bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study
Authors: Brenner Andrew J , Peters Katherine B , Vredenburgh James , Bokstein Felix , Blumenthal Deborah T , Yust-Katz Shlomit , Peretz Idit , Oberman Bernice , Freedman Laurence S , Ellingson Benjamin M , Cloughesy Timothy F , Sher Naamit , Cohen Yael C , Lowenton-Spier Noa , Rachmilewitz Minei Tamar , Yakov Niva , Mendel Itzhak , Breitbart Eyal , Wen Patrick Y 
Published: December 2019

Abstract

Background
VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).

Methods
Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).

Results
VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.

Conclusions
Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.
SAUR49 Can Positively Regulate Leaf Senescence by Suppressing SSPP in Arabidopsis
Authors: Wen Zewen , Mei Yuanyuan , Zhou Jie , Cui Yanjiao , Wang Dan , Wang Ning Ning 
Published: December 2019

Abstract
The involvement of SMALL AUXIN-UP RNA (SAUR) proteins in leaf senescence has been more and more acknowledged, but the detailed mechanisms remain unclear. In the present study, we performed yeast two-hybrid assays and identified SAUR49 as an interactor of SENESCENCE SUPPRESSED PROTEIN PHOSPHATASE (SSPP), which is a PP2C protein phosphatase that negatively regulates Arabidopsis leaf senescence by suppressing the leucine-rich repeat receptor-like protein kinase SENESCENCE-ASSOCIATED RECEPTOR-LIKE KINASE (SARK), as reported previously by our group. The interaction between SAUR49 and SSPP was further confirmed in planta. Functional characterization revealed that SAUR49 is a positive regulator of leaf senescence. The accumulation level of SAUR49 protein increased during natural leaf senescence in Arabidopsis. The transcript level of SAUR49 was upregulated during SARK-induced premature leaf senescence but downregulated during SSPP-mediated delayed leaf senescence. Overexpression of SAUR49 significantly accelerated both natural and dark-induced leaf senescence in Arabidopsis. More importantly, SAUR49 overexpression completely reversed SSPP-induced delayed leaf senescence. In addition, overexpression of SAUR49 reversed the decreased plasma membrane H+-ATPase activity mediated by SSPP. Taken together, the results showed that SAUR49 functions in accelerating the leaf senescence process via the activation of SARK-mediated leaf senescence signaling by suppressing SSPP. We further identified four other SSPP-interacting SAURs, SAUR30, SAUR39, SAUR41 and SAUR72, that may act redundantly with SAUR49 in regulating leaf senescence. All these observations indicated that certain members of the SAUR family may serve as an important hub that integrates various hormonal and environmental signals with senescence signals in Arabidopsis.
Brexit is just a symptom: the constitutional weaknesses it reveals have serious consequences for health
Authors: Jarman Holly , Greer Scott L , McKee Martin 
Published: December 2019

Abstract
Brexit has direct and indirect negative health consequences, whether from economic damage or from the political paralysis and distraction from public health that it has created. Brexit is a public health problem in its own right, as other literature has shown—but, we argue, it is also a symptom of deeper problems in the governance of the United Kingdom. In particular, the combination of executive dominance, partisanship and opacity that give rise to the constitutional casualism of the Brexit decisions has already affected public health policy and will continue to do so unless addressed.
Is background methotrexate advantageous in extending TNF inhibitor drug survival in elderly patients with rheumatoid arthritis? An analysis of the British Society for Rheumatology Biologics Register
Authors: Bechman Katie , Oke Anuoluwapo , Yates Mark , Norton Sam , Dennison Elaine , Cope Andrew P , Galloway James B 
Published: December 2019

Abstract

Objective
To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults.

Methods
Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: &lt;75 and ≥75. Cox-proportional hazards models compared the risk of TNFi discontinuation from (i) any-cause, (ii) inefficacy and (iii) adverse events, between patients prescribed TNFi-monotherapy compared with TNFi MTX combination.

Results
The analysis included 15 700 patients. Ninety-five percent were &lt;75 years old. Comorbidity burden and disease activity were higher in the ≥75 cohort. Fifty-two percent of patients discontinued TNFi therapy during the follow-up period. Persistence with therapy was higher in the &lt;75 cohort. Patients receiving TNFi monotherapy were more likely to discontinue compared with patients receiving concomitant MTX [hazard rate 1.12 (1.06–1.18) P &lt;0.001]. This finding only held true in patients &lt;75 [hazard rate (HR) 1.11 (1.05–1.17) vs ≥75 [HR 1.13 (0.90–1.41)]. Examining TNFi discontinuation by cause revealed patients ≥75 receiving TNFi monotherapy were less likely to discontinue TNFi due to inefficacy [HR 0.66 (0.43–0.99) P=0.04] and more likely to discontinue therapy from adverse events [HR 1.41(1.02–1.96) P =0.04]. These results were supported by the multivariate adjustment in complete case and imputed analyses.

Conclusion
TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.
Determining factors for pertussis vaccination policy: A study in 5 EU countries
Authors: Wong Anabelle , Opinel Annick , Combes Simon Jean-Baptiste , Toubiana Julie , Brisse Sylvain 
Published: December 2019

AbstractPertussis vaccination policy varies across Europe, not only in the type of vaccine – whole cell (wP) vs. acellular (aP1/2/3/5) – but also in the schedule and recommendation for parents. This study aims to investigate the determining factors for the type of vaccine, immunization schedule and maternal immunization recommendation. From March to May 2019, experts in national health agencies and major academic or research institutions from Denmark, France, Poland, Sweden and the UK were invited to a semi-structured interview. Thematic analysis was performed on the transcripts using a codebook formulated by 3 coders. Inter-coder agreement was assessed. Fifteen expert interviews were conducted. The identified driving factors for pertussis vaccine policy were classified into three domains: scientific factors, sociological factors, and pragmatic factors. The determining factors for the type of vaccine were prescriber’s preference, concern of adverse events following immunization (AEFI), effectiveness, and consideration of other vaccine components in combined vaccines. The determining factors for infant schedule were immunity response and the potential to improve coverage and timeliness. The determining factors for maternal immunization were infant mortality and public acceptability. To conclude, socio-political and pragmatic factors were, besides scientific factors, important in determining the vaccine type, schedule of childhood immunization and recommendations for parents.
Urate, blood pressure and cardiovascular disease: updated evidence from Mendelian randomization and meta-analysis of clinical trials
Authors: Gill Dipender , Cameron Alan C. , Burgess Stephen , Li Xue , Doherty Daniel J. , Karhunen Ville , Abdul-Rahim Azmil H , Taylor-Rowan Martin , Zuber Verena , Tsao Philip S. , Klarin Derek ,   VA Million Veteran Program, Evangelou Evangelos , Elliott Paul , Damrauer Scott M. , Quinn Terence J , Dehghan Abbas , Theodoratou Evropi , Dawson Jesse , Tzoulaki Ioanna 
Published: December 2019

AbstractAimsTo investigate the effect of serum urate on blood pressure and cardiovascular disease (CVD) risk by updating evidence from Mendelian randomization (MR) analysis and meta-analysis of randomized controlled trials (RCTs).Methods and ResultsUsing recently available data from the Million Veterans Program and UK Biobank, the main MR analyses showed that every 1-standard deviation increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio 1.19, 95% confidence interval 1.10-1.30,P=4×10−5), peripheral artery disease (1.12, 95%CI 1.03 to 1.21,P=9×10−3), and stroke (1.11, 95%CI 1.05 to 1.18,P=2×10−4). In MR mediation analyses, SBP was estimated to mediate approximately one third the effect of urate on CVD risk. Systematic review and meta-analysis of RCTs showed a favorable effect of urate-lowering treatment on SBP (mean difference -2.55mmHg, 95%CI -4.06 to -1.05,P=1×10−3) and major adverse cardiovascular events (MACE) in those with previous CVD (OR 0.40, 95%CI 0.22 to 0.73,P=3×10−3), but no significant effect on MACE in all individuals (OR 0.73, 95%CI 0.48 to 1.09,P=0.12).ConclusionMR and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on CVD risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate-lowering may be of cardiovascular benefit.
Mendelian randomization of smoking behavior on cognitive status among older Americans
Authors: Fu Mingzhou , Faul Jessica D. , Jin Yuan , Ware Erin B. , Bakulski Kelly M. 
Published: December 2019

AbstractBackgroundSmoking is a likely risk factor for dementia, and smoking behavior has a strong genetic component. In this study, we jointly test the associations between cumulative genetic risk for smoking, smoking behavior, and cognitive status using a Mendelian randomization framework.MethodsWe conducted a cross-sectional study using the 2010 wave of the Health and Retirement Study database. Individuals aged between 50 and 90 were included. Smoking status was self-reported. Polygenic scores (PGSs) were calculated by weighting participant genotype by published smoking genome-wide association estimates. Cognitive status (normal, impaired, dementia) was measured using multiple assessments. A Mendelian randomization framework was used to infer causal relationships between smoking behavior and cognitive status via genetic instruments.ResultsAmong European ancestry participants (N = 8,735), current smoking behavior was positively associated with cognitive impairment (OR = 1.62, 95% CI: 1.29, 2.01) relative to normal cognition. Using smoking PGS as an instrumental variable, a causal relationship was observed between current smoking and cognitive impairment (OR = 1.53, 95% CI: 1.07, 2.18). There were no associations between smoking PGS, smoking behaviors and cognitive status in the African ancestry study sample (N = 2,511).ConclusionsCurrent smoking is a modifiable risk factor which causes cognitive impairment. Promotion of smoking cessation is important for public health. Further studies on dose and duration of smoking behaviors on cognitive impairment are critically needed, as well as in research other ancestries.
Mendelian randomization analysis of smoking behavior and cognitive ability on the Big Five
Authors: Adams Charleen D. 
Published: December 2019

AbstractTobacco smoke, a mutagen that can thin the brain’s cortex, might influence the Big Five (neuroticism, conscientiousness, agreeableness, extraversion, and openness). Cognitive ability, however, is a potential confounder, since it is associated with who smokes and with personality. Mendelian randomization (MR), which uses genetic variants as instrumental variables, can be used to probe the causal nature of these factors on personality. Here, MR was used to appraise smoking and cognitive ability on the Big Five and cognitive ability and neuroticism on social disparity. The results seem to suggest that smoking, independent of cognitive ability, leads people to be more neurotic and less extraverted and conscientious. Higher cognitive ability appears to make people less neurotic and more open, when accounting for smoking. Neuroticism appears to increase disparity, and higher cognitive ability appears to decrease it. Smoking may enhance disparity between those of lower and higher cognitive ability by exacerbating personality differences.
Brain-Computer Interface Robotics for Hand Rehabilitation After Stroke: A Systematic Review
Authors: Baniqued Paul Dominick E , Stanyer Emily C , Awais Muhammad , Alazmani Ali , Jackson Andrew E , Mon-Williams Mark A , Mushtaq Faisal , Holt Raymond J 
Published: December 2019

AbstractBackgroundHand rehabilitation is core to helping stroke survivors regain activities of daily living. Recent studies have suggested that the use of electroencephalography-based brain-computer interfaces (BCI) can promote this process. Here, we report the first systematic examination of the literature on the use of BCI-robot systems for the rehabilitation of fine motor skills associated with hand movement and profile these systems from a technical and clinical perspective.MethodsA search for January 2010-October 2019 articles using Ovid MEDLINE, Embase, PEDro, PsycINFO, IEEE Xplore and Cochrane Library databases was performed. The selection criteria included BCI-hand robotic systems for rehabilitation at different stages of development involving tests on healthy participants or people who have had a stroke. Data fields include those related to study design, participant characteristics, technical specifications of the system, and clinical outcome measures.Results30 studies were identified as eligible for qualitative review and among these, 11 studies involved testing a BCI-hand robot on chronic and subacute stroke patients. Statistically significant improvements in motor assessment scores relative to controls were observed for three BCI-hand robot interventions. The degree of robot control for the majority of studies was limited to triggering the device to perform grasping or pinching movements using motor imagery. Most employed a combination of kinaesthetic and visual response via the robotic device and display screen, respectively, to match feedback to motor imagery.Conclusion19 out of 30 studies on BCI-robotic systems for hand rehabilitation report systems at prototype or pre-clinical stages of development. Three studies report statistically significant improvements in functional recovery after stroke, but there is a need to develop a standard protocol for assessing technical and clinical outcomes so that the necessary evidence base on efficiency and efficacy can be developed.
A brief report: de novo copy number variants in children with attention deficit hyperactivity disorder
Authors: Martin Joanna , Hosking Grace , Wadon Megan , Agha Sharifah Shameem , Langley Kate , Rees Elliott , Owen Michael J , O’Donovan Michael , Kirov George , Thapar Anita 
Published: December 2019

AbstractBackgroundRecent case-control genetic studies of attention deficit hyperactivity disorder (ADHD) have implicated common and rare genetic risk alleles, highlighting the polygenic and complex aetiology of this neurodevelopmental disorder. Studies of other neurodevelopmental disorders, such as autism spectrum disorder (ASD), Tourette disorder, developmental delay/intellectual disability, and schizophrenia indicate that identification of specific risk alleles and additional insights into disorder biology can be gained by studying non-inherited de novo variation. In this study, we aimed to identify large de novo copy number variants (CNVs) in children with ADHD.MethodsChildren with a confirmed diagnosis of ADHD and their parents were genotyped and included in this sample. We used PennCNV to call large (>200kb) CNVs and identified those calls that were present in the proband and absent in both biological parents.ResultsIn 305 parent-offspring trios, we detected 14 de novo CNVs in 13 probands, giving a mutation rate of 4.6% and a per individual rate of 4.3%. This rate is higher than published reports in controls and similar to those observed for ASD, schizophrenia and Tourette disorder. We also identified de novo mutations at 4 genomic loci (15q13.1-13.2 duplication, 16p13.11 duplication, 16p12.2 deletion and 22q11.21 duplication) that have previously been implicated in other neurodevelopmental disorders, two of which (16p13.11 and 22q11.21) have also been implicated in case-control ADHD studies.ConclusionsOur study complements ADHD case-control genomic analyses and demonstrates the need for larger parent-offspring trio genetic studies to gain further insights into the complex aetiology of ADHD.
Hepatitis C Core Antigen test as an alternative for diagnosing HCV infection: mathematical model and cost-effectiveness analysis
Authors: Sadeghimehr Maryam , Keiser Olivia , Negro Francesco , Butsashvili Maia , Shilton Sonjelle , Tskhomelidze Irina , Tsereteli Maia , Bertisch Barbara , Estill Janne 
Published: December 2019

AbstractBackgroundThe cost and complexity of polymerase chain reaction (PCR) testing is a significant barrier for the diagnosis and treatment of patients infected with hepatitis C virus (HCV). We investigated the cost-effectiveness of various testing strategies using antigen as an alternative to PCR.MethodsWe developed a mathematical model for HCV to estimate the number of newly diagnosed individuals and cases of different stages of liver disease. We compared the following testing strategies: antibody test followed by PCR in case of positive antibody (baseline strategy); antibody test followed by HCV-antigen test (antibody-antigen); antigen test alone; and PCR test alone. We conducted cost-effectiveness analyses considering the costs of HCV testing (of both infected and uninfected individuals) (A1), liver-related complications (A2) and all costs including HCV treatment (A3). The model was parameterized for the country of Georgia, and several sensitivity analyses were conducted to generalize the findings for different settings.ResultsUsing the current standard of testing, 89% of infected individuals were detected. Comparatively, antibody-antigen and antigen testing alone detected 86% and 88% of infected individuals, respectively. PCR testing alone detected 91% of the infected individuals with the remaining 9% dying or spontaneously recovering before testing. In analysis A1, antibody-antigen testing was not found to be essentially cheaper compared to the baseline strategy. In analysis A2, strategies using PCR were cheaper than antigen-based strategies. In analysis A3, antibody-antigen testing was the cheapest strategy, followed by the baseline strategy, and PCR testing alone.ConclusionAntigen testing, either following a positive antibody test or alone, performed almost as well as the current practice of HCV testing. The cost-effectiveness of these strategies strongly depends on the inclusion of treatment costs.Lay summaryCore antigen testing is a reliable alternative test for diagnose HCV infection. Antigen-based strategies may be cost-effective, in particular if treatment costs are considered.HighlightsStrategies using an antigen test to diagnose HCV infection performed reasonably well compared with the traditional antibody- and PCR based approach.According to our study, antigen test alone missed about 3%, and antibody followed by PCR test 2% of HCV infected individuals.The maximum difference in quality-adjusted life expectancy across the different strategies of diagnosing HCV was only one month.
ULCERATIVE COLITIS-DERIVED COLONOID CULTURE: A Multi-Mineral-Approach to Improve Barrier Protein Expression
Authors: Aslam Muhammad N , McClintock Shannon D , Attili Durga , Pandya Shailja , Rehman Humza , Nadeem Daniyal M , Jawad-Makki Mohamed Ali H , Rizvi Areeba H , Berner Maliha M , Dame Michael K , Turgeon Danielle Kim , Varani James 
Published: December 2019

ABSTRACTBackgroundRecent studies demonstrated that Aquamin®, a calcium-, magnesium-, and multiple trace element-rich natural product, improves barrier structure and function in colonoids obtained from tissue of healthy subjects. The goal of the present study was to determine if the colonic barrier could be improved in tissue from subjects with ulcerative colitis (UC).MethodsColonoid cultures were established with tissue from 9 individuals with UC. The colonoids were then incubated for a 2-week period under control conditions (i.e., in culture medium with a final calcium concentration of 0.25 mM) or in the same medium supplemented with Aquamin®to provide 1.5 – 4.5 mM calcium. Effects on differentiation and barrier protein expression were determined using several approaches: phase-contrast & scanning electron microscopy, quantitative histology & immunohistology, mass spectrometry-based proteome assessment and transmission electron microscopy.ResultsAquamin®-treated colonoids demonstrated a modest up-regulation of tight junctional proteins but stronger induction of adherens junction proteins and desmosomal proteins. Increased desmosomes were seen at the ultrastructural level. Proteomic analysis also demonstrated increased expression of basement membrane proteins and hemidesmosomal components. Proteins expressed at the apical surface (mucins and trefoils) were also increased as were several additional proteins with anti-microbial activity or that modulate inflammation.ConclusionA majority of individuals including patients with UC do not reach the recommended daily intake for calcium and other minerals. The findings presented here suggest that adequate mineral intake might improve the colonic barrier.