bluuebunny/crossref_metadata_2025_split huggingface dataset:
MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2
Authors: Davies Michael L. , Sei Janet J. , Siciliano Nicholas A. , Xu Ren-Huan , Roscoe Felicia , Sigal Luis J. , Eisenlohr Laurence C. , Norbury Christopher C. 
Published: January 2014

ABSTRACT

Although the pattern recognition receptor Toll-like receptor 2 (TLR2) is typically thought to recognize bacterial components, it has been described to alter the induction of both innate and adaptive immunity to a number of viruses, including vaccinia virus (VACV). However, many pathogens that reportedly encode TLR2 agonists may actually be artifactually contaminated during preparation, possibly with cellular debris or merely with molecules that sensitize cells to be activated by authentic TLR2 agonists. In both humans and mice, the most relevant natural route of infection with VACV is through intradermal infection of the skin. Therefore, we examined the requirement for TLR2 and its signaling adaptor MyD88 in protective immunity to VACV after intradermal infection. We find that although TLR2 may recognize virus preparations
in vitro
and have a minor role in preventing dissemination of VACV following systemic infection with large doses of virus, it is wholly disposable in both control of virus replication and induction of adaptive immunity following intradermal infection. In contrast, MyD88 is required for efficient induction of CD4 T cell and B cell responses and for local control of virus replication following intradermal infection. However, even MyD88 is not required to induce local inflammation, inflammatory cytokine production, or recruitment of cells that restrict virus from spreading systemically after peripheral infection. Thus, an effective antiviral response does require MyD88, but TLR2 is not required for control of a peripheral VACV infection. These findings emphasize the importance of studying relevant routes of infection when examining innate sensing mechanisms.

IMPORTANCE
Vaccinia virus (VACV) provides the backbone for some of the most widely used and successful viral vaccine vectors and is also related to the human pathogens Cantagalo virus and molluscum contagiosum virus that infect the skin of patients. Therefore, it is vital to understand the mechanisms that induce a strong innate immune response to the virus following dermal infection. Here, we compare the ability of the innate sensing molecule Toll-like receptor 2 (TLR2) and the signaling molecule MyD88 to influence the innate and adaptive immune response to VACV following systemic or dermal infection.
The Human Papillomavirus E7 Proteins Associate with p190RhoGAP and Alter Its Function
Authors: Todorovic Biljana , Nichols Anthony C. , Chitilian Jennifer M. , Myers Michael P. , Shepherd Trevor G. , Parsons Sarah J. , Barrett John W. , Banks Lawrence , Mymryk Joe S. 
Published: January 2014

ABSTRACT
Using mass spectrometry, we identified p190RhoGAP (p190) as a binding partner of human papillomavirus 16 (HPV16) E7. p190 belongs to the GTPase activating protein (GAP) family and is one of the primary GAPs for RhoA. GAPs stimulate the intrinsic GTPase activity of the Rho proteins, leading to Rho inactivation and influencing numerous biological processes. RhoA is one of the best-characterized Rho proteins and is specifically involved in formation of focal adhesions and stress fibers, thereby regulating cell migration and cell spreading. Since this is the first report that E7 associates with p190, we carried out detailed interaction studies. We show that E7 proteins from other HPV types also bind p190. Furthermore, we found that conserved region 3 (CR3) of E7 and the middle domain of p190 are important for this interaction. More specifically, we identified two residues in CR3 of E7 that are necessary for p190 binding and used mutants of E7 with mutations of these residues to determine the biological consequences of the E7-p190 interaction. Our data suggest that the interaction of E7 with p190 dysregulates this GAP and alters the actin cytoskeleton. We also found that this interaction negatively regulates cell spreading on a fibronectin substrate and therefore likely contributes to important aspects of the HPV life cycle or HPV-induced tumorigenesis.

IMPORTANCE
This study identifies p190RhoGAP as a novel cellular binding partner for the human papillomavirus (HPV) E7 protein. Our study shows that a large number of different HPV E7 proteins bind p190RhoGAP, and it identifies regions in both E7 and p190RhoGAP which are important for the interaction to occur. This study also highlights the likelihood that the E7-p190RhoGAP interaction may have important biological consequences related to actin organization in the infected cell. These changes could be an important contributor to the viral life cycle and during progression to cancer in HPV-infected cells. Importantly, this work also emphasizes the need for further study in a field which has largely been unexplored as it relates to the HPV life cycle and HPV-induced transformation.
Efficacy of coupled plasma filtration adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial
Authors: Livigni Sergio , Bertolini Guido , Rossi Carlotta , Ferrari Fiorenza , Giardino Michele , Pozzato Marco , Remuzzi Giuseppe ,   GiViTI: Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (Italian Group for the Evaluation of Interventions in Intensive Care Medicine) is an independent collaboration network of Italian Intensive Care units
Published: January 2014

ObjectivesCoupled plasma filtration adsorption (CPFA, Bellco, Italy), to remove inflammatory mediators from blood, has been proposed as a novel treatment for septic shock. This multicenter, randomised, non-blinded trial compared CPFA with standard care in the treatment of critically ill patients with septic shock.DesignProspective, multicenter, randomised, open-label, two parallel group and superiority clinical trial.Setting18 Italian adult, general, intensive care units (ICUs).ParticipantsOf the planned 330 adult patients with septic shock, 192 were randomised to either have CPFA added to the standard care, or not. The external monitoring committee excluded eight ineligible patients who were erroneously included.InterventionsCPFA was to be performed daily for 5 days, lasting at least 10 h/day.Primary and secondary outcome measuresThe primary endpoint was mortality at discharge from the hospital at which the patient last stayed. Secondary endpoints were: 90-day mortality, new organ failures and ICU-free days within 30 days.ResultsThere was no statistical difference in hospital mortality (47.3% controls, 45.1% CPFA; p=0.76), nor in secondary endpoints, namely the occurrence of new organ failures (55.9% vs 56.0%; p=0.99) or free-ICU days during the first 30 days (6.8 vs 7.5; p=0.35). The study was terminated on the grounds of futility. Several patients randomised to CPFA were subsequently found to be undertreated. An a priori planned subgroup analysis showed those receiving a CPFA dose >0.18 L/kg/day had a lower mortality compared with controls (OR 0.36, 95% CI 0.13 to 0.99).ConclusionsCPFA did not reduce mortality in patients with septic shock, nor did it positively affect other important clinical outcomes. A subgroup analysis suggested that CPFA could reduce mortality, when a high volume of plasma is treated. Owing to the inherent potential biases of such a subgroup analysis, this result can only be viewed as a hypothesis generator and should be confirmed in future studies.ClinicalTrials.govNCT00332371;ISRCTN24534559.
Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist—protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol
Authors: Ishøy Pelle L , Knop Filip K , Broberg Brian V , Baandrup Lone , Fagerlund Birgitte , Jørgensen Niklas R , Andersen Ulrik B , Rostrup Egill , Glenthøj Birte Y , Ebdrup Bjørn H 
Published: January 2014

IntroductionAntipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3 months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI.Methods and analysis40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2 mg) or placebo for 3 months, adjunctive to their antipsychotic treatment.Ethics and disseminationThe trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals.Trial registrationClinicalTrials.gov identifier:NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The Danish Data Protection Agency project number: RHP-2012-027.
Performance of coagulation tests in patients on therapeutic doses of rivaroxaban
Authors: Hawes Emily M. , Deal Allison M. , Adcock Dorothy M. , Gosselin Robert , Jeanneret Cheryl , Friedman Kenneth D. , Moll Stephan , Francart Suzanne J. 
Published: January 2014

SummaryKnowledge of anticoagulation status during rivaroxaban therapy is desirable in certain clinical situations. It was the study objective to determine coagulation tests most useful for assessing rivaroxaban’s anticoagulant effect. Peak and trough blood samples from 29 patients taking rivaroxaban 20 mg daily were collected. Mass spectrometry and various coagulation assays were performed. “On-therapy range” was defined as the rivaroxaban concentrations determined by LC-MS/ MS. A “misprediction percentage” was calculated based on how often results of each coagulation assay were in the normal reference range, while the rivaroxaban concentration was in the “on-therapy” range. The on-therapy range was 8.9 – 660 ng/ml. The misprediction percentages for prothrombin time (PT) and activated partial thromboplastin time (aPTT), using multiple reagents and coagulometers, ranged from 10% – 52% and 31% – 59%, respectively. PT, aPTT and activated clotting time (ACT) were insensitive to trough rivaroxaban: 59%, 62%, and 80% of samples had a normal result, respectively. Over 95% of PT and ACT values were elevated at peak. Four different rivaroxaban calibrated anti-Xa assays had R2 values >0.98, demonstrating strong correlations with rivaroxaban drug levels. In conclusion, PT, aPTT and ACT are often normal in patients on therapeutic doses of rivaroxaban. However, PT and ACT may have clinical utility at higher drug plasma levels. Rivaroxaban calibrated anti-factor Xa assays can accurately identify low and high on-therapy rivaroxaban drug levels and, therefore, have superior utility in all clinical situations where assessment of anticoagulation status may be beneficial.This trial is registered at www.clinicaltrials.gov (#NCT01743898).
Prevalence and characteristics of patients with advanced chronic conditions in need of palliative care in the general population: A cross-sectional study
Authors: Gómez-Batiste Xavier , Martínez-Muñoz Marisa , Blay Carles , Amblàs Jordi , Vila Laura , Costa Xavier , Espaulella Joan , Espinosa Jose , Constante Carles , Mitchell Geoffrey K 
Published: January 2014

Background: Of deaths in high-income countries, 75% are caused by progressive advanced chronic conditions. Palliative care needs to be extended from terminal cancer to these patients. However, direct measurement of the prevalence of people in need of palliative care in the population has not been attempted. Aim: Determine, by direct measurement, the prevalence of people in need of palliative care among advanced chronically ill patients in a whole geographic population. Design: Cross-sectional, population-based study. Main outcome measure: prevalence of advanced chronically ill patients in need of palliative care according to the NECPAL CCOMS-ICO© tool. NECPAL+ patients were considered as in need of palliative care. Setting/participants: County of Osona, Catalonia, Spain (156,807 inhabitants, 21.4% > 65 years). Three randomly selected primary care centres (51,595 inhabitants, 32.9% of County’s population) and one district general hospital, one social-health centre and four nursing homes serving the patients. Subjects were all patients attending participating settings between November 2010 and October 2011. Results: A total of 785 patients (1.5% of study population) were NECPAL+: mean age = 81.4 years; 61.4% female. Main disease/condition: 31.3% advanced frailty, 23.4% dementia, 12.9% cancer (ratio of cancer/non-cancer = 1/7), 66.8% living at home and 19.7% in nursing home; only 15.5% previously identified as requiring palliative care; general clinical indicators of severity and progression present in 94% of cases. Conclusions: Direct measurement of prevalence of palliative care needs on a population basis is feasible. Early identification and prevalence determination of these patients is likely to be the cornerstone of palliative care public health policies.
Biomechanical Evaluation of the Quadriceps Tendon Autograft for Anterior Cruciate Ligament Reconstruction
Authors: Sasaki Norihiro , Farraro Kathryn F. , Kim Kwang E. , Woo Savio L-Y. 
Published: January 2014

Background: Recently, many surgeons have chosen the quadriceps tendon (QT) as an autograft for anterior cruciate ligament (ACL) reconstruction. However, there have not been biomechanical studies that quantitatively evaluated knee function after reconstruction using a QT autograft. Purpose: To measure the 6 degrees of freedom knee kinematics and in situ graft forces after reconstruction with a QT autograft compared with a quadrupled semitendinosus and gracilis (QSTG) tendon autograft. Study Design: Controlled laboratory study. Methods: Ten human cadaveric knees (age, 54-64 years) were tested in 3 conditions: (1) intact, (2) ACL deficient, and (3) after ACL reconstruction using a QT or QSTG autograft. With use of a robotic/universal force-moment sensor testing system, knee kinematics and in situ forces in the ACL and autografts were obtained at 5 knee flexion angles under externally applied loads: (1) 134-N anterior tibial load, (2) 134-N anterior tibial load with 200-N axial compression, and (3) 10-N·m valgus and 5-N·m internal tibial torque. Results: Under the anterior tibial load, both autografts restored anterior tibial translation to within 2.5 mm of the intact knee and in situ forces to within 20 N of the intact ACL at 15°, 30°, and 60°. Adding compression did not change these findings. With the combined rotatory load, the anterior tibial translation and graft in situ forces were again not significantly different from the intact ACL. There were no significant differences between the grafts under any experimental condition. Conclusion: Reconstruction of the ACL with a QT autograft restored knee function to similar levels as that reconstructed with a QSTG autograft under loads simulating clinical examinations. Clinical Relevance: The positive biomechanical results of this cadaveric study lend support to the use of a QT autograft for ACL reconstruction, as it could restore knee function immediately after surgery under applied loads that mimic clinical examinations.
Biomechanical Comparison of an All-Soft Suture Anchor With a Modified Broström-Gould Suture Repair for Lateral Ligament Reconstruction
Authors: Brown Christopher A. , Hurwit Daniel , Behn Anthony , Hunt Kenneth J. 
Published: January 2014

Background: Anatomic repair is indicated for patients who have recurrent lateral ankle instability despite nonoperative measures. Hypothesis: There is no difference in repair stiffness, failure torque, or failure angle between specimens repaired with all-soft suture anchors versus the modified Broström-Gould technique with sutures only. Study Design: Controlled laboratory study. Methods: In 10 matched pairs of human cadaveric ankles, the anterior talofibular ligament (ATFL) was incised from its origin on the fibula. After randomization, 1 ankle was repaired to its anatomic insertion using two 1.4-mm JuggerKnot all-soft suture anchors; the other ankle was repaired with a modified Broström-Gould technique using 2-0 FiberWire. All were augmented using the inferior extensor retinaculum. All ankles were mounted to the testing machine in 20° of plantar flexion and 15° of internal rotation and loaded to failure after the repair. Stiffness, failure torque, and failure angle were recorded and compared using a paired Student t test with a significance level set at P < .05. Results: There was no significant difference in failure torque, failure angle, or stiffness. No anchors pulled out of bone. The primary mode of failure was pulling through the ATFL tissue. Conclusion: There was no statistical difference in strength or stiffness between a 1.4-mm all-soft suture anchor and a modified Broström-Gould repair with 2-0 FiberWire. The primary mode of failure was at the tissue level rather than knot failure or anchor pullout. Clinical Relevance: The particular implant choice (suture only, tunnel, anchor) in repairing the lateral ligament complex may not be as important as the time to biological healing. The suture-only construct as described in the Broström-Gould repair was as strong as all-soft suture anchors, and the majority of the ankles failed at the tissue level. For those surgeons whose preference is to use anchor repair, this novel all-soft suture anchor may be an alternative to other larger anchors, as none failed by pullout.
Reducing survey burden: feasibility and validity of PROMIS measures in multiple sclerosis
Authors: Senders Angela , Hanes Douglas , Bourdette Dennis , Whitham Ruth , Shinto Lynne 
Published: January 2014

Background: Patient-reported outcomes are important for clinical research and care, yet administering and scoring the questionnaires requires considerable effort and time. The Patient Reported Outcomes Measurement Information System (PROMIS) could considerably reduce administrative obstacles and lessen survey burden for participants. Objective: Assess the feasibility and validity of PROMIS, compared to commonly-used legacy measures for multiple sclerosis (MS). Methods: In this cross-sectional survey, 133 participants with confirmed MS completed legacy surveys and PROMIS Computerized Adaptive Tests (CATs) for depression, anxiety, pain, fatigue and physical function. We conducted a multi-trait, multi-method analysis and verified results with confirmatory factor analysis. Results: The correlations between PROMIS and the corresponding legacy measures were large (0.67 to 0.87). The multi-trait, multi-method criteria were generally well met, providing good evidence of the validity of PROMIS measures. PROMIS surveys asked fewer questions and required substantially less time to complete than the legacy scales. Conclusions: Our results provide evidence of the construct validity of PROMIS for use with MS patients. Several aspects of the PROMIS CATs made them an important resource, including: (a) less time was required to complete them; (b) missing data was reduced; and (c) the automatic scoring referenced the general population. Our findings support the use of PROMIS in MS research and may have broader implications for clinical care, as well.
Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter, randomized, placebo-controlled, double-blind trial
Authors: Gallien Philippe , Amarenco Gérard , Benoit Nicolas , Bonniaud Véronique , Donzé Cécile , Kerdraon Jacques , de Seze Marianne , Denys Pierre , Renault Alain , Naudet Florian , Reymann Jean Michel 
Published: January 2014

Objective: Our aim was to assess the usefulness of cranberry extract in multiple sclerosis (MS) patients suffering from urinary disorders. Methods: In total, 171 adult MS outpatients with urinary disorders presenting at eight centers were randomized (stratification according to center and use of clean intermittent self-catheterization) to cranberry versus placebo in a 1-year, prospective, double-blind study that was analyzed using a sequential method on an intent-to-treat basis. An independent monitoring board analyzed the results of the analyses each time 40 patients were assessed on the main endpoint. Cranberry extract (36 mg proanthocyanidins per day) or a matching placebo was taken by participants twice daily for 1 year. The primary endpoint was the time to first symptomatic urinary tract infection (UTI), subject to validation by a validation committee. Results: The second sequential analyses allowed us to accept the null hypothesis (no difference between cranberry and placebo). There was no difference in time to first symptomatic UTI distribution across 1 year, with an estimated hazard ratio of 0.99, 95% CI [0.61, 1.60] ( p = 0.97). Secondary endpoints and tolerance did not differ between groups. Conclusion: Taking cranberry extract versus placebo twice a day did not prevent UTI occurrence in MS patients with urinary disorders. Trial Registration NCT00280592.