bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ophthalmic manifestations of myelin oligodendrocyte glycoprotein-IgG-associated disorder other than optic neuritis: a systematic review
Authors: Vosoughi Amir R , Ling Jennifer , Tam Kenneth T , Blackwood Jayden , Micieli Jonathan A 
Published: September 2020

Background/Aims
Optic neuritis (ON) is the primary ophthalmic manifestation of myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD), but numerous reports have expanded the visual manifestations of this condition. The goal of this study was to synthesise the extensive literature on this topic to help ophthalmologists understand when testing for MOG-IgG should be considered.

Method
A systematic review of the English-language literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searches were conducted using Ovid MEDLINE (from January 1, 1948 to April 1, 2020) and Ovid EMBASE (from January 1, 1947 to April 1, 2020). Inclusion criteria included studies describing non-isolated ON ophthalmic manifestations where cell-based assays were used for the detection of MOG antibodies.

Results
Fifty-one articles representing 62 patients with a median age of 32.0 (range 2–65), female gender (51%) and follow-up of 20.0 months (range: 1–240) were included. Twenty-nine patients had non-isolated ON afferent visual manifestations: uveitis, peripheral ulcerative keratitis, acute macular neuroretinopathy, neuroretinitis, venous stasis retinopathy, large preretinal macular haemorrhage, orbital inflammatory syndrome, orbital apex syndrome, optic perineuritis, papilloedema and homonymous visual field defects. Incomplete recovery of ON was associated with a case of Leber’s hereditary optic neuropathy. Efferent ophthalmic manifestations included cranial neuropathies, internuclear ophthalmoplegia, central nystagmus, saccadic intrusions and ocular flutter. Cranial nerve involvement was secondary to enhancement of the cisternal portion or brainstem involvement. All included cases were treated with corticosteroids with 31% of cases requiring additional immunosuppressive therapy.

Conclusions
MOGAD has been associated with various afferent and efferent ophthalmic manifestations apart from isolated ON. Awareness of these findings may result in earlier diagnosis and treatment.
When dispatcher assistance is not saving lives: assessment of process compliance, barriers and outcomes in out-of-hospital cardiac arrest in a metropolitan city in China
Authors: Zhang Lin , Luo Menyue , Myklebust Helge , Pan Chun , Wang Liang , Zhou Zhenxiang , Yang Qiying , Lin Qi , Zheng Zhi-Jie 
Published: September 2020

BackgroundSeveral Chinese cities have implemented dispatcher-assisted cardiopulmonary resuscitation (DA-CPR), although out-of-hospital cardiac arrest (OHCA) survival rates remain low. We aimed to assess the process compliance, barriers and outcomes of OHCA in one of the earliest implemented (DA-CPR) programmes in China.MethodsWe retrospectively reviewed OHCA emergency dispatch records of Suzhou emergency medical service from 2014 to 2015 and included adult OHCA victims (>18 years) with a bystander-witnessed atraumatic OHCA that was subsequently confirmed by on-site emergency physician. The circumstances and DA-CPR process related to the OHCA event were analysed. Dispatch audio records were reviewed to identify potential barriers to implementation during the DA-CPR process.ResultsOf the 151 OHCA victims, none survived. The median time from patient collapse to call for emergency services and that from call to provision of cardiopulmonary resuscitation instructions was 30 (IQR 20–60) min and 115 (IQR 90–153) s, respectively. Only 110 (80.3%) bystanders/rescuers followed the dispatcher instructions; of these, 51 (46.3%) undertook persistent chest compressions. Major barriers to following the DA-CPR instructions were present in 104 (68.9%) cases, including caller disconnection of the call, distraught mood or refusal to carry out either compressions or ventilations.ConclusionsThe OHCA survival rate and the DA-CPR process were far from optimal. The zero survival rate is disproportionally low compared with survival statistics in high-income countries. The prolonged delay in calling the emergency services negated and rendered futile any DA-CPR efforts. Thus, efforts targeted at developing public awareness of OHCA, calling for help and competency in DA-CPR should be increased.
Prevalence and clinical outcomes of triglyceride deposit cardiomyovasculopathy among haemodialysis patients
Authors: Onishi Tomohiro , Nakano Yusuke , Hirano Ken-ichi , Nagasawa Yasuyuki , Niwa Toru , Tajima Atomu , Ishii Hideki , Takahashi Hiroshi , Sakurai Shinichiro , Ando Hirohiko , Takashima Hiroaki , Amano Tetsuya 
Published: September 2020

ObjectiveTo evaluate the effect of triglyceride deposit cardiomyovasculopathy (TGCV) on the cardiovascular outcomes in haemodialysis (HD) patients with suspected coronary artery disease (CAD).MethodsThis retrospective single-centre observational study included data from the cardiac catheter database of Narita Memorial Hospital between April 2011 and March 2017. Among 654 consecutive patients on HD, the data for 83 patients with suspected CAD who underwent both [123I]-β-methyl-iodophenyl-pentadecanoic acid scintigraphy and coronary angiography were analysed. Patients were divided into three groups: definite TGCV (17 patients), probable TGCV (22 patients) and non-TGCV control group (44 patients). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke assessed for up to 5 years of follow-up.ResultsThe prevalence of definite TGCV was approximately 20% and 2.6% among consecutive HD patients with suspected CAD and among all HD patients, respectively. At the end of the median follow-up period of 4.7 years, the primary endpoint was achieved in 52.9% of the definite TGCV patients (HR, 7.45; 95% CI: 2.28 to 24.3; p<0.001) and 27.3% of the probable TGCV patients (HR, 3.28; 95% CI: 0.93 to 11.6; p=0.066), compared with that in 9.1% of the non-TGCV control patients. Definite TGCV was significantly and independently associated with cardiovascular mortality and outcomes among HD patients in all multivariate models.ConclusionsTGCV is not uncommon in HD patients and is associated with an increased risk of cardiovascular events including cardiovascular death. Thus, TGCV might be a potential therapeutic target.
Real-world characteristics and readmissions among patients undergoing ablation for ventricular tachycardia: a retrospective database analysis of commercially insured patients in the USA
Authors: Mehta Vinay , Boo Lee Ming , Ghaly Nader , Kalsekar Iftekhar , Zhang Shumin , Yadalam Sashi , Khanna Rahul , Rahman Motiur 
Published: September 2020

BackgroundRadiofrequency catheter ablation is an effective treatment to alleviate symptoms and reduce recurrent implantable cardioverter-defibrillator (ICD/CRT-D) shocks in patients with ventricular tachycardia (VT).ObjectiveTo assess the characteristics and outcomes (complications, inpatient readmissions) of commercially insured patients in the USA undergoing ablation for ischaemic or non-ischaemic VT.MethodsPatients aged 18–64 years with a primary diagnosis of VT who underwent ablation between 2006 and 2015 were identified using the IBM MarketScan Commercial Database. The rate of complications including vascular complications, pericarditis, pulmonary embolism and pericardial tamponade over a 30-day post-ablation period (including index admission) was examined. Inpatient readmissions (VT-related, heart failure (HF)-related and non-VT arrhythmia-related) over the 12-month post-ablation period were examined. A Cox regression model was used to determine factors associated with inpatient readmissions.Results5242 patients (488 with ischaemic and 4754 with non-ischaemic VT) met the study criteria. The majority of VT ablations occurred in an outpatient setting (57% for ischaemic and 66% for non-ischaemic VT). Among complications, vascular complications were most frequent (2.05% among ischaemic and 1.6% among non-ischaemic VT patients) over the 30-day post-ablation period. Among ischaemic VT patients, 17%, 7.6% and 4.7% had VT-related, HF-related and non-VT arrhythmia-related inpatient readmissions, respectively in the 12-month post-ablation period. For non-ischaemic VT patients, these numbers were 7.5%, 1.7% and 3.1%, respectively. Inpatient setting (vs outpatient), baseline ICD/CRT-D implantation, HF comorbidity and ≥2 prior hospitalisations were associated with a higher risk of post-ablation VT-related inpatient readmissions among ischaemic VT patients. Similar factors also were associated with a higher risk of post-ablation VT-related inpatient readmission among non-ischaemic VT patients.ConclusionSetting of ablation and comorbidity status were found to influence readmission rates. Complication and readmission rates following VT ablation were low indicating towards the favourable safety profile of VT ablation.
Response to abatacept is associated with the inhibition of proteasome β1i expression in T cells of patients with rheumatoid arthritis
Authors: Ghannam Khetam , Martinez Gamboa Lorena , Kedor Claudia , Spengler Lydia , Kuckelkorn Ulrike , Häupl Thomas , Burmester Gerd , Feist Eugen 
Published: September 2020

ObjectiveAbatacept is a biological disease-modifying antirheumatic drug (DMARD) used for the treatment of rheumatoid arthritis (RA) and modulates the costimulatory signal by cluster of differentiation (CD)28:CD80/CD86 interaction required for T cell activation. Since CD28-mediated signalling regulates many T cell functions including cytokine production of, for example, interferons (IFNs), it is of interest to clarify, whether response to abatacept has an effect on the IFN inducible immunoproteasome, as a central regulator of the immune response.MethodsEffects of abatacept on the proteasome were investigated in 39 patients with RA over a period of 24 weeks. Using real-time PCR, transcript levels of constitutive and corresponding immunoproteasome catalytic subunits were investigated at baseline (T0), week 16 (T16) and week 24 (T24) in sorted blood cells. Proteasomal activity and induction of apoptosis after proteasome inhibition were also evaluated.ResultsAbatacept achieved remission or low disease activity in 55% of patients at T16 and in 70% of patients at T24. By two-way analysis of variance (ANOVA), a significant reduction of proteasome immunosubunit β1i was shown only in CD4+ and CD8+ T cells of sustained responders at both T16 and T24. One-way ANOVA analysis for each response group confirmed the results and showed a significant reduction at T24 in CD4+ and CD8+ T cells of the same group. Abatacept did not influence chymotrypsin-like activity of proteasome and had no effect on induction of apoptosis under exposure to a proteasome inhibitor in vitro.ConclusionThe reduction of proteasome immunosubunit β1i in T cells of patients with RA with sustained response to abatacept suggests association of the immunoproteasome of T cells with RA disease activity.
OD-SGD
Authors: Xu Yemao , Dong Dezun , Zhao Yawei , Xu Weixia , Liao Xiangke 
Published: September 2020

The training of modern deep learning neural network calls for large amounts of computation, which is often provided by GPUs or other specific accelerators. To scale out to achieve faster training speed, two update algorithms are mainly applied in the distributed training process, i.e., the Synchronous SGD algorithm (SSGD) and Asynchronous SGD algorithm (ASGD). SSGD obtains good convergence point while the training speed is slowed down by the synchronous barrier. ASGD has faster training speed but the convergence point is lower when compared to SSGD. To sufficiently utilize the advantages of SSGD and ASGD, we propose a novel technology named One-step Delay SGD (OD-SGD) to combine their strengths in the training process. Therefore, we can achieve similar convergence point and training speed as SSGD and ASGD separately.
To the best of our knowledge, we make the first attempt to combine the features of SSGD and ASGD to improve distributed training performance. Each iteration of OD-SGD contains a global update in the parameter server node and local updates in the worker nodes, the local update is introduced to update and compensate the delayed local weights. We evaluate our proposed algorithm on MNIST, CIFAR-10, and ImageNet datasets. Experimental results show that OD-SGD can obtain similar or even slightly better accuracy than SSGD, while its training speed is much faster, which even exceeds the training speed of ASGD.
Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma
Authors: Li Ming , Kirtane Ameya R. , Kiyokawa Juri , Nagashima Hiroaki , Lopes Aaron , Tirmizi Zain A. , Lee Christine K. , Traverso Giovanni , Cahill Daniel P. , Wakimoto Hiroaki 
Published: September 2020

Abstract

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma.

Significance:
Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.
Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy
Authors: Huarte Eduardo , O'Connor Roddy S. , Peel Michael T. , Nunez-Cruz Selene , Leferovich John , Juvekar Ashish , Yang Yan-ou , Truong Lisa , Huang Taisheng , Naim Ahmad , Milone Michael C. , Smith Paul A. 
Published: September 2020

Abstract

Purpose:
T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including IFNγ and IL6.

Experimental Design:
Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor activity, and cytokine levels in in vitro and in vivo models.

Results:
We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T cells adoptively transferred into CD19+ tumor-bearing immunodeficient animals was unabated by oral itacitinib treatment.

Conclusions:
Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T cell–induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).
Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors
Authors: Trendowski Matthew R. , Wheeler Heather E. , El-Charif Omar , Feldman Darren R. , Hamilton Robert J. , Vaughn David J. , Fung Chunkit , Kollmannsberger Christian , Einhorn Lawrence H. , Travis Lois B. , Dolan M. Eileen 
Published: September 2020

Abstract

Purpose:
Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (&gt;1) severe neurotoxicities.

Experimental Design:
The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case–control genome-wide association study (GWAS; cases, n = 104 and controls, n = 196) was also performed.

Results:
Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.

Conclusions:
Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor.
A Novel Bispecific Antibody with PD-L1–assisted OX40 Activation for Cancer Treatment
Authors: Kuang Zhihui , Pu Pu , Wu Min , Wu Zhihai , Wang Li , Li Yiming , Zhang Shaofei , Jing Hua , Wu Weiwei , Chen Bingliang , Liu Junjian 
Published: September 2020

Abstract
Immunotherapy using OX40 agonist antibodies shows great preclinical efficacy in mouse tumor models. But in a clinical setting, OX40 agonist antibody alone or in combination with checkpoint blockade exhibits only modest efficacy due to lack of sufficient activation. We hypothesized that the limited antitumor activity in patients may due to insufficient clustering of OX40 antibody in the tumor. To test this hypothesis, we generated a tetravalent programmed death ligand-1 (PD-L1)/OX40 BsAb by fusing two PD-L1 VHH fragments to the C-terminus of a nonblocking agonistic anti-OX40 antibody. The resulting BsAb had intact function of each parental antibody, including efficiently blocking PD1/PD-L1 interaction and inducing OX40 activation. In addition, this BsAb showed significantly enhanced potency in activation of OX40-expressing T cells when PD-L1–expressing tumor cells or dendrite cells were present, through PD-L1–mediated cross-linking of OX40. Moreover, the BsAb exhibited superior antitumor activities over the parental monospecific antibodies alone or in combination in multiple in vivo tumor models. These results demonstrated a great potential for further clinical development of the potent immunostimulatory PD-L1/OX40 bispecific antibody.
Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer
Authors: Horeweg Nanda , de Bruyn Marco , Nout Remi A. , Stelloo Ellen , Kedzierska Katarzyna , León-Castillo Alicia , Plat Annechien , Mertz Kirsten D. , Osse Michelle , Jürgenliemk-Schulz Ina M. , Lutgens Ludy C.H.W. , Jobsen Jan J. , van der Steen-Banasik Elzbieta M. , Smit Vincent T. , Creutzberg Carien L. , Bosse Tjalling , Nijman Hans W. , Koelzer Viktor H. , Church David N. 
Published: September 2020

Abstract
Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning, image-based algorithm to quantify density of CD8+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular endometrial cancer classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate, and low densities, with highly significant variation in the proportion of molecular endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair–deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular endometrial cancer classification in early-stage endometrial cancer.