bluuebunny/crossref_metadata_2025 huggingface dataset:
Using Discrete Event Simulation (DES) To Support Performance-Driven Healthcare Design
Authors: Cai Hui , Jia Jun
Published: September 2018

Aim:

This article aims to provide a description of fundamental elements of discrete event simulation (DES), the process and the values of applying DES in assisting healthcare design and planning decision-making. More importantly, it explores how new technology such as electronic medical records, real-time location services (RTLS), and other simulation methods such as space syntax analysis (SSA) can facilitate and complement DES.

Background:

Healthcare administrators increasingly recognize DES as an effective tool for allocating resources and process improvement. However, limited studies have described specifically how DES can facilitate healthcare design.

Method:

Three case studies were provided to illustrate the value of DES in supporting healthcare design. The first case study used DES to validate a surgical suite design for shorter surgeon walking distance. The second case study used DES to facilitate capacity planning in a clinic through testing the utilization of exam rooms upon various growth scenario. The detailed process data for the current clinic were captured through RTLS tracking. The third case study applied DES in an emergency department for both site selection in master planning and capacity test at various growth scenarios with seasonal volume swing. In addition, SSA was conducted to evaluate the impacts of design on visual surveillance, team communication, and co-awareness.

Conclusions:

It is recognized that the DES analysis is an effective tool to address the process aspects of healthcare environments and should be combined with post-occupancy evaluation and SSA to address behavioral aspects of operations to provide more solid evidence for future design.
Resection of Inverted Papilloma of the Maxillary Sinus via a Prelacrimal Recess Approach: A Multicenter Retrospective Analysis of Surgical Efficacy
Authors: Zhou Bing , Huang Qian , Sun Jingwu , Li Xuezhong , Zhang Weitian , Cui Shunjiu , Shen Ping-Hung , Wang Chengshuo , Huang Zhenxiao , Dong Yi , Liang Na
Published: September 2018

Background

The intranasal endoscopic prelacrimal recess approach (PLRA) access to all aspects of the maxillary sinus while preserving the inferior turbinate and nasolacrimal duct and its use have been reported in the treatment of many maxillary sinus and lateral skull base diseases.

Objective

To retrospectively assess the effectiveness of a 10-year multicenter follow-up for the resection of inverted papilloma of the maxillary sinus (IPMS) via a PLRA.

Methods

A total of 71 patients were admitted and underwent IPMS excision via an intranasal endoscopic PLRA from 2003 to 2013. All patients underwent high-resolution computed tomography scanning of the nasal sinus, and some also underwent magnetic resonance imaging examination.

Results

Based on the Krouse staging system, all 71 patients belong to T3 staging. The PLRA was employed to remove IPMS in 71 patients. The postoperative pathological examination of the excised tissue revealed inverted papilloma, and cancerization was identified in 3 patients. The median follow-up time was 37.3 months (range: 13–134 months). Of the 71 patients, reoccurrence was seen in 5 patients (7.04%); 5 patients (7.04%) experienced numbness of the upper lid and the ala of the nose and 4 (5.63%) experienced mild collapse of the ala of the nose.

Conclusions

These multicenter follow-up results demonstrated that the PLRA is a safe and effective method for the excision of primary or recurrent IPMS with lower postoperative complications and recurrent rate.
Recent jurisprudence of the European Court of Human Rights relevant to employment law
Authors: Perulli Adalberto , Sychenko Elena
Published: September 2018

In the field of regulatory instruments in the social field, the European Convention on Human Rights (ECHR) and the related jurisprudence of the Court of European Court of Human Rights (ECtHR) deserves renewed focus. In recent years considerable debate has developed over the relationship between social rights and human rights, and the jurisprudence of the ECtHR has clearly demonstrated the growing value of human rights in the workplace. The Court explored the growing facets of the ban on forced labour and discrimination; developed the idea of employee privacy and contributed to the protection of their freedom of religion, expression and association; recognised the ‘vulnerability’ of the employee in the employment relationship and has drawn from it the principle that a restriction on hiring practices or certain dismissal practices may have a ‘chilling effect’ on the exercise of the rights provided for by the Convention. In essence, thanks to a sensitivity towards the social and labour field, and due to the integrated approach adopted by the Court of Strasbourg, the scope of the ECHR has been broadly extended to include the protection of certain social rights of a collective nature.
Traditional approach versus Stewart approach for acid–base disorders: Inconsistent evidence
Authors: Kimura Satoshi , Shabsigh Muhammad , Morimatsu Hiroshi
Published: September 2018

Purpose:

The traditional approach and the Stewart approach have been developed for evaluating acid–base phenomena. While some experts have suggested that the two approaches are essentially identical, clinical researches have still been conducted on the superiority of one approach over the other one. In this review, we summarize the concepts of each approach and investigate the reasons of the discrepancy, based on current evidence from the literature search.

Methods:

In the literature search, we completed a database search and reviewed articles comparing the Stewart approach with the traditional, bicarbonate-centered approach to November 2016.

Results:

Our literature review included 17 relevant articles, 5 of which compared their diagnostic abilities, 9 articles compared their prognostic performances, and 3 articles compared both diagnostic abilities and prognostic performances. These articles show a discrepancy over the abilities to detect acid–base disturbances and to predict patients’ outcomes. There are many limitations that could yield this discrepancy, including differences in calculation of the variables, technological differences or errors in measuring variables, incongruences of reference value, normal range of the variables, differences in studied populations, and confounders of prognostic strength such as lactate.

Conclusion:

In conclusion, despite the proposed equivalence between the traditional approach and the Stewart approach, our literature search shows inconsistent results on the comparison between the two approaches for diagnostic and prognostic performance. We found crucial limitations in those studies, which could lead to the reasons of the discrepancy.
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 Facebook Sabbatical as a Cycle: Describing the Gendered Experience of Young Adults as They Navigate Disconnection and Reconnection
Authors: Franks Jessica , Chenhall Richard , Keogh Louise
Published: September 2018

Young adults are known to adopt Facebook (FB) sabbaticals as a coping strategy for FB-induced technostress, which are often linked to problematic overuse habits. Yet, there has been little investigation of how young adults experience, navigate, and negotiate FB sabbaticals and the impact this has on their social connections and overall well-being. To address this, we conducted a qualitative study of six young adults, aged 18–34 to understand their FB sabbatical experiences, how they negotiated their social connections during their sabbatical and sough to explain the reasons associated with their return to FB. We propose a FB sabbatical support model and offer three research propositions. Our results suggest that (1) FB sabbaticals are of benefit in addressing unhealthy FB habits, yet key supportive factors vary in value of importance and influence between genders; and (2) despite young adults’ efforts to mitigate technostress via FB sabbaticals, this strategy presented multiple challenges that affected their online and offline connections and personal health and well-being in positive and negative ways, contributing to cyclic habits of FB discontinuation and reconnection.
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.
Laparoscopic evaluation of female pelvic neuroanatomy and autonomic plexuses in terms of gynecologic perspective
Authors: Kale Ahmet , Basol Gulfem , Usta Taner , Aytuluk Hande G
Published: September 2018

The nerves located in the deepest areas can be exposed and dissected via laparoscopic magnification. This technological innovation does not only help us to avoid surgery-related complications but also allows us to diagnose the vascular entrapment syndromes. The aim of this article is to demonstrate female neuroanatomy and autonomic plexus via enriched photos and videos to reveal the relationship of the pelvic nervous system with gynecological operations.
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.
The Pupil Dilation Response to Auditory Stimuli: Current State of Knowledge
Authors: Zekveld Adriana A. , Koelewijn Thomas , Kramer Sophia E.
Published: September 2018

The measurement of cognitive resource allocation during listening, or listening effort, provides valuable insight in the factors influencing auditory processing. In recent years, many studies inside and outside the field of hearing science have measured the pupil response evoked by auditory stimuli. The aim of the current review was to provide an exhaustive overview of these studies. The 146 studies included in this review originated from multiple domains, including hearing science and linguistics, but the review also covers research into motivation, memory, and emotion. The present review provides a unique overview of these studies and is organized according to the components of the Framework for Understanding Effortful Listening. A summary table presents the sample characteristics, an outline of the study design, stimuli, the pupil parameters analyzed, and the main findings of each study. The results indicate that the pupil response is sensitive to various task manipulations as well as interindividual differences. Many of the findings have been replicated. Frequent interactions between the independent factors affecting the pupil response have been reported, which indicates complex processes underlying cognitive resource allocation. This complexity should be taken into account in future studies that should focus more on interindividual differences, also including older participants. This review facilitates the careful design of new studies by indicating the factors that should be controlled for. In conclusion, measuring the pupil dilation response to auditory stimuli has been demonstrated to be sensitive method applicable to numerous research questions. The sensitivity of the measure calls for carefully designed stimuli.
Hearing Aids Benefit Recognition of Words in Emotional Speech but Not Emotion Identification
Authors: Goy Huiwen , Pichora-Fuller M. Kathleen , Singh Gurjit , Russo Frank A.
Published: September 2018

Vocal emotion perception is an important part of speech communication and social interaction. Although older adults with normal audiograms are known to be less accurate at identifying vocal emotion compared to younger adults, little is known about how older adults with hearing loss perceive vocal emotion or whether hearing aids improve the perception of emotional speech. In the main experiment, older hearing aid users were presented with sentences spoken in seven emotion conditions, with and without their own hearing aids. Listeners reported the words that they heard as well as the emotion portrayed in each sentence. The use of hearing aids improved word-recognition accuracy in quiet from 38.1% (unaided) to 65.1% (aided) but did not significantly change emotion-identification accuracy (36.0% unaided, 41.8% aided). In a follow-up experiment, normal-hearing young listeners were tested on the same stimuli. Normal-hearing younger listeners and older listeners with hearing loss showed similar patterns in how emotion affected word-recognition performance but different patterns in how emotion affected emotion-identification performance. In contrast to the present findings, previous studies did not find age-related differences between younger and older normal-hearing listeners in how emotion affected emotion-identification performance. These findings suggest that there are changes to emotion identification caused by hearing loss that are beyond those that can be attributed to normal aging, and that hearing aids do not compensate for these changes.
A New Regional Approach toward the Israeli–Palestinian Peace Process
Authors: Eissa Sherif A.
Published: September 2018

There are two principal reasons behind the lack of success in reaching a final peace agreement between the Israelis and the Palestinians, namely, the malfunctioning negotiations’ framework from one side and the complexity of the negotiated issues from the other. This article is mainly addressing the bilateral framework’s flaws when it comes to the Oslo accords and the way the two negotiating parties have perceived them. It is an attempt to overhaul the existing Oslo peace process and not to create a new one. Oslo process has become entrenched over more than twenty years of different practices and legal realities. The article is also introducing a negotiating framework that combines the benefits of a multilateral regional track to the Oslo process aiming to redress the latent structural flaws. It is intended not to tackle the final status issues, as there is a plethora of literature doing so. The extensive focus on those complicated issues without redressing the process’ structural flaws has led partially to the current stalemate. The role of any mediator or external partner is not to solve those issues on behalf of the principal parties, but to work on the negotiating framework and the process itself.
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

Myelodysplastic 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

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

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

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.
Quantifying static and dynamic stiffness anisotropy and nonlinearity in finely laminated shales: Experimental measurement and modeling
Authors: Ramos Matthew J. , Nicolas Espinoza D. , Laubach Stephen E. , Torres-Verdín Carlos
Published: September 2018

Sedimentary rocks contain layers and a wide range of microstructures that may produce mechanical complexities including dynamic and quasistatic stiffness anisotropy and nonlinearity. However, most applications in geophysics and geomechanics disregard these mechanical complexities, which can lead to significant error and uncertainty in rock properties and may increase the risk associated with cost-intensive drilling and completions operations in shales. We have conducted simultaneous triaxial stress tests and ultrasonic wave propagation monitoring to measure and model stiffness anisotropy and nonlinearity of Mancos Shale plugs with varying bedding orientations. Results highlight the need for different sets of nonlinear coefficients to describe different stress loading paths, in which isotropic loading exhibits larger increases in stiffness for a given change in mean stress (and strain) than deviatoric loading. The vertical transverse isotropic (VTI) nonlinear model helps to account for the appreciable anisotropy and nonlinearity of Mancos samples, in which the dynamic Young’s moduli [Formula: see text] are more than 25% higher than [Formula: see text] and [Formula: see text] increases by approximately 35% during deviatoric stress loading. Measured static moduli are typically less than 50% of their dynamic equivalent and exhibit separate anisotropic and nonlinear relationships. Therefore, we have developed anisotropic stress-dependent dynamic-static transforms to estimate the static moduli from the nonlinear VTI model. Although heterogeneity and discontinuities cause samples to deviate from VTI symmetry, our modified dynamic-static transforms provide an excellent fit to the experimentally measured Young’s moduli and Poisson’s ratios. Post-test X-ray micro-CT imaging evidences the impact of sample layering and heterogeneity on rock failure and failure geometry. Bedding planes can act as preferential failure planes, whereas layering-induced mechanical stratigraphy can cause fractures to reorient due to changes in lithology. Our combined experimental, modeling, and imaging results provide insight into the complex deformational and failure behavior of shales. The analysis and results also highlight the need to consider the elastic and plastic deformations in shales.
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.
Real-world antiemetic utilization in patients undergoing carboplatin chemotherapy.
Authors: Polson Michael , Harrow Brooke
Published: September 2018

10

Background: More than 70% of patients receiving chemotherapy will experience chemotherapy-induced nausea and vomiting (CINV). Chemotherapeutic regimens (regimens) are classified as highly emetogenic, moderately emetogenic, low potential, or minimal risk for emesis. The NCCN has recently reclassified carboplatin emetogenicity according to the AUC (target area under the concentration versus time curve) with a carboplatin AUC ≥4 classified as highly emetogenic and carboplatin AUC < 4 as moderately emetogenic - but highly emetogenic in certain patients. This study assessed use of anti-emetic agents in carboplatin based regimens. Methods: This study consisted of a retrospective analysis of administrative claims data from multiple commercial health plans. Claims from 1/1/2010-10/31/2017 were analyzed. Index date for each patient was the first medical claim of the regimen of interest. Included patients had ≥1 medical claim for the selected regimen and were eligible for both medical and pharmacy benefits for ≥6 months prior to, and 12 months post index date. CINV-related hospitalizations and ER cost and utilization were assessed for patients treated with carboplatin based regimens. Results: In total, 4,430 mostly female (74%) patients met criteria for treatment with a carboplatin-based index regimen. Between 2010 and 2017, the following trends were noted in the study population: Adherence to NCCN recommended 3 drug CINV prophylaxis (triplet therapy) ranged from about 23% to 35%. The rate of CINV related emergency department (ED) visits was 5.3% and the overall rate of CINV related inpatient visits was 0.11%. The average cost for CINV related hospitalization for a carboplatin patient was $8,562 (SD 6,207) with an average LOS of 3.1 days. ED visits that were CINV related cost $2,463 on average (SD 3,054). Conclusions: Guidelines recommend use of up to three agents in the prevention of chemotherapy induced nausea and vomiting. Use of a triplet therapy for CINV prophylaxis in carboplatin based highly emetogenic regimens has increased over time in the plans analyzed and may offer an opportunity to reduce rate of CINV related hospitalizations and ED visits, as well as associated costs.
Lessons from Reporting National Performance Measures in a Regional Setting: Washington State Community Cancer Care Report.
Authors: Panattoni Laura Elizabeth , Fedorenko Catherine R. , Kreizenbeck Karma L. , Sun Qin , Li Li , Lyman Gary H. , Ramsey Scott David
Published: September 2018

105

Background: While many quality metrics are generated and reported at a national level, regionally reported metrics may be more meaningful to stakeholders and more amenable to locally-generated interventions aimed at improving quality. We present the lessons learned from adapting national performance reporting standards to our regional setting. Methods: We linked 2014-2016 Washington State cancer registry records with Medicare and commercial insurance claims, capturing about 70% of the state’s cancer patients. A consortium of payers, oncology providers, and patients selected metrics from national initiatives (QOPI, MACRA, OCM, and the Choosing Wisely Campaign). We then searched the National Quality Forum and the National Quality Measures Clearinghouse for published specifications on those metrics. If none were available or there was a lack of consensus, we constructed algorithms with clinical and technical expert review. We calculated clinic-level risk standardized rates (RSRs) using hierarchical regression modeling to adjust for variation in clinic size and constructed quality composites. Results: We generated 13 quality metrics for 36,900 cancer patients cared for at 27 clinics. Our adaptation of national performance measures and implications include: 1) Many treatment process measures had too few numbers to individually report annually requiring us to group quality metrics and cancer types, and report over a three year period. 2) Although we were able to include tumor characteristics (e.g. AJCC stage) from registry records, risk adjustment was challenged by limitations in the number of risk adjustors due to the smaller number of patients. 3) After applying the hierarchical models, risk adjustment had minimal effect on clinic rankings. 4) The small number of clinics and limited range of clinic RSRs were more accurately captured by a quality composite that reflected clinic level differences to the regional average rather than national quintile groupings. Conclusions: Refinement of national metrics is necessary for public reporting in a regional setting. Further methodological development is critical for robust reporting and applications to value based purchasing.
An evaluation of shifting administration of high-cost chemotherapy from the inpatient to an outpatient setting.
Authors: Crosby David L. , Karkowski Katie , Rodriguez Catherine , Lansigan Frederick
Published: September 2018

107

Background: Patients often require critical management during chemotherapy and may need constant monitoring during and post-treatment in an inpatient (IP) unit. However, many patients can receive safe and effective administration of chemotherapy in an outpatient (OP) infusion setting, which respects patient’s wishes to shorten hospitalization stays. Optimizing OP treatment can also result in better utilization of resources that require critical monitoring. Since IP chemotherapy is not reimbursed separately, it is often considered a financial loss. This study evaluated the opportunity to decrease length of stay (LOS), reduce costs for our hematology/oncology inpatient practice, and increase utilization of a new infusion suite adjacent to IP unit. Methods: Work followed a Lean Six Sigma methodology – Define, Measure, Analyze, Improve, and Control. Multi-disciplinary clinical teams worked with quality improvement subject matter experts to explore regimens associated with inpatient administration of high-cost medications. Rituximab-based regimens were identified as the greatest opportunity to optimize cost reduction in the IP unit. The team set a goal to deliver rituximab as an OP in the infusion suite following hospital discharge. Baseline utilization of rituximab in the IP unit, revenue of the new infusion suite, and mean LOS for patients receiving R-EPOCH, a rituximab based regimen, were determined. Results: Percentage of IP rituximab administration was reduced by 56% resulting in $355,506 of cost avoidance in the IP unit. Mean quarterly revenue in the OP infusion suite increased from $104,363 at baseline to $293,607 through the first nine months by shifting rituximab to the OP setting, which projects to an annualized improvement of $756,976. Median LOS for patients receiving R-EPOCH was reduced by 12 hours (p < 0.001). Conclusions: Our intervention has resulted in decreased administration of high-cost chemotherapy in the IP unit, reduced LOS, and increased patient convenience. In addition, the significant revenue generated in the OP infusion suite will support improving patient services at our not-for-profit medical center.
Real-world adherence in patients with metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil (FTD/TPI) or regorafenib (REG).
Authors: Patel Anuj K. , Barghout Victoria , Yenikomshian Mihran Ara , Germain Guillaume , Jacques Philippe , Laliberté François , Duh Mei Sheng
Published: September 2018

11

Background: Adherence to oral chemotherapies is a critical but difficult to measure factor in the care of patients with advanced cancer. FTD/TPI and REG have both demonstrated prolonged survival in patients with refractory mCRC, but with notably different side effect profiles. This study utilizes real-world data to assess adherence and discontinuation of patients treated with FTD/TPI or REG and explore the effect of sequencing on adherence. Methods: Adults diagnosed with mCRC were identified using the nationally representative IQVIA Real-World Data Adjudicated Claims – US database (10/2014–07/2017). The first dispensing date of FTD/TPI or REG (if after FTD/TPI approval [10/2015]) was defined as the index date and the 3 months before as the baseline period. The observation period spanned from the index to the earliest date of a switch to another mCRC agent, end of continuous enrollment, or end of data availability. Medication possession ratio (MPR), proportion of days covered (PDC) at 3 months, and discontinuation (i.e., allowable gap≥45 days) were compared. Logistic (odds ratio [OR]) and Cox proportional hazards (hazard ratio [HR]) regressions, adjusting for baseline characteristics, were used to compare adherence and discontinuation, respectively. A subgroup analysis was conducted among switchers (FTD/TPI to REG vs REG to FTD/TPI). Results: A total of 469 FTD/TPI and 311 REG users were identified. FTD/TPI users had higher compliance with an MPR ≥ 80% (OR = 2.47; p < 0.001) and PDC ≥ 80% (OR = 2.77; p < 0.001). FTD/TPI users had lower risk of discontinuation (HR = 0.76; p = 0.006). Among switchers (96 FTD/TPI to REG; 83 REG to FTD/TPI), those switching from FTD/TPI to REG were more likely to have an MPR ≥ 80% (OR = 2.91; p < 0.001) and PDC ≥ 80% (OR = 4.60; p < 0.001) compared to REG to FTD/TPI switchers. Additionally, FTD/TPI to REG switchers had a lower risk of first treatment discontinuation (HR = 0.66; p = 0.009). Conclusions: In this study, FTD/TPI users had significantly higher compliance, lower discontinuation rate, and switchers treated first with FTD/TPI had better compliance, demonstrating that claims data can provide insight into oral chemotherapy adherence patterns in mCRC.