bluuebunny/crossref_metadata_2025_split huggingface dataset:
Salivary biomarkers may measure stress responses in critically ill children
Authors: Tzira Despoina , Prezerakou Anargyroula , Papadatos Ioannis , Vintila Artemis , Bartzeliotou Anastasia , Apostolakou Filia , Papassotiriou Ioannis , Papaevangelou Vassiliki 
Published: September 2018

Objective: Measurement of salivary biomarkers can provide important information regarding hypothalamic–pituitary–adrenal axis activity both under normal conditions as well as in response to psychological or physical stress. Our aim was to correlate salivary stress markers, such as cortisol, α-amylase and immunoglobulin A, with the Pediatric Risk Index Score of Mortality, underlying disease (pathologic, trauma and postoperative), need for mechanical ventilation/sedation and time lag between onset of illness and admission in children admitted in the pediatric intensive care unit. Methods: We enrolled 79 pediatric intensive care unit patients (2–14 years) over a 2-year period, which satisfy the including criteria, but finally salivary biomarkers were evaluated in 65 patients. Saliva samples were collected within 24 h of admission at 8 a.m., 2 p.m. and 8 p.m. to examine potential disruption of circadian rhythm. Results: Overall, the salivary biomarkers were increased; specifically, median values were (a) cortisol at 8 a.m.: 50.04 nmol/L, 2 p.m.: 30.69 nmol/L and 8 p.m.: 247.12 nmol/L; (b) α-amylase: at 8 a.m.: 22.567 U/L; 2 p.m.: 22.702 U/L and 8 p.m.: 21.484 U/L and (c) IgA at 8 a.m.: 95.10 mg/dL, 2 p.m.: 88.55 mg/dL and 8 p.m.: 80.80 mg/dL. Significantly higher levels were demonstrated in children younger than 6 years and those with Pediatric Risk Index Score of Mortality ⩾8 upon admission. Disturbances in circadian rhythm were observed. Cortisol circadian rhythm disturbance was observed only in children with Pediatric Risk Index Score of Mortality score ⩾8 upon admission while maintaining normal α-amylase circadian rhythm, which was associated with less than 3 days hospitalization in pediatric intensive care unit. No daily variance in IgA was observed. Conclusion: Salivary biomarkers may serve, in critically ill children, as a sensitive, non-invasive method, important for the early recognition of those at high risk and guiding intervention, before clinical deterioration, promoting the quality of health care in pediatric population.
The Coming Hip and Femur Fracture Bundle: A New Inpatient Risk Stratification Tool for Care Providers
Authors: Konda Sanjit R. , Lott Ariana , Egol Kenneth A. 
Published: September 2018

Introduction: In response to increasing health-care costs, Centers for Medicare & Medicaid Services has initiated several programs to transition from a fee-for-service model to a value-based care model. One such voluntary program is Bundled Payments for Care Improvement Advanced (BPCI Advanced) which includes all hip and femur fractures that undergo operative fixation. The purpose of this study was to analyze the current cost and resource utilization of operatively fixed (nonarthroplasty) hip and femur fracture procedure bundle patients at a single level 1 trauma center within the framework of a risk stratification tool (Score for Trauma Triage in the Geriatric and Middle-Aged [STTGMA]) to identify areas of high utilization before our hospitals transition to bundle period. Materials and Methods: A cohort of Medicare-eligible patients discharged with the Diagnosis-Related Group (DRG) codes 480 to 482 (hip and femur fractures requiring surgical fixation) from a level 1 trauma center between October 2014 and September 2016 was evaluated and assigned a trauma triage risk score (STTGMA score). Patients were stratified into groups based on these scores to create a minimal-, low-, moderate-, and high-risk cohort. Length of stay (LOS), discharge location, need for Intensive Care Unit (ICU)/Step Down Unit (SDU) care, inpatient complications, readmission within 90 days, and inpatient admission costs were recorded. Results: One hundred seventy-three patients with a mean age of 81.5 (10.1) years met inclusion criteria. The mean LOS was 8.0 (4.2) days, with high-risk patients having 4 days greater LOS than lower risk patients. The mean number of total complications was 0.9 (0.8) with a significant difference between risk groups ( P = .029). The mean total cost of admission for the entire cohort of patients was US$25,446 (US$9725), with a nearly US$9000 greater cost for high-risk patients compared to the low-risk patients. High-cost areas of care included room/board, procedure, and radiology. Discussion: High-risk patients were more likely to have longer and more costly admissions with average index admission costs nearly US$9000 more than the lower risk patient cohorts. These high-risk patients were also more likely to develop inpatient complications and require higher levels of care. Conclusion: This analysis of a 2-year cohort of patients who would qualify for the BPCI Advanced hip and femur procedure bundle demonstrates that the STTGMA tool can be used to identify high-risk patients who fall outside the bundle.
A New Technique for Distalization of the Tibial Tubercle That Allows Preservation of the Proximal Buttress
Authors: Ambra Luiz Felipe , Phan Amy , Gomoll Andreas H. 
Published: September 2018

Background: Tibial tubercle osteotomy (TTO) is a treatment option for patients with patellofemoral instability and chondrosis. Occasionally, these patients also present with patella alta, and distalization of the tibial tubercle is desirable. Free distal transfer of the tubercle, however, can compromise mechanical stability of the osteotomy construct, leading to loss of fixation. Purpose: To evaluate alternative TTO proximal cut geometries to investigate whether these can result in tubercle distalization while preserving the proximal buttress. Study Design: Descriptive laboratory study. Methods: Three variants of TTO cut geometry were evaluated on Sawbones as well as cadaveric knees. The proximal cut of the osteotomy was modified in 2 axes: anterior-posterior (AP) and medial-lateral (ML). Three variations were used: ML neutral/AP neutral, ML 30° proximal/AP neutral, and ML neutral/AP 30° proximal. The medial cut plane was 45° for all specimens. Tibial tubercle position was evaluated before and after osteotomy to calculate anteriorization, medialization, and distalization. Results: Distalization was achieved with all variants. Increasing the inclination angle of the proximal cut in the AP and ML axes resulted in maximum distalization. A proximally directed cut yielded significantly more distalization when performed in the AP axis than in the ML axis ( P < .05). Even the standard, neutral cut resulted in 5 mm of distalization. Conclusion: Fulkerson osteotomy allows 3-dimensional repositioning of the tibial tubercle and has historically been utilized to achieve anteriorization and medialization. Even the neutral cut of a standard TTO resulted in distalization, which is relevant for patients with preexisting patella baja. Modification of the proximal cut increased distalization of the tubercle while preserving the proximal buttress, a potential benefit for construct stability. Clinical Relevance: These results provide a guideline for adjusting the proximal cut geometry in Fulkerson TTO to meet specific patient needs.
Swept-Source Optical Coherence Tomography Angiography in Central Serous Chorioretinopathy
Authors: Michalewska Zofia , Nawrocki Jerzy 
Published: September 2018

Purpose: This article aims to evaluate the appearance of central serous chorioretinopathy (CSC) with swept-source optical coherence tomography angiography (SS-OCTA), to discuss whether localization of the leakage spot seen on fluorescein angiography (FA) corresponds to any recognizable spot on SS-OCTA, and to provide subsequent diagnosis of choroidal neovascularization (CNV) in the course of CSC. Methods: A prospective interventional case series was conducted in a private outpatient office on 30 eyes of 27 patients. In addition to ophthalmic examination, FA, spectral-domain OCT, SS-OCT and SS-OCTA were performed at least once. If laser photocoagulation or anti-vascular endothelial growth factor (anti-VEGF) injection was administered, then all examinations were repeated afterward. Following SS-OCTA, morphology features of CSC were analyzed: localization of the leakage spot, presence of feeder vessels, and presence of CNV. Changes after treatment were recorded. Results: In 26 of 30 cases the leakage site on FA corresponded to a highly hyporeflective site on SS-OCTA. In 7 of these cases laser was successfully administered. In 20/30 eyes we additionally observed thickened vessels at the level of choriocapillaris in close proximity to the most hyporeflective spot. CNV was observed in 4 cases. The leakage spot is the most hyporeflective spot on SS-OCTA localized at the level of choriocapillaris. Additionally, choroidal feeder vessels might be visualized at the level of choriocapillaris in 66% of cases. In 4 eyes, CNV in the course of CSC was noted. Conclusions: In CSC, SS-OCTA is a valuable diagnostic tool and its results complement FA. It might add to the treatment process, especially regarding the need to start and to monitor anti-VEGF injections. Anti-VEGF treatment results in fading but not in complete disappearance of CNV in the course of CSC.
Ocular Toxoplasmosis Mimicking Choroidal Metastasis From Colorectal Adenocarcinoma
Authors: Fowler Samuel C. , Capiz-Correa Daniel R. , Grossniklaus Hans E. , Shadowen Rebecca D. , Reichstein David A. 
Published: September 2018

Purpose: The purpose of this article is to describe a case of Toxoplasma gondii chorioretinal granuloma mimicking a choroidal metastasis from colorectal adenocarcinoma. Methods: Evaluation included clinical examination with multimodal imaging techniques and chorioretinal biopsy. Results: A 37-year-old white male with a history of colorectal adenocarcinoma presented with painless vision loss in the right eye, and fundoscopic examination revealed an amelanotic choroidal lesion. Patient history, examination, and diagnostic imaging suggested an old choroidal metastatic lesion with the patient electing chorioretinal biopsy. Upon cytologic examination, the biopsy sample indicated absence of malignant cells or tissues; however, the sample demonstrated fibroglial tissue with associated inflammation and toxoplasma organisms. Conclusion: This case demonstrates an atypical presentation of toxoplasma chorioretinitis that can mimic the appearance of a metastasis. Immunocompromised patients may be particularly susceptible to this atypical presentation of chorioretinitis.
TET2 deficiency leads to stem cell factor–dependent clonal expansion of dysfunctional erythroid progenitors
Authors: Qu Xiaoli , Zhang Shijie , Wang Shihui , Wang Yaomei , Li Wei , Huang Yumin , Zhao Huizhi , Wu Xiuyun , An Chao , Guo Xinhua , Hale John , Li Jie , Hillyer Christopher D. , Mohandas Narla , Liu Jing , Yazdanbakhsh Karina , Vinchi Francesca , Chen Lixiang , Kang Qiaozhen , An Xiuli 
Published: September 2018

AbstractMyelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Anemia is the defining cytopenia of MDS patients, yet the molecular mechanisms for dyserythropoiesis in MDSs remain to be fully defined. Recent studies have revealed that heterozygous loss-of-function mutation of DNA dioxygenase TET2 is 1 of the most common mutations in MDSs and that TET2 deficiency disturbs erythroid differentiation. However, mechanistic insights into the role of TET2 on disordered erythropoiesis are not fully defined. Here, we show that TET2 deficiency leads initially to stem cell factor (SCF)–dependent hyperproliferation and impaired differentiation of human colony-forming unit–erythroid (CFU-E) cells, which were reversed by a c-Kit inhibitor. We further show that this was due to increased phosphorylation of c-Kit accompanied by decreased expression of phosphatase SHP-1, a negative regulator of c-Kit. At later stages, TET2 deficiency led to an accumulation of a progenitor population, which expressed surface markers characteristic of normal CFU-E cells but were functionally different. In contrast to normal CFU-E cells that require only erythropoietin (EPO) for proliferation, these abnormal progenitors required SCF and EPO and exhibited impaired differentiation. We termed this population of progenitors “marker CFU-E” cells. We further show that AXL expression was increased in marker CFU-E cells and that the increased AXL expression led to increased activation of AKT and ERK. Moreover, the altered proliferation and differentiation of marker CFU-E cells were partially rescued by an AXL inhibitor. Our findings document an important role for TET2 in erythropoiesis and have uncovered previously unknown mechanisms by which deficiency of TET2 contributes to ineffective erythropoiesis.
A pilot study of lower doses of ibrutinib in patients with chronic lymphocytic leukemia
Authors: Chen Lisa S. , Bose Prithviraj , Cruz Nichole D. , Jiang Yongying , Wu Qi , Thompson Philip A. , Feng Shuju , Kroll Michael H. , Qiao Wei , Huang Xuelin , Jain Nitin , Wierda William G. , Keating Michael J. , Gandhi Varsha 
Published: September 2018

Abstract
Ibrutinib is highly efficacious and used at 420 mg/d for treatment of chronic lymphocytic leukemia (CLL). We previously demonstrated a decline in Bruton’s tyrosine kinase (BTK) protein levels in CLL cells after 1 cycle of ibrutinib, suggesting ibrutinib dose could be lowered after the first cycle without loss of biological effect. To test this postulate, a pilot study (NCT02801578) was designed to systematically reduce ibrutinib dosing within the same patient with CLL over the course of three 28-day cycles. After an initial cycle of 420 mg/d, the dose was reduced to 280 mg/d in cycle 2, and then to 140 mg/d in cycle 3. Eleven patients began study treatment, and 9 completed the 3 cycles. Plasma and intracellular pharmacokinetics (PK), BTK occupancy, and pharmacodynamic (PD) response at different doses of ibrutinib were compared. Plasma and intracellular levels of ibrutinib were dose-dependent, and even the lowest dose was sufficient to occupy, on average, more than 95% of BTK protein. In concert, BTK downstream signaling inhibition was maintained with 140 mg/d ibrutinib in cycle 3, and there were comparable reductions in total and phospho-BTK (Tyr223) protein levels across 3 cycles. Reductions of plasma chemokine CCL3 and CCL4 levels, considered to be biomarkers of ibrutinib response, were similar during the 3 cycles. These PK/PD data demonstrate that after 1 cycle of ibrutinib at the standard 420 mg/d dose, the dose can be reduced without losing biological activity. Clinical efficacy of lower doses needs to be systematically evaluated. Such dose reductions would lower drug cost, lessen untoward toxicity, and facilitate rationale-based combinations. This trial was registered at www.clinicaltrials.gov as #NCT02801578.
T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency
Authors: Brigida Immacolata , Zoccolillo Matteo , Cicalese Maria Pia , Pfajfer Laurène , Barzaghi Federica , Scala Serena , Oleaga-Quintas Carmen , Álvarez-Álvarez Jesus A. , Sereni Lucia , Giannelli Stefania , Sartirana Claudia , Dionisio Francesca , Pavesi Luca , Benavides-Nieto Marta , Basso-Ricci Luca , Capasso Paola , Mazzi Benedetta , Rosain Jeremie , Marcus Nufar , Lee Yu Nee , Somech Raz , Degano Massimo , Raiola Giuseppe , Caorsi Roberta , Picco Paolo , Moncada Velez Marcela , Khourieh Joelle , Arias Andrés Augusto , Bousfiha Aziz , Issekutz Thomas , Issekutz Andrew , Boisson Bertrand , Dobbs Kerry , Villa Anna , Lombardo Angelo , Neven Benedicte , Moshous Despina , Casanova Jean-Laurent , Franco José Luis , Notarangelo Luigi D. , Scielzo Cristina , Volpi Stefano , Dupré Loïc , Bustamante Jacinta , Gattorno Marco , Aiuti Alessandro 
Published: September 2018

Abstract
ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper–immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α−directed migration. Gene transfer of ARPC1B in patients’ T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.
A multiple myeloma classification system that associates normal B-cell subset phenotypes with prognosis
Authors: Bødker Julie Støve , Brøndum Rasmus Froberg , Schmitz Alexander , Schönherz Anna Amanda , Jespersen Ditte Starberg , Sønderkær Mads , Vesteghem Charles , Due Hanne , Nørgaard Caroline Holm , Perez-Andres Martin , Samur Mehmet Kemal , Davies Faith , Walker Brian , Pawlyn Charlotte , Kaiser Martin , Johnson David , Bertsch Uta , Broyl Annemiek , van Duin Mark , Shah Rajen , Johansen Preben , Nørgaard Martin Agge , Samworth Richard J. , Sonneveld Pieter , Goldschmidt Hartmut , Morgan Gareth J. , Orfao Alberto , Munshi Nikhil , Johnsen Hans Erik , El-Galaly Tarec , Dybkær Karen , Bøgsted Martin 
Published: September 2018

Abstract
Despite the recent progress in treatment of multiple myeloma (MM), it is still an incurable malignant disease, and we are therefore in need of new risk stratification tools that can help us to understand the disease and optimize therapy. Here we propose a new subtyping of myeloma plasma cells (PCs) from diagnostic samples, assigned by normal B-cell subset associated gene signatures (BAGS). For this purpose, we combined fluorescence-activated cell sorting and gene expression profiles from normal bone marrow (BM) Pre-BI, Pre-BII, immature, naïve, memory, and PC subsets to generate BAGS for assignment of normal BM subtypes in diagnostic samples. The impact of the subtypes was analyzed in 8 available data sets from 1772 patients’ myeloma PC samples. The resulting tumor assignments in available clinical data sets exhibited similar BAGS subtype frequencies in 4 cohorts from de novo MM patients across 1296 individual cases. The BAGS subtypes were significantly associated with progression-free and overall survival in a meta-analysis of 916 patients from 3 prospective clinical trials. The major impact was observed within the Pre-BII and memory subtypes, which had a significantly inferior prognosis compared with other subtypes. A multiple Cox proportional hazard analysis documented that BAGS subtypes added significant, independent prognostic information to the translocations and cyclin D classification. BAGS subtype analysis of patient cases identified transcriptional differences, including a number of differentially spliced genes. We identified subtype differences in myeloma at diagnosis, with prognostic impact and predictive potential, supporting an acquired B-cell trait and phenotypic plasticity as a pathogenetic hallmark of MM.
Cancer Care Treatment Outcome Ontology: A Novel Computable Ontology for Profiling Treatment Outcomes in Patients With Solid Tumors
Authors: Lin Frank P. , Groza Tudor , Kocbek Simon , Antezana Erick , Epstein Richard J. 
Published: September 2018

Purpose There is as yet no computer-processable resource to describe treatment end points in cancer, hindering our ability to systematically capture and share outcomes data to inform better patient care. To address these unmet needs, we have built an ontology, the Cancer Care Treatment Outcome Ontology (CCTOO), to organize high-level concepts of treatment end points with structured knowledge representation to facilitate standardized sharing of real-world data. Methods End points from oncology trials in ClinicalTrials.gov were extracted, queried using the keyword cancer, and followed by an expert appraisal. Synonyms and relevant terms were imported from the National Cancer Institute Thesaurus and Common Terminology Criteria for Adverse Events. Logical relationships among concepts were manually represented by production rules. The applicability of 1,847 rules was tested in an index case. Results After removing duplicated terms from 54,705 trial entries, an ontology holding 1,133 terms was built. CCTOO organized concepts into four domains (cancer treatment, health services, physical, and psychosocial health–related concepts), 13 subgroups (including efficacy, safety, and quality of life), and two (taxonomic and evaluative) concept hierarchies. This ontology has a comprehensive term coverage in the cancer trial literature: at least one term was mentioned in 98% of MEDLINE abstracts of phase I to III trials, whereas concepts about efficacy were mentioned in 7,208 (79%) phase I, 15,051 (92%) phase II, and 3,884 (86%) phase III trials. The event sequence of the index case was readily convertible to a comprehensive profile incorporating response, treatment toxicity, and survival by applying the set of production rules curated in the CCTOO. Conclusion CCTOO categorizes high-level treatment end points used in oncology and provides a mechanism for profiling individual patient data by outcomes to facilitate translational analysis.