bluuebunny/crossref_metadata_2025 huggingface dataset:
Rheumatologists’ perspective on hydroxychloroquine guidelines
Authors: Winebrake James , Khalili Leila , Weiner Julia , Gartshteyn Yevgeniya , Park Lisa , Askanase Anca D
Published: November 2020

Objective

Hydroxychloroquine (HCQ) retinal toxicity is an ongoing concern for rheumatologists. The revised 2016 American Academy of Ophthalmology (AAO) guidelines created controversy regarding the correct dosing and evaluation of HCQ toxicity. The current study was initiated to further understand rheumatologists’ practices regarding HCQ.

Methods

A questionnaire-based survey was distributed electronically to rheumatologists. We collected information on HCQ dosing, clinical decision-making processes, familiarity with the AAO 2016 guidelines, and perceived disparities between the AAO 2016 guidelines and rheumatological clinical practice.

Results

78 rheumatologists completed the survey (49% from USA, 90% academic practices, 82% self-identified as lupus experts). Only lupus expert (n=64) data were included in subsequent analysis. The mean cohort size was 747 (50–6571), a total cohort 45 612 patients. HCQ was prescribed to >75% of patients with SLE by 81.3% of SLE experts, with routine counselling about ophthalmic risks. The typical dose of HCQ used was 200–400 mg/day. 17% of rheumatologists use doses up to 600 mg/day, while 6.2% use up to 6.5 mg/kg/day. HCQ adherence is routinely assessed. 479 cases of HCQ retinal toxicity (1.05%) and 9 cases of HCQ-associated blindness (1.8 per 10 000 patients) were reported. 89.1% of respondents reported familiarity with the AAO guidelines. Those aware of the guidelines cited limited dosing options (54.7%), lack of supporting evidence (57.8%) and low patient adherence (43.8%) as obstacles to greater implementation of the guidelines.

Conclusion

These data suggest that HCQ toxicity and blindness are rare in patients with SLE. Rheumatologists treating patients with SLE are aware of the guidelines and appreciate the importance of partnering with ophthalmologists in preventing retinal toxicity.
Quaternionic electrodynamics
Authors: Giardino Sergio
Published: November 2020

We develop a quaternionic electrodynamics and show that it naturally supports the existence of magnetic monopoles. We obtained the field equations, the continuity equation, the electrodynamic force law, the Poynting vector, the energy conservation, and the stress-energy tensor. The formalism also enabled us to generalize the Dirac monopole and the charge quantization rule.
DYEING AND COLORFASTNESS PROPERTIES OF TENCEL FABRIC TREATED WITH NATURAL DYE EXTRACTED FROM ORANGE PEEL
Authors: NAVEED TAYYAB , BABAR AIJAZ AHMED , RASHDI SAYED YASEEN , REHMAN FAISAL , NAEEM MUHAMMAD AWAIS , WANG WEI , ABBAS MUDASSAR , RAMZAN MUHAMMAD BABAR
Published: November 2020

The usage of natural dyes for coloration has attained attention in recent years due to their ecofriendly environment. Therefore, in this study, orange peel solvent extract is used as a natural dye for coloring Tencel fabric samples. Pre-mordanting and post-mordanting methods were accomplished with two different mordants, i.e. ferrous sulfate and copper sulfate. The dyeing shade effects were retrieved through colorfastness properties according to the ISO standardizations. The results revealed that the best color shade ([Formula: see text]/[Formula: see text]: 4.56) was achieved using mordant ferrous sulfate through the post-mordanting method. The effect of lightfastness on all dyed Tencel fabric samples was observed good (3–4) in both mordanting methods. However, mordant ferrous sulfate showed better lightfastness (4) than copper sulfate (3–3.5) through both mordanting methods. Comparatively, in the rubbing fastness, copper sulfate has superior results in both mordanting methods. The ferrous and copper sulfates in both mordanting methods have similar tests results (4.5) of washing fastness, acidic and alkaline perspiration. Furthermore, the FTIR test substantiated that not any structural change occurred through orange peel dyed Tencel fabric samples through both methods. TGA observed samples were relatively stable up to 300∘C temperature. Overall, the best results of colorfastness for Tencel fabric samples were obtained with ferrous sulfate mordant through the post-mordanting extraction method.
Thick Sintered Electrode Lithium-Ion Battery Discharge Simulations: Incorporating Lithiation-Dependent Electronic Conductivity and Lithiation Gradient Due to Charge Cycle
Authors: Cai Chen , Nie Ziyang , Robinson J. Pierce , Hussey Daniel S. , LaManna Jacob M. , Jacobson David L. , Koenig Gary M.
Published: November 2020

In efforts to increase the energy density of lithium-ion batteries, researchers have attempted to both increase the thickness of battery electrodes and increase the relative fractions of active material. One system that has both of these attributes are sintered thick electrodes comprised of only active material. Such electrodes have high areal capacities, however, detailed understanding is needed of their transport properties, both electronic and ionic, to better quantify their limitations to cycling at higher current densities. In this report, efforts to improve models of the electrochemical cycling of sintered electrodes are described, in particular incorporation of matrix electronic conductivity which is dependent on the extent of lithiation of the active material and accounting for initial gradients in lithiation of active material in the electrode that develop as a consequence of transport limitations during charging cycles. Adding in these additional considerations to a model of sintered electrode discharge resulted in improved matching of experimental cell measurements.
A Drug-Induced Acute Pancreatitis Retrospective Study
Authors: Gagnon Ann-Lorie , Lavoie Alexandre , Frigon Marie-Pier , Michaud-Herbst Alban , Tremblay Karine
Published: November 2020

Background and Aims. Drugs are considered a relatively rare and understudied cause of acute pancreatitis (AP). The lack of convincing and conclusive data on drug-induced AP (DIAP) complicates the diagnosis as well as the identification of the causative drug. The aim of this study is to document causes of DIAP cases that occurred in the Saguenay-Lac-Saint-Jean (SLSJ) population. Methods. We have conducted a retrospective and descriptive population-based study of DIAP cases that occurred between 2006 and 2014 in the six hospitals serving the entire SLSJ population. Cases were selected from the Quebec Ministry of Health hospitalizations registry (MED-ECHO) administrative public database. A medical chart review was performed in an attempt to characterize DIAP hospitalizations and to identify the imputable drugs. Results. During the studied period, 75 cases (30.7% male, 69.3% female) were included totaling 90 hospitalizations for DIAP. Among them, 50 causative drugs were identified and were distributed in 17 different drug classes. Recurrent DIAPs were documented in 13 cases, and among them, 6 cases have experimented a positive rechallenge. Six drugs (5-fluorouracil, atorvastatin, bortezomib, nilotinib, rosuvastatin, and triamcinolone) were associated with the highest degree of evidence. The most common causative drugs of DIAP hospitalization were azathioprine (n = 7), followed by atorvastatin (n = 6), hydrochlorothiazide (n = 5), rosuvastatin (n = 4), and codeine (n = 4). Conclusions. This study has added new evidences about potentially pancreatitis-associated drugs in literature. This is the first study to report definite 5-fluorouracil- and triamcinolone-induced AP. An updated version of the evidence-based literature review is needed to support the clinicians in the identification of the causative drugs.
A New Empirical Correlation for Estimation of EBF Steel Frame Behavior Factor under Near-Fault Earthquakes Using the Genetic Algorithm
Authors: Razavi Seyed Abdonnabi , Siahpolo Navid , Mahdavi Adeli Mehdi
Published: November 2020

The most important feature of the behavior factor is that it allows the structural designer to be able to evaluate the structural seismic demand, using an elastic analysis, based on force-based principles quickly. In most seismic codes, this coefficient is merely dependent on the type of lateral resistance system and is introduced with a fixed number. However, there is a relationship between the behavior factor, ductility (performance level), structural geometric properties, and type of earthquake (near and far). In this paper, a new and accurate correlation is attempted to predict the behavior factor (q) of EBF steel frames, under near-fault earthquakes, using the genetic algorithm (GA). For this purpose, a databank consisting of 12960 data is created. To establish different geometrical properties of models, 3−, 6−, 9−, 12−, 15, and 20− story steel EBF frames were considered with 3 different types of link beam, 3 different types of column stiffness, and 3 different types of brace slenderness. Using nonlinear time history under 20 near-fault earthquake, all models were analyzed to reach 4 different performance levels. 6769 data were used as GA training data. Moreover, to validate the correlation, 2257 data were used as test data for calculating mean squared error (MSE) and correlation coefficient (R) between the predicted values of (q) and the real values. In addition, the MSE and R were calculated for correlation in the train and test data. Also, the comparison of the response of maximum inelastic displacement of 5 stories EBF from the proposed correlation and the mean inelastic time-history analysis confirms the accuracy of the estimate relationship.
Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis
Authors: Tang Mengshi , Xie Xi , Yi Pengji , Kang Jin , Liao Jiafen , Li Wenqun , Li Fen
Published: November 2020

Objective. To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. Methods. Related compounds were obtained from TCMSP and BATMAN‐TCM database. Oral bioavailability and drug‐likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM‐RA, compounds‐targets, and pathways‐targets‐compounds were visualized through Cytoscape 3.7.1. The protein‐protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). Results. A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds‐targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta‐sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K‐Akt, TNF, and IL‐17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. Conclusion. The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA.
Central Venous Catheter Insertion: A Scoring System for Evaluation of Both the Procedure and the Operator (CVCI Score/Gaber Score)
Authors: Gaber Sayed , Yehia Ahmed , Nabil Beshoy , Samir Ahmed
Published: November 2020

Introduction. Currently, there is no method to assess the performance while inserting a central venous catheter. We suggest a new scoring system for evaluation of both the technique as well as the operator, and then we applied it for the comparison between the landmark and ultrasound techniques to assess its validity. Methods. Four hundred patients were divided into two equal groups: group (A): internal jugular vein (IJV) and group (B): subclavian vein (SV). The landmark technique and the ultrasound guidance were used equally (100 patients for each) in both groups. Results. In group (A), 20% of patients in the landmark group achieved score 4, while 82% of patients in the ultrasound group achieved the same score. This suggests that the ultrasound technique for catheterization of IJV decreased overall complications and improved the success rate. In group (B), there were 70% of patients in the landmark group who achieved score 5, while 49% of patients in the ultrasound group achieved the same score which proposes that the landmark technique might be deceptively better than the ultrasound technique for catheterization of SV. This could be because the time required for catheterization of SV by the ultrasound technique was longer than that in the landmark technique. Overall complications of 15% with the landmark technique vs. 2% with ultrasound guidance in this group of patients are not only statistically significant but also increase morbidity and mortality with a highly invasive procedure. Complications and their incidences are by far more significant than seconds of time. Our results suggest that the ultrasound technique could decrease the incidence of overall complications, but it is time-consuming in group (B). These results support the validity of our new scoring system. Conclusion. We suggest a new scoring system for CVC insertion that can be used for evaluation of both the technique and the operator. It can evaluate the performance of junior staff and follow their progress. It can be applied in the medical and critical care practice as well as the quality management privileges and protocols.
Factors Affecting Persistent Postoperative Pain in Patients with Hip Fractures
Authors: Goto Kyo , Kataoka Hideki , Honda Ayana , Yamashita Junichiro , Morita Kaoru , Hirase Tatsuya , Sakamoto Junya , Okita Minoru
Published: November 2020

Osteoporotic fractures are common among older people, and hip fractures (HF) can be devastating. Surgery is indicated for most cases of HF, and chronic persistent postoperative pain is likely to occur. This study investigated the multifaceted factors related to persistent pain occurring during the acute phase and subacute phase of recovery after HF surgery. We conducted a prospective 8-week study of older HF patients after surgery. We evaluated pain intensity, depression symptoms, the fear of falling, pain catastrophizing, cognition and attention, the ability to perform activities of daily living, and the physical performance at 2 weeks (acute phase) and at 4 weeks (subacute phase) after surgery. Patients were divided into the light group (Verbal Rating Scale (VRS) score ≤1) and severe group (VRS score ≥2) according to pain intensity at 8 weeks (recovery phase) after surgery. Factors affecting persistent postoperative pain during recovery were examined using logistic regression analysis. Seventy-two patients were analyzed: 50 in the light group and 22 in the severe group. In the severe group, pain with movement and Pain Catastrophizing Scale scores were higher than those of the light group at 2 weeks and at 4 weeks after surgery. The regression analysis showed that pain with movement at 2 weeks and at 4 weeks after surgery and pain catastrophizing at 4 weeks after surgery were related to persistent postoperative pain. HF patients may have persistent pain if they continue to experience pain and catastrophize their pain during the acute phase and subacute phase after surgery.
Fault Detection of Aircraft Control System Based on Negative Selection Algorithm
Authors: Chen Jie , Chen Senyao , Ma Cunbao , Jing Zhengdong , Xu Qingshan
Published: November 2020

The aircraft control system controls the whole flight movement process. Its fault detection can assist the aircraft PHM system in making decisions and completing the targeted maintenance, which is of great significance to improve the safety and reliability of the aircraft. In this paper, by taking advantage of the strong leaning and intelligent recognition ability and the characteristic of less information required in the negative selection artificial immune system, a fault detection method is proposed for aircraft control system based on negative selection algorithm. Basically, after extracting the fault characteristics from the aircraft flight parameters, the negative selection module is utilized to generate fault detectors to monitor the aircraft control system. Afterward, the hypothesis test is introduced to evaluate the detector coverage more efficiently, and the detector cover area is optimized by applying geometric mathematics in the optimization of the detector center position and radius. The method is verified by simulation of a certain aircraft control system, and the results show that it has a good detection effect on the system faults.
A Nomogram Model Based on Noninvasive Bioindicators to Predict 3‐Year Risk of Nonalcoholic Fatty Liver in Nonobese Mainland Chinese: A Prospective Cohort Study
Authors: Cai Xintian , Aierken Xiayire , Ahmat Ayguzal , Cao Yuanyuan , Zhu Qing , Wu Ting , Li Nanfang
Published: November 2020

The purpose of this study is to establish and validate an accurate and personalized nonalcoholic fatty liver disease (NAFLD) prediction model based on the nonobese population in China. This study is a secondary analysis of a prospective study. We included 6,155 nonobese adults without NAFLD at baseline, with a median follow‐up of 2.3 years. Univariate and multivariate Cox regression analyses were used to determine independent predictors. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize the selection of variables. Based on the results of multivariate analysis, a prediction model was established. Harrell’s consistency index (C‐index) and area under the curve (AUC) were used to determine the discrimination of the proposed model. The goodness of fit of the calibration model was tested, and the clinical application value of the model was evaluated by decision curve analysis (DCA). The participants were randomly divided into a training cohort (n = 4,605) and a validation cohort (n = 1,550). Finally, seven of the variables (HDL‐c, BMI, GGT, ALT, TB, DBIL, and TG) were included in the prediction model. In the training cohort, the C‐index and AUC value of this prediction model were 0.832 (95% confidence interval (CI), 0.820‐0.844) and 0.861 (95% CI, 0.849‐0.873), respectively. In the validation cohort, the C‐index and AUC values of this prediction model were 0.829 (95% CI, 0.806‐0.852) and 0.859 (95% CI, 0.841‐0.877), respectively. The calibration plots demonstrated good agreement between the estimated probability and the actual observation. DCA demonstrated a clinically effective predictive model. Our nomogram can be used as a simple, reasonable, economical, and widely used tool to predict the 3‐year risk of NAFLD in nonobese populations in China, which is helpful for timely intervention and reducing the incidence of NAFLD.
Construction of Nursing Intervention Model and Clinical Empirical Study on Dopamine Beta Hydroxylase Gene Polymorphism in Children with ADHD
Authors: Zhao Hongyi , Chen Jiangyu
Published: November 2020

ADHD is a common disease in children, and the pathogenesis is still unclear. Attention deficit is the main manifestation of ADHD, which has a serious impact on children’s learning and growth. The treatment of ADHD is mainly western medicine, supplemented by psychotherapy. More and more studies have shown that ADHD has similar characteristics to psychological diseases, and dopamine beta hydroxylase gene abnormality is the common feature of most mental diseases. In view of the potential relationship between ADHD and dopamine β hydroxylase gene, this paper will study the polymorphism of dopamine β hydroxylase gene in children with ADHD under the nursing intervention mode. This paper is divided into three parts. The first part is theoretical research. In this part, we deeply analyze ADHD. We think that the pathogenesis of ADHD mainly comes from four factors: heredity, environment, nutrition, and behavior. In order to further test the relationship between ADHD and dopamine beta hydroxylase gene, the corresponding experimental model was established in the second part of this paper. All the samples in the experiment are from real cases. The experimental principle and specific operation steps are given in detail. In order to facilitate comparison, the same number of control groups was established in addition to the real disease. The third part is the experimental results and analysis. After a number of comparative experiments, through the analysis of experimental data, we believe that ADHD is closely related to the gene of dopamine beta hydroxylase. Among them, the A2 gene in the patient group was significantly more than that in the normal group, which further verified that ADHD has the characteristics of common psychological diseases.
Single-Cell Transcriptomic Heterogeneity in Invasive Ductal and Lobular Breast Cancer Cells
Authors: Chen Fangyuan , Ding Kai , Priedigkeit Nolan , Elangovan Ashuvinee , Levine Kevin M. , Carleton Neil , Savariau Laura , Atkinson Jennifer M. , Oesterreich Steffi , Lee Adrian V.
Published: November 2020

Invasive lobular breast carcinoma (ILC), one of the major breast cancer histologic subtypes, exhibits unique features compared with the well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly caused by inactivating mutations, but the contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single-cell RNA sequencing on a panel of IDC and ILC cell lines, and an IDC cell line (T47D) with CRISPR-Cas9–mediated E-cadherin knockout (KO). Inspection of intracell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of MCF7 cells highly expressing an apoptosis-related signature, positively correlated with a preadaptation signature to estrogen deprivation. Investigation of E-cadherin KO–induced alterations showed transcriptomic membranous systems remodeling, elevated resemblance to ILCs in regulon activation, and increased sensitivity to IFNγ-mediated growth inhibition via activation of IRF1. This study reveals single-cell transcriptional heterogeneity in breast cancer cell lines and provides a resource to identify drivers of cancer progression and drug resistance.

Significance:

This study represents a key step towards understanding heterogeneity in cancer cell lines and the role of E-cadherin depletion in contributing to the molecular features of invasive lobular breast carcinoma.
The Microbiome and Cancer: Creating Friendly Neighborhoods and Removing the Foes Within
Authors: Parida Sheetal , Sharma Dipali
Published: November 2020

The human body is colonized by the microbial cells that are estimated to be as abundant as human cells, yet their genome is roughly 100 times the human genome, providing significantly more genetic diversity. The past decade has observed an explosion of interest in examining the existence of microbiota in the human body and understanding its role in various diseases including inflammatory bowel disease, neurologic diseases, cardiovascular disorders, and cancer. Many studies have demonstrated differential community composition between normal tissue and cancerous tissue, paving the way for investigations focused on deciphering the cause-and-effect relationships between specific microbes and initiation and progression of various cancers. Also, evolving are the strategies to alter tumor-associated dysbiosis and move it toward eubiosis with holistic approaches to change the entire neighborhood or to neutralize pathogenic strains. In this review, we discuss important pathogenic bacteria and the underlying mechanisms by which they affect cancer progression. We summarize key microbiota alterations observed in multiple tumor niches, their association with clinical stages, and their potential use in cancer diagnosis and management. Finally, we discuss microbiota-based therapeutic approaches.
BET Inhibition Enhances the Antileukemic Activity of Low-dose Venetoclax in Acute Myeloid Leukemia
Authors: Ramsey Haley E. , Greenwood Dalton , Zhang Susu , Childress Merrida , Arrate Maria P. , Gorska Agnieszka E. , Fuller Londa , Zhao Yue , Stengel Kristy , Fischer Melissa A. , Stubbs Matthew C. , Liu Phillip C.C. , Boyd Kelli , Rathmell Jeffrey C. , Hiebert Scott W. , Savona Michael R.
Published: November 2020

Purpose:

The BCL2 inhibitor, venetoclax, has transformed clinical care in acute myeloid leukemia (AML). However, subsets of patients do not respond or eventually acquire resistance. Venetoclax-based regimens can lead to considerable marrow suppression in some patients. Bromodomain and extraterminal inhibitors (BETi) are potential treatments for AML, as regulators of critical AML oncogenes. We tested the efficacy of novel BET inhibitor INCB054329, and its synergy with venetoclax to reduce AML without induction of hematopoietic toxicity.

Experimental Design:

INCB054329 efficacy was assessed by changes in cell cycle and apoptosis in treated AML cell lines. In vivo efficacy was assessed by tumor reduction in MV-4-11 cell line–derived xenografts. Precision run-on and sequencing (PRO-seq) evaluated effects of INCB054329. Synergy between low-dose BETi and venetoclax was assessed in cell lines and patient samples in vitro and in vivo while efficacy and toxicity was assessed in patient-derived xenograft (PDX) models.

Results:

INCB054329 induced dose-dependent apoptosis and quiescence in AML cell lines. PRO-seq analysis evaluated the effects of INCB054329 on transcription and confirmed reduced transcriptional elongation of key oncogenes, MYC and BCL2, and genes involved in the cell cycle and metabolism. Combinations of BETi and venetoclax led to reduced cell viability in cell lines and patient samples. Low-dose combinations of INCB054329 and venetoclax in cell line and PDX models reduced AML burden, regardless of the sensitivity to monotherapy without development of toxicity.

Conclusions:

Our findings suggest low dose combinations of venetoclax and BETi may be more efficacious for patients with AML than either monotherapy, potentially providing a longer, more tolerable dosing regimen.
Blocking IL1 Beta Promotes Tumor Regression and Remodeling of the Myeloid Compartment in a Renal Cell Carcinoma Model: Multidimensional Analyses
Authors: Aggen David H. , Ager Casey R. , Obradovic Aleksandar Z. , Chowdhury Nivedita , Ghasemzadeh Ali , Mao Wendy , Chaimowitz Matthew G. , Lopez-Bujanda Zoila A. , Spina Catherine S. , Hawley Jessica E. , Dallos Matthew C. , Zhang Cheng , Wang Vinson , Li Hu , Guo Xinzheng V. , Drake Charles G.
Published: November 2020

Purpose:

Intratumoral immunosuppression mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) represents a potential mechanism of immune checkpoint inhibitor (ICI) resistance in solid tumors. By promoting TAM and MDSC infiltration, IL1β may drive adaptive and innate immune resistance in renal cell carcinoma (RCC) and in other tumor types.

Experimental Design:

Using the RENCA model of RCC, we evaluated clinically relevant combinations of anti-IL1β plus either anti-PD-1 or the multitargeted tyrosine kinase inhibitor (TKI), cabozantinib. We performed comprehensive immune profiling of established RENCA tumors via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA sequencing (RNA-seq). Similar analyses were extended to the MC38 tumor model.

Results:

Analyses via multiparameter flow cytometry, tumor cytokine profiling, and single-cell RNA-seq showed that anti-IL1β reduces infiltration of polymorphonuclear MDSCs and TAMs. Combination treatment with anti-IL1β plus anti-PD-1 or cabozantinib showed increased antitumor activity that was associated with decreases in immunosuppressive MDSCs and increases in M1-like TAMs.

Conclusions:

Single-cell RNA-seq analyses show that IL1β blockade and ICI or TKI remodel the myeloid compartment through nonredundant, relatively T-cell–independent mechanisms. IL1β is an upstream mediator of adaptive myeloid resistance and represents a potential target for kidney cancer immunotherapy.
Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers
Authors: Tsang Erica S. , Grisdale Cameron J. , Pleasance Erin , Topham James T. , Mungall Karen , Reisle Caralyn , Choo Caleb , Carreira Marcus , Bowlby Reanne , Karasinska Joanna M. , MacMillan Daniel , Williamson Laura M. , Chuah Eric , Moore Richard A. , Mungall Andrew J. , Zhao Yongjun , Tessier-Cloutier Basile , Ng Tony , Sun Sophie , Lim Howard J. , Schaeffer David F. , Renouf Daniel J. , Yip Stephen , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Loree Jonathan M.
Published: November 2020

Purpose:

Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design:

Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.

Results:

In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1).

Conclusions:

Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia
Authors: Nagler Arnon , Labopin Myriam , Dholaria Bhagirathbhai , Angelucci Emanuele , Afanasyev Boris , Cornelissen Jan J. , Sica Simona , Meijer Ellen , Ciceri Fabio , Van Gorkom Gwendolyn , Kröger Nicolaus , Martin Hans , Pioltelli Pietro , Risitano Antonio , Canaani Jonathan , Savani Bipin N. , Sanz Jaime , Mohty Mohamad
Published: November 2020

Purpose:

Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor.

Experimental Design:

We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N = 401) versus UD mobilized peripheral blood stem cells (UD-PB, N = 192) transplantation in the setting of PTCy.

Results:

The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (P < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (P < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (P = 0.21). In the multivariate analysis, the risk of grade 2–4 acute GvHD (HR = 0.53, P = 0.01) and chronic GvHD (HR = 0.50, P = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.

Conclusions:

The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
Immune Infiltrate in the Primary Tumor Predicts Effect of Adjuvant Radiotherapy in Breast Cancer; Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Puttonen Henri A.J. , Sjöström Martin , Holmberg Erik , Chang S. Laura , Feng Felix Y. , Speers Corey , Pierce Lori J. , Lundstedt Dan , Killander Fredrika , Niméus Emma , Kovács Anikó , Karlsson Per
Published: November 2020

Purpose:

Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze whether the immune infiltrate predicts benefit from postoperative radiotherapy in a large randomized breast cancer radiotherapy trial.

Experimental Design:

In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast-conserving surgery (BCS) and postoperative radiotherapy or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods: IHC and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8+ T cells and FOXP3+ T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral and protumoral immune cells, respectively.

Results:

An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant radiotherapy. The interaction between radiotherapy and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses (P = 0.039 and P = 0.035) and was also significant for ipsilateral breast tumor recurrence in the gene expression analyses (P = 0.025).

Conclusions:

Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant radiotherapy. These results may impact decisions regarding postoperative radiotherapy in early breast cancer.
Screening for Pancreatic Ductal Adenocarcinoma: Are We Asking the Impossible?
Authors: Caldwell Katharine E. , Conway Alexander P. , Hammill Chet W.
Published: November 2020

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. Because of this, significant interest and research funding has been devoted to development of a screening test to identify individuals during a prolonged asymptomatic period; however, to date, no such test has been developed. We evaluated current NIH spending and clinical trials to determine the focus of research on pancreatic cancer screening as compared with other cancer subtypes. Using statistical methodology, we determined the effects of population-based pancreatic cancer screening on overall population morbidity and mortality. Population-based pancreatic cancer screening would result in significant harm to non-diseased individuals, even in cases where a near-perfect test was developed. Despite this mathematical improbability, NIH funding for pancreatic cancer demonstrates bias toward screening test development not seen in other cancer subtypes. Focusing research energy on development of pancreatic screening tests is unlikely to result in overall survival benefits. Efforts to increase the number of patients who are candidates for surgery and improving surgical outcomes would result in greater population benefit.

Prevention Relevance: For patients with pancreatic cancer, early stage detection offers the greatest survival benefit. However, the incidence of pancreatic cancer and associated mortality of pancreatic resections make development of a screening test a difficult, if not impossible, challenge.
An Unexpected Complication of Endoscopic Retrograde Cholangiopancreatography with a Novel Treatment Approach
Authors: Polman Jeremy , Williams Aaron C. , Ruggiero Gaetano , DeWitt Aaron
Published: November 2020

Splenic injury after endoscopic retrograde cholangiopancreatography (ERCP) has been documented in less than 30 cases. Here, we present a case that involves a 52-year-old male with choledocholithiasis who developed a splenic injury and major hemorrhage immediately after ERCP. The patient ultimately required splenic artery embolization without splenectomy, a novel treatment approach. The case demonstrates the importance of having a high index of suspicion of this rare complication as well as discusses potential causes of post-ERCP splenic injury and a treatment approach that does not involve splenectomy.
Ewingella americana Peritonitis in a Patient on Peritoneal Dialysis: A Case Report and Review of the Literature
Authors: Khurana Shriya , Chemmachel Christina , Saxena Ramesh
Published: November 2020

Most episodes of peritoneal dialysis (PD)-associated peritonitis are caused by skin-dwelling gram-positive bacteria and gram-negative bacteria colonizing gut and urinary tract. Occasionally, however, uncommon bacteria can cause peritonitis in PD patients. We describe a case of Ewingella americana peritonitis, the first such case reported from the United States. A 68-year-old woman with end-stage kidney disease due to hypertension was initiated on PD 2 years prior to the present event. She presented with abdominal pain associated with nausea and vomiting. She was afebrile and hemodynamically stable. Abdomen was diffusely tender with guarding and rebound. No obvious root cause was apparent. Initial PD fluid white count was 502/mm3 with 87% neutrophils. Gram stain was negative. Culture grew gram-negative rods, which were later identified as Ewingella americana, resistant to ampicillin and cefazolin but sensitive to gentamicin, ceftazidime, and cefepime. After empiric intraperitoneal vancomycin and gentamicin, she was continued on intraperitoneal gentamicin for a total period of 21 days. She responded to the treatment rapidly with complete recovery. PD fluid on day four showed 40 nucleated cells with 12% neutrophils. Patient remained on PD without consequences. Ewingella americana is a gram-negative facultative anaerobic bacillus that can survive in water, including domestic water. Inadequate hand hygiene is a potential root cause of infection. Although rare, Ewingella peritonitis can be observed in PD patients and is treatable. Clinicians should be aware of Ewingella as a potential cause of PD peritonitis.
Multistage Latissimus Dorsi Flap with Implant for Complex Post-Mastectomy Reconstruction: An Old but Still Current Technique
Authors: De Lorenzi Francesca , Borelli Francesco , Sala Pietro , Loschi Pietro , Naninato Paola , Vento Anna Rita , Rossi Elisabetta Maria Cristina , Veronesi Paolo
Published: November 2020

Introduction: The latissimus dorsi (LD) flap has been used for reconstructing mastectomy defects since the early 1900s. Although its popularity has declined over the last decades, it still retains an important role in breast reconstruction. We present our recent experience with the multistage LD flap and implant for extremely complex post-mastectomy defects. Patients and Methods: Between 2011 and 2020, 42 consecutive patients underwent post-mastectomy LD reconstruction with an expander (STAGE 1). Some of them received prior fat-grafting of the mammary region (STAGE 0). All patients were scheduled for an expander-definitive implant change (STAGE 2). Some of them completed the program with fat-grafting, nipple and areola reconstruction, and other refinements (STAGE 3 or 4). Results: Two patients underwent fat-grafting at STAGE 0. Mean age at STAGE 1 was 46.7 years, mean BMI was 23.6, 14.4% of the patients were smokers, and 21.4% had comorbidities. Immediate reconstructions were performed in 35.7% and delayed in 64.3%. Mean surgical time at STAGE 1 was 194.7 min for delayed reconstructions and 242.3 min for immediate ones. Mean hospital stay for STAGE 1 procedures was 3.8 days; all other STAGES were performed as ambulatory surgery. No flap necrosis was observed and only 1 patient required a surgical revision for bleeding. Dorsal seroma occurred in 45.2% of cases. Conclusions: The multistage LD flap with implant is a useful and safe tool within the reconstructive armamentarium for post-mastectomy defects. It combines multiple simple procedures and does not require specific skills and surgical training (level of evidence 4).
Social Cognition Deficits Are Pervasive across Both Classical and Overlap Frontotemporal Dementia Syndromes
Authors: Arshad Faheem , Paplikar Avanthi , Mekala Shailaja , Varghese Feba , Purushothaman Vandana Valiyaparambath , Kumar Darshini Jeevandra , Shingavi Leena , Vengalil Seena , Ramakrishnan Subasree , Yadav Ravi , Pal Pramod Kumar , Nalini Atchayaram , Alladi Suvarna
Published: November 2020

Objectives: Frontotemporal dementia (FTD) syndromes are a complex group of disorders characterised by profound changes in behaviour and cognition. Many of the observed behavioural abnormalities are now recognised to be due to impaired social cognition. While deficits in emotion recognition and empathy are well-recognised in behavioural-variant (Bv)FTD, limited information exists about the nature of social cognitive impairment in the language variant primary progressive aphasia (PPA) that includes progressive non-fluent aphasia (PNFA) and semantic dementia (SD), and in the motor variants FTD amyotrophic lateral sclerosis (FTD-ALS) and FTD progressive supranuclear palsy (FTD-PSP). This prospective study sought to explore the nature and profile of social cognition deficits across the spectrum of FTD. Methods: Sixty patients on the FTD spectrum, i.e., classical (16 with BvFTD and 20 with PPA) and overlap FTD syndromes (13 with FTD-ALS and 11 with FTD-PSP) were evaluated by means of the social cognition tasks, the Interpersonal Reactivity Index (IRI) for empathy, and pictures of facial affect (POFA) for emotion recognition. General cognition and behaviour were also assessed. Results: A significant impairment in emotion recognition and empathy was detected in both the classical and overlap FTD syndromes. The recognition of positive emotions was relatively preserved compared to that of negative emotions. Among the FTD subtypes, maximal impairment of empathy was demonstrated in FTD-PSP. Conclusion: Social cognition impairment is pervasive across the spectrum of FTD disorders, and tests of emotion recognition and empathy are clinically useful to identify the nature of behavioural problems in both classical and overlap FTD. Our findings also have implications for understanding the neural basis of social cognition in FTD.
Synergism between vastus lateralis and vastus medialis oblique during gait after anterior cruciate ligament reconstruction
Authors: Leporace Gustavo , Zeitoune Gabriel Gollner , Vivacqua Thiago , Metsavaht Leonardo , Oliveira Liszt Palmeira de , Batista Luiz Batista
Published: November 2020

Objective: The aim of this study was to compare vastus lateralis and vastus medialis oblique (VL/VMO) muscle co-contraction (MCC) and activation ratio during gait between healthy subjects- control group (CG), and those with anterior cruciate ligament reconstruction (ACLR). Methods: Twenty-three subjects participated in this study, 14 CG and 9 ACLR. The myoelectric activities of the VL and VMO were captured to calculate the MCC. The VL/VMO ratio was obtained by dividing the normalized signals of these two muscles at each point of the curve. The MCC values and the activation ratio in the initial double limb stance, single limb stance, terminal double limb stance and swing were obtained by calculating the arithmetic mean of the intensity values ​​of the common curve in each interval. Results: MCC was significantly lower in the ACLR group during the initial double limb stance phase (p=0.001), with a high effect size (1.72). No significant differences were found for the other comparisons. Conclusions: The results of this study showed that the VL and VMO muscles co-contraction in the initial double limb stance phase of gait was different between the healthy and ACLR individuals. This finding may be related to lower patellofemoral stability during the loading response, increasing the potential risk for the development of injuries in this joint.
Efeito em curto prazo de dois protocolos de hidrocinesioterapia em crianças com síndrome congênita associada à infecção do vírus Zika
Authors: Monteiro Milena Guimarães , Tavares Netto Afonso Rodrigues , Brito Patrícia Meireles , Santos Amanda Jayse da Silva , Mattos Rebeca Maranhão de , Wesiolek Carine Carolina , Lambertz Karla Mônica Ferraz
Published: November 2020

Objetivo: Avaliar o efeito em curto prazo de dois protocolos de hidrocinesioterapia sobre o tônus muscular e o nível de estresse de crianças com SCZ. Métodos: Estudo cruzado, randomizado e cego, com crianças com microcefalia/SCZ entre 3-36 meses de idade. O tônus foi avaliado pela Escala Modificada de Tardieu(EMT), analisando-se o grau de tônus muscular e a amplitude de movimento articular(ADM); o nível de estresse, através de Escala visual analógica de faces variando desde um estado sem estresse (1) até estresse intenso (4). Dois protocolos de hidrocinesioterapia(Protocolo PI e PII) foram aplicados em ambiente aquático restrito, por 15 minutos com temperatura da água a 37ºC. Resultados: Doze crianças participaram do estudo(média de idade em meses: 23,9+3,97), 58,7% do sexo feminino. Após PI, observamos redução do grau de tônus dos músculos extensores de cotovelo(p=0,03) e joelho(p=0,04); em PII, não houve mudanças significativas no grau de tônus. Não houve mudanças significativas no nível de estresse em PI e PII, porém 83,3% se encontravam sem estresse ou estresse leve antes das intervenções. Conclusões: O protocolo I acarretou redução do grau de tônus muscular em curto prazo quando comparado com PII. Enfatiza-se que os protocolos aplicados são de baixo custo, e podem ser uma opção de técnica não farmacológica viável no acompanhamento terapêutico destas crianças. Ressalta-se que a experiência do fisioterapeuta deve guiar a escolha do protocolo adequado para o objetivo terapêutico de cada criança e a vantagem de ser uma técnica facilmente replicável em ambiente terapêutico e domiciliar.