bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of TERT promoter mutations in conjunctival melanomas in addition to clinicopathological features
Authors: van Ipenburg J A , Naus N C , Dubbink H J , van Ginderdeuren R , Missotten G S , Paridaens D , Verdijk R M 
Published: October 2020

AimsTo evaluate the prognostic value of clinical, histopathological and molecular features and to relate different treatment modalities to clinical outcome in conjunctival melanomas (CM).MethodsRetrospective review of clinical, histopathological and BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutation status and treatment modalities, correlated to recurrence and metastasis in 79 patients with CM, diagnosed between 1987 and 2015 in three tertiary referral centres in the Netherlands and Belgium.ResultsOut of 78 evaluable patients, recurrences occurred in 16 patients and metastasis in 12 patients (median follow-up time 35 months (0–260 months)). Tumour thickness >2 mm, pT status, the presence of epithelioid cells, ulceration and mitoses was significantly correlated with metastasis (p value 0.046, 0.01, 0.02, 0.001 and 0.003, respectively). Furthermore, CM frequently harbour BRAF V600E and TERT promoter mutations (29% and 43%, respectively). TERT promoter mutations were correlated to shorter metastasis-free survival (p value 0.002). No significant correlation was found for clinical parameters and metastatic disease. Palpebral, forniceal and caruncular melanomas were more prone to develop recurrences (p value: 0.03). Most CM were treated with excision with adjuvant therapy.ConclusionIn line with the recommendations in the Eighth Edition of the American Joint Committee on Cancer Staging for CM, the pathology report should include information about pT status, tumour thickness, presence of epithelioid cells, ulceration and mitoses. Furthermore, information about the presence of a TERT promoter mutation and BRAF V600E mutation is of interest for therapeutic decision making. The presence of a TERT promoter mutation is correlated to metastatic disease.
Employing body-fixed sensors and machine learning to predict physical activity in military personnel
Authors: Papadakis Nikolaos , Havenetidis K , Papadopoulos D , Bissas A 
Published: October 2020

IntroductionThis was a feasibility pilot study aiming to develop and validate an activity recognition system based on a custom-made body-fixed sensor and driven by an algorithm for recognising basic kinetic movements in military personnel. The findings of this study are deemed essential in informing our development process and contributing to our ultimate aim which is to develop a low-cost and easy-to-use body-fixed sensor for military applications.MethodsFifty military participants performed a series of trials involving walking, running and jumping under laboratory conditions in order to determine the optimal, among five machine learning (ML), classifiers. Thereafter, the accuracy of the classifier was tested towards the prediction of these movements (15 183 measurements) and in relation to participants’ gender and fitness level.ResultsRandom forest classifier showed the highest training and validation accuracy (98.5% and 92.9%, respectively) and classified participants with differences in type of activity, gender and fitness level with an accuracy level of 83.6%, 70.0% and 62.2%, respectively.ConclusionsThe study showed that accurate prediction of various dynamic activities can be achieved with high sensitivity using a low-cost easy-to-use sensor and a specific ML model. While this technique is in a development stage, our findings demonstrate that our body-fixed sensor prototype alongside a fully trained validated algorithm can strategically support military operations and offer valuable information to commanders controlling operations remotely. Further stages of our developments include the validation of our refined technique on a larger range of military activities and groups by combining activity data with physiological variables to predict phenomena relating to the onset of fatigue and performance decline.
Proposal of a clinical care pathway for quality and safe management of headache patients: a consensus study report
Authors: Pascual Julio , Pozo-Rosich Patricia , Carrillo Irene , Rodríguez-Justo Sandra , Jiménez-Hernández Dolores , Layos-Romero Almudena , Bailón-Santamaría Cristina , Torres Antonio , Martínez-García Alba , Ignacio Emilio , Mira José Joaquín 
Published: October 2020

BackgroundHeadache is one of the most prevalent and disabling conditions. Its optimal management requires a coordinated and comprehensive response by health systems, but there is still a wide variability that compromises the quality and safety of the care process.PurposeTo establish the basis for designing a care pathway for headache patients through identifying key subpathways in the care process and setting out quality and clinical safety standards that contribute to providing comprehensive, adequate and safe healthcare.MethodA qualitative research study based on the consensus conference technique. Eleven professionals from the Spanish National Health System participated, seven of them with clinical experience in headache and four specialists in healthcare management and quality. First, identification of the key subpathways in the care process for headache, barriers/limitations for optimal quality of care, and quality and safety standards applied in each subpathway. Second, two consecutive consensus rounds were carried out to assess the content of the subpathway level descriptors, until the expert agreement was reached. Third, findings were assessed by 17 external healthcare professionals to determine their understanding, adequacy and usefulness.ResultsSeven key subpathways were identified: (1) primary care, (2) emergency department, (3) neurology department, (4) specialised headache unit, (5) hospitalisation, (6) outpatients and (7) governance and management. Sixty-seventh barriers were identified, the most frequent being related to diagnostic errors (36,1%), resource deficiency (25%), treatment errors (19,4%), lack of health literacy (13,9%) and inadequate communications with care transitions (5,6%). Fifty-nine quality and 31 safety standards were defined. They were related to evaluation (23.3%), patient safety (21.1%), comprehensive care (12.2%), treatment (12.2%), clinical practice guidelines (7.8%), counselling (6.7%), training (4.4%) and patient satisfaction (3.3%).ConclusionsThis proposal incorporates a set of indicators and standards, which can be used to define a pathway for headache patients and determine the levels of quality.
Impact of transition programmes for students and new graduate nurses on workplace bullying, violence, stress and resilience: a scoping review protocol
Authors: Alshawush Khadijah Ali , Hallett Nutmeg , Bradbury-Jones Caroline 
Published: October 2020

IntroductionThe shortage of nurses is projected to grow, and the number of new graduate nurses (NGNs) who are predicted to replace expert nurses has increased. Meanwhile, those NGNs leaving their job within the first year, give various reasons for leaving, including workplace bullying and violence. In response, some hospitals and universities have developed nurse transition programmes such as nurse residency programmes and nurse internship programmes to attract NGNs and to assist in their changing status from education to practice. Although these programmes have been successful in decreasing the turnover rate for new nurses and are cost-effective, their impact on workplace bullying and violence has not been systematically reviewed and is yet to be determined. A scoping review will be conducted to address this gap. The aim is to identify current knowledge regarding the content of transition programmes and their impact in supporting NGNs dealing with workplace violence, bullying and stress.Methods and analysisArksey and O’Malley’s scoping framework and the Joanna Briggs Institute scoping review guidance will guide the methodology process of the review. Published studies, with no date limit, will be identified through the electronic databases (CINAHL, Scopus, MEDLINE, Web of Science, ASSIA, PsycINFO, Embase, PROSPERO and ProQuest Dissertation) and reference lists. Primary key terms will be ‘novice nurse’, ‘new graduate nurses’ and ‘transition programmes’. Two reviewers, guided by standardised procedures, will perform the study selection process independently. Data from the selected studies will be extracted using a data extraction form. Thematic analysis (for qualitative papers) and descriptive summary of the results (for quantitative papers) will be performed.Ethics and disseminationEthical approval is not required for this review. Findings will be used to inform future study designs to evaluate the transition programmes and disseminated via peer-reviewed journals and conferences.
CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation
Authors: Dragon Anna Christina , Zimmermann Katharina , Nerreter Thomas , Sandfort Deborah , Lahrberg Julia , Klöß Stephan , Kloth Christina , Mangare Caroline , Bonifacius Agnes , Tischer-Zimmermann Sabine , Blasczyk Rainer , Maecker-Kolhoff Britta , Uchanska-Ziegler Barbara , Abken Hinrich , Schambach Axel , Hudecek Michael , Eiz-Vesper Britta 
Published: October 2020

BackgroundImmunosuppressive therapy or T-cell depletion in transplant patients can cause uncontrolled growth of Epstein-Barr virus (EBV)-infected B cells resulting in post-transplant lymphoproliferative disease (PTLD). Current treatment options do not distinguish between healthy and malignant B cells and are thereby often limited by severe side effects in the already immunocompromised patients. To specifically target EBV-infected B cells, we developed a novel peptide-selective chimeric antigen receptor (CAR) based on the monoclonal antibody TÜ165 which recognizes an Epstein-Barr nuclear antigen (EBNA)−3C-derived peptide in HLA-B*35 context in a T-cell receptor (TCR)-like manner. In order to attract additional immune cells to proximity of PTLD cells, based on the TÜ165 CAR, we moreover generated T cells redirected for universal cytokine-mediated killing (TRUCKs), which induce interleukin (IL)-12 release on target contact.MethodsTÜ165-based CAR-T cells (CAR-Ts) and TRUCKs with inducible IL-12 expression in an all-in-one construct were generated. Functionality of the engineered cells was assessed in co-cultures with EBNA-3C-peptide-loaded, HLA-B*35-expressing K562 cells and EBV-infected B cells as PTLD model. IL-12, secreted by TRUCKs on target contact, was further tested for its chemoattractive and activating potential towards monocytes and natural killer (NK) cells.ResultsAfter co-cultivation with EBV target cells, TÜ165 CAR-Ts and TRUCKs showed an increased activation marker expression (CD137, CD25) and release of proinflammatory cytokines (interferon-γ and tumor necrosis factor-α). Moreover, TÜ165 CAR-Ts and TRUCKs released apoptosis-inducing mediators (granzyme B and perforin) and were capable to specifically lyse EBV-positive target cells. Live cell imaging revealed a specific attraction of TÜ165 CAR-Ts around EBNA-3C-peptide-loaded target cells. Of note, TÜ165 TRUCKs with inducible IL-12 showed highly improved effector functions and additionally led to recruitment of monocyte and NK cell lines.ConclusionsOur results demonstrate that TÜ165 CAR-Ts recognize EBV peptide/HLA complexes in a TCR-like manner and thereby allow for recognizing an intracellular EBV target. TÜ165 TRUCKs equipped with inducible IL-12 expression responded even more effectively and released IL-12 recruited additional immune cells which are generally missing in proximity of lymphoproliferation in immunocompromised PTLD patients. This suggests a new and promising strategy to specifically target EBV-infected cells while sparing and mobilizing healthy immune cells and thereby enable control of EBV-associated lymphoproliferation.
Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor
Authors: Zhang Boning , Napoleon John Victor , Liu Xin , Luo Qian , Srinivasarao Madduri , Low Philip S 
Published: October 2020

BackgroundMost adoptive cell therapies (ACTs) suffer from an inability to control the therapeutic cell’s behavior following its transplantation into a patient. Thus, efforts to inhibit, activate, differentiate or terminate an ACT after patient reinfusion can be futile, because the required drug adversely affects other cells in the patient.MethodsWe describe here a two domain fusion receptor composed of a ligand-binding domain linked to a recycling domain that allows constitutive internalization and trafficking of the fusion receptor back to the cell surface. Because the ligand-binding domain is designed to bind a ligand not normally present in humans, any drug conjugated to this ligand will bind and endocytose selectively into the ACT.ResultsIn two embodiments of our strategy, we fuse the chronically endocytosing domain of human folate receptor alpha to either a murine scFv that binds fluorescein or human FK506 binding protein that binds FK506, thereby creating a fusion receptor composed of largely human components. We then create the ligand-targeted drug by conjugating any desired drug to either fluorescein or FK506, thereby generating a ligand-drug conjugate with ~10-9M affinity for its fusion receptor. Using these tools, we demonstrate that CAR T cell activities can be sensitively tuned down or turned off in vitro as well as tightly controlled following their reinfusion into tumor-bearing mice.ConclusionsWe suggest this ‘chimeric endocytosing receptor’ can be exploited to manipulate not only CAR T cells but other ACTs following their reinfusion into patients. With efforts to develop ACTs to treat diseases including diabetes, heart failure, osteoarthritis, cancer and sickle cell anemia accelerating, we argue an ability to manipulate ACT activities postinfusion will be important.
Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy
Authors: Cubas Rafael , Khan Zia , Gong Qian , Moskalenko Marina , Xiong Huizhong , Ou Qinglin , Pai Christine , Rodriguez Ryan , Cheung Jeanne , Chan Andrew C 
Published: October 2020

BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors inPtpn22-/-mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibilityPtpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.
Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions
Authors: Bauché David , Mauze Smita , Kochel Christina , Grein Jeff , Sawant Anandi , Zybina Yulia , Blumenschein Wendy , Yang Peng , Annamalai Lakshmanan , Yearley Jennifer H , Punnonen Juha , Bowman Edward P , Chackerian Alissa , Laface Drake 
Published: October 2020

BackgroundProgrammed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.MethodsWe have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.ResultsSustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.ConclusionThese data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.
Toward a more inclusive paradigm: thrombectomy for stroke patients with pre-existing disabilities
Authors: Regenhardt Robert W , Young Michael J , Etherton Mark R , Das Alvin S , Stapleton Christopher J , Patel Aman B , Lev Michael H , Hirsch Joshua A , Rost Natalia S , Leslie-Mazwi Thabele M 
Published: October 2020

BackgroundPersons with pre-existing disabilities represent over one-third of acute stroke presentations, but account for a far smaller proportion of those receiving endovascular thrombectomy (EVT) and thrombolysis. This is despite existing ethical, economic, legal, and social directives to maximize equity for this vulnerable population. We sought to determine associations between baseline modified Rankin Scale (mRS) and outcomes after EVT.MethodsIndividuals who underwent EVT were identified from a prospectively maintained database. Demographics, medical history, presentations, treatments, and outcomes were recorded. Baseline disability was defined as baseline mRS≥2. Accumulated disability was defined as the delta between baseline mRS and absolute 90-day mRS.ResultsOf 381 individuals, 49 had baseline disability (five with mRS=4, 23 mRS=3, 21 mRS=2). Those with baseline disability were older (81 vs 68 years, P<0.0001), more likely female (65% vs 49%, P=0.032), had more coronary disease (39% vs 20%, P=0.006), stroke/TIA history (35% vs 15%, P=0.002), and higher NIH Stroke Scale (19 vs 16, P=0.001). Baseline mRS was associated with absolute 90-day mRS ≤2 (OR=0.509, 95%CI=0.370–0.700). However, baseline mRS bore no association with accumulated disability by delta mRS ≤0 (ie, return to baseline, OR=1.247, 95%CI=0.943–1.648), delta mRS ≤1 (OR=1.149, 95%CI=0.906–1.458), delta mRS ≤2 (OR 1.097, 95% CI 0.869–1.386), TICI 2b–3 reperfusion (OR=0.914, 95%CI=0.712–1.173), final infarct size (P=0.853, β=−0.014), or intracerebral hemorrhage (OR=0.521, 95%CI=0.244–1.112).ConclusionsWhile baseline mRS was associated with absolute 90-day disability, there was no association with accumulated disability or other outcomes. Patients with baseline disability should not be routinely excluded from EVT based on baseline mRS alone.
Association between SARS-CoV-2 infection, exposure risk and mental health among a cohort of essential retail workers in the USA
Authors: Lan Fan-Yun , Suharlim Christian , Kales Stefanos N , Yang Justin 
Published: October 2020

ObjectivesTo investigate SARS-CoV-2 (the virus causing COVID-19) infection and exposure risks among grocery retail workers, and to investigate their mental health state during the pandemic.MethodsThis cross-sectional study was conducted in May 2020 in a single grocery retail store in Massachusetts, USA. We assessed workers’ personal/occupational history and perception of COVID-19 by questionnaire. The health outcomes were measured by nasopharyngeal SARS-CoV-2 reverse transcriptase PCR (RT-PCR) results, General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9).ResultsAmong 104 workers tested, 21 (20%) had positive viral assays. Seventy-six per cent positive cases were asymptomatic. Employees with direct customer exposure had an odds of 5.1 (95% CI 1.1 to 24.8) being tested positive for SARS-CoV-2 after adjustments. As to mental health, the prevalence of anxiety and depression (ie, GAD-7 score >4 or PHQ-9 score >4) was 24% and 8%, respectively. After adjusting for potential confounders, those able to practice social distancing consistently at work had odds of 0.3 (95% CI 0.1 to 0.9) and 0.2 (95% CI 0.03 to 0.99) screening positive for anxiety and depression, respectively. Workers commuting by foot, bike or private cars were less likely to screen positive for depression (OR 0.1, 95% CI 0.02 to 0.7).ConclusionsIn this single store sample, we found a considerable asymptomatic SARS-CoV-2 infection rate among grocery workers. Employees with direct customer exposure were five times more likely to test positive for SARS-CoV-2. Those able to practice social distancing consistently at work had significantly lower risk of anxiety or depression.
Depression and anxiety in an early rheumatoid arthritis inception cohort. associations with demographic, socioeconomic and disease features
Authors: Fragoulis George E , Cavanagh Jonathan , Tindell Alistair , Derakhshan Mohammad , Paterson Caron , Porter Duncan , McInnes Iain B , Siebert Stefan 
Published: October 2020

ObjectiveDepression and anxiety are not uncommon in Rheumatoid arthritis (RA). It is increasingly recognised that they are associated with high disease activity and worse disease outcomes. We aimed to examine the frequency of depression and anxiety in an early RA inception cohort and to explore associations with disease-related measures.MethodsThe Scottish Early Rheumatoid Arthritis inception cohort recruited newly diagnosed RA patients followed-up 6-monthly. Anxiety and depression were assessed using the hospital anxiety and depression scale. Associations with demographic characteristics and disease-related measures were examined at baseline, 6 months and 12 months.Results848 RA patients were included. The prevalence of anxiety and depression at baseline was 19.0% and 12.2%, respectively. Depression and anxiety scores correlated with DAS28 at all time-points (all p<0.0001). In multivariable linear regression, anxiety score at baseline was associated with younger age and Health Assessment Questionnaire (HAQ) score. Anxiety scores at 6 months and 12 months were associated with low body mass index (BMI), baseline anxiety score and current patient global score and HAQ. Depression score at baseline was associated with younger age, being single and HAQ, while depression scores at 6 months and 12 months were associated with male gender (only at 6 months), baseline anxiety and depression scores and current patient global score, HAQ and C-reactive protein (CRP) levels.ConclusionDepression and anxiety are associated with disease activity, worse functional status and other variables in early RA. There is a close relationship between CRP and depression but not anxiety.