bluuebunny/crossref_metadata_2025 huggingface dataset:
[Retracted] The Potential Function of Super Enhancers in Human Bone Marrow Mesenchymal Stem Cells during Osteogenic Differentiation
Authors: Huang Zhijie , Jia Bo , Wang Qian , Wang Naishun , Zhao Jianjiang
Published: January 2021

Super enhancers (SEs) are large clusters of transcriptional activity enhancers, which drive and control the expression of cell identity genes, as well as differentiation of specific cell types. SEs have great application potential in pathogenic mechanism studies in developmental biology, cancer, and other diseases. However, the potential function and regulatory mechanism of SEs in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) are unknown. Therefore, this study investigated the potential function of SEs in the osteogenic differentiation of hBMSCs and their target genes. Osteogenesis was induced in three hBMSCs groups for 14 days. Further, ChIP‐seq was performed on cells before and after osteogenic differentiation. Two target genes were then selected from cells before and after osteogenic differentiation for RT‐qPCR. Finally, the selected SE target genes were analyzed by bioinformatics. In total, 1,680 SEs were identified in hBMSCs. After 14 days of osteogenic induction, only 342 SEs were detected in cells, among which 1,380 unique SEs were detected in hBMSCs, 42 unique SEs were found in cells induced by osteoblast differentiation after 14 days, and 300 SEs were common in both groups. Further, 1,680 genes were found to be regulated by SEs in hBMSCs, including 1,094 genes with protein‐coding function and 586 noncoding genes. Additionally, 342 genes were regulated by SEs in cells after 14 days of osteogenic differentiation induction, of which 223 and 119 had protein‐coding and noncoding functions, respectively. KEGG analysis of SE target genes before and after osteogenic differentiation showed the TGF‐β, PI3K‐Akt, and ECM receptor signaling pathways as highly enriched and closely related to osteogenic differentiation. Further, RT‐qPCR results of four selected target genes confirmed the sequencing results. Taken together, osteogenic differentiation of hBMSCs involves changes in multiple SEs, which may regulate the osteogenic differentiation of hBMSCs by regulating the expression of target genes.
A Study on Stock Graph Recognition Based on Wavelet Denoising and DTW Algorithm
Authors: Luo Ji Wei
Published: January 2021

The “classical pattern” of stock price formation has long been widely used in the determination of future price trends of stocks, and the identification and analysis of classical price patterns have an important guiding role in investors’ decision-making and trading. The wavelet transform is a useful tool to remove some of the noise of time series because it has the characteristic of multiresolution. In this study, we propose a method for stock price pattern recognition based on the wavelet transform and dynamic time warp (DTW). A pattern recognition method with similar quantified results is developed to obtain accurate pattern recognition results. That is, using the wavelet transform to smooth the original price graph, and then using the DTW algorithm improved in this study to find the graph with the smallest distance from the target graph under the sliding window method, the identification and analysis of the target graph can be realized. In order to improve the recognition rate of the target graph, we preprocessed the raw price sequence using the moving average convergence and divergence (MACD) algorithm based on the control experiments set up in this study. The pattern recognition method used in this study will identify the price patterns of a certain time window as a whole, thus avoiding the problem of how to objectively select the important points that constitute a price pattern and the mathematical definition of different price patterns in the previous traditional methods.
An Improved Linear State Error Feedback Synchronization Control Criteria for a Six-Axis Duffing Chaotic System
Authors: Jia Hao , Guo Chen
Published: January 2021

By the employment of an improved linear state error feedback method, the synchronization control of a six-axis Duffing chaotic system was studied. Compared with previous methods, it has two advantages: the nonlinear term of the Duffing chaotic system is reserved in the synchronization error system, and the trajectory bound of the response system is predicted in advance to deduce the synchronization criteria. First, a typical ship parametric excitation roll chaotic system with parametric and forced excitation is taken as the control object to realize chaos synchronization control. Then, the control method is applied to the conventional six-axis Duffing oscillatory chaotic system and the four-axis Duffing oscillatory chaotic system. Finally, three simulation cases are presented to illustrate the validity of the synchronization criteria.
FedEx and UPS Network Structure and Accessibility Analysis Based on Complex Network Theory
Authors: Zhao Changsong , Xiu Chunliang , Yu Guanyi
Published: January 2021

With the expansion of the global air cargo transport system, the operating structure of air cargo has become increasingly separate from passenger counterpart, forming an independent organization model. Despite the Chinese air cargo capacity has grown exponentially in the past, its network is still in its infancy. FedEx and UPS have well‐established air cargo networks and have operated effectively on both international and domestic scale; thus, understanding the structure and evolution of their air cargo networks is of a high reference value. In conjunction with the division of US regions from the United States Geological Survey (USGS), this paper refers to FedEx and UPS as FEPS and analyzes its topological structure, complexity properties, and air cargo accessibility by using social network analysis (SNA) and accessibility evaluation methods. The results suggest that (1) the structure of the FEPS air cargo network is in the highly developed states and has the typical “small‐world” and “scale‐free” network characteristics; (2) the degree centrality values for the nodes in the FEPS network suggest that the network complexity has increased; (3) airports in Memphis (MEM), Louisville (SDF), Indianapolis (IDN), and Ontario (ONT) are the major hubs with both high centrality values and air cargo accessibility; and (4) the FEPS network presents a unique hub‐and‐spoke structure compared with the passenger counterpart.
Intratumoral STING Agonist Injection Combined with Irreversible Electroporation Delays Tumor Growth in a Model of Hepatocarcinoma
Authors: Lasarte-Cia Aritz , Lozano Teresa , Cano David , Martín-Otal Celia , Navarro Flor , Gorraiz Marta , Casares Noelia , Vivas Isabel , Lasarte Juan José
Published: January 2021

Background/Aim. Irreversible electroporation (IRE) showed promising results for small‐size tumors and very early cancers. However, further development is needed to evolve this procedure into a more efficient ablation technique for long‐term control of tumor growth. In this work, we show that it is possible to increase the antitumor efficiency of IRE by simmultaneously injecting c‐di‐GMP, a STING agonist, intratumorally. Materials and Methods. Intratumoral administration of c‐di‐GMP simultaneously to IRE was evaluated in murine models of melanona (B16.OVA) and hepatocellular carcinoma (PM299L). Results. The combined therapy increased the number of tumor‐infiltrating IFN‐γ/TNF‐α‐producing CD4 and CD8 T cells and delayed tumor growth, as compared to the effect observed in groups treated with c‐di‐GMP or IRE alone. Conclusion. These results can lead to the development of a new therapeutic strategy for the treatment of cancer patients refractory to other therapies.
Prognostic Value of Soluble Suppression of Tumorigenicity 2 in Chronic Kidney Disease Patients: A Meta-Analysis
Authors: Guo Guangying , Huang Aoran , Huang Xin , Xu Tianhua , Yao Li
Published: January 2021

Objective. Previous studies have controversial results about the prognostic role of soluble suppression of tumorigenicity 2 (sST2) in chronic kidney disease (CKD). Therefore, we conduct this meta-analysis to access the association between sST2 and all-cause mortality, cardiovascular disease (CVD) mortality, and CVD events in patients with CKD. Methods. The publication studies on the association of sST2 with all-cause mortality, CVD mortality, and CVD events from PubMed and Embase were searched through August 2020. We pooled the hazard ratio (HR) comparing high versus low levels of sST2 and subgroup analysis based on treatment, continent, and diabetes mellitus (DM) proportion, and sample size was also performed. Results. There were 15 eligible studies with 11,063 CKD patients that were included in our meta-analysis. Elevated level of sST2 was associated with increased risk of all-cause mortality (HR 2.05; 95% confidence interval (CI), 1.51–2.78), CVD mortality (HR 1.68; 95% CI, 1.35–2.09), total CVD events (HR 1.88; 95% CI, 1.26–2.80), and HF (HR 1.35; 95% CI, 1.11–1.64). Subgroup analysis based on continent, DM percentage, and sample size showed that these factors did not influence the prognostic role of sST2 levels to all-cause mortality. Conclusions. Our results show that high levels of sST2 could predict the all-cause mortality, CVD mortality, and CVD events in CKD patients.
Peripheral Inflammatory Cytokines and Lymphocyte Subset Features of Deceased COVID‐19 Patients
Authors: Jiang Nan , Li Zhijun , Yang Bo , Jin Mengdi , Sun Yaoyao , He Yang , Liu Yang , Wang Yueying , Si Daoyuan , Ma Piyong , Zhang Jinnan , Liu Tianji , Yu Qiong
Published: January 2021

Objective. To compare the difference of inflammatory cytokines and lymphocyte subsets between deceased patients and survivors with COVID‐19. Methods. This retrospective study included 254 confirmed patients from 10 January to 11 March, 2020, at Tongji Hospital of Wuhan, China. Laboratory and immunologic features were collected and analyzed, and the main outcomes focused on inflammatory cytokines and lymphocyte subsets. Results. A trend of markedly higher levels of inflammatory cytokines as well as lower lymphocyte subset levels in deceased patients was observed compared with survivors. ROC curve analyses indicated that inflammatory cytokines and the decrease levels of T cell, Th (helper T cells) cell, Ts (suppressor T cells) cell, B cell, and NK cell along with Th/Ts ratio increase could be used to predict the death of COVID‐19. Multivariate analyses showed that higher levels of IL‐6, IL‐8, and IL‐10 remained significantly correlated with shorter survival time and that the amount of Ts cells was negatively associated with the possibility of death in COVID‐19 patients. In conclusion, SARS‐CoV‐2 would cause lymphopenia and result in decreased lymphocyte subset cells, particularly in Ts cell counts, which further induces hyperinflammatory response and cytokine storm. IL‐6, IL‐8, IL‐10, and Ts cell might be independent predictors for the poor outcome of COVID‐19.
The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
Authors: Deegen Petra , Thomas Oliver , Nolan-Stevaux Olivier , Li Shyun , Wahl Joachim , Bogner Pamela , Aeffner Famke , Friedrich Matthias , Liao Michael Z. , Matthes Katja , Rau Doris , Rattel Benno , Raum Tobias , Kufer Peter , Coxon Angela , Bailis Julie M.
Published: January 2021

Purpose:

Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.

Experimental Design:

We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated.

Results:

AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6–42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68–labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs.

Conclusions:

The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.

See related commentary by Kamat et al., p. 2675
Long-Term Follow-up of a Phase III Study of ch14.18 (Dinutuximab) + Cytokine Immunotherapy in Children with High-Risk Neuroblastoma: COG Study ANBL0032
Authors: Yu Alice L. , Gilman Andrew L. , Ozkaynak M. Fevzi , Naranjo Arlene , Diccianni Mitchell B. , Gan Jacek , Hank Jacquelyn A. , Batova Ayse , London Wendy B. , Tenney Sheena C. , Smith Malcolm , Shulkin Barry L. , Parisi Marguerite , Matthay Katherine K. , Cohn Susan L. , Maris John M. , Bagatell Rochelle , Park Julie R. , Sondel Paul M.
Published: January 2021

Purpose:

Previously our randomized phase III trial demonstrated that immunotherapy including dinutuximab, a chimeric anti-GD2 mAb, GM-CSF, and IL2 improved survival for children with high-risk neuroblastoma that had responded to induction and consolidation therapy. These results served as the basis for FDA approval of dinutuximab. We now present long-term follow-up results and evaluation of predictive biomarkers.

Patients and Methods:

Patients recieved six cycles of isotretinoin with or without five cycles of immunotherapy which consists of dinutuximab with GM-CSF alternating with IL2. Accrual was discontinued early due to meeting the protocol-defined stopping rule for efficacy, as assessed by 2-year event-free survival (EFS). Plasma levels of dinutuximab, soluble IL2 receptor (sIL2R), and human anti-chimeric antibody (HACA) were assessed by ELISA. Fcγ receptor 2A and 3A genotypes were determined by PCR and direct sequencing.

Results:

For 226 eligible randomized patients, 5-year EFS was 56.6 ± 4.7% for patients randomized to immunotherapy (n = 114) versus 46.1 ± 5.1% for those randomized to isotretinoin only (n = 112; P = 0.042). Five-year overall survival (OS) was 73.2 ± 4.2% versus 56.6 ± 5.1% for immunotherapy and isotretinoin only patients, respectively (P = 0.045). Thirteen of 122 patients receiving dinutuximab developed HACA. Plasma levels of dinutuximab, HACA, and sIL2R did not correlate with EFS/OS, or clinically significant toxicity. Fcγ receptor 2A and 3A genotypes did not correlate with EFS/OS.

Conclusions:

Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample size than originally planned, yet clinically significant long-term differences in survival were observed.
An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth
Authors: Lam Hubert , McNeil Lisa K. , Starobinets Hanna , DeVault Victoria L. , Cohen Roger B. , Twardowski Przemyslaw , Johnson Melissa L. , Gillison Maura L. , Stein Mark N. , Vaishampayan Ulka N. , DeCillis Arthur P. , Foti James J. , Vemulapalli Vijetha , Tjon Emily , Ferber Kyle , DeOliveira Daniel B. , Broom Wendy , Agnihotri Parul , Jaffee Elizabeth M. , Wong Kwok-Kin , Drake Charles G. , Carroll Pamela M. , Davis Thomas A. , Flechtner Jessica Baker
Published: January 2021

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens.

Significance:

Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.

This article is highlighted in the In This Issue feature, p. 521
Metabolic Codependencies in the Tumor Microenvironment
Authors: Dey Prasenjit , Kimmelman Alec C. , DePinho Ronald A.
Published: January 2021

Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell–intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription factors that in turn increase expression of metabolic regulators. Extrinsic signaling mechanisms involve host-derived factors that further promote and amplify metabolic reprogramming in cancer cells. This review describes intrinsic and extrinsic mechanisms driving cancer metabolism in the tumor microenvironment and how such mechanisms may be targeted therapeutically.

Significance:

Cancer cell metabolic reprogramming is a consequence of the converging signals originating from both intrinsic and extrinsic factors. Intrinsic signaling maintains the baseline metabolic state, whereas extrinsic signals fine-tune the metabolic processes based on the availability of metabolites and the requirements of the cells. Therefore, successful targeting of metabolic pathways will require a nuanced approach based on the cancer's genotype, tumor microenvironment composition, and tissue location.
Mitochondrial and Metabolic Pathways Regulate Nuclear Gene Expression to Control Differentiation, Stem Cell Function, and Immune Response in Leukemia
Authors: Egan Grace , Khan Dilshad H. , Lee Jong Bok , Mirali Sara , Zhang Li , Schimmer Aaron D.
Published: January 2021

Mitochondria are involved in many biological processes including cellular homeostasis, energy generation, and apoptosis. Moreover, mitochondrial and metabolic pathways are interconnected with gene expression to regulate cellular functions such as cell growth, survival, differentiation, and immune recognition. Metabolites and mitochondrial enzymes regulate chromatin-modifying enzymes, chromatin remodeling, and transcription regulators. Deregulation of mitochondrial pathways and metabolism leads to alterations in gene expression that promote cancer development, progression, and evasion of the immune system. This review highlights how mitochondrial and metabolic pathways function as a central mediator to control gene expression, specifically on stem cell functions, differentiation, and immune response in leukemia.

Significance:

Emerging evidence demonstrates that mitochondrial and metabolic pathways influence gene expression to promote tumor development, progression, and immune evasion. These data highlight new areas of cancer biology and potential new therapeutic strategies.
Dietary Choline Intake during Pregnancy and PEMT rs7946 Polymorphism on Risk of Preterm Birth: A Case-Control Study
Authors: Zhu Jie , Liu Yu-Hong , He Xiang-Long , Kohlmeier Martin , Zhou Li-Li , Shen Li-Wei , Yi Xin-xuan , Tang Qing-Ya , Cai Wei , Wang Bei
Published: January 2021

Introduction and Aims: Choline-metabolizing genetic variation may interact with choline intake on fetal programming and pregnancy outcome. This case-control study aims to explore the association of maternal choline consumption and phosphatidylethanolamine N-methyltransferase (PEMT) gene polymorphism rs7946 with preterm birth risk. Methods: 145 Han Chinese women with preterm delivery and 157 Han Chinese women with term delivery were recruited in Shanghai. Dietary choline intake during pregnancy was assessed using a validated food frequency questionnaire. Additionally, DNA samples were genotyped for PEMT rs7946 (G5465A) with plasma homocysteine (Hcy) levels measured. Results: Compared with the lowest quartile of choline intake, women within the highest consumption quartile had adjusted odds ratio (aOR) for preterm birth of 0.48 (95% confidence interval, CI [0.24, 0.95]). There was a significant interaction between maternal choline intake and PEMT rs7946 (p for interaction = 0.04), where the AA genotype carriers who consumed the energy-adjusted choline <255.01 mg/day had aOR for preterm birth of 3.75 (95% CI [1.24, 11.35]), compared to those with GG genotype and choline intake >255.01 mg/day during pregnancy. Additionally, the greatest elevated plasma Hcy was found in the cases with AA genotype and choline consumption <255.01 mg/day (p < 0.001). Conclusion: The AA genotype of PEMT rs7946 may be associated with increased preterm birth in these Han Chinese women with low choline intake during pregnancy.
A Case of Pneumocystis jirovecii Pneumonia under Belatacept and Everolimus: Benefit-Risk Balance between Renal Allograft Function and Infection
Authors: Perrier Quentin , Portais Antoine , Terrec Florian , Cerba Yann , Romanet Thierry , Malvezzi Paolo , Bedouch Pierrick , Tetaz Rachel , Rostaing Lionel
Published: January 2021

Pneumocystis jirovecii pneumonia is an opportunistic disease usually prevented by trimethoprim-sulfamethoxazole. A 49-year-old HLA-sensitized male with successful late conversion from tacrolimus-based to belatacept-based immunosuppression developed P. jirovecii pneumonia for which he presented several risks factors: low lymphocyte count with no CD4+ T cells detected since 2 years, hypogammaglobulinemia, history of acute cellular rejection 3 years before, and immunosuppressive treatment (belatacept, everolimus). Because of respiratory gravity in the acute phase, the patient was given oxygen, corticosteroids, and trimethoprim-sulfamethoxazole. Thanks to the improvement of respiratory status, and because of the renal impairment, trimethoprim-sulfamethoxazole was converted to atovaquone for 21 days. Indeed, after 1 week on intensive treatment, the benefit-risk balance favored preserving renal function according to respiratory improvement status. P. jirovecii pneumonia prophylaxis for the next 6 months was monthly aerosol of pentamidine. Long-term safety studies or early/late conversion to belatacept did not report on P. jirovecii pneumonia. Four other cases of P. jirovecii pneumonia under belatacept therapy were previously described in patients having no P. jirovecii pneumonia prophylaxis. Studies on the reintroduction of P. jiroveciipneumonia prophylaxis after conversion to belatacept would be of interest. It could be useful to continue regular evaluation within the second-year post-transplantation regarding immunosuppression: T-cell subsets and immunoglobulin G levels.
Dynamic Perfusion Computed Tomography and Apparent Diffusion Coefficient as Potential Markers for Poorly Differentiated Pancreatic Adenocarcinoma
Authors: Zaboriene Inga , Zviniene Kristina , Lukosevicius Saulius , Ignatavicius Povilas , Barauskas Giedrius
Published: January 2021

Introduction: Tumor grade, one of the most important risk factors for survival, is routinely determined after examining the biopsy material or a surgically removed specimen. The aim of the study was to analyze computed tomography (CT) perfusion parameters and diffusion-weighted imaging apparent diffusion coefficient (ADC) values in pancreatic ductal adenocarcinoma (PDAC) and to establish the diagnostic value of these modalities determining the tumor grade. Materials and Methods: A prospective clinical study included 56 subjects with PDAC. All the patients had a local perfusion assessment and ADC measurement of the tumor. For the prediction of poor tumor differentiation sensitivity, specificity, positive, and negative predictive values for each perfusion CT and ADC parameters based on cutoff values from ROC analysis were calculated. Results: Mean transit time (MTT) and ADC values were found to be independent prognosticators for the presence of G3 PDAC. MTT and ADC at the cutoff of 17.37 s and 1.15 × 10−3 mm2/s, respectively, appeared to be significant parameters discriminating against the differentiation grade of PDAC. If both values exceeded the defined cutoff point, the estimated probability for the presence of G3 PDAC was 89.29%. Conclusion: The MTT parameter, calculated with the deconvolution method, and the ADC value may serve as effective independent prognosticators identifying poorly differentiated PDAC.
Noonan Syndrome with Multiple Lentigines and PTPN11 Mutation: A Case with Intracerebral Hemorrhage
Authors: Orrego-González Eduardo , Martin-Restrepo Carlos , Velez-Van-Meerbeke Alberto
Published: January 2021

Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome, is a rare autosomal dominant disorder with an unknown prevalence. Characteristics of this disease include cutaneous, neurologic, and cardiologic abnormalities. In this case report, we present a 12-year-old girl who was admitted to the emergency department for acute-onset left weakness, unsteady gait, nausea, and vomiting. Her physical exam notably showed left side upper motor neuron signs and dysmetria. CT scan revealed an acute hemorrhage of the right thalamus. Physical exam exhibited several craniofacial dysmorphisms and lentigines. The genetic test revealed a heterozygous missense mutation in the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene and a variant of unknown significance of the MYH11 gene. To the best of our knowledge, this is the first case of a patient with NSML presenting an intracerebral hemorrhage.
Clinical Features of Asymptomatic SARS-CoV-2 Infection in Hemodialysis Patients
Authors: Pizarro-Sánchez Maria Soledad , Avello Alejandro , Mas-Fontao Sebastian , Stock da Cunha Teresa , Goma-Garcés Elena , Pereira Mónica , Ortíz Alberto , González-Parra Emilio
Published: January 2021

Background: CKD is a risk factor for severe COVID-19. However, the clinical spectrum of COVID-19 in hemodialysis patients is still poorly characterized. Objective: To analyze the clinical spectrum of COVID-19 on hemodialysis patients. Method: A retrospective observational study was conducted on 66 hemodialysis patients. Nasopharyngeal swab PCR and serology for SARS-CoV-2, blood analysis, chest radiography, treatment, and outcomes were assessed. Results: COVID-19 was diagnosed in 50 patients: 38 (76%) were PCR-positive and 12 (24%) were PCR-negative but developed anti-SARS-CoV-2 antibodies. By contrast, 17% of PCR-positive patients failed to develop detectable antibodies against SARS-CoV-2. Among PCR-positive patients, 5/38 (13%) were asymptomatic, while among PCR-negative patients 7/12 (58%) were asymptomatic (p = 0.005) for a total of 12/50 (24%) asymptomatic patients. No other differences were found between PCR-positive and PCR-negative patients. No differences in potential predisposing factors were found between asymptomatic and symptomatic patients except for a lower use of ACE inhibitors among asymptomatic patients. Asymptomatic patients had laboratory evidence of milder disease such as higher lymphocyte counts and oxygen saturation and lower troponin I and interleukin-6 levels than symptomatic patients. Overall mortality was 7/50 (14%) and occurred only in symptomatic PCR-positive patients in whom mortality was 7/33 (21%). Conclusions: Asymptomatic SARS-CoV-2 infection is common in hemodialysis patients, especially among patients with initial negative PCR that later seroconvert. Thus COVID-19 mortality in hemodialysis patients may be lower than previously estimated based on PCR tests alone.
Accelerated Dose Escalation with 3 Injections of an Aluminum Hydroxide-Adsorbed Allergoid Preparation of 6 Grasses Is Safe for Children and Adolescents with Moderate to Severe Allergic Rhinitis
Authors: Bovermann Xenia , Ricklefs Isabell , Vogelberg Christian , Klimek Ludger , Kopp Matthias V.
Published: January 2021

A high-dose, accelerated escalation schedule during subcutaneous allergen-specific immunotherapy (AIT) is safe and well-tolerated in adults. However, there are no data in children and adolescents. The aim of the present trial was to assess safety and tolerability of an accelerated dose escalation schedule of an AIT with a grass pollen allergoid in children and adolescents with moderate to severe seasonal rhinoconjunctivitis in a multicenter, open-label, randomized phase II trial. The dose escalation scheme for patients in the One Strength Group included 3 injections with 1 strength B (10,000 TU/mL), whereas the dose escalation scheme for the Standard group included 7 injections with 2 strengths A (1,000 TU/mL) and B (10,000 TU/mL) of an allergoid grass pollen preparation. Overall, n = 50 children (n = 25 in each group; mean age 8.9 + 1.54 years) and n = 37 adolescents (n = 20 and n = 17; 14.2 + 1.62 years) were randomized. For all patients, the mean treatment duration was 59.4 days in the One Strength group and 88.6 days in the Standard group. Treatment-emergent adverse events (TEAEs) related to AIT were reported in 52 and 40% in children and 35 and 35.3% in adolescents, respectively. Systemic allergic reactions occurred in about 5% of our patients and were reported in more patients of the One Strength group (6.7 vs. 2.4%). All systemic reactions were classified as WAO Grade 1. Accelerated high-dose escalation with an aluminum hydroxide-adsorbed grass pollen allergoid can be initiated with a safety and tolerability profile comparable to the standard dose escalation schedule in children and adolescents with allergic rhinitis with or without asthma.
Cost-Effectiveness and Cost-Utility of a Home-Based Exercise Program in Geriatric Patients with Cognitive Impairment
Authors: Eckert Tobias , Wronski Pamela , Bongartz Martin , Ullrich Phoebe , Abel Bastian , Kiss Rainer , Wensing Michel , Koetsenruijter Jan , Hauer Klaus
Published: January 2021

Introduction: There is a substantial lack of home-based exercise programs in the highly vulnerable group of geriatric patients with cognitive impairment (CI) after discharge from ward rehabilitation. Beyond clinical effectiveness, the cost-effectiveness of intervention programs to enhance physical performance is not well investigated in this target group. Objective: The aim of the study was to determine the cost-effectiveness of a 12-week home-based exercise intervention following discharge from ward rehabilitation compared to unspecified flexibility training for geriatric patients with CI from a societal perspective. Methods: This cost-effectiveness study was conducted alongside a randomized placebo-controlled trial. A total of 118 geriatric patients with CI (Mini-Mental State Examination score: 17–26) were randomized either to the intervention group (IG, n = 63) or control group (CG, n = 55). Participants in the IG received a home-based individually tailored exercise program to increase physical performance, while participants in the CG received unspecific flexibility training (placebo control). Healthcare service use, physical performance (Short Physical Performance Battery, SPPB), and quality of life (EQ-5D-3L) were measured over 24 weeks. The net monetary benefit (NMB) approach was applied to calculate incremental cost-effectiveness of the exercise intervention compared to the CG with respect to improvement of (a) physical performance on the SPPB and (b) quality-adjusted life years (QALYs). Results: Physical performance was significantly improved in the IG compared to the CG (mean difference at 24 weeks: 1.3 points; 95% confidence interval [95% CI] = 0.5–2.2; p = 0.003), while health-related quality of life did not significantly differ between the groups at 24 weeks (mean difference: 0.08; 95% CI = −0.05 to 0.21; p = 0.218). Mean costs to implement the home-based exercise intervention were EUR 284 per patient. The probability of a positive incremental NMB of the intervention reached a maximum of 92% at a willingness to pay (WTP) of EUR 500 per point on the SPPB. The probability of cost-utility referring to QALYs was 85% at a WTP of EUR 5,000 per QALY. Conclusion: The home-based exercise intervention demonstrated high probability of cost-effectiveness in terms of improved physical performance in older adults with CI following discharge from ward rehabilitation, but not in terms of quality of life.
MRI Findings of Isolated Oculomotor Nerve Palsy after Mild Head Trauma in a Pediatric Patient: Case Report
Authors: Im Yunjin , Kim Jeong Rye
Published: January 2021

Introduction: Traumatic oculomotor nerve injury is usually caused by severe head trauma and is generally associated with other neurological deficits such as basilar skull fracture, orbital injury, or subarachnoid hemorrhage. Isolated traumatic oculomotor nerve injury after minor head trauma and its MRI findings are rarely reported. Case Presentation: We report a case of a 13-year-old girl with mydriasis, limited inferior and medial movement of the left eyeball, and left ptosis after a mild bump of the left forehead and eye into an electricity pole. The symptoms suggested left oculomotor nerve palsy, but initial facial computed tomography and brain MRI did not reveal any intracranial lesions or fractures in the skull and orbit. Cranial nerve MRI showed segmental hyperintensities and mild thickening of the left oculomotor nerve from the cavernous segment to the proximal orbital segment on T2 short tau inversion recovery and 3D fluid-attenuated inversion recovery volume isotropic turbo spin-echo acquisition sequences. The patient received treatment with oral pyridostigmine for 7 days and was fully recovered at 14 months after injury. Discussion: As traumatic oculomotor nerve palsy can occur without intracranial hematomas or skull base fractures, routine brain MRI may not always reveal abnormalities; thus, MRI dedicated to imaging of the oculomotor nerve using FS T2WI and high-resolution 3D sequences can be helpful for the diagnosis and management of patients suspected of isolated oculomotor nerve injury.
Delayed Maturation of the Middle Cerebellar Peduncles at Near-Term Age Predicts Abnormal Neurodevelopment in Preterm Infants
Authors: Choi Yong-Ho , Lee Jong-Min , Lee Joo Young , Lee Ji Young , Lee Young-Jun , Ahn Ja Hye , Lee Hyun Ju
Published: January 2021

Background: The infant brain grows quickly with elaborate microstructural development during the neonatal period. The white matter, during critical periods of development, is selectively vulnerable to altered maturation and impaired growth in very-low-birth-weight (VLBW) infants. Objective: To evaluate whether abnormal white matter maturation in VLBW infants is associated with poor neurodevelopmental outcomes at 18 months of corrected age. Methods: Between 2015 and 2017, we recruited 60 VLBW infants at 24–32 weeks of gestational age and 15 full-term controls. All participants underwent magnetic resonance imaging at near-term age and were assessed at 18 months of corrected age with the Bayley Scales of Infant and Toddler Development, Third Edition. The associations between regional white matter fractional anisotropy (FA) and mean diffusivity on diffusion tensor imaging (DTI) and developmental outcomes were explored using multivariable linear regression after correcting for gestational age, postmenstrual age at DTI scan, and maternal education level. Results: The FA values of the splenium of the corpus callosum (p = 0.032), corticospinal tract (p = 0.025), middle cerebellar peduncle (MCP) (p < 0.001), and cingulum (p = 0.043) were significantly related to cognitive scores; however, only the association corresponding to the MCP remained significant after correcting for multiple comparisons. The MCP FA (p = 0.008) was associated with motor scores after correction for multiple comparisons (p = 0.008). Cognitive impairment (area under the curve [AUC] = 0.823, 95% confidence interval [CI] = 0.722–0.911) and motor impairment (AUC = 0.776, 95% CI = 0.656–0.899) were predicted by MCP FA. Conclusions: The FA of MCP at near-term age may predict developmental outcomes of VLBW infants at 18 months of corrected age.
Iodine, Seaweed, and the Thyroid
Authors: Smyth Peter P.A.
Published: January 2021

Backgound: Even a minor iodine deficiency can result in adverse thyroidal health consequences while excess iodine intake can also result in thyroid function disorders. One source of iodine is seaweed which as a foodstuff is enjoying an increasing profile in Western countries. Apart from its potential involvement in thyroidal health, gaseous iodine released from seaweeds plays a significant role in influencing coastal climate through cloud formation. Summary: Sources of dietary iodine, its assessment, recommended dietary intake, and consequences of iodine excess are outlined. The benefits and possible dangers of dietary intake of iodine-rich seaweed are described. Studies linking seaweed intake to breast cancer prevalence are discussed as is the role of gaseous iodine released from seaweeds influencing weather patterns and contributing to iodine intake in coastal populations. Key Messages: Universal salt iodization remains the optimum method of achieving optimum iodine status. Promoting increased dietary iodine intake is recommended in young women, in early pregnancy, and in vegan and vegetarian diets. Even where iodine intake is enhanced, regular assessment of iodine status is necessary. Caution against consumption of brown seaweeds (kelps) is required as even small amounts can have antithyroid actions while product labelling may be insufficient. Gaseous iodine produced from seaweeds can have a significant effect on cloud formation and associated global warming/cooling. Increased overall iodine deposition through rainfall and apparent uptake in populations dwelling in seaweed-rich coastal regions may provide a partial natural remedy to global iodine deficits.
Pumpless Extracorporeal Hemadsorption Technique: A New Method for Early Cytokine Elimination?
Authors: Fiedler Mascha O. , Reyher Christian , Kalenka Armin , Rolfes Caroline , Lotz Christopher , Muellenbach Ralf M.
Published: January 2021

In recent years, extracorporeal hemadsorption (HA) techniques capable of adsorbing pro- and anti-inflammatory cytokines are increasingly used in various clinical situations. The therapeutic benefit of cytokine elimination likely depends on timing. Although treatment seems to be most effective when started within the first 24 h, therapy is often delayed as it must be combined with another extracorporeal circuit. Thus, using a pumpless extracorporeal HA technique might be a valuable option in order to expedite the commencement of cytokine elimination in critically ill patients.
Exploring Agreement between MB-CDI Short Forms for Evaluating the Language Skills of Italian Children Aged 18–24 Months
Authors: Lasorsa Francesca Romana , Caselli Maria Cristina , Simonelli Ilaria , Stefanini Silvia , Pasqualetti Patrizio , Rinaldi Pasquale
Published: January 2021

Introduction: The short forms of MacArthur-Bates Communicative Development Inventories (MB-CDI) are widely used for assessing communicative and linguistic development in infants and toddlers. Italian norms for the Words and Gestures (WG) and Words and Sentences (WS) short forms overlap between 18 and 24 months. Objective: To evaluate the agreement between these two forms. Methods: Parents of 104 children aged 18–24 months filled in both questionnaires. Results: The two questionnaires showed high agreement in measuring expressive vocabulary size and the percentile of lexical production and good agreement in identifying children at-risk for language delay (75% of the cases were accurately identified). Both short forms include a list of 100 words and a set of questions investigating potential risk factors for communication and language disorders. Ten children with an expressive vocabulary <10th percentile were compared to 10 with typical language development. Scores for children <10th percentile were significantly lower than their peers, in addition to scores of lexical comprehension, gesture-word, and 2-word combinations, and phonological accuracy, imitation of new words, and decontextualized use of language. Conclusions: Short forms of the Italian MB-CDI can be used interchangeably for evaluating lexical production, but each one offers different quantitative and qualitative information on the behaviours related to language acquisition.
Practice Variation in Skin Cancer Treatment and Follow-Up Care: A Dutch Claims Database Analysis
Authors: van Egmond Sven , Hollestein Loes M. , Uyl-de Groot Carin A. , van Erkelens Judith A. , Wakkee Marlies , Nijsten Tamar E.C.
Published: January 2021

Background: Quality indicators are used to benchmark and subsequently improve quality of healthcare. However, defining good quality indicators and applying them to high-volume care such as skin cancer is not always feasible. Objectives: To determine whether claims data could be used to benchmark high-volume skin cancer care and to assess clinical practice variation. Methods: All skin cancer care-related claims in dermatology in 2016 were extracted from a nationwide claims database (Vektis) in the Netherlands. Results: For over 220,000 patients, a skin cancer diagnosis-related group was reimbursed in 124 healthcare centres. Conventional excision reflected 75% of treatments for skin cancer but showed large variation between practices. Large practice variation was also found for 5-fluorouracil and imiquimod creams. The practice variation of Mohs micrographic surgery and photodynamic therapy was low under the 75th percentile, but outliers at the 100th percentile were detected, which indicates that few centres performed these therapies far more often than average. On average, patients received 1.8 follow-up visits in 2016. Conclusions: Claims data demonstrated large practice variation in treatments and follow-up visits of skin cancer and may be a valid and feasible data set to extract quality indicators. The next step is to investigate whether detected practice variation is unwarranted and if a reduction improves quality and efficiency of care.
O reconhecimento ético e jurídico do cuidado familiar: o contexto da síndrome congênita do vírus zika no Brasil
Authors: Globekner Osmir Antonio , Cornelli Gabriele
Published: January 2021

O presente artigo trata do reconhecimento ético e jurídico das relações de cuidado desenvolvidas no âmbito afetivo familiar. Parte-se da descrição da situação concreta de demandas por cuidados que se apresentam às famílias no contexto da epidemia da síndrome congênita do vírus Zika, incidente no Brasil em 2015 e 2016, para se analisarem as contribuições teóricas à discussão sobre a proteção das relações familiares de cuidado no campo da moral e do direito, respectivamente, pela ética do cuidado na abordagem proposta inicialmente por Carol Gilligan e pela abordagem jurídica das relações de cuidado, conforme formulações de Jonathan Herring e José Roque Junges.
Is Bombus pomorum (Panzer, 1805) (Hymenoptera: Apidae) a new bumblebee for Siberia or an indigenous species?
Authors: Byvaltsev Alexandr , Knyazev Svyatoslav , Afinogenov Anatoly
Published: January 2021

Bombus pomorum (Panzer, 1805) is known from Europe, Anatolia, the Caucasus, and to the Urals in Russia.  Two specimens have been collected in the south of western Siberia for the first time.  It is possible that the species is indigenous to Siberia but was not discovered until regular observations were made.  There is also a possibility that this observation results from an expansion of the range of B. pomorum.  We consider the evidence that our study coincided with a range expansion of the bumblebee species B. pomorum and B. sylvarum (Linnaeus,1761) near the end of 20th century.  The distribution and abundance of B. pomorum in Russia and conservation efforts are also discussed.
An assessment of the population status of the threatened medicinal plant Illicium griffithii Hook.f. & Thomson in West Kameng District of Arunachal Pradesh, India
Authors: Bapu Tashi Dorjee , Nimasow Gibji
Published: January 2021

Illicium griffithii Hook.f. & Thomson, a medicinal plant of the family Schisandraceae, is an Endangered species listed by the IUCN.  A decline in population of this plant due to climate change as well as increasing human influences on the natural resources has been a matter of great concern among the researchers.  In order to estimate the existing population of this plant, a field-based study employing linear transect method was conducted in four phases, May–June 2017, May–June 2018, April–May 2019, October–November 2019 covering an area of 700km² (approx.) in West Kameng District of Arunachal Pradesh that lies within the Himalayan biodiversity hotspot.  The study recorded 3,044 live individuals of I. griffithii including 1,372 seedlings, 1,358 saplings, and only 314 mature trees.  Additionally, 126 dead trees were also recorded.  The study confirmed that the plant has a good regeneration rate but with a poor survival rate of saplings.  Besides, large-scale collection of its fruits for trade and anthropogenic disturbances in the study area appears to be the major threat to its existing population.  Therefore, proper training of the local people on large-scale cultivation of this plant together with awareness towards judicious harvesting of fruits from the wild may be the significant approach to conservation.