bluuebunny/crossref_metadata_2025 huggingface dataset:
The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment
Authors: Williams Jason B. , Horton Brendan L. , Zheng Yan , Duan Yukan , Powell Jonathan D. , Gajewski Thomas F.
Published: April 2017

Although the presence of tumor-infiltrating lymphocytes (TILs) indicates an endogenous antitumor response, immune regulatory pathways can subvert the effector phase and enable tumor escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell–intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. In this study, we show that the Egr2-driven cell surface proteins LAG-3 and 4-1BB can identify dysfunctional tumor antigen–specific CD8+ TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ TILs, but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF production yet retained expression of IFN-γ and regulatory T cell–recruiting chemokines. Transcriptional and phenotypic characterization revealed coexpression of multiple additional co-stimulatory and co-inhibitory receptors. Administration of anti–LAG-3 plus anti–4-1BB mAbs was therapeutic against tumors in vivo, which correlated with phenotypic normalization. Our results indicate that coexpression of LAG-3 and 4-1BB characterize dysfunctional T cells within tumors, and that targeting these receptors has therapeutic utility.
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
Authors: Daley Donnele , Mani Vishnu R. , Mohan Navyatha , Akkad Neha , Pandian Gautam S.D. Balasubramania , Savadkar Shivraj , Lee Ki Buom , Torres-Hernandez Alejandro , Aykut Berk , Diskin Brian , Wang Wei , Farooq Mohammad S. , Mahmud Arif I. , Werba Gregor , Morales Eduardo J. , Lall Sarah , Wadowski Benjamin J. , Rubin Amanda G. , Berman Matthew E. , Narayanan Rajkishen , Hundeyin Mautin , Miller George
Published: April 2017

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3−/− hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
Highly efficient inverted organic light emitting diodes by inserting a zinc oxide/polyethyleneimine (ZnO:PEI) nano-composite interfacial layer
Authors: Kaçar Rifat , Mucur Selin Pıravadılı , Yıldız Fikret , Dabak Salih , Tekin Emine
Published: April 2017

The electrode/organic interface is one of the key factors in attaining superior device performance in organic electronics, and inserting a tailor-made layer can dramatically modify its properties. The use of nano-composite (NC) materials leads to many advantages by combining materials with the objective of obtaining a desirable combination of properties. In this context, zinc oxide/polyethyleneimine (ZnO:PEI) NC film was incorporated as an interfacial layer into inverted bottom-emission organic light emitting diodes (IBOLEDs) and fully optimized. For orange-red emissive MEH-PPV based IBOLEDs, a high power efficiency of 6.1 lm W−1 at a luminance of 1000 cd m−2 has been achieved. Notably, the external quantum efficiency (EQE) increased from 0.1 to 4.8% and the current efficiency (CE) increased from 0.2 to 8.7 cd A−1 with rise in luminance (L) from 1000 to above 10 000 cd m−2 levels when compared to that of pristine ZnO-based devices. An identical device architecture containing a ZnO:PEI NC layer has also been used to successfully fabricate green and blue emissive IBOLEDs. The significant enhancement in the inverted device performance, in terms of luminance and efficiency, is attributed to a good energy-level alignment between the cathode/organic interface which leads to effective carrier balance, resulting in efficient radiative-recombination.
Water treatment: Chitosan associated with electrochemical methods
Authors: Tamiasso-Martinhon Priscila , de Souza João Marques Teixeira , da Silva Silvia Maria Cruzeiro , Pessoa Fernando Luiz Pellegrini , Sousa Célia
Published: April 2017

Pollution of water bodies due to the presence of toxic metals and organic compounds, bring out a series of environmental problems of public, government and social character. In addition, water pollution, has become the target and source of concern in many industrial sectors. Therefore, it is essential to develop technologies for treatment and purification of water. Chitosan is a natural product derived from chitin, extracted mainly from the shells of crustaceans. It is a low cost, renewable and biodegradable biopolymer of great socioeconomic and environmental importance. The classic treatment of wastewater containing metals involves physical chemistry processes of precipitation, ion exchange and electrochemistry. Electrochemical technology has been presented as the most promising methods for treating wastewater polluted with metals, colloids, dyes or oil in water emulsions; besides being used in removing organic compounds. Alternative methods like adsorption with biosorbents have been investigated. The great advantage of this latter over other techniques is the low generation of residues, easy recovery of metals and the possibility of reuse of the adsorbent. This article aimed to carry out an exploratory study, of bibliographical nature, on the use of chitosan in electrochemical methods for water treatment.
Portraits by the Artists as Young Men: Proust, Valéry, Colour
Authors: Watt Adam
Published: April 2017

Marcel Proust and Paul Valéry have received very little comparative critical attention. My article undertakes the first comparative analysis of works written and published by Proust and Valéry just four years apart when both were in their early twenties: Valéry’s prose ‘Glose sur quelques peintures’ (1891), which focuses on portraits by Cristofano Allori and Francisco de Zurbarán, and Proust’s ‘Portraits de peintres’ (1895), verse poems in which he celebrates paintings by Albert Cuyp, Paulus Potter, Antoine Watteau, and Anthony Van Dyck. My focus will be on the role colour plays in these brief, intense texts that are structurally at odds with the much more expansive spaces of the authors’ later works —
À la recherche du temps perdu
(1913–27) and the
Cahiers
(compiled 1894–1945). How do Proust and Valéry use colour when transposing the visual medium of painting into text? Proust is above all a prose writer and Valéry made his name as a poet. Does Proust’s handling of colour in his poetic texts differ from the ways in which colour figures in
À la recherche
? How does Valéry’s use of colour in his prose ‘Glose’ relate to the chromatic features of his verse? By taking colour in works written about paintings as a common thread I aim to determine the similarities and divergences of Proust and Valéry during the years of their apprenticeship as writers.
Calculating the quality of public high-throughput sequencing data to obtain a suitable subset for reanalysis from the Sequence Read Archive
Authors: Ohta Tazro , Nakazato Takeru , Bono Hidemasa
Published: April 2017

It is important for public data repositories to promote the reuse of archived data. In the growing field of omics science, however, the increasing number of submissions of high-throughput sequencing (HTSeq) data to public repositories prevents users from choosing a suitable data set from among the large number of search results. Repository users need to be able to set a threshold to reduce the number of results to obtain a suitable subset of high-quality data for reanalysis. We calculated the quality of sequencing data archived in a public data repository, the Sequence Read Archive (SRA), by using the quality control software FastQC. We obtained quality values for 1 171 313 experiments, which can be used to evaluate the suitability of data for reuse. We also visualized the data distribution in SRA by integrating the quality information and metadata of experiments and samples. We provide quality information of all of the archived sequencing data, which enable users to obtain sufficient quality sequencing data for reanalyses. The calculated quality data are available to the public in various formats. Our data also provide an example of enhancing the reuse of public data by adding metadata to published research data by a third party.
Applications of network analysis to routinely collected health care data: a systematic review
Authors: Brunson Jason Cory , Laubenbacher Reinhard C
Published: April 2017

Objective

To survey network analyses of datasets collected in the course of routine operations in health care settings and identify driving questions, methods, needs, and potential for future research.

Materials and Methods

A search strategy was designed to find studies that applied network analysis to routinely collected health care datasets and was adapted to 3 bibliographic databases. The results were grouped according to a thematic analysis of their settings, objectives, data, and methods. Each group received a methodological synthesis.

Results

The search found 189 distinct studies reported before August 2016. We manually partitioned the sample into 4 groups, which investigated institutional exchange, physician collaboration, clinical co-occurrence, and workplace interaction networks. Several robust and ongoing research programs were discerned within (and sometimes across) the groups. Little interaction was observed between these programs, despite conceptual and methodological similarities.

Discussion

We use the literature sample to inform a discussion of good practice at this methodological interface, including the concordance of motivations, study design, data, and tools and the validation and standardization of techniques. We then highlight instances of positive feedback between methodological development and knowledge domains and assess the overall cohesion of the sample.
A Phase 1 Dose-Escalation Study of Oral 5-Aminolevulinic Acid in Adult Patients Undergoing Resection of a Newly Diagnosed or Recurrent High-Grade Glioma
Authors: Cozzens Jeffrey W. , Lokaitis Barbara C. , Moore Brian E. , Amin Devin V. , Espinosa José A. , MacGregor Margaret , Michael Alex P. , Jones Breck A.
Published: April 2017

BACKGROUND: The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented. This drug has received regulatory approval in Europe but awaits approval in the United States.

OBJECTIVE: To identify the appropriate dose and toxicity or harms of 5-ALA used for enhanced intraoperative visualization of malignant brain tumors, reported from a single medical center in the United States.

METHODS: Prior to craniotomy for resection of a presumed high-grade glioma, individuals were given oral 5-ALA as part of a rapid dose-escalation scheme. At least 3 patients were selected for each dose level from 10 to 50 mg/kg in 10 mg/kg increments. Adverse events, intensity of tumor fluorescence, and results of biopsies in areas of tumor and the tumor bed under white light and deep blue light were recorded.

RESULTS: A total of 19 patients were studied in this phase 1 study. Serious adverse events were unrelated to the ingestion of 5-ALA. At the highest dose level studied (50 mg/kg), 2 out of 6 patients were observed to have transient dermatologic redness and peeling. These were grade 1 adverse events, which were not serious enough to be dose limiting. Patients at higher dose levels (>40 mg/kg) were more likely to have strong tumor fluorescence. There were no instances of false positive fluorescence.

CONCLUSION: The use of 5-ALA for brain tumor fluorescence is safe and effective to a dose of 50 mg/kg. Dose-limiting toxicity was not reached in this study.
Selection and Assessment of Plant Growth-Promoting Rhizobacteria for Biological Control of Multiple Plant Diseases
Authors: Liu Ke , Newman Molli , McInroy John A. , Hu Chia-Hui , Kloepper Joseph W.
Published: April 2017

A study was designed to screen individual strains of plant growth-promoting rhizobacteria (PGPR) for broad-spectrum disease suppression in vitro and in planta. In a preliminary screen, 28 of 196 strains inhibited eight different tested pathogens in vitro. In a secondary screen, these 28 strains showed broad spectrum antagonistic activity to six different genera of pathogens, and 24 of the 28 strains produced five traits reported to be related to plant growth promotion, including nitrogen fixation, phosphate solubilization, indole-3-acetic acid production, siderophore production, and biofilm formation. In advanced screens, the 28 PGPR strains selected in vitro were tested in planta for biological control of multiple plant diseases including bacterial spot of tomato caused by Xanthomonas axonopodis pv. vesicatoria, bacterial speck of tomato caused by Pseudomonas syringae pv. tomato, damping-off of pepper caused by Rhizoctonia solani, and damping-off of cucumber caused by Pythium ultimum. In all, 5 of the 28 tested strains significantly reduced three of the four tested diseases, and another 19 strains showed biological control to two tested diseases. To understand the observed broad-spectrum biocontrol capacity, antiSMASH was used to predict secondary metabolite clusters of selected strains. Multiple gene clusters encoding for secondary metabolites, e.g., bacillibactin, bacilysin, and microcin, were detected in each strain. In conclusion, selected individual PGPR strains showed broad-spectrum biocontrol activity to multiple plant diseases.
Managing herpes zoster in older adults
Authors: Beuscher Linda , Reeves Geri , Harrell Debbie
Published: April 2017

NPs must be aware of special prescribing considerations for medication safety when managing the care of older adults with herpes zoster. Age-related physiologic changes of the body impact the pharmacokinetics and pharmacodynamics of antiviral and pain medications and can lead to potential adverse events.
Case Report of Physiologic Phenibut Dependence Treated With a Phenobarbital Taper in a Patient Being Treated With Buprenorphine
Authors: Brunner Emily , Levy Robert
Published: April 2017

This case report describes the development of dependence to phenibut, a gamma-aminobutyric acid-receptor type B agonist, in a patient concurrently being treated with buprenorphine. The patient experienced withdrawal symptoms which were successfully treated with a phenobarbital taper based on a protocol to treat sedative use disorder. This case report provided an example of the development of a phenibut use disorder and also brought up a public health question of whether phenibut should therefore be officially classified and monitored.
Modifiable risk factors and preoperative optimization of the primary total arthroplasty patient
Authors: Romero Jose A. , Jones Richard E. , Brown Timothy
Published: April 2017

The bundle payment system combined with the current medical utilization climate has placed pressure on surgeons to produce excellent results with early functional recovery and short hospital stays after total hip arthroplasty (THA). There is concern that patients with comorbidities may encounter difficulty finding a surgeon willing to perform elective arthroplasty because of their increased risk of complications. Treating modifiable preoperative risk factors can reduce postoperative complications, re-admission rates, length of hospital stay, and adverse surgical outcomes. In this article we review the recent literature on clinical strategies for improving modifiable risk factors to meet patient expectations and achieve good outcomes.
Current management techniques for acetabular defects in revision total hip arthroplasty
Authors: Landrum Matthew , Huo Michael
Published: April 2017

The rate of total hip arthroplasty (THA) continues to increase. The incidence of revision total hip arthroplasty will also continue to increase. Revision THAs pose significant challenges to the orthopaedic surgeon. One of the most formidable challenges is the management of major acetabular bone defects in revision THA. There have been many advances in both implant options as well as augmentation capabilities for acetabular defects. This review will focus on some of the newest surgical innovations and techniques in managing major acetabular bone defects.
Step-by-Step Technique for Segmental Reconstruction of Reverse Hill-Sachs Lesions Using Homologous Osteochondral Allograft
Authors: Alkaduhimi Hassanin , van den Bekerom Michel P.J. , van Deurzen Derek F.P.
Published: April 2017

Posterior shoulder dislocations are accompanied by high forces and can result in an anteromedial humeral head impression fracture called a reverse Hill-Sachs lesion. This reverse Hill-Sachs lesion can result in serious complications including posttraumatic osteoarthritis, posterior dislocations, osteonecrosis, persistent joint stiffness, and loss of shoulder function. Treatment is challenging and depends on the amount of bone loss. Several techniques have been reported to describe the surgical treatment of lesions larger than 20%. However, there is still limited evidence with regard to the optimal procedure. Favorable results have been reported by performing segmental reconstruction of the reverse Hill-Sachs lesion with bone allograft. Although the procedure of segmental reconstruction has been used in several studies, its technique has not yet been well described in detail. In this report we propose a step-by-step description of the technique how to perform a segmental reconstruction of a reverse Hill-Sachs defect.
Noninvasive Ventilation in Acute Hypoxemic Nonhypercapnic Respiratory Failure: A Systematic Review and Meta-Analysis
Authors: Xu Xiu-Ping , Zhang Xin-Chang , Hu Shu-Ling , Xu Jing-Yuan , Xie Jian-Feng , Liu Song-Qiao , Liu Ling , Huang Ying-Zi , Guo Feng-Mei , Yang Yi , Qiu Hai-Bo
Published: April 2017

Objective:

To evaluate the effectiveness of noninvasive ventilation in patients with acute hypoxemic nonhypercapnic respiratory failure unrelated to exacerbation of chronic obstructive pulmonary disease and cardiogenic pulmonary edema.

Data Sources:

PubMed, EMBASE, Cochrane library, Web of Science, and bibliographies of articles were retrieved inception until June 2016.

Study Selection:

Randomized controlled trials comparing application of noninvasive ventilation with standard oxygen therapy in adults with acute hypoxemic nonhypercapnic respiratory failure were included. Chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients were excluded. The primary outcome was intubation rate; ICU mortality and hospital mortality were secondary outcomes.

Data Extraction:

Demographic variables, noninvasive ventilation application, and outcomes were retrieved. Internal validity was assessed using the risk of bias tool. The strength of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology.

Data Synthesis:

Eleven studies (1,480 patients) met the inclusion criteria and were analyzed by using a random effects model. Compared with standard oxygen therapy, the pooled effect showed that noninvasive ventilation significantly reduced intubation rate with a summary risk ratio of 0.59 (95% CI, 0.44–0.79; p = 0.0004). Furthermore, hospital mortality was also significantly reduced (risk ratio, 0.46; 95% CI, 0.24–0.87; p = 0.02). Subgroup meta-analysis showed that the application of bilevel positive support ventilation (bilevel positive airway pressure) was associated with a reduction in ICU mortality (p = 0.007). Helmet noninvasive ventilation could reduce hospital mortality (p = 0.0004), whereas face/nasal mask noninvasive ventilation could not.

Conclusions:

Noninvasive ventilation decreased endotracheal intubation rates and hospital mortality in acute hypoxemia nonhypercapnic respiratory failure excluding chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients. There is no sufficient scientific evidence to recommend bilevel positive airway pressure or helmet due to the limited number of trials available. Large rigorous randomized trials are needed to answer these questions definitely.
Patient-Specific Classification of ICU Sedation Levels From Heart Rate Variability*
Authors: Nagaraj Sunil B. , Biswal Siddharth , Boyle Emily J. , Zhou David W. , McClain Lauren M. , Bajwa Ednan K. , Quraishi Sadeq A. , Akeju Oluwaseun , Barbieri Riccardo , Purdon Patrick L. , Westover M. Brandon
Published: April 2017

Objective:

To develop a personalizable algorithm to discriminate between sedation levels in ICU patients based on heart rate variability.

Design:

Multicenter, pilot study.

Setting:

Several ICUs at Massachusetts General Hospital, Boston, MA.

Patients:

We gathered 21,912 hours of routine electrocardiogram recordings from a heterogenous group of 70 adult ICU patients. All patients included in the study were mechanically ventilated and were receiving sedatives.

Measurements and Main Results:

As “ground truth” for developing our method, we used Richmond Agitation Sedation Scale scores grouped into four levels denoted “comatose” (–5), “deeply sedated” (–4 to –3), “lightly sedated” (–2 to 0), and “agitated” (+1 to +4). We trained a support vector machine learning algorithm to calculate the probability of each sedation level from heart rate variability measures derived from the electrocardiogram. To estimate algorithm performance, we calculated leave-one-subject out cross-validated accuracy. The patient-independent version of the proposed system discriminated between the four sedation levels with an overall accuracy of 59%. Upon personalizing the system supplementing the training data with patient-specific calibration data, consisting of an individual’s labeled heart rate variability epochs from the preceding 24 hours, accuracy improved to 67%. The personalized system discriminated between light- and deep-sedation states with an average accuracy of 75%.

Conclusions:

With further refinement, the methodology reported herein could lead to a fully automated system for depth of sedation monitoring. By enabling monitoring to be continuous, such technology may help clinical staff to monitor sedation levels more effectively and to reduce complications related to over- and under sedation.
Validation of an Administrative Definition of ICU Admission Using Revenue Center Codes
Authors: Weissman Gary E. , Hubbard Rebecca A. , Kohn Rachel , Anesi George L. , Manaker Scott , Kerlin Meeta Prasad , Halpern Scott D.
Published: April 2017

Objectives:

Describe the operating characteristics of a proposed set of revenue center codes to correctly identify ICU stays among hospitalized patients.

Design:

Retrospective cohort study. We report the operating characteristics of all ICU-related revenue center codes for intensive and coronary care, excluding nursery, intermediate, and incremental care, to identify ICU stays. We use a classification and regression tree model to further refine identification of ICU stays using administrative data. The gold standard for classifying ICU admission was an electronic patient location tracking system.

Setting:

The University of Pennsylvania Health System in Philadelphia, PA, United States.

Patients:

All adult inpatient hospital admissions between July 1, 2013, and June 30, 2015.

Interventions:

None.

Measurements and Main Results:

Among 127,680 hospital admissions, the proposed combination of revenue center codes had 94.6% sensitivity (95% CI, 94.3–94.9%) and 96.1% specificity (95% CI, 96.0–96.3%) for correctly identifying hospital admissions with an ICU stay. The classification and regression tree algorithm had 92.3% sensitivity (95% CI, 91.6–93.1%) and 97.4% specificity (95% CI, 97.2–97.6%), with an overall improved accuracy (χ
2 = 398; p < 0.001).

Conclusions:

Use of the proposed combination of revenue center codes has excellent sensitivity and specificity for identifying true ICU admission. A classification and regression tree algorithm with additional administrative variables offers further improvements to accuracy.
Acute Respiratory Distress Syndrome Due To Tuberculosis in a Respiratory ICU Over a 16-Year Period
Authors: Muthu Valliappan , Dhooria Sahajal , Aggarwal Ashutosh N. , Behera Digambar , Sehgal Inderpaul Singh , Agarwal Ritesh
Published: April 2017

Objective:

Whether tuberculosis-related acute respiratory distress syndrome is associated with worse outcomes when compared with acute respiratory distress syndrome secondary to other causes remains unknown. Herein, we compare the outcomes between the two groups.

Design:

Retrospective analysis of all subjects admitted with acute respiratory distress syndrome over the last 16 years.

Setting:

Respiratory ICU of a tertiary care hospital in North India.

Subjects:

Consecutive subjects with acute respiratory distress syndrome.

Intervention:

Subjects were categorized as tuberculosis-related acute respiratory distress syndrome and acute respiratory distress syndrome-others and were managed with mechanical ventilation using the low tidal volume strategy as per the Acute Respiratory Distress Syndrom Network protocol.

Measurements and Main Results:

The baseline clinical and demographic characteristics, lung mechanics, and mortality were compared between the two groups. Factors predicting ICU survival were analyzed using multivariate logistic regression analysis. During the study period, 469 patients (18 tuberculosis-related acute respiratory distress syndrome and 451 acute respiratory distress syndrome-others) with acute respiratory distress syndrome were admitted. The mean (sd) age of the study population (52.9% women) was 33.6 years (14.8 yr). The baseline parameters and the lung mechanics were similar between the two groups. There were 132 deaths (28.1%) with no difference between the two groups (tuberculosis-related acute respiratory distress syndrome vs acute respiratory distress syndrome-others; 27.7% vs 28.2%; p = 0.71). There was also no significant difference in the ventilator-free days, ICU, and the hospital length of stay. On multivariate logistic regression analysis, the factors predicting survival were the admission Acute Physiology and Chronic Health Evaluation II score and baseline driving pressure after adjusting for Pao
2:Fio
2 ratio, gender, and the etiology of acute respiratory distress syndrome.

Conclusions:

Tuberculosis is an uncommon cause of acute respiratory distress syndrome even in high tuberculosis prevalence countries. Acute respiratory distress syndrome due to tuberculosis behaves like acute respiratory distress syndrome due to other causes and does not affect the ICU survival.
CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis
Authors: Fischer Jeannette , Paret Claudia , El Malki Khalifa , Alt Francesca , Wingerter Arthur , Neu Marie A. , Kron Bettina , Russo Alexandra , Lehmann Nadine , Roth Lea , Fehr Eva-M. , Attig Sebastian , Hohberger Alexander , Kindler Thomas , Faber Jörg
Published: April 2017

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer and the prognosis of children with relapsed or therapy refractory disease remains a challenge. Treatment with chimeric antigen receptor-modified T cells targeting the CD19 antigen (CART-19 therapy) has been presented as a promising approach toward improving the outcome of relapsed or refractory disease. However, 10%–20% of the patients suffer another relapse. Epitope-loss under therapy pressure has been suggested as a mechanism of tumor cells to escape the recognition from CART-19 therapy. In this work, we analyzed the expression of CD19 isoforms in a cohort of 14 children with CD19+ B-ALL and 6 nonleukemia donors. We showed that an alternatively spliced CD19 mRNA isoform lacking exon 2, and therefore the CART-19 epitope, but not isoforms lacking the transmembrane and cytosolic domains are expressed in leukemic blasts at diagnosis in children and in the bone marrow of nonleukemia donors. Furthermore, we clarified the sequence of a further isoform lacking the epitope recognized by CART-19 therapy and disclosed the presence of new isoforms. In comparison with the children, we showed that alternatively spliced CD19 mRNA isoforms affecting exon 2 are also expressed in 6 adult patients with CD19+ B-ALL. On top of that, one of the adults expressed an isoform lacking the CD19 transmembrane and cytosolic domains. In conclusion, we proved that some of the CD19 isoforms contributing to CART-19 escape already preexist at diagnosis and could evolve as a dominant clone during CART-19 therapy suggesting the application of combined treatment approaches.
Regenerative Medicine and Stem Cells in Dermatology
Authors: Moioli Eduardo K. , Bolotin Diana , Alam Murad
Published: April 2017

BACKGROUND

Clinically relevant regenerative medicine is still in its early stages of development. Difficulties in regenerating large-scale and complex structures, the lack of safety data, and the paucity of clinical trials have slowed the process of technological advance.

OBJECTIVE

To familiarize the clinician with techniques available in the laboratory and experimental approaches being tested clinically. In addition, a layout is discussed for how dermatologists can lead the way in bringing regenerative medicine to clinical reality.

METHODS

This article reviews the relevant literature on regenerative medicine for dermatological applications and discusses findings and techniques in a clinically relevant context.

RESULTS

Multiple cell-free and cell-based approaches for regenerating dermatologic tissues have been reported in the basic science and clinical literature. These are reviewed in the order of complexity.

CONCLUSION

Incremental steps are needed to apply the principles of regenerative medicine to simple medical problems first. Such a stepwise approach would commence, for example, with creation of single-function tissues that could fill soft-tissue defects and proceed to the development of fully functional skin grafts. Likewise, cell-free approaches can build the foundation for the more technically demanding cell-based strategies that are likely necessary for achieving the ultimate goal of regenerative dermatology.
Surgical Techniques for Closure of a Scalp Defect After Resection of Skin Malignancy
Authors: Rysz Maciej , Grzelecki Dariusz , Mazurek Maciej , Starościak Stanisław , Krajewski Romuald
Published: April 2017

BACKGROUND

Surgery for scalp malignancies is aimed at the complete resection and a good aesthetic outcome. The goal was to develop an algorithm for scalp reconstruction based on the authors' surgical experience.

METHODS

This is a retrospective analysis of 123 procedures of scalp malignancies in 105 patients. Twenty eight procedures were for resection of squamous cell carcinoma, 54 for basal cell carcinoma, and 41 for suspected melanomas.

RESULTS

Primary closure (27 procedures), local flap (LF; 19), split-thickness skin graft (SG; 64), rotated LF and SG (9), and free vascularized flaps (4) were used. Complications were partial (4) and total (1) necrosis of SG, free-flap atrophy (1), infection (2), wound dehiscence (1), and death due to cardiovascular complications (1). During follow-up, recurrence occurred in 22 patients (21%) and metastases to lymph nodes in 3 (3%).

CONCLUSION

Surface area size and the presence of the periosteum as well as a bone infiltration are important factors that can guide selection of a reconstruction method after resection of scalp malignancy.
The Use of a Fresh-Tissue Cadaver Model for the Instruction of Dermatological Procedures: A Laboratory Study for Training Medical Students
Authors: Cervantes Jose A. , Costello Collin M. , Maarouf Melody , McCrary Hilary C. , Zeitouni Nathalie C.
Published: April 2017

BACKGROUND

A realistic model for the instruction of basic dermatologic procedural skills was developed, while simultaneously increasing medical student exposure to the field of dermatology.

OBJECTIVE

The primary purpose of the authors' study was to evaluate the utilization of a fresh-tissue cadaver model (FTCM) as a method for the instruction of common dermatologic procedures. The authors' secondary aim was to assess students' perceived clinical skills and overall perception of the field of dermatology after the lab.

METHODS

Nineteen first- and second-year medical students were pre- and post-tested on their ability to perform punch and excisional biopsies on a fresh-tissue cadaver. Students were then surveyed on their experience.

RESULTS

Assessment of the cognitive knowledge gain and technical skills revealed a statistically significant improvement in all categories (p < .001). An analysis of the survey demonstrated that 78.9% were more interested in selecting dermatology as a career and 63.2% of participants were more likely to refer their future patients to a Mohs surgeon.

CONCLUSION

An FTCM is a viable method for the instruction and training of dermatologic procedures. In addition, the authors conclude that an FTCM provides realistic instruction for common dermatologic procedures and enhances medical students' early exposure and interest in the field of dermatology.
Simultaneous Determination of Imatinib, Dasatinib, and Nilotinib by Liquid Chromatography-Tandem Mass Spectrometry and Its Application to Therapeutic Drug Monitoring
Authors: Wojnicz Aneta , Colom-Fernández Beatriz , Steegmann Juan L. , Muñoz-Calleja Cecilia , Abad-Santos Francisco , Ruiz-Nuño Ana
Published: April 2017

Background:

Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) used as first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring is important to achieve treatment efficacy in the case of imatinib and nilotinib, and to control toxicity in the case of dasatinib. New high-sensitivity methods to monitor those drugs are needed, especially for dasatinib. Thus, a simple method to determine plasma levels of imatinib, dasatinib, and nilotinib for application in clinical practice was developed.

Methods:

TKIs were eluted with a Poroshell 120 EC-C18 column (2.1 × 75 mm, 2.7 μm) at 0.5 mL/min and 60°C, under gradient conditions through a mobile phase consisting of 4 mmol/L ammonium formate, pH 3.2 (65%), and acetonitrile (35%). TKIs were detected and quantified by liquid chromatography in tandem with mass spectrometry (LC/MS–MS) with positive electrospray ionization and analytes were extracted using solid phase extraction (Versaplate-SCX). Internal standards were isotope-labeled for each analyte.

Results:

The method was linear in the range of 2.5–5000 ng/mL for imatinib, 0.75–400 ng/mL for dasatinib, and 2–4000 ng/mL for nilotinib. The validation assays for accuracy and precision, matrix effect, extraction recovery, carryover, and stability of the samples for all the TKIs were appropriate according to regulatory agencies. Furthermore, imatinib plasma samples, stored for 4 years at −80°C were quite stable in approximately half of the samples.

Conclusions:

The method enables rapid quantification of TKI concentrations and is being applied to therapeutic drug monitoring to adjust dose and to manage adverse reactions in clinical practice.
Preliminary Model for the Design of a Custom Middle Ear Prosthesis
Authors: Kamrava Brandon , Gerstenhaber Jonathan A. , Amin Mamta , Har-el Yah-el , Roehm Pamela C.
Published: April 2017

Hypothesis:

Custom prostheses could be used to recreate the ossicular chain and improve hearing.

Background:

Ossicular discontinuity or fixation occurs in 55% of cases of conductive hearing loss, with most cases involving the incus. Reconstruction has been achieved by a variety of methods; however, there has been little improvement in hearing outcomes in decades.

Methods:

Precise measurements of anatomic dimensions, weight, and center of gravity were taken from 19 cadaveric incudes. These measurements were combined with measurements from the medical literature and micro-computed tomography (micro-CT) of cadaveric temporal bones to generate a rasterizable incus model. As a proof of concept, incudal replacements including possible anatomic variations were then three-dimensionally (3-D) printed and inserted into a cadaveric temporal bone.

Results:

Our measurements of cadaveric incudes corresponded well with those from the medical literature. These measurements were combined with anatomical information from micro-CT allowing identification of critical features of the incus, which remained constant. Other model features were modified to increase stability and facilitate synthesis, including broadening and thickening of the lenticular process and the incudomalleolar articulation. 3-D printed incudal replacements based on this model readily fit into a cadaveric temporal bone and successfully bridged the gap between malleus and incus.

Conclusion:

We have generated a model for custom 3-D synthesis of incudal prostheses. While current 3-D printing in biocompatible materials at the size required is limited, the technology is rapidly advancing, and 3-D printing of incudal replacements with polylactic acid (PLA) is of the correct size and shape.
Cochlear Implantation in Adults With Asymmetric Hearing Loss: Benefits of Bimodal Stimulation
Authors: van Loon Maarten Caspar , Smits Cas , Smit Conrad F. , Hensen Erik F. , Merkus Paul
Published: April 2017

Objective:

This study addresses the outcome of cochlear implantation in addition to hearing aid use in patients with asymmetric sensorineural hearing loss.

Study Design:

Prospective longitudinal study.

Setting:

Tertiary referral center.

Patients:

Seven adults with asymmetric sensorineural hearing loss, i.e., less than 30% aided speech recognition in their worst hearing ear and 60 to 85% speech recognition in their best hearing ear. All patients had a postlingual onset of their hearing loss and less than 20 years of auditory deprivation of their worst hearing ear.

Intervention:

Cochlear implantation in the functionally deaf ear.

Main Outcome Measures:

Speech recognition in quiet, speech recognition in noise, spatial speech recognition, localization abilities, music appreciation, and quality of life. Measurements were performed before cochlear implantation and 3, 6, and 12 months after cochlear implantation.

Results:

Before cochlear implantation, the average speech recognition of the ear fitted with a hearing aid was 74%. Cochlear implantation eventually resulted in an average speech recognition of 75%. Bimodal stimulation yielded speech recognition scores of 82, 86, and 88% after 3, 6, and 12 months, respectively. At all time intervals, bimodal stimulation resulted in a significantly better speech recognition as compared with stimulation with only hearing aid or only cochlear implant (CI). Speech recognition in noise and spatial speech recognition significantly improved as well as the ability to localize sounds and the quality of life.

Conclusion:

This study demonstrated that patients are able to successfully integrate electrical stimulation with contralateral acoustic amplification and benefit from bimodal stimulation. Therefore, we think that cochlear implantation should be considered in this particular group of patients, even in the presence of substantial residual hearing on the contralateral side.
Recent Trends in the Epidemiology of Hepatocellular Carcinoma in Olmsted County, Minnesota
Authors: Yang Ju Dong , Ahmed Mohammed Hager , Harmsen William S. , Enders Felicity , Gores Gregory J. , Roberts Lewis R.
Published: April 2017

Background/Aim:

The epidemiology of hepatocellular carcinoma (HCC) has changed in the United States recently. The aim of this study is to evaluate the recent trends of HCC epidemiology in Olmsted County, MN.

Methods:

Residents aged over 20 with newly diagnosed HCC were identified using the Rochester Epidemiology Project database. Clinical information was compared among patients diagnosed between 2000 and 2009 (era 1) and 2010 to 2014 (era 2).

Results:

Over 1.6 million person years of follow-up, 93 residents were diagnosed with HCC. The mean age was 67 and 71% were male. The age-adjusted and sex-adjusted incidence rates were 6.3 and 7.0 per 100,000 person years in the first and second eras (P=0.64). The proportion with hepatitis B virus etiology increased from 4% to 21% between the 2 eras (P<0.01), whereas there was a trend toward a decreasing proportion of hepatitis C virus etiology from 42% to 29% (P=0.20). Only 39% of HCC surveillance candidates had HCCs detected under surveillance and 41% of cirrhotic patients had unrecognized cirrhosis at the time of HCC diagnosis. Nonalcoholic fatty liver disease was associated with unrecognized cirrhosis and absence of cirrhosis at HCC diagnosis. More than half (56%) of patients presented at Barcelona Clinic Liver Cancer stage C or D and the median survival was 9.7 months. The overall survival had not changed over time.

Conclusions:

The incidence of HCC remained stable after 2010 in Olmsted County. The proportion of hepatitis B virus-induced HCC increased, whereas there was a trend of decreasing proportion of hepatitis C virus-induced HCC. The overall survival in community residents with HCC remains poor.
Religiosity in Acute Psychiatric Inpatients
Authors: AbdelGawad Noha , Chotalia Jigar , Parsaik Ajay , Pigott Teresa , Allen Melissa
Published: April 2017

This study examined the relationship between religiosity in 175 psychiatric inpatients as measured by the subscales of the Duke University Religion Index (DUREL) and sociodemographic (age, sex, and race), clinical (primary diagnosis, suicidality, and psychotic symptoms), and outcome (length of stay [LOS] and readmission rates) measures. Psychosis was assessed by Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS) scale. Bivariate and multivariate analyses were used to examine the association between the DUREL subscales and the outcome measures. High scorers on the nonorganized religiosity subscale were less likely to have psychosis (47% vs. 52%; p < 0.05) but had greater psychosis severity (mean ± SD, 14.5 ± 5 vs.12.4 ± 6; p < 0.05), as measured by the CRDPSS scale, and significantly longer LOS (mean ± SD, 8.3 ± 3.8 vs. 6.9 ± 3.4; p < 0.05). Conversely, they were less likely to report previous suicide attempts than low scorers (p < 0.05). These results suggest that a brief measure of religious activities may identify psychiatric inpatients at greater risk for psychosis, suicidality, and longer hospitalizations.
Inhaled Treprostinil Drug Delivery During Mechanical Ventilation and Spontaneous Breathing Using Two Different Nebulizers
Authors: Parker Donna K. , Shen Shuijie , Zheng Jiang , Ivy D. Dunbar , Crotwell Dave N. , Hotz Justin C. , DiBlasi Robert M.
Published: April 2017

Objectives:

To determine the feasibility of delivering inhaled treprostinil during mechanical ventilation and spontaneous unassisted ventilation using the Tyvaso Inhalation System and the vibrating mesh nebulizer. We sought to compare differences in fine particle fraction, and absolute inhaled treprostinil mass delivered to neonatal, pediatric, and adult models affixed with a face mask, conventional, and high-frequency ventilation between Tyvaso Inhalation System and with different nebulizer locations between Tyvaso Inhalation System and vibrating mesh nebulizer.

Design:

Fine particle fraction was first determined via impaction with both the Tyvaso Inhalation System and vibrating mesh nebulizer. Next, a test lung configured with neonatal, pediatric, and adult mechanics and a filter to capture medication was attached to a realistic face model during spontaneous breathing or an endotracheal tube during conventional ventilation and high-frequency oscillator ventilator. Inhaled treprostinil was then nebulized with both the Tyvaso Inhalation System and vibrating mesh nebulizer, and the filter was analyzed via high-performance liquid chromatography. Testing was done in triplicate. Independent two-sample t tests were used to compare mean fine particle fraction and inhaled mass between devices. Analysis of variance with Tukey post hoc tests were used to compare within device differences.

Setting:

Academic children’s hospital aerosol research laboratory.

Measurements and Main Results:

Fine particle fraction was not different between the Tyvaso Inhalation System and vibrating mesh nebulizer (0.78 ± 0.04 vs 0.77 ± 0.08, respectively; p = 0.79). The vibrating mesh nebulizer delivered the same or greater inhaled treprostinil than the Tyvaso Inhalation System in every simulated model and condition. When using the vibrating mesh nebulizer, delivery was highest when using high-frequency oscillator ventilator in the neonatal and pediatric models, and with the nebulizer in the distal position in the adult model.

Conclusions:

The vibrating mesh nebulizer is a suitable alternative to the Tyvaso Inhalation System for inhaled treprostinil delivery. Fine particle fraction is similar between devices, and vibrating mesh nebulizer delivery meets or exceeds delivery of the Tyvaso Inhalation System. Delivery for infants and children during high-frequency oscillator ventilator with the vibrating mesh nebulizer may result in higher than expected dosages.
X-ray Imaging Analysis of Intrathecal Baclofen Pumps for Pediatric Emergency Medicine
Authors: Carr Brianna Nicole , Sernas Thomas , Mazzola Catherine A.
Published: April 2017

Intrathecal baclofen therapy has become increasingly popular because of its effectiveness in treating spasticity in pediatric patients. The device implanted into each patient is structurally similar. However, x-ray imaging can give the appearance of missing or extraneous objects on or near the intrathecal baclofen device. The composition of the material used in making the catheters is transparent on x-ray images. In addition, the connection port between the pump and catheter may resemble the shape of a needle. This has led to confusion among emergency room personnel, and unnecessary panic for other people involved. It is important that medical professionals understand many of the new designs of the pump-connector system to avoid further complications.