bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel anti‐HIV‐1 bispecific bNAb‐lectin fusion protein engineered in a plant‐based transient expression system
Authors: Seber Kasinger Lauren E. , Dent Matthew W. , Mahajan Garima , Hamorsky Krystal Teasley , Matoba Nobuyuki 
Published: February 2019

SummaryThe discovery of broadly neutralizing antibodies (bNAbs) has been a major step towards better prophylactic and therapeutic agents against human immunodeficiency virus type 1 (HIV‐1). However, effective therapy will likely require a combination of anti‐HIV agents to avoid viral evasion. One possible solution to this problem is the creation of bispecific molecules that can concurrently target two vulnerable sites providing synergistic inhibitory effects. Here, we describe the production in plants and anti‐HIV activity of a novel bispecific fusion protein consisting of the antigen‐binding fragment (Fab) of the CD4 binding site‐specific bNAb VRC01 and the antiviral lectin Avaren, which targets the glycan shield of the HIV‐1 envelope (VRC01Fab‐Avaren). This combination was justified by a preliminary experiment demonstrating the synergistic HIV‐1 neutralization activity of VRC01 and Fc‐fused Avaren dimer (Avaren‐Fc). Using the GENEWARE® tobacco mosaic virus vector, VRC01Fab‐Avaren was expressed in Nicotiana benthamiana and purified using a three‐step chromatography procedure. Surface plasmon resonance and ELISA demonstrated that both the Avaren and VRC01Fab moieties retain their individual binding specificities. VRC01Fab‐Avaren demonstrated enhanced neutralizing activity against representative HIV‐1 strains from A, B and C clades, compared to equimolar combinations of VRC01Fab and Avaren. Notably, VRC01Fab‐Avaren showed significantly stronger neutralizing effects than the bivalent parent molecules VRC01 IgG and Avaren‐Fc, with IC50 values ranging from 48 to 310 pm. These results support the continued development of bispecific anti‐HIV proteins based on Avaren and bNAbs, to which plant‐based transient overexpression systems will provide an efficient protein engineering and production platform.
Impact of sensory adapted dental environment on children with developmental disabilities
Authors: Kim Gail , Carrico Caroline , Ivey Carole , Wunsch Patrice B. 
Published: February 2019

AbstractAimsThis was a pilot study assessing the impact of a sensory adapted dental environment (SADE) on children with developmental disabilities (DD) receiving routine dental care.MethodsA crossover study of 22 children with DD, aged 6 through 21, was conducted at a University Pediatric Dental clinic. Each participant was randomized to a sequence of two dental cleanings on a 3‐ to 4‐month recall schedule, one with a regular dental environment (RDE) and one with SADE. Outcomes included physiological measures (heart rate and oxygen saturation) and cooperation (Frankl scores).ResultsStudy subjects completed 36 visits. None of the physiological measures differed at either time point between the two treatment settings. The Frankl scores were significantly higher with SADE setting than RDE (P = 0.0368). Forty‐six percent of parents strongly agreed that they would prefer the SADE for their child's next visit.ConclusionSADE may be associated with improved behavior in children with DD.
Berkeley Moynihan – early transfusionist and blood transfusion recipient
Authors: Learoyd P. 
Published: February 2019

SUMMARYLord Sir Berkeley Moynihan (1865–1936) was a surgeon at the General Infirmary in Leeds (Yorkshire) from 1893, rising during his career to be one of the foremost surgeons in the UK whose reputation reached its pinnacle at the outbreak of the First World War (WW1). He was the only surgeon after Lister to be made a Baronet. In a letter to The Lancet in 1918, he claimed to have used blood transfusion on some of his patients during the 10‐year period prior to that date. If true, this statement would make him the first surgeon in England to routinely use transfusion prior to WW1. This review investigates this claim using currently available evidence from Moynihan's personal records and publications, as well as published information from his colleagues.
Management of postpartum hemorrhage in a rural hospital in Kenya: a best practice implementation project
Authors: Kinuthia Kelvin , Stephenson Matthew , Maogoto Edwin 
Published: February 2019

ABSTRACT

Introduction:
Postpartum hemorrhage accounts for 34% of maternal deaths in Kenya. The World Health Organization guidelines on postpartum hemorrhage are not always followed despite being prominently promoted in hospitals.

Objectives:
The objectives of this study were to assess the current practice of health workers in the prevention and management of postpartum hemorrhage and to implement strategies to promote best practice.

Methods:
A baseline audit with five evidence-based audit criteria was conducted using the Joanna Briggs Institute Practical Application of Clinical Evidence System. Strategies to improve compliance were implemented and a follow-up audit was carried out using the same data collection methods. Results of both audits were compared.

Results:
The baseline audit showed that 90% of health workers were aware of the existence and location of the national guidelines. Almost two thirds (65%) of staff had received education on postpartum hemorrhage within the last two years. Only 30% had received specific training on the use of the guidelines and compliance with the guidelines was 0%. At the follow-up audit, the proportion of health workers who had received recent education on postpartum hemorrhage and specific training on the use of a protocol increased to 90%. The use and documentation of a protocol for postpartum hemorrhage increased to 100%. Compliance in prenatal risk assessment for postpartum hemorrhage decreased from 65% to 35%.

Conclusions:
Knowledge of the guidelines did not translate into their use during management of patients with postpartum hemorrhage. The introduction of a tool and staff education and training improved compliance.
Effects
of Gamma Irradiation Upon the Mechanical and Chemical Properties of 3D-Printed Samples of Polylactic
Acid
Authors: West Conrad , McTaggart Robert , Letcher Todd , Raynie Douglas , Roy Ranen 
Published: February 2019

Abstract
3D printing offers the opportunity to design and make replacement parts to exacting specifications when needed. This is particularly helpful for space applications where stand-alone replacement mechanisms are required. Samples of 3D-printed polylactic acid (PLA) were subjected with up to 200 kGy of gamma radiation from a Cobalt-60 irradiator. The mechanical responses to destructive testing were successfully modeled with a combination of linear and exponential functions and may be understood given the underlying chemical changes due to said radiation exposures. We find that for doses up to 50 kGy, the performance of 3D-printed PLA is largely unaffected, which is beneficial for applications in space and in medicine. At larger doses, it appears that decomposition processes win out over cross-linking, which may aid in the degradation of PLA in waste streams.
Modeling the Bending Behavior of Fiber-Reinforced Pneumatic Actuators Using a Pseudo-Rigid-Body Model
Authors: Satheeshbabu Sreeshankar , Krishnan Girish 
Published: February 2019

Abstract
Fiber reinforced elastomeric enclosures (FREEs) are soft pneumatic representative elements that can form the basis for building soft self-actuating structures/mechanisms. When placed in different configurations, they exhibit unique stroke amplification characteristics that can be leveraged to create interesting deformation patterns. Such deformations occur as a combination of axial and bending deflection due to internal pressurization and external forces. This paper presents a lumped reduced-order model that enables quick and accurate analysis of mechanisms made from FREEs grouped as a system. The model proposed is a modified four-spring pseudo-rigid-body (PRB) model that effectively captures the axial and bending stiffnesses of contracting FREEs. Parametric estimation of the model is performed using a multistart optimization routine to fit the PRB model with results from experiments and finite element analysis (FEA). The model is also generalized and statistically verified for FREEs with different fiber angles, length-to-diameter ratios, and different actuation pressures. Finally, efficacy of the approach is validated through three case studies that involve a planar arrangement of FREEs at different orientations.
Subacromial decompression surgery for adults with shoulder pain: a clinical practice guideline
Authors: Vandvik Per Olav , Lähdeoja Tuomas , Ardern Clare , Buchbinder Rachelle , Moro Jaydeep , Brox Jens Ivar , Burgers Jako , Hao Qiukui , Karjalainen Teemu , van den Bekerom Michel , Noorduyn Julia , Lytvyn Lyubov , Siemieniuk Reed A C , Albin Alexandra , Shunjie Sean Chua , Fisch Florian , Proulx Laurie , Guyatt Gordon , Agoritsas Thomas , Poolman Rudolf W 
Published: February 2019

AbstractClinical questionDo adults with atraumatic shoulder pain for more than 3 months diagnosed as subacromial pain syndrome (SAPS), also labelled as rotator cuff disease, benefit from subacromial decompression surgery? This guideline builds on to two recent high quality trials of shoulder surgery.Current practiceSAPS is the common diagnosis for shoulder pain with several first line treatment options, including analgesia, exercises, and injections. Surgeons frequently perform arthroscopic subacromial decompression for prolonged symptoms, with guidelines providing conflicting recommendations.RecommendationThe guideline panel makes a strong recommendation against surgery.How this guideline was createdA guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines and the GRADE system. The recommendation is based on two linked systematic reviews on (a) the benefits and harms of subacromial decompression surgery and (b) the minimally important differences for patient reported outcome measures. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of surgery in multilayered evidence summaries and decision aids available in MAGIC (www.magicapp.org) to support shared decisions and adaptation.The evidenceSurgery did not provide important improvements in pain, function, or quality of life compared with placebo surgery or other options. Frozen shoulder may be more common with surgery.Understanding the recommendationThe panel concluded that almost all informed patients would choose to avoid surgery because there is no benefit but there are harms and it is burdensome. Subacromial decompression surgery should not be offered to patients with SAPS. However, there is substantial uncertainty in what alternative treatment is best.
Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study)
Authors: Gay-Escoda Cosme , Hanna Magdi , Montero Antonio , Dietrich Thomas , Milleri Stefano , Giergiel Ewa , Zoltán Tóth Bagi , Varrassi Giustino 
Published: February 2019

ObjectivesTo compare efficacy/safety of oral tramadol 75 mg/dexketoprofen 25 mg (TRAM/DKP) and TRAM 75 mg/paracetamol 650 mg (TRAM/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar.DesignMulticentre, randomised, double-blind, placebo-controlled, phase IIIb study.ParticipantsHealthy adult patients scheduled for surgical extraction of at least one fully/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis.InterventionsSurgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM/DKP 75/25 mg, TRAM/paracetamol 75/650 mg or placebo.Main outcome measuresEfficacy was based patients’ electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0=‘no relief’, 1=‘a little (perceptible) relief’, 2=‘some (meaningful) relief’, 3=‘lot of relief’, 4=‘complete relief’) at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6 hours (TOTPAR6). Rescue medication was available during the treatment period.ResultsTRAM/DKP was superior to TRAM/paracetamol and placebo at the primary endpoint TOTPAR6 (p<0.0001). Mean (SD) TOTPAR6 in the TRAM/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups.ConclusionsTRAM/DKP (75/25 mg) is effective and superior to TRAM/paracetamol (75/650 mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profile.Trial registration numberEudraCT 2015-004152-22 andNCT02777970.
A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)
Authors: Geven Christopher , Blet Alice , Kox Matthijs , Hartmann Oliver , Scigalla Paul , Zimmermann Jens , Marx Gernot , Laterre Pierre-François , Mebazaa Alexandre , Pickkers Peter 
Published: February 2019

IntroductionSepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock.Methods and analysisWe describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period.Ethics and disseminationThis study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.Trial registration numberNCT03085758; Pre-results.
Cardiac remodeling in aortic and mitral valve disease: a simulation study with clinical validation
Authors: Maksuti Elira , Westerhof Berend E. , Ugander Martin , Donker Dirk W. , Carlsson Marcus , Broomé Michael 
Published: February 2019

Remodeling is an important long-term determinant of cardiac function throughout the progression of heart disease. Numerous biomolecular pathways for mechanosensing and transduction are involved. However, we hypothesize that biomechanical factors alone can explain changes in myocardial volume and chamber size in valve disease. A validated model of the human vasculature and the four cardiac chambers was used to simulate aortic stenosis, mitral regurgitation, and aortic regurgitation. Remodeling was simulated with adaptive feedback preserving myocardial fiber stress and wall shear stress in all four cardiac chambers. Briefly, the model used myocardial fiber stress to determine wall thickness and cardiac chamber wall shear stress to determine chamber volume. Aortic stenosis resulted in the development of concentric left ventricular hypertrophy. Aortic and mitral regurgitation resulted in eccentric remodeling and eccentric hypertrophy, with more pronounced hypertrophy for aortic regurgitation. Comparisons with published clinical data showed the same direction and similar magnitudes of changes in end-diastolic volume index and left ventricular diameters. Changes in myocardial wall volume and wall thickness were within a realistic range in both stenotic and regurgitant valvular disease. Simulations of remodeling in left-sided valvular disease support, in both a qualitative and quantitative manner, that left ventricular chamber size and hypertrophy are primarily determined by preservation of wall shear stress and myocardial fiber stress. NEW & NOTEWORTHY Cardiovascular simulations with adaptive feedback that normalizes wall shear stress and fiber stress in the cardiac chambers could predict, in a quantitative and qualitative manner, remodeling patterns seen in patients with left-sided valvular disease. This highlights how mechanical stress remains a fundamental aspect of cardiac remodeling. This in silico study validated with clinical data paves the way for future patient-specific predictions of remodeling in valvular disease.
Loss of FOXP3 and TSC1 Accelerates Prostate Cancer Progression through Synergistic Transcriptional and Posttranslational Regulation of c-MYC
Authors: Wu Lianpin , Yi Baozhu , Wei Shi , Rao Dapeng , He Youhua , Naik Gurudatta , Bae Sejong , Liu Xiaoguang M. , Yang Wei-Hsiung , Sonpavde Guru , Liu Runhua , Wang Lizhong 
Published: February 2019

Abstract

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3–c-MYC and TSC1–mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR–4EBP1–c-MYC and FOXP3–c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3–c-MYC and TSC1–mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells.

Significance:
These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.
Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer
Authors: Shinde Aparna , Hardy Shana D. , Kim Dongwook , Akhand Saeed Salehin , Jolly Mohit Kumar , Wang Wen-Hung , Anderson Joshua C. , Khodadadi Ryan B. , Brown Wells S. , George Jason T. , Liu Sheng , Wan Jun , Levine Herbert , Willey Christopher D. , Krusemark Casey J. , Geahlen Robert L. , Wendt Michael K. 
Published: February 2019

Abstract

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells.

Significance:
These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy.
See related commentary by Farrington and Narla, p. 1756