bluuebunny/crossref_metadata_2025_split huggingface dataset:
A fatal case of Immune thrombocytopenia secondary to the immune checkpoint inhibitor ipilimumab in a patient with BRAF wild type metastatic melanoma
Authors: Hadfield Matthew J , Mui Gracia 
Published: February 2020

Introduction Immune checkpoint inhibitors have revolutionized the field of oncology in recent years. Ipilimumab is a monoclonal antibody that targets the protein cytotoxic T-lymphocyte 4, which is involved in the inhibition of cytotoxic T-lymphocytes. When uninhibited, cytotoxic T-lymphocytes can act to recognize and kill cancer cells. This increased activity of immune cells can inadvertently destroy healthy tissue leading to a class of side effects known as immune-related adverse events. Immune thrombocytopenia purpura secondary to checkpoint inhibitors is an uncommon complication (<1%) and in most instances resolve spontaneously without aggressive treatment. Case report We present a case of immune thrombocytopenia purpura developing in a patient recently started on ipilimumab for BRAF wild-type metastatic melanoma. The patient presented to his primary oncologist with confusion and lethargy. Subsequent blood work revealed a platelet count of 16,000 ng/mL. The patient was transferred to the emergency department where a computed tomography scan revealed bilateral frontal lobe hemorrhages. The patient was admitted to the intensive care unit for further management. Management and outcome The patient received IV immunoglobulins at 1 g/kg every 24 h in addition to IV Decadron 40 mg daily. In addition, the patient continued to receive significant platelet transfusions. The patient’s platelet count recovered to 78,000 ng/mL (baseline for this patient > 130,000 ng/mL.) The patient developed worsening mental status and was found to have significant increase in previously found bilateral frontal hemorrhages. The patient was transitioned to comfort measures only due to very poor prognosis and passed away in hospice care. Discussion Checkpoint inhibitors have provided durable responses in multiple cancers that previously had a paucity of treatment options. This case demonstrates that immune thrombocytopenia purpura is a possible adverse event of these therapies and thus platelet monitoring should be included in all patients.
Very high-dose methylprednisolone for treatment of nivolumab-induced limbic encephalitis: A case report
Authors: Taillefer Vincent-Thierry , Pigeon Marjorie , Chen Michelle , Larochelle Catherine , Florescu Marie , Bélanger Karl , Adam Jean-Philippe 
Published: February 2020

Introduction Nivolumab is a programmed death 1 (PD-1) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of eight different cancers including metastatic melanoma. Immune checkpoint blockade may lead to a range of neurologic immune-related adverse events (irAEs) with severity varying from mild to life-threatening, including encephalitis. Case report We describe a case of a 68-year-old man who developed alteration in mental status, physical weakness and fatigue after nine cycles of nivolumab 3 mg/kg every two weeks. These symptoms were compatible with a clinical diagnosis of autoimmune limbic encephalitis, although no specific antibodies were detected and the initial MRI was normal. Management and outcome The patient received intravenous methylprednisolone 1 g daily for 5 days, which was then converted to a maintenance dose of oral prednisone. The patient made a full clinical recovery but relapsed clinically upon steroid tapering, while hypersignal in the left mesial temporal suggestive of limbic encephalitis was observed on repeated MRI. Discussion Because of the prevailing usage of nivolumab in many cancer protocols, this case highlights the importance of rapidly recognising neurological impairment in patients treated with nivolumab and of initiating very high doses of corticosteroids.
The prognostic importance of VEGF-A, PDGF-BB and c-MET in patients with metastatic colorectal cancer
Authors: Inanc Mevlude , Sirakaya Hatice Aslan , Karaman Hatice , Bozkurt Oktay 
Published: February 2020

Introduction We aimed to assess the effect of VEGF-A, PDGF-BB, and c-Met expression levels on survival in patients with metastatic colorectal cancer receiving bevacizumab therapies. Patients and methods A total of 105 patients diagnosed with metastatic colorectal cancer between the years 2006 and 2016 were included in the research retrospectively. Results The progression-free survival (PFS) durations of patients with high expression levels of VEGF-A and with low expression levels of VEGF-A were 11 months and 10 months (p = 0.44), respectively. The PFS durations of patients with high PDGF-BB expression and low PDGF-BB expression were 12 months and 10 months (p = 0.16), respectively, while the PFS durations of patients with high and low c-Met expression were 8 months and 13 months (p = 0.005), respectively. Metastatic overall survival was 27 months and 18 months (p = 0.05) in patients with high and low VEGF-A expression levels, respectively, 31 months and 21 months (p = 0.16) in patients with high and low PDGF-BB expression levels, respectively, and 21 months and 26 months (p = 0.11) in patients with high and low c-Met expression levels, respectively. Conclusion The results of this research revealed a high c-Met expression relationship with worse PFS and low VEGF-A expression associated with poor metastatic overall survival in patients with metastatic colorectal cancer receiving bevacizumab therapies.
Predictors of long-term outcomes after polytetrafluoroethylene-covered stent-graft repair of peripheral arterial aneurysms, pseudo-aneurysms, and arterio-venous fistulas
Authors: Topcuoglu Osman Melih , Altay Cetin Murat , Alpar Ayhan , Kucukay Fahrettin 
Published: February 2020

Objectives To evaluate the primary patency rate at three years for the infra-aortic peripheral arterial pathologies treated with polytetrafluoroethylene-covered stent-grafts. Methods Patients treated with self-expandable polytetrafluoroethylene-covered stent-grafts for infra-aortic peripheral arterial aneurysms, pseudo-aneurysms, and arterio-venous fistulas were evaluated retrospectively. A total of 48 patients (35 male, 13 female; mean age: 53.8 ± 13.5) were included with 29.0 ± 16.5 months (median 27, range 4–70) mean follow-up period. The primary objective was to determine the primary patency rate at three years. The secondary objectives were to compare type and localization of pathology, and length and diameter of the stent-grafts with primary patency rate. Kaplan–Meier test was used as the main statistical method. Results Overall mean primary patency rate at three years was 77.10%. Polytetrafluoroethylene-covered stent-graft implantation in aneurysms had worse primary patency rate than pseudo-aneurysms and arterio-venous fistulas (66.6%, P = 0.03; 76.9%, P = 0.03; 88.2%, P = 0.01, respectively). Stent-graft location, length, and diameter are not associated with primary patency rate ( P > 0.05) but stent diameter is associated with better primary assisted and secondary patency rates ( P < 0.05). Conclusions Pathology of the lesion is associated with the long-term primary patency rate of polytetrafluoroethylene-covered stent-grafts but not the stent-graft location, length, or diameter. Stent diameter is associated with primary assisted and secondary patency rates.
Changes and significance of T helper-9 cells and interleukin-9 in patients with atherosclerotic chronic lower limb ischemia: Effect on IL-17 release
Authors: Moaaz Mai , Lotfy Hassan 
Published: February 2020

Objectives Atherosclerosis is considered as a chronic inflammatory disorder where the central role of T cells in its pathogenesis is well known. T helper-9 cells have a distinctive effect upon the inflammatory processes. They stimulate macrophages via secretion of their cytokine interleukin-9. Based on its known involvement with other inflammatory disorders, we hypothesized that interleukin-9 might be associated with the inflammatory limb of peripheral atherosclerotic disease. Methods We tested this hypothesis on peripheral blood mononuclear cells (PBMCs) and freshly resected arterial tissues from 84 patients with peripheral arterial occlusive disease (PAOD) and 50 non-atherosclerotic subjects. A number of experimental methods were used including flow cytometry analysis of T helper-9 cells using anti-CD3, anti-CD4, and anti-interleukin-9monoclonal antibodies as well as real-time polymerase chain reaction for the assessment of gene expression of interleukin-9. In addition, circulating serum levels of interleukin-9 were measured using enzyme linked immunosorbent assay. We also evaluated the ability of recombinant interleukin-9 to modulate IL-17 release in cultured isolated CD3+ T cells with relation to atherosclerotic disorder in vitro. Results and conclusions Here we report increased percentages of T helper-9 cells and interleukin-9 levels in patients with chronic lower limb atherosclerotic ischemia, compared to healthy controls. Through investigation of different atherosclerotic patient populations with different disease stages, we found elevated interleukin-9 level both systemically and within the lesion and increased expression of cells in severe disease stages. The current study also revealed enhanced expression of mRNA levels of interleukin-9 within the atherosclerotic lesion when compared with non-atherosclerotic vessels. Levels of released IL-17 in CD3+ T cell culture supernatants supplemented with interleukin-9 were significantly positively correlated in the enrolled patients. The results suggest a role for T helper-9 cells and IL-9 in atherosclerotic process, potentially involving IL-17-mediated mechanisms. Indeed, we found that interleukin-9 promoted IL-17 release in PBMCs, with a particularly marked response in severe disease.
A review of available software for adaptive clinical trial design
Authors: Grayling Michael John , Wheeler Graham Mark 
Published: February 2020

Background/aims: The increasing cost of the drug development process has seen interest in the use of adaptive trial designs grow substantially. Accordingly, much research has been conducted to identify barriers to increasing the use of adaptive designs in practice. Several articles have argued that the availability of user-friendly software will be an important step in making adaptive designs easier to implement. Therefore, we present a review of the current state of software availability for adaptive trial design. Methods: We review articles from 31 journals published in 2013–2017 that relate to methodology for adaptive trials to assess how often code and software for implementing novel adaptive designs is made available at the time of publication. We contrast our findings against these journals’ policies on code distribution. We also search popular code repositories, such as Comprehensive R Archive Network and GitHub, to identify further existing user-contributed software for adaptive designs. From this, we are able to direct interested parties toward solutions for their problem of interest. Results: Only 30% of included articles made their code available in some form. In many instances, articles published in journals that had mandatory requirements on code provision still did not make code available. There are several areas in which available software is currently limited or saturated. In particular, many packages are available to address group sequential design, but comparatively little code is present in the public domain to determine biomarker-guided adaptive designs. Conclusions: There is much room for improvement in the provision of software alongside adaptive design publications. In addition, while progress has been made, well-established software for various types of trial adaptation remains sparsely available.
Rethinking the allocation criteria of the labour law rights and protections: A risk-based approach
Authors: Fusco Federico 
Published: February 2020

The present paper investigates the ongoing validity of the notion of subordination as selection criteria to allocate the labour protections in the contemporary economic framework. The gig economy is deeply affecting the way of working, transforming the employee in a service provider. This phenomenon is partially due to the progressive shift from a firm-based production model towards a market transaction based one. Although its lawfulness is still unclear, it highlights that the way of working is changing in a way that struggles to fit into the classic legal categories. This is mainly due to the fact that the labour protections are usually bestowed moving from a notion of subordination highly focused on the organisational element. Thus, economic actors suffering from the same economic weakness of the employees, but organisationally independent, struggle to obtain the necessary protections. Moving from those remarks the author suggests rethinking the allocation criteria of the labour protections, adopting economic weakness as the main criterion. This category should encompass all the individuals performing a working activity that are not able to significantly influence its financial outcome. The aim of such reform should be to extend the labour protections to all the subjects needing them. The final part of the paper investigates the possible solutions under the current legal framework. The major finding is that under certain circumstances the gig workers can be qualified as temporary employees not of the platform, but of the contractor. In this scenario, the digital platforms should be deemed as job-placement service providers and, thus, they should comply with the relevant provisions. These include the eventual need of administrative authorisations and the free-of-charge principle, whose violations represent, in several jurisdictions, a criminal offence
The load factor in bolted timber joints under external tensile loads
Authors: Matsubara Doppo , Wakashima Yoshiaki , Shimizu Hidemaru , Kitamori Akihisa 
Published: February 2020

AbstractThese experiments sought to empirically determine how the initial tightening force influences the ratio of the axial bolt force to the tensile load (load factor) and the load required to separate the joint interface (interface separation load) in tensile bolted joints of glued laminated timber. Load factor decreases with increasing initial tightening force; however, this tendency is reduced the greater the washer–member-end distance. In addition, tensile stiffness increases with decreasing load factor, and the interface separation load increases with increasing initial tightening force. However, in actual testing, the joint interface separated at a lower load that predicted mathematically based on the load factor and initial tightening force.
Altered expression levels of autophagy-associated proteins during exercise preconditioning indicate the involvement of autophagy in cardioprotection against exercise-induced myocardial injury
Authors: Yuan Jian-Qi , Yuan Yang , Pan Shan-Shan , Cai Ke 
Published: February 2020

AbstractExercise has been reported to induce autophagy. We hypothesized that exercise preconditioning (EP)-related autophagy in cardiomyocytes could be attributed to intermittent ischemia–hypoxia, allowing the heart to be protected for subsequent high-intensity exercise (HE). We applied approaches, chromotrope-2R brilliant green (C-2R BG) staining and plasma cTnI levels measuring, to characterize two periods of cardioprotection after EP: early EP (EEP) and late EP (LEP). Further addressing the relationship between ischemia–hypoxia and autophagy, key proteins, Beclin1, LC3, Cathepsin D, and p62, were determined by immunohistochemical staining, western blotting, and by their adjacent slices with C-2R BG. Results indicated that exercise-induced ischemia–hypoxia is a key factor in Beclin1-dependent autophagy. High-intensity exercise was associated with the impairment of autophagy due to high levels of LC3II and unchanged levels of p62, intermittent ischemia–hypoxia by EP itself plays a key role in autophagy, which resulted in more favorable cellular effects during EEP-cardioprotection compared to LEP.
Inducible nitric oxide synthase and systemic lupus erythematosus: a systematic review and meta-analysis
Authors: Pan Lu , Yang Sirui , Wang Jinghua , Xu Meng , Wang Shaofeng , Yi Huanfa 
Published: February 2020

AbstractBackgroundThere is a growing body of evidences indicating iNOS has involved in the pathogenesis of SLE. However, the role of iNOS in SLE is inconsistency. This systematic review was designed to evaluate the association between iNOS and SLE.ResultsSix studies were included, reporting on a total of 277 patients with SLE. The meta-analysis showed that SLE patients had higher expression of iNOS at mRNA level than control subjects (SMD = 2.671, 95%CI = 0.446–4.897, z = 2.35,p = 0.019), and a similar trend was noted at the protein level (SMD = 3.602, 95%CI = 1.144–6.059, z = 2.87,p = 0.004) and positive rate of iNOS (OR = 9.515, 95%CI = 1.915–47.281, z = 2.76,p = 0.006) were significantly higher in SLE group compared with control group. No significant difference was observed on serum nitrite level between SLE patients and control subjects (SMD = 2.203, 95%CI = -0.386–4.793, z = 1.64,p = 0.095). The results did not modify from different sensitivity analysis, representing the robustness of this study. No significant publication bias was detected from Egger’s test.ConclusionsThere was a positive correlation between increasing iNOS and SLE. However, the source of iNOS is unknown. Besides NO pathway, other pathways also should be considered. More prospective random studies are needed in order to certify our results.
Crosstalk in the darkness: bulb vernalization activates meristem transition via circadian rhythm and photoperiodic pathway
Authors: Ben Michael Tomer E. , Faigenboim Adi , Shemesh-Mayer Einat , Forer Itzhak , Gershberg Chen , Shafran Hadass , Rabinowitch Haim D. , Kamenetsky-Goldstein Rina 
Published: February 2020

AbstractBackgroundGeophytes possess specialized storage organs - bulbs, tubers, corms or rhizomes, which allow their survival during unfovarable periods and provide energy support for sprouting and sexual and vegetative reproduction. Bulbing and flowering of the geophyte depend on the combined effects of the internal and external factors, especially temperature and photoperiod. Many geophytes are extensively used in agriculture, but mechanisms of regulation of their flowering and bulbing are still unclear.ResultsComparative morpho-physiological and transcriptome analyses and quantitative validation of gene expression shed light on the molecular regulation of the responses to vernalization in garlic, a typical bulbous plant. Long dark cold exposure of bulbs is a major cue for flowering and bulbing, and its interactions with the genetic makeup of the individual plant dictate the phenotypic expression during growth stage. Photoperiod signal is not involved in the initial nuclear and metabolic processes, but might play role in the later stages of development, flower stem elongation and bulbing. Vernalization for 12 weeks at 4 °C and planting in November resulted in flower initiation under short photoperiod in December–January, and early blooming and bulbing. In contrast, non-vernalized plants did not undergo meristem transition. Comparisons between vernalized and non-vernalized bulbs revealed ~ 14,000 differentially expressed genes.ConclusionsLow temperatures stimulate a large cascades of molecular mechanisms in garlic, and a variety of flowering pathways operate together for the benefit of meristem transition, annual life cycle and viable reproduction results.The circadian clock appears to play a central role in the transition of the meristem from vegetative to reproductive stage in bulbous plant, serving as integrator of the low-temperature signals and the expression of the genes associated with vernalization, photoperiod and meristem transition. The reserved photoperiodic pathway is integrated at an upstream point, possibly by the same receptors. Therefore, in bulb, low temperatures stimulate cascades of developmental mechanisms, and several genetic flowering pathways intermix to achieve successful sexual and vegetative reproduction.
The methods and baseline characteristics of a VA randomized controlled study evaluating supported employment provided in primary care patient aligned care teams
Authors: Davis Lori L. , Blansett Catherine M. , Mumba Mercy N. , MacVicar David , Toscano Richard , Pilkinton Patricia , Gay Whitney , Bartolucci Al 
Published: February 2020

AbstractBackgroundThis article describes the design and baseline sample of a single-site trial comparing Individual Placement and Support (IPS) supported employment delivered within a Veterans Health Administration (VHA) primary care Patient Aligned Care Team (PACT) to treatment-as-usual vocational rehabilitation (TAU-VR) that includes transitional work.MethodsUnemployed U.S. military veterans receiving care in a VHA PACT who were seeking competitive work, otherwise eligible for vocational rehabilitation, and diagnosed with a mental health condition other than a psychotic or bipolar I disorder were prospectively randomized to receive either IPS or TAU-VR. Employment outcomes and measures of quality of life, self-esteem, and community reintegration are being collected for 12 months.ResultsThe participant sample (n = 119) is comprised of 17.6% female, 73.1% African-Americans, and 1.7% Hispanic. Average age is 38.2 (SD ± 8.41) years; 80.7% served in the military since 2001; 78% are receiving or applying for U.S. Department of Veterans Affairs (VA) service-connected disability; 26.9% have not held a competitive job in the past 3 years; and the average length of pre-randomization unemployment is 1.4 (SD ± 2.3) years.ConclusionsUnique design features include evaluating the efficacy of evidenced-based IPS within the primary care setting, having broad diagnostic eligibility, and defining the primary outcome criterion as “steady employment”, i.e. holding a competitive job for ≥26 weeks of the 12-month follow-up period. The findings illustrate the characteristics of a primary care veteran sample in need of employment services.Trial registrationwww.clinicaltrials.govIdentifier: NCT02400736.