bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cyberdivisions Produced by the Design of VGI under the Platform Economy: The Case of the Restaurant Sector in TripAdvisor
Authors: Ferreira Daniela , Vale Mário , Carmo Renato Miguel
Published: October 2021

There is increasing concern regarding the inequalities produced by digital platforms based on volunteered geographic information (VGI). Several forms of inequalities have been observed, namely the unequal spatial coverage and the uneven levels of usage even in territories with good coverage. However, VGI platforms under the logic of platform economy have generated other forms of spatial inequality that require more attention. The cyberspace within VGI platforms is producing different cyberspatialities, especially with the platformisation processes that have made this type of inequality more evident. With this in mind, this paper aims to explore the making of cyberdivisions under the platform economy. We argue that the design of VGI within digital platforms is generating cyberdivisions in the urban economy. This research is particularly interested in exploring the restaurant sector in the TripAdvisor platform in the city of Lisbon. In this paper, we draw on a representative survey by questionnaire to restaurant firm owners. We obtained 385 responses out of a universe of 3453 restaurants. This sample provides a confidence level of 95% and a confidence interval of 5%. In addition, we webscraped data from TripAdvisor to assess its coverage in Lisbon. This study reveals that there are different forms of online presence and engagement which have generated cyberdivisions.
Stress Driven Discovery of Natural Products From Actinobacteria with Anti-Oxidant and Cytotoxic Activities Including Docking and ADMET Properties
Authors: Hassan Syed Shams ul , Muhammad Ishaq , Abbas Syed Qamar , Hassan Mubashir , Majid Muhammad , Jin Hui-Zi , Bungau Simona
Published: October 2021

Elicitation through abiotic stress, including chemical elicitors like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metals on actinobacteria Streptomyces sp. SH-1312 for secondary metabolite production, with strong pharmacological activity, along with pharmacokinetics profile, was firstly investigated. The optimum metal stress conditions consisted of actinobacteria strain Streptomyces sp. SH-1312 with addition of mix metals (Co2+ + Zn2+) ions at 0.5 mM in Gause’s medium. Under these conditions, the stress metabolite anhydromevalonolactone (MVL) was produced, which was absent in the normal culture of strain and other metals combinations. Furthermore, the stress metabolite was also evaluated for its anti-oxidant and cytotoxic activities. The compound exhibited remarkable anti-oxidant activities, recording the IC50 value of 19.65 ± 5.7 µg/mL in DPPH, IC50 of 15.49 ± 4.8 against NO free radicals, the IC50 value of 19.65 ± 5.22 µg/mL against scavenging ability, and IC50 value of 19.38 ± 7.11 µg/mL for iron chelation capacity and the cytotoxic activities against PC3 cell lines were recorded with IC50 values of 35.81 ± 4.2 µg/mL after 24 h, 23.29 ± 3.8 µg/mL at 48 h, and 16.25 ± 6.5 µg/mL after 72 h. Further mechanistic studies have revealed that the compound MVL has shown its pharmacological efficacy by upregulation of P53 and BAX while downregulation of BCL-2 expression, indicating that MVL is following apoptosis in varying degrees. To better understand the pharmacological properties of MVL, in this work, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) were also evaluated. During ADMET predictions, MVL has displayed a safer profile in case of hepatotoxicity, cytochrome inhibition and also displayed as non-cardiotoxic. The compound MVL showed good binding energy in the molecular docking studies, and the results revealed that MVL bind in the active region of the target protein of P53 and BAX. This work triumphantly announced a prodigious effect of heavy metals on actinobacteria with fringe benefits as a key tool of MVL production with a strong pharmacological and pharmacokinetic profile.
NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML
Authors: Nagel Stefan , Pommerenke Claudia , Meyer Corinna , MacLeod Roderick A. F.
Published: October 2021

NKL homeobox genes encode transcription factors that impact normal development and hematopoietic malignancies if deregulated. Recently, we established an NKL-code that describes the physiological expression pattern of eleven NKL homeobox genes in the course of hematopoiesis, allowing evaluation of aberrantly activated NKL genes in leukemia/lymphoma. Here, we identify ectopic expression of NKL homeobox gene NKX2-4 in an erythroblastic acute myeloid leukemia (AML) cell line OCI-M2 and describe investigation of its activating factors and target genes. Comparative expression profiling data of AML cell lines revealed in OCI-M2 an aberrantly activated program for endothelial development including master factor ETV2 and the additional endothelial signature genes HEY1, IRF6, and SOX7. Corresponding siRNA-mediated knockdown experiments showed their role in activating NKX2-4 expression. Furthermore, the ETV2 locus at 19p13 was genomically amplified, possibly underlying its aberrant expression. Target gene analyses of NKX2-4 revealed activated ETV2, HEY1, and SIX5 and suppressed FLI1. Comparative expression profiling analysis of public datasets for AML patients and primary megakaryocyte–erythroid progenitor cells showed conspicuous similarities to NKX2-4 activating factors and the target genes we identified, supporting the clinical relevance of our findings and developmental disturbance by NKX2-4. Finally, identification and target gene analysis of aberrantly expressed NKX2-3 in AML patients and a megakaryoblastic AML cell line ELF-153 showed activation of FLI1, contrasting with OCI-M2. FLI1 encodes a master factor for myelopoiesis, driving megakaryocytic differentiation and suppressing erythroid differentiation, thus representing a basic developmental target of these homeo-oncogenes. Taken together, we have identified aberrantly activated NKL homeobox genes NKX2-3 and NKX2-4 in AML, deregulating genes involved in megakaryocytic and erythroid differentiation processes, and thereby contributing to the formation of specific AML subtypes.
Ex Vivo Human Colon Tissue Exposure to Pristine Graphene Activates Genes Involved in the Binding, Adhesion and Proliferation of Epithelial Cells
Authors: Lahiani Mohamed H. , Gokulan Kuppan , Williams Katherine , Khare Sangeeta
Published: October 2021

Toxicology studies on pristine graphene are limited and lack significant correlations with actual human response. The goal of the current study was to determine the response of total colonic human tissue to pristine graphene exposure. Biopsy punches of colon tissues from healthy human were used to assess the biological response after ex vivo exposure to graphene at three different concentrations (1, 10, and 100 µg/mL). mRNA expression of specific genes or intestinal cytokine abundance was assessed using real-time PCR or multiplex immunoassays, respectively. Pristine graphene-activated genes that are related to binding and adhesion (GTPase and KRAS) within 2 h of exposure. Furthermore, the PCNA (proliferating cell nuclear antigen) gene was upregulated after exposure to graphene at all concentrations. Ingenuity pathway analysis revealed that STAT3 and VEGF signaling pathways (known to be involved in cell proliferation and growth) were upregulated. Graphene exposure (10 µg/mL) for 24 h significantly increased levels of pro-inflammatory cytokines IFNγ, IL-8, IL-17, IL-6, IL-9, MIP-1α, and Eotaxin. Collectively, these results indicated that graphene may activate the STAT3–IL23–IL17 response axis. The findings in this study provide information on toxicity evaluation using a human-relevant ex vivo colon model and serve as a basis for further exploration of its bio-applications.
Targetable Pathways for Alleviating Mitochondrial Dysfunction in Neurodegeneration of Metabolic and Non-Metabolic Diseases
Authors: Millichap Lauren Elizabeth , Damiani Elisabetta , Tiano Luca , Hargreaves Iain P.
Published: October 2021

Many neurodegenerative and inherited metabolic diseases frequently compromise nervous system function, and mitochondrial dysfunction and oxidative stress have been implicated as key events leading to neurodegeneration. Mitochondria are essential for neuronal function; however, these organelles are major sources of endogenous reactive oxygen species and are vulnerable targets for oxidative stress-induced damage. The brain is very susceptible to oxidative damage due to its high metabolic demand and low antioxidant defence systems, therefore minimal imbalances in the redox state can result in an oxidative environment that favours tissue damage and activates neuroinflammatory processes. Mitochondrial-associated molecular pathways are often compromised in the pathophysiology of neurodegeneration, including the parkin/PINK1, Nrf2, PGC1α, and PPARγ pathways. Impairments to these signalling pathways consequently effect the removal of dysfunctional mitochondria, which has been suggested as contributing to the development of neurodegeneration. Mitochondrial dysfunction prevention has become an attractive therapeutic target, and there are several molecular pathways that can be pharmacologically targeted to remove damaged mitochondria by inducing mitochondrial biogenesis or mitophagy, as well as increasing the antioxidant capacity of the brain, in order to alleviate mitochondrial dysfunction and prevent the development and progression of neurodegeneration in these disorders. Compounds such as natural polyphenolic compounds, bioactive quinones, and Nrf2 activators have been reported in the literature as novel therapeutic candidates capable of targeting defective mitochondrial pathways in order to improve mitochondrial function and reduce the severity of neurodegeneration in these disorders.
Chlorogenic Acid Decreases Glutamate Release from Rat Cortical Nerve Terminals by P/Q-Type Ca2+ Channel Suppression: A Possible Neuroprotective Mechanism
Authors: Hung Yi-Chieh , Kuo Yi-Hsiu , Hsieh Pei-Wen , Hsieh Ting-Yang , Kuo Jinn-Rung , Wang Su-Jane
Published: October 2021

The glutamatergic neurotransmitter system has received substantial attention in research on the pathophysiology and treatment of neurological disorders. The study investigated the effect of the polyphenolic compound chlorogenic acid (CGA) on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). CGA inhibited 4-aminopyridine (4-AP)-induced glutamate release from synaptosomes. This inhibition was prevented in the absence of extracellular Ca2+ and was associated with the inhibition of 4-AP-induced elevation of Ca2+ but was not attributed to changes in synaptosomal membrane potential. In line with evidence observed through molecular docking, CGA did not inhibit glutamate release in the presence of P/Q-type Ca2+ channel inhibitors; therefore, CGA-induced inhibition of glutamate release may be mediated by P/Q-type Ca2+ channels. CGA-induced inhibition of glutamate release was also diminished by the calmodulin and Ca2+/calmodilin-dependent kinase II (CaMKII) inhibitors, and CGA reduced the phosphorylation of CaMKII and its substrate, synapsin I. Furthermore, pretreatment with intraperitoneal CGA injection attenuated the glutamate increment and neuronal damage in the rat cortex that were induced by kainic acid administration. These results indicate that CGA inhibits glutamate release from cortical synaptosomes by suppressing P/Q-type Ca2+ channels and CaMKII/synapsin I pathways, thereby preventing excitotoxic damage to cortical neurons.
The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts
Authors: Galicka Anna , Sutkowska-Skolimowska Joanna
Published: October 2021

Benzophenone-3 (BP-3) is one of the most widely used chemical sunscreens. The results of many in vitro and in vivo tests confirm its high percutaneous penetration and systemic absorption, which question the safety of its wide use. The aim of our research was to assess the effect of this compound on components of the skin extracellular matrix, and to investigate whether rosmarinic acid (RA) could reduce BP-3-induced changes in human skin fibroblasts. BP-3 used at concentrations of 0.1–100 µM caused a number of unfavorable changes in the level of type I collagen, decorin, sulfated glycosaminoglycans, hyaluronic acid, elastin, and expression or activity of matrix metalloproteinases (MMP-1, MMP-2), elastase and hyaluronidase. Moreover, the intracellular retention of collagen was accompanied by changes in the expression of proteins modifying and controlling the synthesis and secretion of this protein. Most importantly, RA at a concentration of 100 µM significantly reduced or completely abolished the adverse effects of BP-3. Based on these findings, it can be concluded that this polyphenol may provide effective protection against BP-3-induced disturbances in skin cells, which may have important clinical implications.
Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells
Authors: Lorentzon Emma , Horvath Istvan , Kumar Ranjeet , Rodrigues Joana Isabel , Tamás Markus J. , Wittung-Stafshede Pernilla
Published: October 2021

Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.
An ATP-Binding Cassette Transporter, LaABCB11, Contributes to Alkaloid Transport in Lycoris aurea
Authors: Wang Rong , Liu Yantong , Xu Sheng , Li Jie , Zhou Jiayu , Wang Ren
Published: October 2021

As a kind of Amaryllidaceae alkaloid which is accumulated in the species of Lycoris plants, lycorine has a range of physiological effects. The biosynthesis pathway of lycorine has been partly revealed, but the transport and accumulation mechanisms of lycorine have rarely been studied. In this study, an ATP-binding cassette (ABC) transporter from Lycoris aurea (L’Hér) Herb., namely LaABCB11, was cloned and functionally characterized. Heterologous expression showed that LaABCB11 transported lycorine in an outward direction, increased the tolerance of yeast cells to lycorine, and caused a lower lycorine accumulation in transformants than control or mutant in yeast. LaABCB11 is associated with the plasma membrane, and in situ hybridization indicated that LaABCB11 was mainly expressed in the phloem of leaves and bulbs, as well as in the cortical cells of roots. These findings suggest that LaABCB11 functions as a lycorine transport and it might be related to the translocation and accumulation of lycorine from the leaves and bulbs to the roots.
Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages
Authors: Koike Masao , Saito Hitoki , Kohno Genta , Takubo Masahiro , Watanabe Kentaro , Ishihara Hisamitsu
Published: October 2021

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.
Modification of Variance-Based Sensitivity Indices for Stochastic Evaluation of Monitoring Measures
Authors: Sanio David , Ahrens Mark Alexander , Mark Peter
Published: October 2021

In complex engineering models, various uncertain parameters affect the computational results. Most of them can only be estimated or assumed quite generally. In such a context, measurements are interesting to determine the most decisive parameters accurately. While measurements can reduce parameters’ variance, structural monitoring might improve general assumptions on distributions and their characteristics. The decision on variables being measured often relies on experts’ practical experience. This paper introduces a method to stochastically estimate the potential benefits of measurements by modified sensitivity indices. They extend the established variance-based sensitivity indices originally suggested by Sobol’. They do not quantify the importance of a variable but the importance of its variance reduction. The numerical computation is presented and exemplified on a reference structure, a 50-year-old pre-stressed concrete bridge in Germany, where the prediction of the fatigue lifetime of the pre-stressing steel is of concern. Sensitivity evaluation yields six important parameters (e.g., shape of the S–N curve, temperature loads, creep, and shrinkage). However, taking into account individual monitoring measures and suited measurements identified by the modified sensitivity indices, creep and shrinkage, temperature loads, and the residual pre-strain of the tendons turn out to be most efficient. They grant the highest gains of accuracy with respect to the lifetime prediction.
Improvement of Pavement Subgrade by Adding Cement and Fly Ash to Natural Desert Sand
Authors: Amhadi Talal S. , Assaf Gabriel J.
Published: October 2021

Soil characteristics are paramount to design pavements and to assess the economic viability of a road. In the desert, such as that found in southern Libya, the very poor quality of soils leads to important pavement distress such as cracks, rutting, potholes, and lateral shear failure on the edges. To improve the strength of desert sand, an innovative approach is proposed, consisting of adding manufactured sand, ordinary Portland cement (OPC), and fly ash (FA) as a binder. OPC and FA improve the characteristics of mixes of crushed fine aggregate (CFA) and natural desert sand (NDS). These results are based on a gradation of two sand sources to determine the particle distribution and X-ray fluorescence (XRF) to determine their chemical and physical properties, respectively. This research assesses the effect of cement and fly ash on the geotechnical behavior of two mixtures of fine desert and manufactured sands (30:70% and 50:50%). The mix composed of 26% of CFA, 62% of NDS, 5% of OPC, and 7% of FA shows optimal results in terms of strength, compaction, and bearing capacity characteristics.
COVID-19 Pandemic and Patients with Rare Inherited Metabolic Disorders and Rare Autoinflammatory Diseases—Organizational Challenges from the Point of View of Healthcare Providers
Authors: Tobór-Świętek Ewa , Sykut-Cegielska Jolanta , Bik-Multanowski Mirosław , Walczak Mieczysław , Rokicki Dariusz , Kałużny Łukasz , Wierzba Joanna , Pac Małgorzata , Jahnz-Różyk Karina , Więsik-Szewczyk Ewa , Kieć-Wilk Beata
Published: October 2021

COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one year of coronavirus pandemic has impacted the treatment of patients with IMD and AD in Poland. Surveys were distributed to all healthcare providers that coordinate the treatment of IMD and AD patients. Thirty-two responders (55%) answered the survey. They provide care to 1726 patients with IMD/AD, including 246 patients on dedicated treatment. In 35% of units, the regular appointments were disrupted, primarily because of patient infection. In 18 hospitals, remote visits were implemented, but only 66.6% of patients used this form of consultation. In 14/32 hospitals, administration of the therapy was delayed (median: 17.4 days). Forty-four patients suffered from SARS-COV-2 infection, in majority with mild symptoms. However, four adult patients developed complications, and one died following a SARS-COV-2 infection. Although most hospitals managed to maintain regular visits during the pandemic, more comprehensive implementation of telemedicine and switch to oral therapy or home infusions would be a reasonable solution for the current epidemic situation.
Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation
Authors: Lai Chia-Yeh , Yang Sheng-Shun , Lee Shou-Wu , Tsai Hsin-Ju , Lee Teng-Yu
Published: October 2021

Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. Methods: In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). Results: The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95% CI: 27.84–57.73% vs. 25.42%, 95% CI: 16.26–34.58%; p = 0.045) and SAE recurrence (25.91%, 95% CI: 10.91–40.91% vs. 1.04%, 95% CI: 0–3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95% CI: 1.04–3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95% CI: 2.34–31.30% vs. 6.02%, 95% CI: 0–13.23%; p = 0.049). Conclusions: Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.
Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis
Authors: Ventura-Cots Meritxell , Simón-Talero Macarena , Poca Maria , Ariza Xavier , Masnou Helena , Sanchez Jordi , Llop Elba , Cañete Núria , Martín-Llahí Marta , Amador Alberto , Martínez Javier , Clemente-Sanchez Ana , Puente Angela , Torrens Maria , Alvarado-Tapias Edilmar , Napoleone Laura , Miquel-Planas Mireia , Ardèvol Alba , Casas Rodrigo Meritxell , Calleja Jose Luís , Solé Cristina , Soriano German , Genescà Joan
Published: October 2021

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. Methods: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient’s data for survival including two clinical trials (BETA and ALFAE) was performed. Results: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21–0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). Conclusions: Repeated doses of albumin might be beneficial for patient’s survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.
Cross-Cultural Adaptation, Reliability, and Psychophysical Validation of the Pain and Sleep Questionnaire Three-Item Index in Finnish
Authors: Mikkonen Jani , Leinonen Ville , Luomajoki Hannu , Kaski Diego , Kupari Saana , Tarvainen Mika , Selander Tuomas , Airaksinen Olavi
Published: October 2021

Reciprocal relationships between chronic musculoskeletal pain and various sleep disturbances are well established. The Pain and Sleep Questionnaire three-item index (PSQ-3) is a concise, valid, and reliable patient-reported outcome measure (PROM) that directly evaluates how sleep is affected by chronic low back pain (CLBP). Translation and cross-cultural validation of The Pain and Sleep Questionnaire three-item index Finnish version (PSQ-3-FI) were conducted according to established guidelines. The validation sample was 229 subjects, including 42 pain-free controls and 187 subjects with chronic musculoskeletal pain. Our aims were to evaluate internal consistency, test–retest reliability, measurement error, structural validity, convergent validity, and discriminative validity and, furthermore, to study the relationships between dizziness, postural control on a force plate, and objective sleep quality metrics and total PSQ-3-FI score. The PSQ-3-FI demonstrated good internal consistency, excellent test–retest reliability, and small measurement error. Confirmatory factor analysis confirmed acceptable fit indices to a one-factor model. Convergent validity indicated fair to good correlation with pain history and well-established pain-related PROMs. The PSQ-3-FI total score successfully distinguished between the groups with no pain, single-site pain, and multisite pain. A higher prevalence of dizziness, more impaired postural control, and a general trend towards poorer sleep quality were observed among subjects with higher PSQ-3-FI scores. Postural control instability was more evident in eyes-open tests. The Finnish PSQ-3 translation was successfully cross-culturally adapted and validated. The PSQ-3-FI appears to be a valid and reliable PROM for the Finnish-speaking CLBP population. More widespread implementation of PSQ-3 would lead to better understanding of the direct effects of pain on sleep.
Community-Acquired Pneumonia among Patients with COPD in Spain from 2016 to 2019. Cohort Study Assessing Sex Differences in the Incidence and Outcomes Using Hospital Discharge Data
Authors: de Miguel-Diez Javier , Lopez-Herranz Marta , Hernandez-Barrera Valentin , de Miguel-Yanes Jose M. , Perez-Farinos Napoleon , Wärnberg Julia , Carabantes-Alarcon David , Jimenez-Garcia Rodrigo , Lopez-de-Andres Ana
Published: October 2021

Background: To describe and analyze the incidence and hospital outcomes of patients admitted with community-acquired pneumonia (CAP) according to Chronic Obstructive Pulmonary Disease (COPD) status and sex in Spanish hospitals from 2016 to 2019. Methods: We conducted a cohort study using national hospital discharge data of all patients ≥40 years with CAP. Results: A total of 500,833 patients (59.0% men) was identified. Incidence of CAP increased over time. Age-adjusted incidence was 4.42-times higher in COPD patients. In-hospital mortality (IHM) was lower in men and women with COPD than in those without COPD (14.41% vs. 10.70% in men; 11.12% vs. 8.58%. in women; p < 0.001). The risk of dying in hospital increased with age, presence of several comorbidities (excluding T2DM that was a protective factor), and need for mechanical ventilation (non-invasive and invasive) during admission, irrespective of sex. Over time, the IHM decreased significantly in men and women with COPD. Men with COPD were significantly more likely to die in hospital than were COPD women (OR 1.13; 95% CI 1.07–1.21). Conclusions: Incidence of CAP was higher among subjects with COPD, although the effect of COPD was higher in men than in women. By contrast, IHM was lower in COPD patients, but men with COPD were significantly more likely to die in hospital than were COPD women.
Voluntary Modulation of Evoked Responses Generated by Epidural and Transcutaneous Spinal Stimulation in Humans with Spinal Cord Injury
Authors: Calvert Jonathan S. , Gill Megan L. , Linde Margaux B. , Veith Daniel D. , Thoreson Andrew R. , Lopez Cesar , Lee Kendall H. , Gerasimenko Yury P. , Edgerton Victor R. , Lavrov Igor A. , Zhao Kristin D. , Grahn Peter J. , Sayenko Dimitry G.
Published: October 2021

Transcutaneous (TSS) and epidural spinal stimulation (ESS) are electrophysiological techniques that have been used to investigate the interactions between exogenous electrical stimuli and spinal sensorimotor networks that integrate descending motor signals with afferent inputs from the periphery during motor tasks such as standing and stepping. Recently, pilot-phase clinical trials using ESS and TSS have demonstrated restoration of motor functions that were previously lost due to spinal cord injury (SCI). However, the spinal network interactions that occur in response to TSS or ESS pulses with spared descending connections across the site of SCI have yet to be characterized. Therefore, we examined the effects of delivering TSS or ESS pulses to the lumbosacral spinal cord in nine individuals with chronic SCI. During low-frequency stimulation, participants were instructed to relax or attempt maximum voluntary contraction to perform full leg flexion while supine. We observed similar lower-extremity neuromusculature activation during TSS and ESS when performed in the same participants while instructed to relax. Interestingly, when participants were instructed to attempt lower-extremity muscle contractions, both TSS- and ESS-evoked motor responses were significantly inhibited across all muscles. Participants with clinically complete SCI tested with ESS and participants with clinically incomplete SCI tested with TSS demonstrated greater ability to modulate evoked responses than participants with motor complete SCI tested with TSS, although this was not statistically significant due to a low number of subjects in each subgroup. These results suggest that descending commands combined with spinal stimulation may increase activity of inhibitory interneuronal circuitry within spinal sensorimotor networks in individuals with SCI, which may be relevant in the context of regaining functional motor outcomes.
The Effect of Recombinant Human TSH on Sclerostin and Other Selected Bone Markers in Patients after Total Thyroidectomy for Differentiated Thyroid Cancer
Authors: Zygmunt Arkadiusz , Krawczyk-Rusiecka Kinga , Skowrońska-Jóźwiak Elżbieta , Wojciechowska-Durczyńska Katarzyna , Głowacka Ewa , Adamczewski Zbigniew , Lewiński Andrzej
Published: October 2021

The direct effect of TSH on bone metabolism in vivo is difficult to capture as the changes of its concentrations are followed by respective alterations of thyroid hormone levels. We evaluated the effect of recombinant human TSH (rhTSH) on sclerostin and other bone markers in 29 patients after total thyroidectomy for differentiated thyroid cancer (DTC), without any signs of disease recurrence, who received L-thyroxine, most at non-suppressive doses. For two consecutive days, the patients were administered a standard dose of 0.9 mg rhTSH, i.m. Concentrations of sclerostin, osteocalcin, β-CrossLaps, PTH, and some other parameters, were measured before and five days after the first rhTSH administration. The greater the increase in TSH concentration (∆TSH), the greater the decrease in: ∆sclerostin (r = −0.672; p < 0.001), ∆β-CrossLaps (r = −0.580; p < 0.001) and ∆osteocalcin (r = −0.405; p = 0.029) levels, were recorded. The degree of TSH increase depended on the baseline PTH (r = 0.651; p < 0.001), age, and creatinine concentrations. rhTSH strongly inhibited bone turnover, thus, TSH—independently of thyroid hormones—exerted a direct protective effect on bone metabolism. Baseline PTH affected the magnitude of TSH increase and the degree of lowering in sclerostin and β-CrossLaps that suggest factors affecting PTH may play a role in the effect of TSH on the bone.
Potential Targets Other Than PSMA for Prostate Cancer Theranostics: A Systematic Review
Authors: Gauthé Mathieu , Sargos Paul , Barret Eric , Fromont-Hankard Gaëlle , Beauval Jean-Baptiste , Brureau Laurent , Créhange Gilles , Renard-Penna Raphaële , Dariane Charles , Fiard Gaëlle , Mathieu Romain , Roubaud Guilhem , Ruffion Alain , Rouprêt Morgan , Ploussard Guillaume ,   on behalf of the CC-AFU
Published: October 2021

Background: Prostate-specific membrane antigen (PSMA) is not sufficiently overexpressed in a small proportion of prostate cancer (PCa) patients, who require other strategies for imaging and/or treatment. We reviewed potential targets other than PSMA for PCa theranostics in nuclear medicine that have already been tested in humans. Methods: We performed a systematic web search in the PubMed and Cochrane databases, with no time restrictions by pooling terms (“prostate cancer”, “prostatic neoplasms”) and (“radioligand”, “radiotracer”). Included articles were clinical studies. The results were synthetized by the target type. Results: We included 38 studies on six different targets: gastrin-releasing peptide receptors (GRPRs) (n = 23), androgen receptor (n = 11), somatostatin receptors (n = 6), urokinase plasminogen activator surface receptor (n = 4), fibroblast activation protein (n = 2 studies) and integrin receptors (n = 1). GRPRs, the most studied target, has a lower expression in high-grade PCa, CRPC and bone metastases. Its use might be of higher interest in treating earlier stages of PCa or low-grade PCa. Radiolabeled fibroblast activation protein inhibitors were the most recent and promising molecules, but specific studies reporting their interest in PCa are needed. Conclusion: Theranostics in nuclear medicine will continue to develop in the future, especially for PCa patients. Targets other than PSMA exist and deserve to be promoted.
Good Metabolic Control in Children with Type 1 Diabetes Mellitus: Does Glycated Hemoglobin Correlate with Interstitial Glucose Monitoring Using FreeStyle Libre?
Authors: Porcel-Chacón Rocio , Antúnez-Fernández Cristina , Mora Loro Maria , Ariza-Jimenez Ana-Belen , Tapia Ceballos Leopoldo , Jimenez Hinojosa Jose Manuel , Lopez-Siguero Juan Pedro , Leiva Gea Isabel
Published: October 2021

Background: Good metabolic control of Type 1 diabetes (T1D) leads to a reduction in complications. The only validated parameter for establishing the degree of control is glycated hemoglobin (HbA1c). We examined the relationship between HbA1c and a continuous glucose monitoring (CGM) system. Materials and methods: A cohort prospective study with 191 pediatric patients with T1D was conducted. Time in range (TIR), time below range (TBR), coefficient of variation (CV), number of capillary blood glucose tests, and HbA1c before sensor insertion and at one year of use were collected. Results: Patients were classified into five groups according to HbA1c at one year of using CGM. They performed fewer capillary blood glucose test at one year using CGM (−6 +/− 2, p < 0.0001). We found statistically significant differences in TIR between categories. Although groups with HbA1c < 6.5% and HbA1c 6.5–7% had the highest TIR (62.214 and 50.462%), their values were highly below optimal control according to CGM consensus. Groups with TBR < 5% were those with HbA1c between 6.5% and 8%. Conclusions: In our study, groups classified as well-controlled by guidelines were not consistent with good control according to the CGM consensus criteria. HbA1c should not be considered as the only parameter for metabolic control. CGM parameters allow individualized targets.
Correlation between Ultra-Wide-Field Retinal Imaging Findings and Vascular Supra-Aortic Changes in Takayasu Arteritis
Authors: Poignet Barthelemy , Bonnin Philippe , Gaudric Julien , Chehaibou Ismael , Vautier Mathieu , Tadayoni Ramin , Gaudric Alain , Paques Michel , Bodaghi Bahram , Saadoun David , Bonnin Sophie
Published: October 2021

(1) Background: Takayasu arteritis (TA) is a chronic inflammatory large-vessel vasculitis. Ultra-wide-field imaging allows describing the retinal lesions in these patients and correlating them with vascular supra-aortic stenosis. (2) Methods: In total, 54 eyes of 27 patients diagnosed with TA were included, and a complete ophthalmological examination was performed, including UWF color fundus photography (UWF-CFP), fluorescein angiography (UWF-FA), and computed tomography angiography measuring supra-aortic stenosis. Eleven patients underwent Doppler ultrasound imaging assessing the blood flow velocity (BFV) in the central retinal artery (CRA). (3) Results: Microaneurysms were detected in 18.5% of eyes on fundus examination, in 24.4% of eyes on UWF-CFP, and in 94.4% of eyes on UWF-FA. The number of microaneurysms significantly correlated with the presence of an ipsilateral supra-aortic stenosis (p = 0.026), the presence of hypertension (p = 0.0011), and the duration of the disease (p = 0.007). The number of microaneurysms per eye negatively correlated with the BFV in the CRA (r = −0.61; p = 0.003). (4) Conclusions: UWF-FA improved the assessment of TA-associated retinal findings. The significant correlation between the number of microaneurysms and the BFV in the CRA gives new insight to our understanding of Takayasu retinopathy. The total number of microaneurysms could be used as an interesting prognostic factor for TA.
How to Manage Withdrawal of Sedation and Analgesia in Mechanically Ventilated COVID-19 Patients?
Authors: Ego Amédée , Halenarova Katarina , Creteur Jacques , Taccone Fabio Silvio
Published: October 2021

COVID-19 patients suffering from severe acute respiratory distress syndrome (ARDS) require mechanical ventilation (MV) for respiratory failure. To achieve these ventilatory goals, it has been observed that COVID-19 patients in particular require high regimens and prolonged use of sedatives, analgesics and neuromuscular blocking agents (NMBA). Withdrawal from analgo-sedation may induce a “drug withdrawal syndrome” (DWS), i.e., clinical symptoms of anxiety, tremor, agitation, hallucinations and vomiting, as a result of adrenergic activation and hyperalgesia. We describe the epidemiology, mechanisms leading to this syndrome and our strategies to prevent and treat it.
AUV Obstacle Avoidance Planning Based on Deep Reinforcement Learning
Authors: Yuan Jianya , Wang Hongjian , Zhang Honghan , Lin Changjian , Yu Dan , Li Chengfeng
Published: October 2021

In a complex underwater environment, finding a viable, collision-free path for an autonomous underwater vehicle (AUV) is a challenging task. The purpose of this paper is to establish a safe, real-time, and robust method of collision avoidance that improves the autonomy of AUVs. We propose a method based on active sonar, which utilizes a deep reinforcement learning algorithm to learn the processed sonar information to navigate the AUV in an uncertain environment. We compare the performance of double deep Q-network algorithms with that of a genetic algorithm and deep learning. We propose a line-of-sight guidance method to mitigate abrupt changes in the yaw direction and smooth the heading changes when the AUV switches trajectory. The different experimental results show that the double deep Q-network algorithms ensure excellent collision avoidance performance. The effectiveness of the algorithm proposed in this paper was verified in three environments: random static, mixed static, and complex dynamic. The results show that the proposed algorithm has significant advantages over other algorithms in terms of success rate, collision avoidance performance, and generalization ability. The double deep Q-network algorithm proposed in this paper is superior to the genetic algorithm and deep learning in terms of the running time, total path, performance in avoiding collisions with moving obstacles, and planning time for each step. After the algorithm is trained in a simulated environment, it can still perform online learning according to the information of the environment after deployment and adjust the weight of the network in real-time. These results demonstrate that the proposed approach has significant potential for practical applications.
How Does El Niño Affect Predictability Barrier of Its Accompanied Positive Indian Ocean Dipole Event?
Authors: Liu Da , Duan Wansuo , Feng Rong
Published: October 2021

The effects of El Niño on the predictability of positive Indian Ocean dipole (pIOD) events are investigated by using the GFDL CM2p1 coupled model from the perspective of error growth. The results show that, under the influence of El Niño, the summer predictability barrier (SPB) for pIOD tends to intensify and the winter predictability barrier (WPB) is weakened. Since the reason for the weakening of WPB has been explained in a previous study, the present study attempts to explore why the SPB is enhanced. The results demonstrate that the initial sea temperature errors, which are most likely to induce SPB for pIOD with El Niño, possess patterns similar to those for pIOD without El Niño, whose dominant errors concentrate in the tropical Pacific Ocean (PO), with a pattern of negative SST errors occurring in the eastern and central PO and subsurface sea temperature errors being negative in the eastern PO and positive in the western PO. By tracking the development of such initial errors, it is found that the initial errors over PO lead to anomalous westerlies in the southeastern Indian Ocean (IO) through the effect of double-cell Walker circulation. Such westerly anomalies are inhibited by the strongest climatological easterly wind and the southeasterlies related to the pIOD event itself in summer, while they are enhanced by El Niño. This competing effect causes the intensified seasonal variation in latent heat flux, with much less loss in summer under the effect of El Niño. The greater suppression of the loss of latent heat flux favors the positive sea surface temperature (SST) errors developing much faster in the eastern Indian Ocean in summer, and eventually induces an enhanced SPB for pIOD due to El Niño.
Purified Native and Recombinant Major Alternaria alternata Allergen (Alt a 1) Induces Allergic Asthma in the Murine Model
Authors: Vélez-del-Burgo Ainara , Sánchez Patricia , Suñen Ester , Martínez Jorge , Postigo Idoia
Published: October 2021

Aeroallergens such us the spores of Alternaria alternata are described as the most important agents associated with respiratory allergies and severe asthma. Various experimental models of asthma have been developed using A. alternata extracts to study the pathogenesis of asthma, establishing the main parameters that trigger the asthmatic response. In this study, we describe a mouse model of asthma induced only by Alt a 1. To induce the allergic response, mice were challenged intranasally with the major allergen of A. alternata, Alt a 1. The presence of eosinophils in the lungs, elevated concentrations of Th2 family cytokines, lymphocyte proliferation and elevated IgE total serum levels indicated that the sensitisation and challenge with Alt a 1 induced the development of airway inflammation. Histological studies showed an eosinophilic cellular infiltrate in the lung tissue of mice instilled with Alt a 1. We demonstrate that Alt a 1 alone is capable of inducing a lung inflammatory response with an increase in IgE serum levels mimicking the allergic asthma immunoresponse when it is administered into BALB/c mice. This model will allow the evaluation of the immunoregulatory or immunotolerant capacity of several molecules that can be used in targeted immunotherapy for fungal allergic asthma.
Comprehensive Combined Proteomics and Genomics Analysis Identifies Prognostic Related Transcription Factors in Breast Cancer and Explores the Role of DMAP1 in Breast Cancer
Authors: Li Xuan , Sun Hefen , Hou Yifeng , Jin Wei
Published: October 2021

Transcription factors (TFs) are important for regulating gene transcription and are the hallmark of many cancers. The identification of breast cancer TFs will help in developing new diagnostic and individualized cancer treatment tools. In this study, we used quantitative proteomic analyses of nuclear proteins and massive transcriptome data to identify enriched potential TFs and explore the possible role of the transcription factor DMAP1 in breast cancer. We identified 13 prognostic-related TFs and constructed their regulated genes, alternative splicing (AS) events, and splicing factor (SF) regulation networks. DMAP1 was reported less in breast cancer. The expression of DMAP1 decreased in breast cancer tumors compared with normal tissues. The poor prognosis of patients with low DMAP1 expression may relate to the activated PI3K/Akt signaling pathway, as well as other cancer-relevant pathways. This may be due to the low methylation and high expression of these pathway genes and the fact that such patients show more sensitivity to some PI3K/Akt signaling pathway inhibitors. The high expression of DMAP1 was correlated with low immune cell infiltration, and the response to immune checkpoint inhibitor treatment in patients with high DMAP1 expression was low. Our study identifies some transcription factors that are significant for breast cancer progression, which can be used as potential personalized prognostic markers in the future.