedation during hospitalisation.
Investigation of Thulium and Other Rare Earth Element Mass Fractions in NIST SRM 1632a Bituminous Coal Reference Material by Quadrupole ICP‐MS
Authors: Roth Elliot , Bank Tracy L. , Granite Evan 
Published: January 2018

Inductively coupled plasma‐mass spectrometry after lithium metaborate fusion and digestion was used to measure the rare earth element (REE) mass fractions of several reference materials including NIST SRM 1632a, a historical bituminous Pennsylvania seam coal. While most of the REE mass fractions measured in this study were consistent with the published consensus data, the measured mass fraction of thulium for NIST SRM 1632a was consistently lower compared with the published data. Chondrite normalisation of the published consensus data for NIST SRM 1632a produced a positive thulium anomaly (Tm = 1.78), which is inconsistent with a terrestrial source of sediment. Normalisation of REE mass fractions collected in this study produced no significant Tm anomaly (Tm = 0.93), which agrees with the sedimentary depositional environment of coal. Therefore, a revised mass fraction of 0.16 mg kg−1 Tm in NIST SRM 1632a is recommended.
Multicenter, randomized, controlled trial of S‐1 monotherapy versus S‐1 and interferon‐α combination therapy for hepatocellular carcinoma with extrahepatic metastases
Authors: Nagano Hiroaki , Obi Shuntaro , Hatano Etsuro , Kaneko Shuichi , Kanai Fumihiko , Omata Masao , Tsuji Akihito , Itamoto Toshiyuki , Yamamoto Kazuhide , Tanaka Masatoshi , Kubo Shoji , Hirata Koichi , Nakamura Hideji , Tomimaru Yoshito , Yamanaka Takeharu , Kojima Shinsuke , Monden Morito 
Published: January 2018

AimNo effective therapies for extrahepatic metastases from hepatocellular carcinoma (HCC) have yet been identified. Previous studies suggested a potentially promising antitumor effect of combination therapy of S‐1, a novel oral dihydropyrimidine dehydrogenase inhibitor, and interferon (IFN)‐α. The present study aimed to investigate the clinical efficacy of single agent S‐1 and S‐1/IFN‐α for HCC patients with extrahepatic metastases in a randomized, open‐label, multicenter trial.MethodsA total of 103 patients with HCC with extrahepatic metastases were randomly assigned to the S‐1/IFN‐α group, receiving the combination of S‐1 and IFN‐α, or the S‐1 group, receiving the single agent of S‐1. Clinical efficacy and adverse events were compared between the two groups.ResultsA total of 49 patients in the S‐1/IFN‐α group and 51 patients in the S‐1 group were included in the efficacy analysis. The response rate was 22.4% (11/49) in the S‐1/IFN‐α group and 13.7% (7/51) in the S‐1 group; there was no significant difference. Overall and progression‐free survival in the two groups were also not significantly different (1‐year overall survival 50.8% vs. 72.4%, median progression‐free survival 127 days vs. 157 days). The incidence of grade ≥3 adverse events in the S‐1/IFN‐α group was 62.7% (32/51), which tended to be higher than in the S‐1 group (43.1% [22/51]).ConclusionsOncological outcomes in both treatment groups were favorable compared with previous reports, though there was no significant beneficial effect of adding IFN‐α to S‐1 for the treatment of HCC patients with extrahepatic metastases.