bluuebunny/crossref_metadata_2025_split huggingface dataset:
High INtensity Interval Training In pATiEnts with intermittent claudication (INITIATE): protocol for a multicentre, proof-of-concept, prospective interventional study
Authors: Pymer Sean , Harwood Amy , Ibeggazene Said , McGregor Gordon , Huang Chao , Twiddy Maureen , Nicholls Adam R , Ingle Lee , Carroll Sean , Long Judith , Rooms Marjorie , Chetter I C 
Published: July 2020

IntroductionThe first-line recommended treatment for patients with intermittent claudication (IC) is a supervised exercise programme (SEP), which includes a minimum of 2-hours of exercise per week over a 12-week period. However, provision, uptake and adherence rates for these SEP programmes are poor, with time constraints cited as a common participant barrier. High-intensity interval training (HIIT) is more time-efficient and therefore has the potential to overcome this barrier. However, evidence is lacking for the role of HIIT in those with IC. This proof-of-concept study aims to consider the safety, feasibility, tolerability and acceptability of a HIIT programme for patients with IC.Methods and analysisThis multicentre, single-group, prospective, interventional feasibility study will recruit 40 patients with IC, who will complete 6 weeks of HIIT, 3 times a week. HIIT will involve a supervised programme of 10×1 min high-intensity cycling intervals at 85%–90% peak power output (PPO), interspaced with 10×1 min low intensity intervals at 20%–25% PPO. PPO will be determined from a baseline cardiopulmonary exercise test (CPET) and it is intended that patients will achieve ≥85% of maximum heart rate from CPET, by the end of the second HIIT interval. Primary outcome measures are safety (occurrence of adverse events directly related to the study), programme feasibility (including participant eligibility, recruitment and completion rates) and HIIT tolerability (ability to achieve and maintain the required intensity). Secondary outcomes include patient acceptability, walking distance, CPET cardiorespiratory fitness measures and quality of life outcomes.Ethics and disseminationEthical approval was obtained via a local National Health Service research ethics committee (Bradford Leeds – 18/YH/0112) and recruitment began in August 2019 and will be completed in October 2020. Results will be published in peer-reviewed journals and presented at international conferences and are expected to inform a future pilot randomised controlled trial of HIIT versus usual-care SEPs.Trial registration numberNCT04042311; Pre-results.
Broad Spectrum project: factors determining the quality of antibiotic use in primary care: an observational study protocol from Italy
Authors: Kurotschka Peter Konstantin , Serafini Alice , Massari Marco , Da Cas Roberto , Figueiras Adolfo , Forte Viviana , Moro Maria Francesca , Massidda Matteo , Contu Federico , Minerba Luigi , Marcias Maurizio , Nardelli Marco , Perra Alessandra , Carta Mauro Giovanni , Spila Alegiani Stefania 
Published: July 2020

IntroductionThe overuse of antibiotics is causing worldwide spread of antimicrobial resistance (AMR). Compared with other countries, Italy has both high antibiotic consumption rates and high rates of AMR. Due to the fact that around 90% of antibiotics are prescribed by general practitioners (GPs), this study aims to measure the impact of knowledge, attitudes and sociodemographic and workplace-related factors on the quality of antibiotic prescriptions filled by GPs in the Italian Region of Sardinia.Methods and analysisKnowledge, attitude, sociodemographic and workplace-related factors deemed to influence physicians prescribing behaviour will be evaluated in a cross-sectional study conducted among all GPs of the Italian Region of Sardinia (n=1200). A knowledge and attitudes questionnaire (Knowledge and Attitudes on Antibiotics and Resistance - Italian version: ITA-KAAR) accompanied by a sociodemographic form will be linked to drug prescription data reimbursed by the National Health System. European Surveillance of Antibiotic Consumption quality indicators for outpatient antibiotic use will be calculated from drug prescription records. Every GP will be deemed to have demonstrated an adequate quality of prescriptions of antibiotics if half of the indicator score plus one is better than the median of the region. A multivariate Poisson regression model with robust variance estimation will be used to evaluate the impact of the determinants of antibiotic prescriptions on the actual prescribing quality of each physician.Ethics and disseminationThe project has been approved by the ethics committee of the Regional Health Trust of Sardinia (176/2019/CE, 24 September 2019). The results will be useful to inform evidence-based interventions to tackle irrational antibiotic use in the community.
From kamishibai card to key card: a family-targeted quality improvement initiative to reduce paediatric central line-associated bloodstream infections
Authors: Kamity Ranjith , Grella Melissa , Kim Maureen L , Akerman Meredith , Quintos-Alagheband Maria Lyn 
Published: July 2020

BackgroundCentral line-associated bloodstream infections (CLABSIs) are major contributors to preventable harm in the inpatient paediatric setting. Despite multiple guidelines to reduce CLABSI, sustaining reliable central line maintenance bundle compliance remains elusive. We identified frontline and family engagement as key drivers for this initiative. The baseline CLABSI rate for all our paediatric inpatient units (January 2016–January 2017) was 1.71/1000 central line days with maintenance bundle compliance at 87.9% (monthly range 44%–100%).ObjectiveTo reduce CLABSI by increasing central line maintenance bundle compliance to greater than 90% using kamishibai card (K-card) audits and family ‘key card’ education.MethodsWe transitioned our central line maintenance bundle audits from checklists to directly observed K-card audits. K-cards list the central line maintenance bundle elements to be reviewed with frontline staff. Key cards are cue cards developed using a plain-language summary of CLABSI K-cards and used by frontline staff to educate families. Key cards were distributed to families of children with central lines to simultaneously engage patients, families and frontline staff after a successful implementation of the K-card audit process. A survey was used to obtain feedback from families.ResultsIn the postintervention period (February 2017–December 2019), our CLABSI rate was 0.63/1000 central line days, and maintenance bundle compliance improved to 97.1% (monthly range 86%–100%, p<0.001). Of the 45 family surveys distributed, 20 (44%) were returned. Nineteen respondents (95%) reported being extremely satisfied with the key card programme and provided positive comments.ConclusionCombining the key card programme with K-card audits was associated with improved maintenance bundle compliance and a reduction in CLABSI. This programme has the potential for use in multiple healthcare improvement initiatives.
Systematic review of motor control and somatosensation assessment tests for the ankle
Authors: Bertrand-Charette Michaël , Dambreville Charline , Bouyer Laurent J , Roy Jean-Sébastien 
Published: July 2020

Background/AimAnkle sprains are frequent musculoskeletal injuries that can lead to sensorimotor deficits provoking long-term instability at the ankle joint. A broad variety of clinical tests currently exist to assess sensorimotor processing, and are commonly clinically referred to as proprioceptive tests. However, there is a discrepancy in the use of the term proprioception when looking at the main outcome of these tests. As identifying specific deficits is important for motor recovery, it is critical for clinicians to select the most appropriate tests.MethodsA systematic review of four databases was performed to provide an up-to-date review of the psychometric properties of available tests referred to as proprioceptive tests. Seventy-nine articles on eight ankle proprioceptive tests were included and critically appraised. Data on validity, reliability and responsiveness were extracted from the included articles and synthesised. The tests reviewed were then divided into two categories based on their main outcome: motor control or somatosensation.ResultsStrong evidence showed that theStar Excursion Balance Test, a motor control test, is capable of differentiating between stable and unstable ankles. Moderate evidence suggests that somatosensation tests, such asJoint Position Sense, are also valid and reliable, but their responsiveness has yet to be evaluated.ConclusionsTogether, these findings indicate that theStar Excursion Balance Testcan be used in the clinic to assess motor control based on its excellent psychometric properties. However, as ankle stability control involves complex sensorimotor interactions, care has to be taken regarding the use of this test as a specific tool for proprioception assessment.
Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans
Authors: Perrot Nicolas , Thériault Sébastien , Rigade Sidwell , Chen Hao Yu , Dina Christian , Martinsson Andreas , Boekholdt S Matthijs , Capoulade Romain , Le Tourneau Thierry , Messika-Zeitoun David , Engert James C , Wareham Nicholas J , Clavel Marie-Annick , Pibarot Philippe , Smith J Gustav , Schott Jean Jacques , Mathieu Patrick , Bossé Yohan , Thanassoulis George , Arsenault Benoit J 
Published: July 2020

BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans.Methods and resultsLp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at thePLA2G7locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351).ConclusionsHigher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
Planar Graphs Have Bounded Queue-Number
Authors: Dujmović Vida , Joret Gwenaël , Micek Piotr , Morin Pat , Ueckerdt Torsten , Wood David R. 
Published: July 2020

We show that planar graphs have bounded queue-number, thus proving a conjecture of Heath et al. [66] from 1992. The key to the proof is a new structural tool called
layered partitions
, and the result that every planar graph has a vertex-partition and a layering, such that each part has a bounded number of vertices in each layer, and the quotient graph has bounded treewidth. This result generalises for graphs of bounded Euler genus. Moreover, we prove that every graph in a minor-closed class has such a layered partition if and only if the class excludes some apex graph. Building on this work and using the graph minor structure theorem, we prove that every proper minor-closed class of graphs has bounded queue-number.

Layered partitions have strong connections to other topics, including the following two examples. First, they can be interpreted in terms of strong products. We show that every planar graph is a subgraph of the strong product of a path with some graph of bounded treewidth. Similar statements hold for all proper minor-closed classes. Second, we give a simple proof of the result by DeVos et al. [31] that graphs in a proper minor-closed class have low treewidth colourings.
Formal Verification of Spacecraft Control Programs
Authors: Lukyanov Georgy , Mokhov Andrey , Lechner Jakob 
Published: July 2020

Verification of correctness of control programs is an essential task in the development of space electronics; it is difficult and typically outweighs design and programming tasks in terms of development hours. This article presents a verification approach designed to help spacecraft engineers reduce the effort required for formal verification of low-level control programs executed on custom hardware.
The verification approach is demonstrated on an industrial case study. We present a REDuced instruction set for Fixed-point and INteger arithmetic (REDFIN), a processing core used in space missions, and its formal semantics expressed using the proposed metalanguage for state transformers, followed by examples of verification of simple control programs.
Serum Alpha-fetoprotein Levels and Clinical Outcomes in the Phase III CELESTIAL Study of Cabozantinib versus Placebo in Patients with Advanced Hepatocellular Carcinoma
Authors: Kelley Robin Kate , Meyer Tim , Rimassa Lorenza , Merle Philippe , Park Joong-Won , Yau Thomas , Chan Stephen L. , Blanc Jean-Frederic , Tam Vincent C. , Tran Albert , Dadduzio Vincenzo , Markby David W. , Kaldate Rajesh , Cheng Ann-Lii , El-Khoueiry Anthony B. , Abou-Alfa Ghassan K. 
Published: July 2020

Abstract

Purpose:
The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes.

Patients and Methods:
Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics.

Results:
Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62–1.04] for patients with baseline AFP &lt;400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54–0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45–0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35–0.71)]. HRs for PFS were consistent with those for OS.

Conclusions:
Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib.
A Phase II Trial of Tipifarnib for Patients with Previously Treated, Metastatic Urothelial Carcinoma HarboringHRASMutations
Authors: Lee Hye Won , Sa Jason K. , Gualberto Antonio , Scholz Catherine , Sung Hyun Hwan , Jeong Byong Chang , Choi Han Yong , Kwon Ghee Young , Park Se Hoon 
Published: July 2020

AbstractPurpose:To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missense HRAS mutations.Patients and Methods:A total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6).Results:We identified 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11:rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as an STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The overall response rate by intent-to-treat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response was observed in patients with urothelial carcinoma with wild-type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations.Conclusions:Oral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing HRAS mutations.
Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography
Authors: Hintz Hallie M. , Gallant Joseph P. , Vander Griend Donald J. , Coleman Ilsa M. , Nelson Peter S. , LeBeau Aaron M. 
Published: July 2020

Abstract

Purpose:
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, heterogeneous disease with few therapeutic strategies that significantly prolong survival. Innovative therapies for mCRPC are needed; however, the development of new therapies relies on accurate imaging to assess metastasis and monitor response. Standard imaging modalities for prostate cancer require improvement and there remains a need for selective and sensitive imaging probes that can be widely used in patients with mCRPC.

Experimental Design:
We evaluated the transmembrane protease fibroblast activation protein alpha (FAP) as a targetable cell surface antigen for mCRPC. Genomic and IHC analyses were performed to investigate FAP expression in prostate cancer. Our FAP-targeted antibody imaging probe, [89Zr]Zr-B12 IgG, was evaluated by PET/CT imaging in preclinical prostate cancer models.

Results:
Analysis of patient data documented FAP overexpression in metastatic disease across tumor subtypes. PET imaging with [89Zr]Zr-B12 IgG demonstrated high tumor uptake and long-term retention of the probe in the preclinical models examined. FAP-positive stroma tumor uptake of [89Zr]Zr-B12 IgG was 5-fold higher than the isotype control with mean %ID/cc of 34.13 ± 1.99 versus 6.12 ± 2.03 (n = 3/group; P = 0.0006) at 72 hours. Ex vivo biodistribution corroborated these results documenting rapid blood clearance by 24 hours and high tumor uptake of [89Zr]Zr-B12 IgG by 72 hours.

Conclusions:
Our study reveals FAP as a target for imaging the tumor microenvironment of prostate cancer. Validation of [89Zr]Zr-B12 IgG as a selective imaging probe for FAP-expressing tumors presents a new approach for noninvasive PET/CT imaging of mCRPC.
Comparison of Survival Estimates Following Recurrence, Persistence, or Second Primary Malignancy in Oropharyngeal Squamous Cell Carcinoma
Authors: Asarkar Ameya , Flores José Miguel , Nathan Cherie‐Ann O. 
Published: July 2020

ObjectiveThis study investigated survival among patients with oropharyngeal squamous cell carcinoma (OPSCC) after recurrence, persistence, and second primary malignancies (SPMs).Study DesignRetrospective cohort study.SettingPatients were treated at a tertiary cancer center.Subjects and MethodsPatients with OPSCC who had completed treatment between 2001 and 2017 were included. Survival estimates of 4 groups of patients were calculated: (1) patients who were disease free after initial treatment, (2) patients who had persistent disease, (3) those with recurrent disease, and (4) patients with SPMs. Cox proportional hazard models and parametric survival analyses (using Weibull distributions) were used to obtain hazard ratios (HRs) and time ratios (TRs).ResultsThe cohort included 364 patients. The crude overall SPM prevalence was 8.2%. Mean overall survival (OS) time in years for patients who remained disease free after treatment was 4.02 years. Among patients who experienced recurrence, the recurrence‐free survival (RFS) was 2.58 years while their mean (SD) OS was 3.67 (2.7) years. Participants who experienced persistence had a mean (SD) OS of 1.67 (1.68) years. Patients with observed SPMs had a mean (SD) OS of 6.39 (4.06) years since their primary cancer but shortened survivals of 1.75 (2.34) years since the secondary diagnosis. Differences were present even after accounting for human papillomavirus (HPV) and smoking status.ConclusionsOur findings stress the importance of active surveillance as per current National Comprehensive Cancer Network guidelines, irrespective of the HPV status or smoking status. Prospective studies with a larger number of SPM cases and longer follow‐up are needed to validate survival trends even beyond 5 years.
Pathologic Tumor Size as a Predictor of the Survival Outcomes of Patients With Glottic Carcinoma
Authors: Gong Hongli , Zhou Liang , Wu Haitao , Tao Lei , Zhang Ming , Chen Xiaoling , Li Xiaoming , Li Cai , Zhou Jian , Wang Shuyi 
Published: July 2020

ObjectivesThe purpose of this study was to evaluate the potential predictor of tumor size on rates of overall and disease‐free survival (OS and DFS) as determined by postoperative pathologic examination in patients with glottic carcinoma.Study DesignRetrospective cohort study.SettingTertiary care university hospital.Subjects and MethodsIn this study, 1337 consecutive patients with glottic carcinoma who underwent surgical treatment from 2005 to 2010 were retrospectively reviewed. The influence of tumor size that was evaluated by tumor area (tumor length × tumor width) on OS and DFS outcomes was assessed by Cox regression analyses.ResultsIn all, 1303 (97.5%) patients were male, and 34 (2.5%) were female, with a mean ± SD age of 60.4 ± 10 years. The 10‐year OS and DFS rates were 72.9% and 69.9%, respectively. The tumor area cutoff values that best discriminated OS and DFS rates were both 1.80 cm2. Patients with glottic carcinoma with a larger tumor area had inferior OS and DFS rates. Based on the results of multivariate analyses, tumor area was an independent prognostic factor for rates of OS (hazard ratio, 1.87; 95% CI, 1.37‐2.56; P <. 001) and DFS (hazard ratio, 1.79; 95% CI, 1.34‐2.38; P <. 001) in patients with glottic carcinoma.ConclusionsThe results of this study indicate that patients with glottic carcinoma with a tumor area >1.8 cm2 have inferior survival outcomes, and this factor independently predicts survival outcomes in these patients.