bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical outcome of renal cancer patients who early interrupted immunotherapy due to serious immune-related adverse events. Meet-Uro 13 trial on behalf of the MeetUro investigators
Authors: Stellato Marco , Procopio Giuseppe , De Giorgi Ugo , Maruzzo Marco , Bimbatti Davide , Mennitto Alessia , Sbrana Andrea , Roviello Giandomenico , Casadei Chiara , Sepe Pierangela , Pignata Sandro , Santini Daniele 
Published: August 2021

Abstract
Background
Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, 2020); Haanen (Ann Oncol 28:119–142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs.

Methods
We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group.
Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago).

Results
18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0).

Conclusions
ICIs seem to maintain efficacy even after early interruption due to severe irAE.
Targeted provider education and pre-visit planning increase rates of formal depression screening in childhood-onset SLE
Authors: Mulvihill Evan , Furru Rebecca , Goldstein-Leever Alana , Driest Kyla , Lemle Stephanie , MacDonald Darby , Frost Emily , Sivaraman Vidya 
Published: August 2021

Abstract
Background
Despite being at high risk for depression, patients with childhood-onset systemic lupus erythematosus (c-SLE) are infrequently and inconsistently screened for depression by their pediatric rheumatologists. We aimed to systematically increase rates of formal depression screening for c-SLE patients in an academic Pediatric Rheumatology clinic.

Methods
Our multi-disciplinary quality improvement (QI) team used electronic health record (EHR) documentation to retroactively calculate baseline rates of documented depression screening using the Patient Health Questionnaire-9 (PHQ-9). We then engaged key stakeholders to develop a clinical workflow for formal depression screening in the clinic. We also provided education to providers regarding mental health disorders in c-SLE, with an emphasis on prevalence, screening methods, and management of positive screens. We then used the Plan-Do-Study Act (PDSA) method of QI to systematically evaluate and adjust our process in real time. The primary outcome was the percentage of patients with c-SLE seen per month who had a documented PHQ-9 screening within the past year.

Results
The percentage of children with documented PHQ-9 results ranged from 0 to 4.5 % at baseline to 91.0 % within 12 months of project initiation. By the end of the project, monthly screening rates greater than 80 % has been sustained for 10 months. As a result of these efforts, twenty-seven (48.2 %) patients with at least mild depressive symptoms were identified while seven (12.5 %) with thoughts of self-harm were referred to appropriate mental health resources.

Conclusions
Routine formal depression screening is feasible in a busy subspecialty clinic. Using QI methods, rates of formal depression screening among children with c-SLE were increased from an average of 3.3 % per month to a sustained monthly rate of greater than 80 %. Individuals with depressive symptoms and/or thoughts of self-harm were identified and referred to appropriate mental health resources.
Cannons and sparrows II: the enhanced Bernoulli exact method for determining statistical significance and effect size in the meta-analysis of k 2 × 2 tables
Authors: Paul Lawrence M. 
Published: August 2021

Abstract
Background
The use of meta-analysis to aggregate the results of multiple studies has increased dramatically over the last 40 years. For homogeneous meta-analysis, the Mantel–Haenszel technique has typically been utilized. In such meta-analyses, the effect size across the contributing studies of the meta-analysis differs only by statistical error. If homogeneity cannot be assumed or established, the most popular technique developed to date is the inverse-variance DerSimonian and Laird (DL) technique (DerSimonian and Laird, in Control Clin Trials 7(3):177–88, 1986). However, both of these techniques are based on large sample, asymptotic assumptions. At best, they are approximations especially when the number of cases observed in any cell of the corresponding contingency tables is small.

Results
This research develops an exact, non-parametric test for evaluating statistical significance and a related method for estimating effect size in the meta-analysis of k 2 × 2 tables for any level of heterogeneity as an alternative to the asymptotic techniques. Monte Carlo simulations show that even for large values of heterogeneity, the Enhanced Bernoulli Technique (EBT) is far superior at maintaining the pre-specified level of Type I Error than the DL technique. A fully tested implementation in the R statistical language is freely available from the author. In addition, a second related exact test for estimating the Effect Size was developed and is also freely available.

Conclusions
This research has developed two exact tests for the meta-analysis of dichotomous, categorical data. The EBT technique was strongly superior to the DL technique in maintaining a pre-specified level of Type I Error even at extremely high levels of heterogeneity. As shown, the DL technique demonstrated many large violations of this level. Given the various biases towards finding statistical significance prevalent in epidemiology today, a strong focus on maintaining a pre-specified level of Type I Error would seem critical. In addition, a related exact method for estimating the Effect Size was developed.
Similarities and differences in the localization, trafficking, and function of P-glycoprotein in MDR1-EGFP-transduced rat versus human brain capillary endothelial cell lines
Authors: Gericke Birthe , Borsdorf Saskia , Wienböker Inka , Noack Andreas , Noack Sandra , Löscher Wolfgang 
Published: August 2021

AbstractBackgroundIn vitro models based on brain capillary endothelial cells (BCECs) are among the most versatile tools in blood–brain barrier research for testing drug penetration into the brain and how this is affected by efflux transporters such as P-glycoprotein (Pgp). However, compared to freshly isolated brain capillaries or primary BCECs, the expression of Pgp in immortalized BCEC lines is markedly lower, which prompted us previously to transduce the widely used human BCEC line hCMEC/D3 with a doxycycline-inducibleMDR1-EGFP fusion plasmid. The EGFP-labeled Pgp in these cells allows studying the localization and trafficking of the transporter and how these processes are affected by drug exposure. Here we used this strategy for the rat BCEC line RBE4 and performed a face-to-face comparison of RBE4 and hCMEC/D3 wild-type (WT) andMDR1-EGFP transduced cells.MethodsMDR1-EGFP-transduced variants were derived from WT cells by lentiviral transduction, using anMDR1-linker-EGFP vector. Localization, trafficking, and function of Pgp were compared in WT andMDR1-EGFP transduced cell lines. Primary cultures of rat BCECs and freshly isolated rat brain capillaries were used for comparison.ResultsAll cells exhibited typical BCEC morphology. However, significant differences were observed in the localization of Pgp in that RBE4-MDR1-EGFP cells expressed Pgp primarily at the plasma membrane, whereas in hCMEC/D3 cells, the Pgp-EGFP fusion protein was visible both at the plasma membrane and in endolysosomal vesicles. Exposure to doxorubicin increased the number of Pgp-EGFP-positive endolysosomes, indicating a lysosomotropic effect. Furthermore, lysosomal trapping of doxorubicin was observed, likely contributing to the protection of the cell nucleus from damage. In cocultures of WT andMDR1-EGFP transduced cells, intercellular Pgp-EGFP trafficking was observed in RBE4 cells as previously reported for hCMEC/D3 cells. Compared to WT cells, theMDR1-EGFP transduced cells exhibited a significantly higher expression and function of Pgp. However, the junctional tightness of WT andMDR1-EGFP transduced RBE4 and hCMEC/D3 cells was markedly lower than that of primary BCECs, excluding the use of the cell lines for studying vectorial drug transport.ConclusionsThe present data indicate thatMDR1-EGFP transduced RBE4 cells are an interesting tool to study the biogenesis of lysosomes and Pgp-mediated lysosomal drug trapping in response to chemotherapeutic agents and other compounds at the level of the blood–brain barrier.
Trans-apical aortic valve implantation for quadricuspid aortic valve with aortic regurgitation using J-valve system: a case reports
Authors: Luo Chaodi , Jiang Yi , Chen Qiang , Yan Yang , Han Dan 
Published: August 2021

Abstract
Background
Quadricuspid aortic valve (QAV) is a rare congenital heart defect usually accompanied with different hemodynamic abnormalities. Due to the rarity of QAV, treatment and prognosis of QAV patients with aortic regurgitation still remain challenging. We here present the first case of a patient with severe QAV regurgitation who underwent successful treatment and performed favorable prognosis with transapical aortic valve implantation (TAVI) using J-Valve system.

Case presentation
A 62-year-old man experienced intermittent palpitation, shortness of breath and chest pain. Echocardiography revealed congenital QAV with massive aortic regurgitation and mild aortic stenosis, left ventricular enlargement. Aortic valve replacement was successfully performed with TAVI using J-Valve system. The postoperation and follow-up was uneventful.

Conclusion
TAVI using J-Valve system has emerged as a new high success rate method for treatment of patients with simple non-calcified aortic valve insufficiency.
A population-based study to estimate survival and standardized mortality of tuberous sclerosis complex (TSC) in Taiwan
Authors: Peng Jui-Hui , Tu Hung-Pin , Hong Chien-Hui 
Published: August 2021

Abstract
Background
Tuberous sclerosis complex (TSC) is an autosomal dominant disease with systemic manifestations, which can cause significant mortality and morbidity. Population-based epidemiological studies on TSC mortality and survival remain scarce, though several recent studies provide evidence that TSC survival rates are high and disease prognosis is fair for most patients. This study aims to estimate the life expectancy and mortality statistics in Taiwanese TSC patients, investigate prognosis and associations of TSC mortality based on demographic variables, and compare these results to past literature, especially for Asian patients.

Methods
Taiwanese National Health Insurance (NHI) insurees can obtain Catastrophic Illness Certificates (CIC) for certain eligible diseases to waive copayments after diagnosis by two independent physicians. CIC holders for TSC during 1997–2010 were identified from the NHI Research Database. Queries on enrollment (CIC acquisition) age, endpoint (end of query period or death) age, sex, and comorbidities were obtained. Patients were separated into cohorts (endpoint age, sex, and age of diagnosis), and analyzed accordingly.

Results
471 patients (232 male, 239 female) were identified, of which 14 died. Compared to literature, patients showed similar demographics (age range, diagnosis age, sex distribution); similar manifestations and prevalence (epilepsy, intellectual disability, renal disease); lower disease prevalence (1 in 63,290); lower mortality (0.21% per year); and near-identical standardized mortality ratio (4.99). A cumulative mortality of 4.08% was found over 14 years, though mortality plateaued at 7 years post-enrollment, suggesting a good overall survival rate; comparable with previous studies in Asian patients. Enrollment age was a significant prognostic factor, with late-enrollment (age > 18) patients at higher risk for all-cause mortality (Hazard ratio = 6.54). Average remaining lifetime was significantly lower than the general population, and decreased with age.

Conclusions
This study reports a population-based disease database, highlights the importance of diagnosis age in prognosis prediction, and suggests the role of renal manifestations in mortality. Furthermore, it corroborates recent TSC studies in the Asian population in terms of survival. Overall, physician vigilance, early diagnosis, and careful monitoring are beneficial for disease outcome and patient survival.
Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration
Authors: Mohan Swetha , Sampognaro Paul J. , Argouarch Andrea R. , Maynard Jason C. , Welch Mackenzie , Patwardhan Anand , Courtney Emma C. , Zhang Jiasheng , Mason Amanda , Li Kathy H. , Huang Eric J. , Seeley William W. , Miller Bruce L. , Burlingame Alma , Jacobson Mathew P. , Kao Aimee W. 
Published: August 2021

Abstract
Background
Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints.

Results
In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP-Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease.

Conclusions
This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP-Pgrn. Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD-Pgrn and other progranulin-related diseases.
A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials
Authors: Hills N. K. , Lyimo J. , Nahid P. , Savic R. M. , Lienhardt C. , Phillips P. P. J. 
Published: August 2021

Abstract
Background
Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies

Methods
We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described.

Results
From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes.

Conclusions
In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal.

PROSPERO registration
PROSPERO CRD42020197993. Registration 11 August 2020.
Low level laser therapy promotes bone regeneration by coupling angiogenesis and osteogenesis
Authors: Bai Jie , Li Lijun , Kou Ni , Bai Yuwen , Zhang Yaoyang , Lu Yun , Gao Lu , Wang Fu 
Published: August 2021

AbstractBackgroundBone tissue engineering is a new concept bringing hope for the repair of large bone defects, which remains a major clinical challenge. The formation of vascularized bone is key for bone tissue engineering. Growth of specialized blood vessels termed type H is associated with bone formation. In vivo and in vitro studies have shown that low level laser therapy (LLLT) promotes angiogenesis, fracture healing, and osteogenic differentiation of stem cells by increasing reactive oxygen species (ROS). However, whether LLLT can couple angiogenesis and osteogenesis, and the underlying mechanisms during bone formation, remains largely unknown.MethodsMouse bone marrow mesenchymal stem cells (BMSCs) combined with biphasic calcium phosphate (BCP) grafts were implanted into C57BL/6 mice to evaluate the effects of LLLT on the specialized vessel subtypes and bone regeneration in vivo. Furthermore, human BMSCs and human umbilical vein endothelial cells (HUVECs) were co-cultured in vitro. The effects of LLLT on cell proliferation, angiogenesis, and osteogenesis were assessed.ResultsLLLT promoted the formation of blood vessels, collagen fibers, and bone tissue and also increased CD31hiEMCNhi-expressing type H vessels in mBMSC/BCP grafts implanted in mice. LLLT significantly increased both osteogenesis and angiogenesis, as well as related gene expression (HIF-1α, VEGF, TGF-β) of grafts in vivo and of co-cultured BMSCs/HUVECs in vitro. An increase or decrease of ROS induced by H2O2or Vitamin C, respectively, resulted in an increase or decrease of HIF-1α, and a subsequent increase and decrease of VEGF and TGF-β in the co-culture system. The ROS accumulation induced by LLLT in the co-culture system was significantly decreased when HIF-1α was inhibited with DMBPA and was followed by decreased expression of VEGF and TGF-β.ConclusionsLLLT enhanced vascularized bone regeneration by coupling angiogenesis and osteogenesis. ROS/HIF-1α was necessary for these effects of LLLT. LLLT triggered a ROS-dependent increase of HIF-1α, VEGF, and TGF-β and resulted in subsequent formation of type H vessels and osteogenic differentiation of mesenchymal stem cells. As ROS also was a target of HIF-1α, there may be a positive feedback loop between ROS and HIF-1α, which further amplified HIF-1α induction via the LLLT-mediated ROS increase. This study provided new insight into the effects of LLLT on vascularization and bone regeneration in bone tissue engineering.
The function of LncRNA-H19 in cardiac hypertrophy
Authors: Su Wenhua , Huo Qian , Wu Hao , Wang Lulin , Ding Xiaoxue , Liang Liwen , Zhou Liang , Zhao Yan , Dan Juhua , Zhang Hong 
Published: August 2021

AbstractCardiac hypertrophy, characterized by the enlargement of cardiomyocytes, is initially an adaptive response to physiological and pathological stimuli. Decompensated cardiac hypertrophy is related to fibrosis, inflammatory cytokine, maladaptive remodeling, and heart failure. Although pathological myocardial hypertrophy is the main cause of hypertrophy-related morbidity and mortality, our understanding of its mechanism is still poor. Long noncoding RNAs (lncRNAs) are noncoding RNAs that regulate various physiological and pathological processes through multiple molecular mechanisms. Recently, accumulating evidence has indicated that lncRNA-H19 is a potent regulator of the progression of cardiac hypertrophy. For the first time, this review summarizes the current studies about the role of lncRNA-H19 in cardiac hypertrophy, including its pathophysiological processes and underlying pathological mechanism, including calcium regulation, fibrosis, apoptosis, angiogenesis, inflammation, and methylation. The context within which lncRNA-H19 might be developed as a target for cardiac hypertrophy treatment is then discussed to gain better insight into the possible biological functions of lncRNA-H19 in cardiac hypertrophy.
On Green’s function of Cauchy–Dirichlet problem for hyperbolic equation in a quarter plane
Authors: Sadybekov Makhmud , Derbissaly Bauyrzhan 
Published: August 2021

AbstractThe definition of a Green’s function of a Cauchy–Dirichlet problem for the hyperbolic equation in a quarter plane is given. Its existence and uniqueness have been proven. Representation of the Green’s function is given. It is shown that the Green’s function can be represented by the Riemann–Green function.