bluuebunny/crossref_metadata_2025_split huggingface dataset:
The natural history of infantile neuroaxonal dystrophy
Authors: Altuame Fadie D. , Foskett Gretchen , Atwal Paldeep S. , Endemann Sarah , Midei Mark , Milner Peter , Salih Mustafa A. , Hamad Muddathir , Al-Muhaizea Mohammad , Hashem Mais , Alkuraya Fowzan S. 
Published: May 2020

Abstract
Background
Infantile neuroaxonal dystrophy (INAD) is a rapidly progressive neurodegenerative disorder of early onset causing premature death. It results from biallelic pathogenic variants in PLA2G6, which encodes a calcium-independent phospholipase A2.

Objective
We aim to outline the natural history of INAD and provide a comprehensive description of its clinical, radiological, laboratory, and molecular findings.

Materials and methods
We comprehensively analyzed the charts of 28 patients: 16 patients from Riyadh, Saudi Arabia, 8 patients from North and South America and 4 patients from Europe with a molecularly confirmed diagnosis of PLA2G6-associated neurodegeneration (PLAN) and a clinical history consistent with INAD.

Results
In our cohort, speech impairment and loss of gross motor milestones were the earliest signs of the disease. As the disease progressed, loss of fine motor milestones and bulbar dysfunction were observed. Temporo-frontal function was among the last of the milestones to be lost. Appendicular spastic hypertonia, axial hypotonia, and hyperreflexia were common neurological findings. Other common clinical findings include nystagmus (60.7%), seizures (42.9%), gastrointestinal disease (42.9%), skeletal deformities (35.7%), and strabismus (28.6%). Cerebellar atrophy and elevations in serum AST and LDH levels were consistent features of INAD. There was a statistically significant difference when comparing patients with non-sense/truncating variants compared with missense/in-frame deletions in the time of initial concern (p = 0.04), initial loss of language (p = 0.001), initial loss of fine motor skills (p = 0.009), and initial loss of bulbar skills (p = 0.007).

Conclusion
INAD is an ultra-rare neurodegenerative disorder that presents in early childhood, with a relentlessly progressive clinical course. Knowledge of the natural history of INAD may serve as a resource for healthcare providers to develop a targeted care plan and may facilitate the design of clinical trials to treat this disease.
Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation
Authors: Yu Xinfang , Li Wei , Liu Haidan , Deng Qipan , Wang Xu , Hu Hui , Xu-Monette Zijun Y. , Xiong Wei , Lu Zhongxin , Young Ken H. , Wang Wei , Li Yong 
Published: May 2020

Abstract
Background
Aberrant activation of DNA damage response (DDR) is a major cause of chemoresistance in colorectal cancer (CRC). CHK1 is upregulated in CRC and contributes to therapeutic resistance. We investigated the upstream signaling pathways governing CHK1 activation in CRC.

Methods
We identified CHK1-binding proteins by mass spectrometry analysis. We analyzed the biologic consequences of knockout or overexpression of TRAF4 using immunoblotting, immunoprecipitation, and immunofluorescence. CHK1 and TRAF4 ubiquitination was studied in vitro and in vivo. We tested the functions of TRAF4 in CHK1 phosphorylation and CRC chemoresistance by measuring cell viability and proliferation, anchorage-dependent and -independent cell growth, and mouse xenograft tumorigenesis. We analyzed human CRC specimens by immunohistochemistry.

Results
TRAF4 catalyzed the ubiquitination of CHK1 in multiple CRC cell lines. Following DNA damage, ubiquitination of CHK1 at K132 by TRAF4 is required for CHK1 phosphorylation and activation mediated by ATR. Notably, TRAF4 was highly expressed in chemotherapy-resistant CRC specimens and positively correlated with phosphorylated CHK1. Furthermore, depletion of TRAF4 impaired CHK1 activity and sensitized CRC cells to fluorouracil and other chemotherapeutic agents in vitro and in vivo.

Conclusions
These data reveal two novel steps required for CHK1 activation in which TRAF4 serves as a critical intermediary and suggest that inhibition of the ATR–TRAF4–CHK1 signaling may overcome CRC chemoresistance.
The application and prospect of CDK4/6 inhibitors in malignant solid tumors
Authors: Du Qi , Guo Xiang , Wang Miao , Li Yongfu , Sun Xiaoyi , Li Qin 
Published: May 2020

AbstractCyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which block the transition from the G1 to S phase of the cell cycle by interfering with Rb phosphorylation and E2F release, have shown potent antitumor activity and manageable toxicity in HR+/HER2− breast cancer patients. Some clinical trials involving CDK4/6 inhibitors in other tumors have achieved preliminary impressive efficacy. Whether CDK4/6 inhibitors possess great potential as broad-spectrum antitumor drugs and how to maximize their clinical benefits remain uncertain. TCGA database analysis showed that CDK4/6 genes and related genes are widely expressed among various tumors, and high or moderate expression of CDK4/6 genes commonly indicates poor survival. CDK4/6 gene expression is significantly higher in COAD, ESCA, STAD, LIHC, and HNSC, suggesting that CDK4/6 inhibitors could be more efficacious in those tumors. Moreover, network analysis with the STRING database demonstrated that CDK4/6-related proteins were co-expressed or co-occurred with the classical tumor signaling pathways, such as the cell cycle pathway, RAS pathway, PI3K pathway, Myc pathway, and p53 pathway. The extensive antitumor effects of CDK4/6 inhibitors may be achieved by synergizing or antagonizing with other signaling molecule inhibitors, and combination therapy might be the most effective treatment strategy. This article analyzed the feasibility of expanding the application of CDK4/6 inhibitors at the genetic level and further summarized the associated clinical/preclinical studies to collect supportive evidence. This is the first study that presents a theoretical foundation for CDK4/6 inhibitor precision therapy via combined analysis of comprehensive gene information and clinical research results.
Peer support for people with severe mental illness versus usual care in high-, middle- and low-income countries: study protocol for a pragmatic, multicentre, randomised controlled trial (UPSIDES-RCT)
Authors: Moran Galia S. , Kalha Jasmine , Mueller-Stierlin Annabel S. , Kilian Reinhold , Krumm Silvia , Slade Mike , Charles Ashleigh , Mahlke Candelaria , Nixdorf Rebecca , Basangwa David , Nakku Juliet , Mpango Richard , Ryan Grace , Shamba Donat , Ramesh Mary , Ngakongwa Fileuka , Grayzman Alina , Pathare Soumitra , Mayer Benjamin , Puschner Bernd 
Published: May 2020

AbstractBackgroundPeer support is an established intervention involving a person recovering from mental illness supporting others with mental illness. Peer support is an under-used resource in global mental health. Building upon comprehensive formative research, this study will rigorously evaluate the impact of peer support at multiple levels, including service user outcomes (psychosocial and clinical), peer support worker outcomes (work role and empowerment), service outcomes (cost-effectiveness and return on investment), and implementation outcomes (adoption, sustainability and organisational change).MethodsUPSIDES-RCT is a pragmatic, parallel-group, multicentre, randomised controlled trial assessing the effectiveness of using peer support in developing empowering mental health services (UPSIDES) at four measurement points over 1 year (baseline, 4-, 8- and 12-month follow-up), with embedded process evaluation and cost-effectiveness analysis. Research will take place in a range of high-, middle- and low-income countries (Germany, UK, Israel, India, Uganda and Tanzania). The primary outcome is social inclusion of service users with severe mental illness (N = 558;N = 93 per site) at 8-month follow-up, measured with the Social Inclusion Scale. Secondary outcomes include empowerment (using the Empowerment Scale), hope (using the HOPE scale), recovery (using Stages of Recovery) and health and social functioning (using the Health of the Nations Outcome Scales). Mixed-methods process evaluation will investigate mediators and moderators of effect and the implementation experiences of four UPSIDES stakeholder groups (service users, peer support workers, mental health workers and policy makers). A cost-effectiveness analysis examining cost-utility and health budget impact will estimate the value for money of UPSIDES peer support.DiscussionThe UPSIDES-RCT will explore the essential components necessary to create a peer support model in mental health care, while providing the evidence required to sustain and eventually scale-up the intervention in different cultural, organisational and resource settings. By actively involving and empowering service users, UPSIDES will move mental health systems toward a recovery orientation, emphasising user-centredness, community participation and the realisation of mental health as a human right.Trial registrationISRCTN,ISRCTN26008944. Registered on 30 October 2019.
Validity and diagnostic performance of fluorescence optical imaging measuring synovitis in hand osteoarthritis: baseline results from the Nor-Hand cohort
Authors: Maugesten Øystein , Mathiessen Alexander , Hammer Hilde Berner , Hestetun Sigrid Valen , Kvien Tore Kristian , Uhlig Till , Ohrndorf Sarah , Haugen Ida Kristin 
Published: May 2020

Abstract
Objective
Fluorescence optical imaging (FOI) demonstrates enhanced microcirculation in finger joints as a sign of inflammation. We wanted to assess the validity and diagnostic performance of FOI measuring synovitis in persons with hand OA, comparing it with magnetic resonance imaging (MRI)- and ultrasound-detected synovitis.

Methods
Two hundred and twenty-one participants with hand OA underwent FOI and ultrasound (gray-scale synovitis and power Doppler activity) of the bilateral hands and contrast-enhanced MRI examination of the dominant hand. Fifteen joints in each hand were scored on semi-quantitative scales (grade 0–3) for all modalities. Four FOI images were evaluated: one composite image (Prima Vista Mode (PVM)) and three images representing phases of fluorescent dye distribution. Spearman’s correlation coefficients were calculated between sum scores of FOI, MRI, and ultrasound. Sensitivity, specificity, and area under the curve (AUC) were calculated for FOI using MRI or ultrasound as reference.

Results
FOI did not demonstrate enhancement in the thumb base, and the joint was excluded from further analyses. FOI sum scores showed poor to fair correlations with MRI (rho 0.01–0.24) and GS synovitis sum scores (rho 0.12–0.25). None of the FOI images demonstrated both good sensitivity and specificity, and the AUC ranged from 0.50–0.61 and 0.51–0.63 with MRI and GS synovitis as reference, respectively. FOI demonstrated similar diagnostic performance with PD activity and GS synovitis as reference.

Conclusion
FOI enhancement correlated poorly with synovitis assessed by more established imaging modalities, questioning the value of FOI for the evaluation of synovitis in hand OA.
MiR-21-5p regulates extracellular matrix degradation and angiogenesis in TMJOA by targeting Spry1
Authors: Ma Shixing , Zhang Aobo , Li Xiaole , Zhang Shizhou , Liu Shaopeng , Zhao Haoming , Wu Shichao , Chen Lei , Ma Chuan , Zhao Huaqiang 
Published: May 2020

Abstract
Background
Due to the lack of research on the pathological mechanism of temporomandibular joint osteoarthritis (TMJOA), there are few effective treatment measures in the clinic. In recent years, microRNAs (miRs) have been demonstrated to play an important role in the pathogenesis of osteoarthritis (OA) by regulating a variety of target genes, and the latest evidence shows that miR-21-5p is specifically overexpressed in OA. The purpose of this project was to clarify whether miR-21-5p can regulate the TMJOA process by targeting Spry1.

Methods
TMJOA was induced by a unilateral anterior crossbite (UAC) model, and the effect of miR-21-5p knockout on TMJOA was evaluated by toluidine blue (TB), immunohistochemical (IHC) staining, Western blotting (WB) and RT-qPCR. Primary mouse condylar chondrocytes (MCCs) were isolated, cultured and transfected with a series of mimics, inhibitors, siRNA-Spry1 or cDNA Spry1. WB, RT-qPCR, IHC and TB were used to detect the effect of miR-21-5p and its target gene Spry1 on the expression of MMP-13, VEGF and p-ERK1/2 in TMJOA. The effect of miR-21-5p on angiogenesis was evaluated by chick embryo chorioallantoic membrane (CAM) assay and WB.

Results
In the UAC model, the cartilage thickness and extracellular matrix of miR-21-5p knockout mice were less damaged, and miR-21-5p and UAC model were shown to affect the expression of Spry1, IL-1β, MMP-13, and VEGF. Luciferase experiments confirmed that Spry1 was the direct target of miR-21-5p. The expression levels of Spry1, MMP-13, VEGF and p-ERK1/2 in MCCs transfected with miR-21-5p mimic were higher than those in the inhibitor group. Under the simulated inflammatory environment of IL-1β, the expression levels of MMP-13, VEGF and p-ERK1/2 were positively correlated with miR-21-5p, while Spry1 was negatively correlated with miR-21-5p. Inhibition of miR-21-5p expression and overexpression of Spry1 enhanced the inhibition of MMP-13, VEGF and p-ERK1/2 expression. MiR-21-5p had a significant role in promoting angiogenesis in the chick embryo CAM assay, and this role was clearly mediated by the ERK-MAPK signalling pathway.

Conclusion
This study verified that miR-21-5p can promote the process of TMJOA by targeting Spry1, which provides a new direction for future research on the treatment of this disease.
Is real time PCR preferable to the direct immunofluorescence in the diagnosis of Pneumocystis jirovecii pneumonia in HIV-infected patients?
Authors: Bossart Simon , Mühlethaler Konrad , Garzoni Christian , Furrer Hansjakob 
Published: May 2020

Abstract
Objectives
In this study, we compared IFA and real-time PCR in bronchoalveolar lavage specimens of HIV infected patients. A total of 66 BALs from 62 HIV patients were included in the study. 30 IFA positive and 36 IFA negative specimens were tested with real-time PCR, targeting the major surface glycoprotein. We performed a retrospective analysis of the patient’s medical records, compared the results of the IFA and PCR tests and analyzed costs, expenditure of time and personal expenses.

Results
All of the 30 IFA positive samples were PCR positive. 35 of 36 IFA negative probes were also negative in the PCR assay. Considering the PCR results as a binary outcome (positive/negative) sensitivity was 100%, specificity 97.2%. The patient with negative IFA and positive PCR had a clear clinical picture of PCP and responded to PCP treatment. PCR was more than twice as expensive and time-consuming as IFA. Diagnostic accuracy for PCP of PCR and IFA was comparable in HIV-infected patients, but IFA was significantly less expensive and less time-consuming. Therefore, IFA testing can continue to be used as gold standard in the diagnosis of PCP in HIV patients. However, in special cases, IFA may lack sensitivity and PCR should be added to the diagnostic armamentarium.
Sex-related differences in markers of immune activation in virologically suppressed HIV-infected patients
Authors: Santinelli Letizia , Ceccarelli Giancarlo , Borrazzo Cristian , Innocenti Giuseppe Pietro , Frasca Federica , Cavallari Eugenio Nelson , Celani Luigi , Nonne Chiara , Mastroianni Claudio Maria , d’Ettorre Gabriella 
Published: May 2020

Abstract
Objectives
Gender-specific studies remain a neglected area of biomedical research. Recent reports have emphasized that sex-related biological factors may affect disease progression during HIV-1 infection. The aim of this study was to investigate the influence of sex on the levels of immune activation in the gut and in peripheral blood of individuals with HIV treated with fully suppressive antiretroviral therapy (ART).

Methods
Thirty individuals with HIV undergoing long-term fully suppressive ART were enrolled in this study. Lamina propria lymphocytes (LPL) and peripheral blood mononuclear cells (PBMCs) were isolated from gut biopsies collected by pancolonoscopy and peripheral blood samples. The expression of markers of immune activation was evaluated by multi-parametric flow cytometry. This is a sub analysis of ClinicalTrials.gov Identifier: NCT02276326

Results
We observed differences in the levels of immune activation in the gut and in PBMCs, with values higher in the gut compartment compared to PBMCs.
In addition, we found that the mean value of the levels of immune activation was higher in the women than in the men. Finally, we measured the markers of immune activation by mean relative difference (MRD) and confirmed the higher value in the women.

Conclusion
A significant sex-related difference in the level of immune activation was observed in a population of individuals with HIV on long-term ART. A more complete characterization of these differences may support the introduction of sex-specific approaches in the clinical management of individuals with HIV.
Elderly bedridden patients with dementia use over one quarter of resources in internal medicine wards in an Israeli hospital
Authors: Salz Inbal Weiss , Carmeli Yehuda , Levin Avi , Fallach Noga , Braun Tali , Amit Sharon 
Published: May 2020

Abstract
Background
Elderly bedridden patients with dementia (EBRPD) are a growing segment of the population. We aimed to describe acute care hospitalization of EBRPD in internal medicine wards: the prevalence of EBRPD, their impact on hospital resources and hospital ecology, one-year survival, and one-year readmission-free survival.

Methods
The study setting was the internal medicine division of one tertiary care hospital in Israel. We conducted a point-prevalence survey to measure the prevalence of EBRPD and the prevalence of multidrug-resistant organism (MDRO) carriage. We also conducted a retrospective chart review of EBRPD who were hospitalized in the internal medicine division in order to assess resource use, survival, and readmission.

Results
In the point prevalence surveys (N = 1667 patients), EBRPD comprised 24.3% of patients and 59.0% of mechanically ventilated patients. EBRPD were twice as likely to be colonized or infected by MDROs as other patients (39.3% vs. 18%, p < 0.001); thus, 41% of MDRO carriers during the survey days were EBRPD. In the retrospective study (N = 517 EBRPD), 80% of EBRPD received antibiotics; on average, they received an antibiotic on 87.7% of their hospital days. One-year survival was 35.6% and one-year readmission-free survival was 16.4%.

Conclusions
Acute care hospitalization of EBRPD accounted for a high proportion of bed occupancy and ventilator use in internal medicine wards. EBRPD significantly increase the potential for MDRO transmission. Policymakers should seek alternatives to acute care hospitalization for EBRPD.
Iodine deficiency in Israeli pregnant women – a time for action
Authors: Lazarus John H. 
Published: May 2020

AbstractIodine is an essential micronutrient for thyroid gland function. Iodine deficiency disorders are a spectrum of conditions affecting the fetus, child, adolescent and adult. Iodine requirements are increased in pregnancy in order that the fetus receives enough maternal thyroxine via transplacental passage. Previous studies in Israel have shown widespread iodine deficiency by measurement of urinary iodine concentrations in school age children and adults. The present study clearly shows iodine deficiency in a group of 2nd trimester women as judged by measurement of serum thyroglobulin (a recently evaluated marker of iodine deficiency). An additional factor in this work is that the subjects all resided in an area using desalinated water. Desalination has previously been shown to significantly reduce the iodine content of water compared to water in Israel not subject to this process.The data in this group of pregnant women should serve as a wakeup call to the public health community to correct this deficiency which is known to significantly affect child neurodevelopment. There are several issues to be addressed. The knowledge base relating to iodine nutrition especially during pregnancy is low. An educational plan is required. The strategy for achieving adequate iodine nutrition in the population and particularly before and during pregnancy requires urgent review. While iodine supplementation before and during gestation can correct iodine deficiency, the provision of iodised salt in the community is recommended, similar to more than 80% of countries in the world.It is indeed a time for action to ensure the adequate intellectual performance of Israel’s children.
Time-frequency feature extraction for classification of episodic memory
Authors: Anderson Rachele , Sandsten Maria 
Published: May 2020

AbstractThis paper investigates the extraction of time-frequency (TF) features for classification of electroencephalography (EEG) signals and episodic memory. We propose a model based on the definition of locally stationary processes (LSPs), estimate the model parameters, and derive a mean square error (MSE) optimal Wigner-Ville spectrum (WVS) estimator for the signals. The estimator is compared with state-of-the-art TF representations: the spectrogram, the Welch method, the classically estimated WVS, and the Morlet wavelet scalogram. First, we evaluate the MSE of each spectrum estimate with respect to the true WVS for simulated data, where it is shown that the LSP-inference MSE optimal estimator clearly outperforms other methods. Then, we use the different TF representations to extract the features which feed a neural network classifier and compare the classification accuracies for simulated datasets. Finally, we provide an example of real data application on EEG signals measured during a visual memory encoding task, where the classification accuracy is evaluated as in the simulation study. The results show consistent improvement in classification accuracy by using the features extracted from the proposed LSP-inference MSE optimal estimator, compared to the use of state-of-the-art methods, both for simulated datasets and for the real data example.
Approximation by modified Kantorovich–Szász type operators involving Charlier polynomials
Authors: Ansari K. J. , Mursaleen M. , Shareef KP M. , Ghouse M. 
Published: May 2020

AbstractIn this paper, we give some direct approximation results by modified Kantorovich–Szász type operators involving Charlier polynomials. Further, approximation results are also developed in polynomial weighted spaces. Moreover, for the functions of bounded variation, approximation results are proved. Finally, some graphical examples are provided to show comparisons of convergence between old and modified operators towards a function under different parameters and conditions.