bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme
Authors: Jena Lynn N , Bennie Lindsey A , McErlean Emma M , Pentlavalli Sreekanth , Glass Kim , Burrows James F , Kett Vicky L , Buckley Niamh E , Coulter Jonathan A , Dunne Nicholas J , McCarthy Helen O
Published: May 2021

Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50,significantly decreased colony formation, induced apoptosis and slowed spheroid growthin vitro.In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up andin vivoapplication. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.
Systemic factors for enhancing intersectoral collaboration for the operationalization of One Health: a case study in India
Authors: Yasobant Sandul , Bruchhausen Walter , Saxena Deepak , Falkenberg Timo
Published: May 2021

Background

One Health is a collaborative, multisectoral, and transdisciplinary approach—working at the local, regional, national, and global levels—with the goal of achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment. Operationalization of the One Health approach is still unclear for various local health systems with their respective targets. In this scenario, the empirical study of intersectoral collaboration between the human and animal health systems provides an opportunity to investigate the appropriate strategies and their enabling factors at the local health system level. Thus, this study documented and validated the innovative strategy for intersectoral collaboration, focusing on effectual prevention and control of zoonotic diseases with its enabling factors for a city in western India, Ahmedabad.

Methods

This case study was conducted in three phases: phase I (qualitative data collection, i.e., vignette interview), phase II (quantitative data collection through modified policy Delphi), and phase III (participatory workshop). The vignette data were handled for content analysis, and the Delphi data, like other quantitative data, for descriptive statistics. The participatory workshop adapts the computerized Sensitivity Model® developed by Vester to analyse the health system dynamics.

Result

Out of the possible 36 strategies, this study validated the top 15 essential (must-have) and five preferred (should-have) strategies for the study area. For operationalization of the One Health approach, the enabling factors that were identified through the systems approach are micro-level factors at the individual level (trust, leadership, motivation, knowledge), meso-level factors at the organizational level (human resource, capacity-building, shared vision, decision-making capacity, laboratory capacity, surveillance), macro-level factors at the system level (coordinated roles, relationships, common platform), and external factors outside of the system (guidelines/policies, community participation, a specific budget, political will, smart technology).

Discussion

This study reveals that the micro-level factors at the individual level are potential levers of the health system. More attention to these factors could be beneficial for the operationalization of the One Health approach. This study recommends a systems approach through a bottom-up exploration to understand the local health system and its enabling factors, which should be accounted for in formulating future One Health policies.
TV advertising and dietary intake in adolescents: a pre- and post- study of Chile’s Food Marketing Policy
Authors: Jensen Melissa L. , Dillman Carpentier Francesca R. , Adair Linda , Corvalán Camila , Popkin Barry M. , Taillie Lindsey Smith
Published: May 2021

Background

The first phase of a comprehensive marketing policy was implemented in Chile in 2016. The policy restricted child-directed marketing of foods and beverages considered high in energy, total sugars, sodium or saturated fat (“high-in”). The objective of this study was to examine the role of high-in TV food advertising as a mediator in the association between policy implementation and consumption of high-in foods and beverages between 2016 and 2017.

Methods

Dietary data were from 24-hour diet recalls collected in 2016 and 2017 in a cohort of 12–14 y children (n = 721). Television use was assessed concurrently and linked to analyses of food advertisements on broadcast and paid television to derive individual-level estimates of exposure to high-in food advertising. A multilevel mediation analysis examined direct and indirect effects of the policy through advertising exposure.

Results

Following the policy implementation, high-in advertising exposure was significantly reduced (p < 0.01). High-in food intake decreased in adolescents with lower levels, but not higher levels, of high-in advertising at baseline. We did not find evidence of mediation by changes in high-in ad exposure.

Conclusions

Adolescents’ exposure to high-in TV advertising decreased after the 2016 implementation of the Chilean Food Labeling and Marketing Law. However, evidence that changes in advertisement mediated dietary changes was not found. Further research is needed to understand how marketing changes will relate to dietary changes after full implementation of the law and in the long term.
Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)
Authors: van Campen C. (Linda) M. C. , Rowe Peter C. , Visser Frans C.
Published: May 2021

Background

Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).

Methods and results

In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.

Conclusion

This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.
Optimizing the timing of diagnostic testing after positive findings in lung cancer screening: a proof of concept radiomics study
Authors: Wang Zixing , Li Ning , Zheng Fuling , Sui Xin , Han Wei , Xue Fang , Xu Xiaoli , Yang Cuihong , Hu Yaoda , Wang Lei , Song Wei , Jiang Jingmei
Published: May 2021

Background

The timeliness of diagnostic testing after positive screening remains suboptimal because of limited evidence and methodology, leading to delayed diagnosis of lung cancer and over-examination. We propose a radiomics approach to assist with planning of the diagnostic testing interval in lung cancer screening.

Methods

From an institute-based lung cancer screening cohort, we retrospectively selected 92 patients with pulmonary nodules with diameters ≥ 3 mm at baseline (61 confirmed as lung cancer by histopathology; 31 confirmed cancer-free). Four groups of region-of-interest-based radiomic features (n = 310) were extracted for quantitative characterization of the nodules, and eight features were proven to be predictive of cancer diagnosis, noise-robust, phenotype-related, and non-redundant. A radiomics biomarker was then built with the random survival forest method. The patients with nodules were divided into low-, middle- and high-risk subgroups by two biomarker cutoffs that optimized time-dependent sensitivity and specificity for decisions about diagnostic workup within 3 months and about repeat screening after 12 months, respectively. A radiomics-based follow-up schedule was then proposed. Its performance was visually assessed with a time-to-diagnosis plot and benchmarked against lung RADS and four other guideline protocols.

Results

The radiomics biomarker had a high time-dependent area under the curve value (95% CI) for predicting lung cancer diagnosis within 12 months; training: 0.928 (0.844, 0.972), test: 0.888 (0.766, 0.975); the performance was robust in extensive cross-validations. The time-to-diagnosis distributions differed significantly between the three patient subgroups,p < 0.001: 96.2% of high-risk patients (n = 26) were diagnosed within 10 months after baseline screen, whereas 95.8% of low-risk patients (n = 24) remained cancer-free by the end of the study. Compared with the five existing protocols, the proposed follow-up schedule performed best at securing timely lung cancer diagnosis (delayed diagnosis rate: < 5%) and at sparing patients with cancer-free nodules from unnecessary repeat screenings and examinations (false recommendation rate: 0%).

Conclusions

Timely management of screening-detected pulmonary nodules can be substantially improved with a radiomics approach. This proof-of-concept study’s results should be further validated in large programs.
Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts
Authors: Moon Jeonghyeon , Lee Seon-yeong , Choi Jeong Won , Lee A Ram , Yoo Jin Hee , Moon Su-Jin , Park Sung-Hwan , Cho Mi-La
Published: May 2021

Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.
Severe COVID-19 in pediatric age: an update on the role of the anti-rheumatic agents
Authors: Costagliola Giorgio , Spada Erika , Consolini Rita
Published: May 2021

Background

SARS-CoV-2 can induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators (cytokine storm), strongly contributing to the pulmonary and systemic manifestations in severe coronavirus disease 2019 (COVID-19). As a consequence, different drugs active on the immune system have been proposed for the treatment of the disease in adults.

Role of the anti-rheumatic agents in children

Children are more likely to develop a mild disease course, as the severe form of COVID-19 is identified in less than 5% of the pediatric patients. Moreover, in children a peculiar disease phenotype, defined as multisystem inflammatory syndrome in children (MIS-C) is observed, representing the most severe expression of the inflammatory dysregulation caused by SARS-CoV-2. The limited experience with the severe pediatric COVID-19 and MIS-C does not allow conclusions about the role of the immune pharmacological approach, and therefore the treatment of these conditions represents a considerable clinical challenge. The use of chloroquine, hydroxychloroquine, and colchicine in the early disease stages is not sufficiently supported by evidence, and there is an increasing interest in the role of biologic agents, including anti-IL-1 and anti-IL-6 agents, in the prevention and treatment of the severe manifestations of COVID-19.

Conclusion

The therapeutic approach to pediatric COVID-19 is multidisciplinary, and anti-rheumatic agents have a prominent role in severe disease. This paper reviews the rationale for the use of anti-rheumatic agents in pediatric COVID-19 and MIS-C and the clinical experience with the single drugs. Finally, the areas of potential improvement in the use of anti-rheumatic agents, including the optimization of the drug choice and the timing of administration, are discussed.
The immune cell landscape of metastatic uveal melanoma correlates with overall survival
Authors: Tosi Anna , Cappellesso Rocco , Dei Tos Angelo Paolo , Rossi Valentina , Aliberti Camillo , Pigozzo Jacopo , Fabozzi Alessio , Sbaraglia Marta , Blandamura Stella , Del Bianco Paola , Chiarion-Sileni Vanna , Rosato Antonio
Published: May 2021

Background

Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.

Methods

We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.

Results

Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.

Conclusion

The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.
Ovarian endometrioid carcinoma and clear cell carcinoma: A 21-year retrospective study
Authors: Zhou Ling , Yao Liqing , Dai Lin , Zhu Honglan , Ye Xue , Wang Shang , Cheng Hongyan , Ma Ruiqiong , Liu Huiping , Cui Heng , Chang Xiaohong
Published: May 2021

Objective

This study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group.

Methods

The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018.

Results

Of 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p = 0.001).

Compared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p = 0.000). And more patients were in premenopausal state in EC group(p = 0.040).

In the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p = 0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p = 0.001).

Conclusions

CCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections.
Short‐term rapamycin administration elevated testosterone levels and exacerbated reproductive disorder in dehydroepiandrosterone‐induced polycystic ovary syndrome mice
Authors: Guo Zaixin , Chen Xiaohan , Feng Penghui , Yu Qi
Published: May 2021

Background

Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice.

Results

Female C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term.

Conclusions

Rapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.
Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease
Authors: Gockley Jake , Montgomery Kelsey S. , Poehlman William L. , Wiley Jesse C. , Liu Yue , Gerasimov Ekaterina , Greenwood Anna K. , Sieberts Solveig K. , Wingo Aliza P. , Wingo Thomas S. , Mangravite Lara M. , Logsdon Benjamin A.
Published: May 2021

Background

Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions.

Methods

A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues.

Results

Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1.

Conclusions

We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.
Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET
Authors:   the Alzheimer’s Disease Neuroimaging Initiative, Guo Yu , Huang Yu-Yuan , Shen Xue-Ning , Chen Shi-Dong , Hu Hao , Wang Zuo-Teng , Tan Lan , Yu Jin-Tai
Published: May 2021

Background

We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET).

Methods

In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared.

Results

Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology.

Conclusions

Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.
Primary malignant melanoma of the esophagus successfully treated with nivolumab: a case report
Authors: Ito Shingo , Tachimori Yuji , Terado Yuichi , Sakon Ryota , Narita Kazuhiro , Goto Manabu
Published: May 2021

Introduction

Primary malignant melanoma of the esophagus is a rare and aggressive disease that tends to have a poor response to chemotherapies. Previous studies have indicated that currently available treatment for primary malignant melanoma of the esophagus is insufficient. Here, we describe a case of recurrent primary malignant melanoma of the esophagus successfully treated with the immune checkpoint inhibitor nivolumab.

Case presentation

An 81-year-old Japanese female presented with a 3-month history of dysphagia. She was medicated for hypertension and sarcoidosis. The patient had no past history of cutaneous, ocular, or other-site melanomas. An esophagoscopy identified a 30-mm giant tumor in the lower esophagus, at a site 30 cm from the incisors. Enhanced computed tomography revealed wall thickening measuring 30 mm in size at the middle-third of the intrathoracic esophagus, with no significant lymph node infiltration or distant metastasis. Esophageal biopsy showed proliferation of large round tumor cells and melanophages. On the basis of these findings, the patient was diagnosed with esophageal malignant melanoma and underwent esophagectomy and lymph node dissection with gastric tube reconstruction. Although the pathological diagnosis was primary malignant melanoma of the esophagus, the patient presented with multiple lymph node and bone metastases 4 months after surgery. Subsequently, treatment with nivolumab 240 mg every 2 weeks was administered as the first-line treatment. Diffusion-weighted imaging with background body signal suppression following eight courses of nivolumab revealed that the multiple lymph node and bone metastases were markedly reduced. The patient received 30 courses of nivolumab and has maintained the partial response. No severe adverse events related to the immunotherapy were recorded.

Conclusion

The current study suggests that nivolumab may be a viable option for patients with metastatic primary malignant melanoma of the esophagus. Additional evidence from future clinical trials and research is necessary to fully validate these findings.
Further results on Mittag-Leffler synchronization of fractional-order coupled neural networks
Authors: Wang Fengxian , Wang Fang , Liu Xinge
Published: May 2021

In this paper, we focus on the synchronization of fractional-order coupled neural networks (FCNNs). First, by taking information on activation functions into account, we construct a convex Lur’e–Postnikov Lyapunov function. Based on the convex Lyapunov function and a general convex quadratic function, we derive a novel Mittag-Leffler synchronization criterion for the FCNNs with symmetrical coupled matrix in the form of linear matrix inequalities (LMIs). Then we present a robust Mittag-Leffler synchronization criterion for the FCNNs with uncertain parameters. These two Mittag-Leffler synchronization criteria can be solved easily by LMI tools in Matlab. Moreover, we present a novel Lyapunov synchronization criterion for the FCNNs with unsymmetrical coupled matrix in the form of LMIs, which can be easily solved by YALMIP tools in Matlab. The feasibilities of the criteria obtained in this paper are shown by four numerical examples.
Establishment of a population pharmacokinetics model of vancomycin in 94 infants with septicemia and its application in individualized therapy
Authors: Li Zhiling , Li Hongjing , Wang Chenyu , Jiao Zheng , Xu Feng , Sun Huajun
Published: May 2021

Background

We aim to develop a population pharmacokinetics (PopPK) model of vancomycin for the treatment of septicemia in infants younger than one year. Factors influence of the PK was investigated to optimize vancomycin dosing regimen.

Methods

The nonlinear mixed effects modelling software (NONMEM) was used to develop the PopPK model of vancomycin. The stability and predictive ability of the final model were assessed by using normalized prediction distribution errors (NPDE) and bootstrap methods. The final model was subjected to Monte Carlo simulation in order to determine the optimal dose.

Results

A total of 205 trough and peak concentrations in 94 infants (0–1 year of age) with septicemia were analyzed. The interindividual variability of the PK parameter was described by the exponential model. Residual error was better described by the proportional model than the mixed proportional and addition models. Serum creatinine concentration and body weight are the major factors that affect the PK parameters of vancomycin. The clearance was shown to be higher when ceftriaxone was co-treated. More than two model evaluation methods showed better stability than the base model, with superior predictive performance, which can develop individualized dosing regimens for clinical reference. Through prediction of final model, the trough concentration was more likely < 5 mg/L when a routine dose of 10 mg/kg is administered every 6 h to 3–9-month-old infants. Therefore, the dose should be increased in the treatment of infant septicemia.

Conclusions

The stable and effective PopPK model of vancomycin in Chinese infants with septicemia was established. This model has satisfactory predictive ability for clinically individualized dosing regimens in this vulnerable population.
Predictors of Cognitive Performance Among Infants Treated for Brain Tumors: Findings From a Multisite, Prospective, Longitudinal Trial
Authors: Ali Jeanelle S. , Ashford Jason M. , Swain Michelle A. , Harder Lana L. , Carlson-Green Bonnie L. , Miller Jonathan M. , Wallace Joanna , Kaner Ryan J. , Billups Catherine A. , Onar-Thomas Arzu , Merchant Thomas E. , Gajjar Amar , Conklin Heather M.
Published: May 2021

PURPOSE

Infants treated for CNS malignancies experience a significantly poorer response to treatment and are particularly at risk for neuropsychological deficits. The literature is limited and inconsistent regarding cognitive outcomes among this group. We investigated predictors of cognitive outcomes in children treated for brain tumors during infancy as part of a large, prospective, multisite, longitudinal trial.

PATIENTS AND METHODS

One hundred thirty-nine infants with a newly diagnosed CNS tumor were treated with chemotherapy, with or without focal proton or photon radiation therapy (RT). Cognitive assessments were conducted at baseline, 6 months, 1 year, and then annually for 5 years. The median length of follow-up was 816 days (26.8 months). Neurocognitive testing included assessment of intellectual functioning (intellectual quotient [IQ]), parent ratings of executive functioning and emotional and behavioral functioning, and socioeconomic status.

RESULTS

At baseline, IQ, parent-reported working memory, and parent-reported adaptive functioning were worse than normative expectations. Baseline cognitive difficulties were associated with younger age at diagnosis and lower socioeconomic status. Linear mixed models did not demonstrate a decline in IQ over time. There were increased parent-reported attention and executive problems over time. Increased concerns were related to supratentorial tumor location and CSF diversion. There were no differences in cognitive outcomes based on treatment exposure (chemotherapy-only v chemotherapy with RT and proton v photon focal RT).

CONCLUSION

Even before adjuvant therapy, young children with brain tumors experience cognitive difficulties that can affect quality of life. Changes in cognitive functioning over time were dependent on tumor location and surgical factors rather than adjuvant therapy. These findings may serve to guide treatment planning and indicate targets for cognitive monitoring and intervention.
Mineralocorticoid Receptor Antagonist Effect on Aldosterone to Renin Ratio in Patients With Primary Aldosteronism
Authors: Pecori Alessio , Buffolo Fabrizio , Burrello Jacopo , Mengozzi Giulio , Rumbolo Francesca , Avataneo Valeria , D’Avolio Antonio , Rabbia Franco , Bertello Chiara , Veglio Franco , Mulatero Paolo , Monticone Silvia
Published: May 2021

Context

Although current international guidelines recommend to avoid mineralocortcoid receptor antagonists in patients undergoing screening test for primary aldosteronism, a recent report suggested that mineralocorticoid receptor antagonist treatment can be continued without significant influence on screening results.

Objective

We aimed to evaluate the effect of mineralocorticoid receptor antagonists on the aldosterone to renin ratio in patients with primary aldosteronism.

Methods

We prospectively enrolled 121 patients with confirmed primary aldosteronism who started mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) constituted the short-term study cohort and underwent aldosterone, renin, and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy.

Results

Renin and potassium levels showed a significant increase, and the aldosterone to renin ratio displayed a significant reduction compared with baseline after both a short- and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests was raised to 16.7%, 38.9%, 54.5%, and 72.5% after 2 weeks, 8 weeks, 2 to 6 months, and 7 to 12 months of mineralocorticoid receptor antagonist treatment, respectively.

Conclusion

Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.
Alternative Technique for Difficult Epidural Needle Placement: A Case Report
Authors: Ejaimi Gamal , Zakaria Alrossasy , Ahmed Areeg , Ahmed Sitelnissa , Maaly Mohamed Ezzat
Published: May 2021

A central neuraxial block may be difficult to perform in elderly patients with lumbar spine deformities, calcified ligaments, and narrowing of the epidural space. We report a case of difficult epidural needle placement in an elderly patient scheduled for bilateral total knee replacement (TKR). We attempted epidural needle placement many times without success. However, when a modified technique was used, the epidural space was identified easily and confirmed, the epidural catheter was inserted and fixed, and the postoperative epidural analgesia was effective.
Rethinking the Boundaries of Class: Labor History and Theories of Class and Capitalism
Authors: Greene Julie
Published: May 2021

This article examines how the field of labor and working-class history has conceptualized class and assesses theories of class that can help us develop maximally illuminating concepts. Labor historians, particularly those whose work employs a transnational, gender, or racial lens of analysis, have advanced our understanding of how working people's lives are shaped by class. By connecting that scholarship to class theory, the article argues for reconceptualizing class to focus on the complex ways capitalism generates class relationships, embedding race, gender, and other historical dynamics within its formative parameters. It relies on work by Tithi Bhattacharya and Stuart Hall to articulate a specific vision of class relations under capitalism. Finally, the article concludes with praxis by applying Hall's and Bhattacharya's insights to the challenges academic knowledge workers face today amid the crisis of higher education, which is growing more pressing as a result of the economic disaster related to the COVID-19 pandemic. It concludes by addressing how our conceptualizations of class could shape efforts to build broad solidarities among knowledge workers in higher education.
(Dis)Solving the problem of aberrant protein states
Authors: Fare Charlotte M. , Shorter James
Published: May 2021

Neurodegenerative diseases and other protein-misfolding disorders represent a longstanding biomedical challenge, and effective therapies remain largely elusive. This failure is due, in part, to the recalcitrant and diverse nature of misfolded protein conformers. Recent work has uncovered that many aggregation-prone proteins can also undergo liquid–liquid phase separation, a process by which macromolecules self-associate to form dense condensates with liquid properties that are compositionally distinct from the bulk cellular milieu. Efforts to combat diseases caused by toxic protein states focus on exploiting or enhancing the proteostasis machinery to prevent and reverse pathological protein conformations. Here, we discuss recent advances in elucidating and engineering therapeutic agents to combat the diverse aberrant protein states that underlie protein-misfolding disorders.
Problems of Social Adaptation of Russian Labor Resources to Labor Activity in the Context of Global Changes
Authors: Garnik Sergey , Belova O.
Published: May 2021

The article analyzes the factors that affect the social adaptation of labor resources in the context of global changes associated with man-made, epidemiological, and socio-political threats. The negative factors hindering social adaptation related to the problems of the development of the human resources management system in Russia are highlighted. The authors, relying on the historical experience of mankind in adapting to the industrial revolutions of the past, associate the success of social adaptation with the activation of state policy in the field of regulating social and labor relations and cultural and educational activities, as well as the transformation of human resource management systems in organizations, the transformation of the type of leadership in commercial and non-profit organizations, changes in the system of training managers, their ability to adequately respond to global changes, and the renewal of the trade union movement in Russia.
Moral Standards in the Organization: the Regulatory Nature and Management of Ethical Behavior of Employees
Authors: Romanova I. , Laas N. , Gurova E.
Published: May 2021

The article presents the results of a study (questionnaire survey) of managers and ordinary employees of public and private Russian organizations on the problem of the regulatory role of ethical rules for labor / organizational behavior and the management of ethical actions of personnel. The answers of respondents to the questionnaire about the mission of moral standards in the organization and the importance of their observance are analyzed in detail and presented; on the state of compliance with ethical canons in the organization, detailed reasons and forms of their violation; on the preferred sanctions for violation / observance of moral standards; o the presence of Ethical Codes in companies and their purpose.

The results of the survey showed that ethical norms are the most important regulator of labor / organizational behavior, and their most important purpose is "the development of good relations between employees." Most of the respondents are satisfied with the state of observance of moral standards in their organizations, and also believe that the management pays sufficient attention to their observance. The study revealed that the main cause of violation of moral standards in companies is the personal characteristics of employees, then the management style, and then organizational factors. The most “popular” form of deviation from moral rules in the eyes of respondents is shirking orders. At the same time, the leading role of management is indicated as a role model, which is followed by ordinary employees when choosing ethical or unethical actions. For the most part, the organizations have not developed and do not have Codes of Ethics, the mission of which, according to the participants of the survey, is to orient staff towards ethical behavior and resolve the moral problems of the organization. At the same time, the respondents indicated that it is necessary to apply sanctions both for deviating from moral rules and for observing them.

The research results are practice-oriented. At the same time, they cannot reflect the entire variety of aspects of the influence of the regulatory essence of moral canons on labor / organizational behavior and its management system.
Ethics of Artificial Intelligence: Problems and Initiatives in the Social Environment
Authors: Leonov V. , Kashtanova YEkatyerina , Lobacheva A.
Published: May 2021

Technologies based on artificial intelligence (AI) have achieved significant results, including facial recognition, medical diagnostics, self-driving cars, insurance management and exchange assets, property, human resources, search and recruitment. Artificial intelligence promises huge benefits for economic growth, social development, and improving the well-being and people security. Of course, artificial intelligence and robotics are among the most discussed issues and technological trends around the world today. In the light of their widespread use and implementation in all spheres of human life, often the expected opportunities, achievements and scientific breakthroughs overshadow the reasonableness and expediency of using artificial intelligence technologies in a particular field from a legal and ethical point of view. Companies, in the pursuit of profit and leading positions in the market, are often irresponsible about the legal and ethical issues of interaction with artificial intelligence technologies. Nevertheless, the ethical aspects of the use of artificial intelligence technologies are gaining high importance these days. The emergence of high-tech systems and software that can function more and more independently of humans and can replace the performance of tasks by humans requires special attention. These systems raise a number of important and tough moral questions. The article discusses the main directions of the artificial intelligence technologies spread and the ethical consequences and moral issues that arise in this regard, both at the state and organizational levels. The main trends characteristic of the labor market that arise in the process of workplaces robotization and the intelligent robots introduction into the production process are studied. The authors convincingly prove the priority of ethics and human safety issues in the design and implementation of AI systems. During the discussion of the ethical problems of the artificial intelligence introduction in organizations, the emphasis is placed on the use of these technologies not from the point of view of automation and improving the efficiency of performing direct management functions, but from the point of view of the organization of personnel work. Based on this, the article concludes with recommendations for the development of ethical principles adapted to the design and use of AI systems.
The Situation of SME Workers as a Result of the Pandemic
Authors: Degtyareva Ekaterina
Published: May 2021

The article considers the problems associated with the consequences of the pandemic for employees of small and medium enterprises in the Moscow region, namely a reduction in their wages and termination of the employment contract due to a reduction of the wage Fund SMEs, despite government measures. The article presents statistics on dismissals of employees in SMEs, data on the volume of labor violations in the Moscow region at SME enterprises, the volume of citizens ' appeals to the labor inspectorate. Innovations in the Russian labor legislation introduced due to the pandemic, as well as violations of the Labor Code of the Russian Federation, are considered. They also discussed current measures to support small and medium-sized enterprises in order to save jobs, as well as measures to support families who are in a difficult situation due to job loss. The article defines the ways for SMEs to get out of the crisis situation with their personnel in order to preserve it, by reducing working hours and emotional support for employees.
Current Trends in the Development of the Labor Market in the Era of Digitalization of the Economy
Authors: Svistunov Vasiliy , Lobachyev Vitaliy , Golyshkova I.
Published: May 2021

The article examines the problems of the labor market from the perspective of employment, the impact on these processes of such global trends in modern economic development as digitalization and globalization. Attention is drawn to the negative trend of employment of a large number of graduates of domestic universities not in their specialty. Special emphasis is placed on the need for the education system to take into account the professional qualification requirements for specialists in the process of their training and retraining.
New to entrepreneurship? Part 1: from finding your purpose to developing your big idea
Authors: Ratcliffe Jason
Published: May 2021

For those who are starting out in aesthetics, creating a standout business can be a daunting prospect. Jason Ratcliffe will discuss what mindset you need to adopt and how to develop your first big idea