bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing the impact of efficacy stopping rules on the error rates under the multi-arm multi-stage framework
Authors: Blenkinsop Alexandra , Parmar Mahesh KB , Choodari-Oskooei Babak 
Published: January 2019

Background The multi-arm multi-stage framework uses intermediate outcomes to assess lack-of-benefit of research arms at interim stages in randomised trials with time-to-event outcomes. However, the design lacks formal methods to evaluate early evidence of overwhelming efficacy on the definitive outcome measure. We explore the operating characteristics of this extension to the multi-arm multi-stage design and how to control the pairwise and familywise type I error rate. Using real examples and the updated nstage program, we demonstrate how such a design can be developed in practice. Methods We used the Dunnett approach for assessing treatment arms when conducting comprehensive simulation studies to evaluate the familywise error rate, with and without interim efficacy looks on the definitive outcome measure, at the same time as the planned lack-of-benefit interim analyses on the intermediate outcome measure. We studied the effect of the timing of interim analyses, allocation ratio, lack-of-benefit boundaries, efficacy rule, number of stages and research arms on the operating characteristics of the design when efficacy stopping boundaries are incorporated. Methods for controlling the familywise error rate with efficacy looks were also addressed. Results Incorporating Haybittle–Peto stopping boundaries on the definitive outcome at the interim analyses will not inflate the familywise error rate in a multi-arm design with two stages. However, this rule is conservative; in general, more liberal stopping boundaries can be used with minimal impact on the familywise error rate. Efficacy bounds in trials with three or more stages using an intermediate outcome may inflate the familywise error rate, but we show how to maintain strong control. Conclusion The multi-arm multi-stage design allows stopping for both lack-of-benefit on the intermediate outcome and efficacy on the definitive outcome at the interim stages. We provide guidelines on how to control the familywise error rate when efficacy boundaries are implemented in practice.
Biomechanical comparison of transosseous cortical button and Footprint repair techniques for acute distal biceps tendon ruptures
Authors: Bellringer Simon F , Phadnis Joideep , Human Taaibos , Redmond Christine L , Bain Gregory I 
Published: January 2019

Background The biceps brachii is the main forearm supinator, which is a direct consequence of its anatomic arrangement. The primary aim of distal biceps rupture is to restore supination strength and function. Cadaveric studies demonstrate that anatomic repairs significantly improve the supination moment when compared to more anterior repairs; however, this has not been tested in the clinical setting. The aim of this study was to compare biomechanical and clinical outcomes of an anatomic repair (Footprint), with a widely used transosseous technique (Endobutton). Methods Twenty-two patients were retrospectively identified from a clinical database (11 Footprint versus 11 Endobutton). Biomechanical performance of strength and endurance for flexion and supination was assessed using a validated isokinetic dynamometry protocol and clinical outcome scores (Quick Disabilities of the Arm, Shoulder and Hand Outcome Measure and the Mayo Elbow Performance Score) were collected for all patients. Results For supination, the Footprint group demonstrated a superior trend for all biomechanical parameters tested. This was statistically significant for mean peak torque, total work of maximal repetition and work in the last third of repetitive testing (p = 0.031, p = 0.036 and p = 0.048). For flexion, the Footprint group demonstrated a superior trend for all biomechanical parameters tested but this was only statistically significant for work in the last third of repetitive testing (p = 0.039). The clinical outcomes were good or excellent for all patients in both groups. Conclusion This study is the first to demonstrate that an anatomic Footprint repair restores superior biomechanical supination strength and endurance compared to a conventional Endobutton technique in a clinical setting. Both techniques, however, provide good or excellent clinical outcomes.
Improvement of Blood Samples Preanalytic Management Alters the Clinical Results of Glucose Values: Population Study
Authors: Codish Shlomi , Amichay Doron , Yitshak-Sade Maayan , Gat Roni , Liberty Idit F. , Novack Lena 
Published: January 2019

Background: Prolonged time elapsing between the blood drawing and separation of the cell mass may result in decreased sample glucose levels due to continuous glycolysis. This can lead to underdiagnoses of hyperglycemic states and overdiagnosis of hypoglycemia. We aimed to evaluate the clinical impact of shortened transit time and earlier centrifugation of laboratory specimens on reported glucose results and diagnosis of clinically significant hypoglycemia (<50 mg/dL) or elevated glucose levels (>100 mg/dL). Methods: We assessed all fasting-serum glucose tests from the adult population (190 767 subjects) without known diabetes residing in Southern Israel. Before and after intervention periods were compared: 268 359 blood tests were performed during 2009-2010, and 317 336 during 2012-2013. Results: While glucose levels were 94.17 mg/dL ± 14.12 in 2012-2013 versus 83.53 mg/dL ± 14.50 in 2009-2010 (12.75% ± 0.88 increase, P < .001), the difference in glycated hemoglobin levels was statistically significant but clinically negligible: 5.84% ± 0.56 in 2012-2013 versus 5.88% ± 0.56 in 2009-2010 (0.53% ± 0.78 decrease, P < .01). There was an increased likelihood of a glucose result to be above 100 mg/dL following intervention: 9.80% versus 25.90%, P < .001. For clinics distanced over 40 km from the laboratory, age-adjusted odds ratio value was 1.26 (95% CI 1.13, 1.41). The proportion of samples with hypoglycemia values decreased from 0.33% to 0.03% ( P < .001). Conclusions: We demonstrated an important change in glucose values over a two-year period following an improvement of the preanalytic processes. The intervention was related to an increase in the frequency of hyperglycemia results and a decrease in the number of hypoglycemia results. Future administrative projects should consider clinical consequences with involvement of all relevant stakeholders.
Differential Expression of Fas in Moderate/Severe and Mild Persistent Allergic Rhinitis and Its Correlation With Pathological Parameters
Authors: Pirayesh Ashkan , Shahsavan Shaghayegh , Zargari Samani Omid , Shirzad Hedayatollah , Amani Soroush , Zamani Mohamad Ali , Salimzadeh Loghman , Bagheri Nader , Moghni Mandana , Deris Fatemeh 
Published: January 2019

Background and Aims The roles of Fas in immune system are multifaceted, and the interaction between Fas receptor and Fas ligand is essential for maintaining the immune tolerance. We aimed to assess the level of the expression of Fas receptor on nasal inferior turbinate mucosa in patients with mild persistent allergic rhinitis (M PAR) and moderate to severe (M/S) PAR and determined the relationship between disease severity and production of Fas. Methods A total of 70 patients with M/S PAR, 70 patients with M PAR, and 70 healthy individuals were enrolled in this study. We obtained biopsies of nasal inferior turbinate mucosa from the participants. The expression of Fas mRNA was evaluated by real-time polymerase chain reaction. The presence and location of Fas were determined by immunohistochemistry. The number of eosinophils per field, blood eosinophils, total serum IgE levels, and specific serum IgE levels were measured. Clinical manifestations of patients were assessed by Total Nasal Syndrome Score (TNSS). Results The expression of Fas in patients with M/S PAR was decreased significantly compared to the control group and patients with M PAR. Local mucosal expression of Fas was correlated with specific IgE, nasal eosinophil count, and TNSS. Conclusion According to the results of this study, there might be a relationship between the expression of Fas receptor on nasal turbinate mucosa and the severity of persistent allergic rhinitis.
Protocol for constructing a support model for family caregivers of people with dementia: Barriers and requirements
Authors: Yen Chia-Ming 
Published: January 2019

Background: This report describes a protocol for determining the barriers and requirements of family caregivers for people with dementia. The perspectives of healthcare professionals, family caregivers, and dementia patients will be collected and analyzed to construct a support model of requirements. Methods: An in-depth interview and care diary will be adopted during Phase I. Subsequently, the Delphi technique will be conducted to transform opinions from participants into a group consensus. In total, 38 participants are expected to be recruited from the outpatients of the neurology, psychiatry, geriatrics, and family medicine departments of a medical center in central Taiwan. Five domains are to be examined systematically in terms of the barriers and requirements of family caregivers for people with dementia: (1) knowledge of dementia and care skills to cope with problem behaviors; (2) medication and comorbidity management; (3) family relationships and psychological support; (4) resources and benefits; and (5) education and skills training. Conclusion: Overall, the proposed protocol will construct a support model of requirements for family caregivers, which is expected to provide healthcare professionals, family caregivers, researchers, and policymakers with more concise information and insights into associated problems.
Advanced imaging findings in progressive solitary sclerosis: a single lesion or a global disease?
Authors: Lee Lisa Eunyoung , Chan Jillian K , Nevill Emilie , Soares Adam , Vavasour Irene M , MacMillan Erin L , Garren Hideki , Clayton David , Keegan B Mark , Tam Roger , Traboulsee Anthony L , Kolind Shannon H , Carruthers Robert L 
Published: January 2019

Background Progressive solitary sclerosis is a unifocal demyelinating disease recently proposed as a possible multiple sclerosis variant. Objective To compare myelin content and brain metabolite ratio qualitatively in the normal-appearing white matter of progressive solitary sclerosis cases compared to multiple sclerosis and healthy control participants. Methods Case report. Results Progressive solitary sclerosis cases showed abnormal myelin in normal-appearing white matter tracts and global normal-appearing white matter as well as lower N-acetyl-aspartate to total creatine ratio compared to multiple sclerosis and healthy control groups. Conclusion Despite a single demyelinating lesion along the corticospinal tract in progressive solitary sclerosis, we showed evidence of more extensive abnormality within the normal-appearing white matter.
Cathepsin C promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway
Authors: Liu Qing , Zhang Yanli , Liu Shuang , Liu Yanna , Yang Xiaohan , Liu Gang , Shimizu Takahiro , Ikenaka Kazuhiro , Fan Kai , Ma Jianmei 
Published: January 2019

Abstract
Background
Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinflammation. Moreover, CatC can induce chemokine production in brain inflammatory processes. In vitro studies further confirmed that CatC is secreted extracellularly from LPS-treated microglia. However, the mechanisms of CatC affecting neuroinflammatory responses are not known yet.

Methods
CatC over-expression (CatCOE) and knock-down (CatCKD) mice were treated with intraperitoneal and intracerebroventricular LPS injection. Morris water maze (MWM) test was used to assess the ability of learning and memory. Cytokine expression in vivo was detected by in situ hybridization, quantitative PCR, and ELISA. In vitro, microglia M1 polarization was determined by quantitative PCR. Intracellular Ca2+ concentration was determined by flow cytometry, and the expression of NR2B, PKC, p38, IkBα, and p65 was determined by western blotting.

Results
The LPS-treated CatCOE mice exhibited significantly increased escape latency compared with similarly treated wild-type or CatCKD mice. The highest levels of TNF-α, IL-1β, and other M1 markers (IL-6, CD86, CD16, and CD32) were found in the brain or serum of LPS-treated CatCOE mice, and the lowest levels were detected in CatCKD mice. Similar results were found in LPS-treated microglia derived from CatC differentially expressing mice or in CatC-treated microglia from wild-type mice. Furthermore, the expression of NR2B mRNA, phosphorylation of NR2B, Ca2+ concentration, phosphorylation of PKC, p38, IκBα, and p65 were all increased in CatC-treated microglia, while addition of E-64 and MK-801 reversed the phosphorylation of above molecules.

Conclusion
The data suggest that CatC promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. CatC may be one of key molecular targets for alleviating and controlling neuroinflammation in neurological diseases.
Adjunctive simvastatin for treatment-resistant depression: study protocol of a 12-week randomised controlled trial
Authors: Husain Muhammad I. , Chaudhry Imran B. , Khoso Ameer B. , Husain Mohammad Omair , Rahman Raza R. , Hamirani Munir M. , Hodsoll John , Carvalho Andre F. , Husain Nusrat , Young Allan H. 
Published: January 2019

BackgroundA third of patients diagnosed with major depressive disorder (MDD) experience treatment-resistant depression (TRD). Relatively few pharmacological agents have established efficacy for TRD. Therefore, the evaluation of novel treatments for TRD is a pressing priority. Statins are pleiotropic agents and preclinical studies as well as preliminary clinical trials have suggested that these drugs may have antidepressant properties.AimsTo report on a protocol for a 12-week, randomised, double-blind, placebo-controlled trial of add-on treatment with simvastatin for patients meeting DSM-5 criteria for MDD who have failed to respond to at least two adequate trials with approved antidepressants. The trial has been registered with Clinicaltrials.gov in (ClinicalTrials.gov identifier: NCT03435744).MethodAfter screening and randomisation to the two parallel arms of the trial, 75 patients will receive simvastatin and 75 patients will receive placebo as adjuncts to treatment as usual. The primary outcome is change in Montgomery–Åsberg Depression Rating Scale scores from baseline to week 12 and secondary outcomes include changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. Assessments will take place at screening, baseline, and weeks 2, 4, 8 and 12. Checklists for adverse effects will be undertaken at each visit. Simvastatin (20 mg) will be given once daily. Other secondary outcomes include C-reactive protein and plasma lipids measured at baseline and week 12.ResultsThis trial will assess simvastatin's efficacy and tolerability as an add-on treatment option for patients with TRD and provide insights into its putative mechanisms of action.ConclusionsAs the first trial investigating the use of simvastatin as an augmentation strategy in patients with TRD, if the results indicate that adjuvant simvastatin is efficacious in reducing depressive symptoms, it will deliver immediate clinical benefit.Declaration of interestI.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. R.R. and M.M.H. have received educational grants and support for academic meetings from Pfizer, Roche, Novartis and Nabiqasim. A.H.Y. has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders. A.H.Y. has undertaken investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. None of the companies have a financial interest in this research.
National Survey of Oncologists at National Cancer Institute–Designated Comprehensive Cancer Centers: Attitudes, Knowledge, and Practice Behaviors About LGBTQ Patients With Cancer
Authors: Schabath Matthew B. , Blackburn Catherine A. , Sutter Megan E. , Kanetsky Peter A. , Vadaparampil Susan T. , Simmons Vani N. , Sanchez Julian A. , Sutton Steven K. , Quinn Gwendolyn P. 
Published: January 2019

PURPOSETo identify potential gaps in attitudes, knowledge, and institutional practices toward lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) patients, a national survey of oncologists at National Cancer Institute–Designated Comprehensive Cancer Centers was conducted to measure these attributes related to LGBTQ patients and desire for future training and education.METHODSA random sample of 450 oncologists from 45 cancer centers was selected from the American Medical Association’s Physician Masterfile to complete a survey measuring attitudes and knowledge about LGBTQ health and institutional practices. Results were quantified using descriptive and stratified analyses and by a novel attitude summary measure.RESULTSOf the 149 respondents, there was high agreement (65.8%) regarding the importance of knowing the gender identity of patients, which was contrasted by low agreement (39.6%) regarding the importance of knowing sexual orientation. There was high interest in receiving education regarding the unique health needs of LGBTQ patients (70.4%), and knowledge questions yielded high percentages of “neutral” and “do not know or prefer not to answer” responses. After completing the survey, there was a significant decrease ( P < .001) in confidence in knowledge of health needs for LGB (53.1% agreed they were confident during survey assessment v 38.9% postsurvey) and transgender patients (36.9% v 19.5% postsurvey). Stratified analyses revealed some but limited influence on attitudes and knowledge by having LGBTQ friends and/or family members, political affiliation, oncology specialty, years since graduation, and respondents’ region of the country.CONCLUSIONThis was the first nationwide study, to our knowledge, of oncologists assessing attitudes, knowledge, and institutional practices of LGBTQ patients with cancer. Overall, there was limited knowledge about LGBTQ health and cancer needs but a high interest in receiving education regarding this community.
Wnt produced by stretched roof-plate cells is required for the promotion of cell proliferation around the central canal of the spinal cord
Authors: Shinozuka Takuma , Takada Ritsuko , Yoshida Shosei , Yonemura Shigenobu , Takada Shinji 
Published: January 2019

ABSTRACTCell morphology changes dynamically during embryogenesis, and these changes create new interactions with surrounding cells, some of which are presumably mediated by intercellular signaling. However, the effects of morphological changes on intercellular signaling remain to be fully elucidated. In this study, we examined the effect of morphological changes in Wnt-producing cells on intercellular signaling in the spinal cord. After mid-gestation, roof-plate cells stretched along the dorsoventral axis in the mouse spinal cord, resulting in new contact at their tips with the ependymal cells that surround the central canal. Wnt1 and Wnt3a were produced by the stretched roof-plate cells and delivered to the cell process tip. Whereas Wnt signaling was activated in developing ependymal cells, Wnt activation in dorsal ependymal cells, which were close to the stretched roof plate, was significantly suppressed in embryos with roof plate-specific conditional knockout of Wls, which encodes a factor that is essential for Wnt secretion. Furthermore, proliferation of these cells was impaired in Wls conditional knockout mice during development and after induced spinal cord injury in adults. Therefore, morphological changes in Wnt-producing cells appear to generate new Wnt signal targets.
Integration between swim speed and mouth size evolves repeatedly in Trinidadian guppies and aligns with suction-feeding fishes
Authors: Kane Emily A. , Roeder Megan M. , DeRue McKenna L. , Ghalambor Cameron K. 
Published: January 2019

ABSTRACTWell-supported correlations between swim speed and mouth size during prey capture suggest the broad existence of an integrated relationship between locomotion and feeding in suction-feeding fishes. However, the influence of specialization on this relationship is unclear. We used divergent populations of Trinidadian guppies (Poecilia reticulata) to test whether integration during suction is generalizable to a non-suction specialist and whether intraspecific specialization of component systems affects their integration. Guppies from replicate high- and low-predation streams were recorded capturing wild-type zooplankton using suction. Alternative general linear models supported a positive correlation between swim speed and mouth size in derived low-predation populations, suggesting that the relationship can be extended in some cases. High-predation populations lack this integration, which may be the result of direct selection or constraints imposed by selection on locomotion. As guppies invade new habitats they may be evolving a new, integrated performance phenotype from a non-integrated ancestor.
The influence of added mass on muscle activation and contractile mechanics during submaximal and maximal countermovement jumping in humans
Authors: Wade Logan , Lichtwark Glen A. , Farris Dominic J. 
Published: January 2019

ABSTRACTMuscle contractile mechanics induced by the changing demands of human movement have the potential to influence our movement strategies. This study examined fascicle length changes of the triceps surae during jumping with added mass or increasing jump height to determine whether the chosen movement strategies were associated with relevant changes in muscle contractile properties. Sixteen participants jumped at sub-maximal and maximal intensities while total net work was matched via two distinct paradigms: (1) adding mass to the participant or (2) increasing jump height. Electromyography (EMG) and ultrasound analyses were performed to examine muscle activation, fascicle length and fascicle velocity changes of the triceps surae during jumping. Integrated EMG was significantly higher in the added mass paradigm with no difference in mean or maximal EMG, indicating that the muscle was activated for a significantly longer period of time but not activated to a greater intensity. Fascicle shortening velocity was slower with added mass compared than with increasing jump height; therefore, intrinsic force–velocity properties probably enabled increased force production. Improved fascicle contractile mechanics paired with a longer activation period probably produced a consistently larger fascicle force, enabling a greater impulse about the ankle joint. This may explain why previous research found that participants used an ankle-centred strategy for work production in the added mass paradigm and not in the jump height paradigm. The varied architecture of muscles within the lower limb may influence which muscles we choose to employ for work production under different task constraints.