bluuebunny/crossref_metadata_2025 huggingface dataset:
Respiratory Symptoms, Allergies, and Environmental Exposures in Children with and without Asthma
Authors: Wypych-Ślusarska Agata , Grot Martina , Kujawińska Maria , Nigowski Maciej , Krupa-Kotara Karolina , Oleksiuk Klaudia , Głogowska-Ligus Joanna , Grajek Mateusz
Published: September 2022

Background: Epidemiological data concerning the level of asthma morbidity indicate that in Poland, asthma is diagnosed in 5–10% of the pediatric population. Aim The purpose of this study was to compare the prevalence of respiratory symptoms and allergies in a group of children with and without asthma and to evaluate the association between exposure to environmental factors and the prevalence of bronchial asthma in a pediatric population. Material and Methods: A cross-sectional study was conducted on a group of 995 children attending primary schools in the province of Silesia in 2018–2019. The research tool was an anonymous questionnaire developed based on the form used in The International Study of Asthma and Allergies in Childhood (ISAAC). Children’s health status, the prevalence of bronchial asthma, and the performance of allergic skin tests were assessed based on parents’ indications in a questionnaire. Environmental exposures such as mold and dampness in apartments or ETS were similarly assessed. Analyses were performed using Statistica 13.0; p < 0.05. Results: A total of 88 subjects (8.8%) suffered from bronchial asthma. Parents of children with asthma, compared to parents of children without the disease, were more likely to rate their children’s health as rather good (43.2% vs. 38.0%) or average (21.6% vs. 3.1%). All analyzed respiratory symptoms, as well as allergies, were statistically more frequent in children with bronchial asthma. Conclusions: The parent’s subjective assessment of the child’s health varied significantly according to the asthma diagnosis. Asthma is also associated with other diseases: allergic reactions to pollen, house dust, hay fever, and AD (atopic dermatitis) were statistically significantly more frequent among children diagnosed with bronchial asthma.
How Medical Staff Alleviates Job Burnout through Sports Involvement: The Mediating Roles of Health Anxiety and Self-Efficacy
Authors: Chen Xiuyu , Jing Longjun , Wang Huilin , Yang Jingyu
Published: September 2022

In the current healthcare environment, job burnout among medical staff is increasingly evident. Burnout not only affects the mental and physical health and career development of individuals but also affects the quality of care and the doctor–patient relationship. This paper investigates the influence of sports involvement on burnout in medical staff based on the job demands–resources theory, focusing on the mediating role of health anxiety and self-efficacy in the relationship between sports involvement and job burnout. A questionnaire survey was used to collect data from 444 medical staff in public hospitals in Wuhan, China. Structural equation modeling (SEM) with a bootstrapping approach was conducted to test the hypothesis and mediating effects. It was found that health anxiety and self-efficacy played a significant mediating role between sports involvement and job burnout. The results indicate the important role that sports involvement plays in addressing burnout, revealing that decreasing health anxiety and increasing self-efficacy attenuated job burnout. This finding suggests that hospital administrators should not only pay attention to medical staff’s health conditions and improve their enthusiasm for work but also encourage them to become more engaged in sports.
The Utility of Capsicum annuum L. in Internal Medicine and In Dentistry: A Comprehensive Review
Authors: Catalfamo Luciano Maria , Marrone Giulia , Basilicata Michele , Vivarini Ilaria , Paolino Vincenza , Della-Morte David , De Ponte Francesco Saverio , Di Daniele Francesca , Quattrone Domenico , De Rinaldis Danilo , Bollero Patrizio , Di Daniele Nicola , Noce Annalisa
Published: September 2022

Capsaicin is a chili peppers extract, genus Capsicum, commonly used as a food spice. Since ancient times, Capsaicin has been used as a “homeopathic remedy” for treating a wild range of pathological conditions but without any scientific knowledge about its action. Several studies have demonstrated its potentiality in cardiovascular, nephrological, nutritional, and other medical fields. Capsaicin exerts its actions thanks to the bond with transient receptor potential vanilloid subtype 1 (TRPV1). TRPV1 is a nociceptive receptor, and its activation starts with a neurosensitive impulse, responsible for a burning pain sensation. However, constant local application of Capsaicin desensitized neuronal cells and leads to relief from neuropathic pain. In this review, we analyze the potential adjuvant role of Capsaicin in the treatment of different pathological conditions either in internal medicine or dentistry. Moreover, we present our experience in five patients affected by oro-facial pain consequent to post-traumatic trigeminal neuropathy, not responsive to any remedy, and successfully treated with topical application of Capsaicin. The topical application of Capsaicin is safe, effective, and quite tolerated by patients. For these reasons, in addition to the already-proven beneficial actions in the internal field, it represents a promising method for the treatment of neuropathic oral diseases.
Detection and Visualisation of Pneumoconiosis Using an Ensemble of Multi-Dimensional Deep Features Learned from Chest X-rays
Authors: Devnath Liton , Fan Zongwen , Luo Suhuai , Summons Peter , Wang Dadong
Published: September 2022

Pneumoconiosis is a group of occupational lung diseases induced by mineral dust inhalation and subsequent lung tissue reactions. It can eventually cause irreparable lung damage, as well as gradual and permanent physical impairments. It has affected millions of workers in hazardous industries throughout the world, and it is a leading cause of occupational death. It is difficult to diagnose early pneumoconiosis because of the low sensitivity of chest radiographs, the wide variation in interpretation between and among readers, and the scarcity of B-readers, which all add to the difficulty in diagnosing these occupational illnesses. In recent years, deep machine learning algorithms have been extremely successful at classifying and localising abnormality of medical images. In this study, we proposed an ensemble learning approach to improve pneumoconiosis detection in chest X-rays (CXRs) using nine machine learning classifiers and multi-dimensional deep features extracted using CheXNet-121 architecture. There were eight evaluation metrics utilised for each high-level feature set of the associated cross-validation datasets in order to compare the ensemble performance and state-of-the-art techniques from the literature that used the same cross-validation datasets. It is observed that integrated ensemble learning exhibits promising results (92.68% accuracy, 85.66% Matthews correlation coefficient (MCC), and 0.9302 area under the precision–recall (PR) curve), compared to individual CheXNet-121 and other state-of-the-art techniques. Finally, Grad-CAM was used to visualise the learned behaviour of individual dense blocks within CheXNet-121 and their ensembles into three-color channels of CXRs. We compared the Grad-CAM-indicated ROI to the ground-truth ROI using the intersection of the union (IOU) and average-precision (AP) values for each classifier and their ensemble. Through the visualisation of the Grad-CAM within the blue channel, the average IOU passed more than 90% of the pneumoconiosis detection in chest radiographs.
Fluorescence-Guided Surgery and Novel Innovative Technologies for Improved Visualization in Pediatric Urology
Authors: Paraboschi Irene , Mantica Guglielmo , Minoli Dario Guido , De Marco Erika Adalgisa , Gnech Michele , Bebi Carolina , Manzoni Gianantonio , Berrettini Alfredo
Published: September 2022

Fluorescence-guided surgery (FGS), three-dimensional (3D) imaging technologies, and other innovative devices are rapidly revolutionizing the field of urology, providing surgeons with powerful tools for a more complete understanding of patient-specific anatomy. Today, several new intraoperative imaging technologies and cutting-edge devices are available in adult urology to assist surgeons in delivering personalized interventions. Their applications are also gradually growing in general pediatric surgery, where the detailed visualization of normal and pathological structures has the potential to significantly minimize perioperative complications and improve surgical outcomes. In the field of pediatric urology, FGS, 3D reconstructions and printing technologies, augmented reality (AR) devices, contrast-enhanced ultrasound (CEUS), and intraoperative magnetic resonance imaging (iMRI) have been increasingly adopted for a more realistic understanding of the normal and abnormal anatomy, providing a valuable insight to deliver customized treatments in real time. This narrative review aims to illustrate the main applications of these new technologies and imaging devices in the clinical setting of pediatric urology by selecting, with a strict methodology, the most promising articles published in the international scientific literature on this topic. The purpose is to favor early adoption and stimulate more research on this topic for the benefit of children.
Risk Factors Attributable to Hypertension among HIV-Infected Patients on Antiretroviral Therapy in Selected Rural Districts of the Eastern Cape Province, South Africa
Authors: Tsuro Urgent , Oladimeji Kelechi E. , Pulido-Estrada Guillermo-Alfredo , Apalata Teke R.
Published: September 2022

Background: Antiretroviral therapy has improved HIV patients’ quality of life and life expectancy. However, complications have emerged in the form of hypertension. In the rural Eastern Cape, there is minimal information about HIV-infected people. The current study intended to evaluate the factors associated with hypertension in HIV-infected individuals receiving antiretroviral therapy in rural areas of South Africa’s Eastern Cape. Methods: For this cohort study, HIV-positive people taking antiretroviral therapy aged 15 and up were recruited at random from several rural locations in the Eastern Cape. Using Cox univariate and multivariate analyses, the key predictors of hypertension were found. Results: Of the total participants (n = 361), 53% of individuals had hypertension. In the Cox multivariate model, patients that had hypertension heredity, BMI ≥ 25 kg/m2, eGFR < 60 mL/min/1.73 m2, advanced and severe CD4 counts, 1TFE and 1T3E regimens, and the male gender were found to be at greater risk of hypertension. Conclusions: The findings of this study indicate that hypertension is a prevalent concern among HIV patients receiving antiretroviral therapy. HIV patients should have their blood pressure checked regularly, and they should be screened for high blood pressure and given treatment for it.
The Impact of Body Posture on Heart Rate Strain during Tree Felling
Authors: Tsioras Petros A. , Khooshdohbat Mahmoud , Nikooy Mehrdad , Naghdi Ramin , Heidari Mahmoud
Published: September 2022

Tree felling is recognized as one of the most difficult and physically demanding work phases in motor–manual wood harvesting, during which maintaining good posture can avert unnecessary loadings to the spine and the consequent musculoskeletal disorders to forestry professionals. This study aimed to (a) quantify the impact of posture selection by means of heart rate measurements and (b) analyze its interactions with the anthropometric and personal information of study subjects. Thirteen forest workers were asked to fell thirty trees in each of the four most common body postures during motor–manual forest operations: (i) stooping, (ii) flexed stooping, (iii) squatting, and (iv) half kneeling. Posture had a significant impact on the amount of heart strain measured as mean heart rate during work (HRwork), heart rate increase over resting heart rate (ΔHR), and relative heart rate index (HRR). The most popular position among the forest workers was flexed stooping, which also caused the most damage, compared with the least physiologically damaging position, half kneeling: HRwork by 12.40 bpm, ΔHR by 10.24 bpm, and HRR by 11.51. On the contrary, overweight and older subjects experienced lower heart rate strain, a finding that has to be further investigated.
Assessing the Impact of Green Transformation on Ecological Well-Being Performance: A Case Study of 78 Cities in Western China
Authors: Wu Chuansheng , Li Yuyue , Qi Lingling
Published: September 2022

The contradiction between the endless pursuit of material possessions and finite natural resources hampers ecological well-being performance (EWP) improvement. Green transformation, recognized as an emerging strategy in sustainable development, can help to coordinate ecological, social, and economic growth by optimizing resource usage, with the ultimate objective of enhancing EWP. This research quantifies how green transformation influences EWP by using panel data from 78 prefecture-level cities in western China from 2012 to 2019. Using the super-SBM and entropy weight models, we assess the EWP and green transformation index (GTI) of 78 prefecture-level cities in western China. On this basis, we quantify the spatial characteristics of EWP by an analysis of the Theil index and spatial autocorrelation. Finally, we examine how GTI affects EWP using the Spatial Durbin model. The results demonstrate that the GTI can raise the EWP of local and nearby cities in western China. According to a GTI analysis of internal indicators, the industrial solid waste usage, harm-less treatment rate of domestic waste, savings level, and R&D expenditure significantly affect EWP. In contrast, the soot emission and consumption levels impede EWP advancement. The analysis of effect decomposition indicates that the sewage treatment rate, expenditure on science and technology, and green patents have a significant spatial spillover effect on the improvement of EWP.
The Psychological Well-Being and Civic Engagement of Polish, Croatian and Lithuanian Academic Students during COVID-19 Outbreak
Authors: Marciniak Mateusz , Jaskulska Sylwia , Gasparovic Slaven , Janiūnaitė Brigita , Horbačauskienė Jolita , Glavak Tkalić Renata
Published: September 2022

The aim of this research was to recognize the relationship between well-being and civic engagement under the difficult circumstances of the COVID-19 pandemic amongst students from Poland, Lithuania and Croatia. Overall, 1362 academic students (Poland, n = 596, Croatia, n = 386, and Lithuania, n = 379) participated in the study. Mean rank differences in civic engagement level (overall CE) were analysed by levels of psychological well-being (overall PWB and its subscales) using the Kruskal–Wallis test (one-way ANOVA on ranks). We conducted post hoc analysis with Bonferroni tests to measure the significance of differences in CE between the detailed levels of PWB. To avoid biases due to interaction effects between dependent variables, the analysis of mean ranks was followed by a binomial logistic regression analysis model and subgroups analysis (by gender and by country). Results obtained showed that students with higher levels of psychological well-being have higher levels of civic engagement. The differences in the CE level are most pronounced in relation to the dimension of a PWB, such as “positive relations with others”, followed by “personal growth”, “autonomy”, and “self-acceptance”. In a crisis, such as a pandemic, it is worth encouraging students to take targeted actions, as well as to create actions referring to personal development and relationships. There were no differences in the direction and shape of the associations between psychological well-being and civic engagement with respect to the country and the gender of the participants, which leads us to draw conclusions pointing to the globalised nature of student experience during the pandemic in this part of Europe.
How Does Digitalization Affect Haze Pollution? The Mediating Role of Energy Consumption
Authors: Wang Jing , Xu Yubing
Published: September 2022

In the context of digital technology innovation, an in-depth investigation into the impact of digitalization on haze pollution is of great significance for scientifically understanding environmental effects of digitalization and building a livable civic environment. From the perspective of energy consumption intensity and structure, this paper theoretically analyzes the direct and indirect effects of digitalization on haze pollution. On this basis, the impact of digitalization on haze pollution for 81 countries over the period 2010–2019 is empirically investigated by using the system GMM and mediating effects model. Empirical results show that digitalization can effectively suppress haze pollution, and there is significant heterogeneity in this inhibiting effect. In addition, digitalization can indirectly restrain haze pollution by reducing energy consumption intensity and optimizing energy consumption structure. The findings of this paper can provide enlightenment for countries to promote digitalization, combat haze pollution, and thus enhance the health of community residents.
Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations
Authors: De Bie Felix Rafael , Basurto David , Kumar Sailesh , Deprest Jan , Russo Francesca Maria
Published: September 2022

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.
Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study
Authors: Reece Albert Stuart , Hulse Gary Kenneth
Published: September 2022

Introduction: Laboratory data link cannabinoid exposure to chromosomal mis-segregation errors. Recent epidemiological reports confirm this link and raise concern that elevated chromosomal congenital anomaly rates (CCAR) may be occurring in Europe which is experiencing increased cannabis use, daily intensity of use and cannabinoid potency. Methods: CCAR data from Eurocat. Drug use data from the European Monitoring Centre for Drugs and Drug Addiction. Income from World Bank. Bivariate, multivariate, panel and geotemporospatial regressions analyzed. Inverse probability weighting of panel models and E-values used as major quantitative causal inferential methodologies. Results: In countries where daily cannabis use was rising the trend for CCA’s was upwards whereas in those where daily use was declining it was usually downwards (p = 0.0002). In inverse probability weighted panel models terms for cannabis metrics were significant for chromosomal disorders, trisomies 21 and 13 and Klinefelters syndrome from p < 2.2 × 10−16. In spatiotemporal models cannabis terms were positive and significant for chromosomal disorders, genetic disorders, trisomies 21, 18 and 13, Turners and Klinefelters syndromes from 4.28 × 10−6, 5.79 × 10−12, 1.26 × 10−11, 1.12 × 10−7, 7.52 × 10−9, 7.19 × 10−7 and 7.27 × 10−7. 83.7% of E-value estimates and 74.4% of minimum E-values (mEV) > 9 including four values each at infinity. Considering E-values: the sensitivity of the individual disorders was trisomy 13 > trisomy 21 > Klinefelters > chromosomal disorders > Turners > genetic syndromes > trisomy 18 with mEV’s 1.91 × 1025 to 59.31; and daily cannabis use was the most powerful covariate (median mEV = 1.91 × 1025). Conclusions: Data indicate that, consistent with reports from Hawaii, Canada, Colorado, Australia and USA, CCARs are causally and spatiotemporally related to metrics and intensity of cannabis exposure, directly impact 645 MB (21.5%) of the human genome and may implicate epigenomic-centrosomal mechanisms.
Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas
Authors: Braig David , Runkel Alexander , Eisenhardt Anja E. , Schmid Adrian , Zeller Johannes , Pauli Thomas , Lausch Ute , Wehrle Julius , Bronsert Peter , Jung Matthias , Kiefer Jurij , Boerries Melanie , Eisenhardt Steffen U.
Published: September 2022

Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future.
The Role of miR-29 Family in TGF-β Driven Fibrosis in Glaucomatous Optic Neuropathy
Authors: Smyth Aoife , Callaghan Breedge , Willoughby Colin E. , O’Brien Colm
Published: September 2022

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-β) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-β signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.
Recent Advances on the Roles of PCSK-9 Inhibitors in the Management of Acute Ischemic Stroke Patients
Authors: Ilut Silvina , Pirlog Bianca O. , Pirlog Radu , Nutu Andreea , Vacaras Vitalie , Armean Sebastian M.
Published: September 2022

Acute ischemic stroke (AIS) represents an important cause of disability and death. Since only a minor percentage of patients with AIS are eligible for acute therapy, the management of risk factors is mandatory. An important risk factor of AIS is hyperlipemia. The current guidelines recommend a strict correction of it. Statins are recommended as the first-line treatment, while proprotein convertase subtilin/kexin type 9 (PCSK-9) inhibitors are administered as a second or even third option when the goal for a low-density lipoprotein cholesterol (LDL-C) level is not achieved. PCSK-9 inhibitors effectively decrease the LDL-C levels through the inhibition of PCSK-9-LDL-receptor complex formation. The in-depth understanding of the PCSK-9 protein mechanism in the metabolism of LDL-C led to the development of effective targeted approaches. Furthermore, a better understanding of the LDL-C metabolic pathway led to the development of newer approaches, which increased the therapeutic options. This article aims to offer an overview of the PCSK-9 inhibitors and their mechanism in reducing the LDL-C levels. Moreover, we will present the main indications of the current guidelines for patients with hyperlipemia and for those who have suffered an acute ischemic stroke, as well as the importance of LDL-C reduction in decreasing the rate of a recurrence.
The New Microtubule-Targeting Agent SIX2G Induces Immunogenic Cell Death in Multiple Myeloma
Authors: Grillone Katia , Riillo Caterina , Rocca Roberta , Ascrizzi Serena , Spanò Virginia , Scionti Francesca , Polerà Nicoletta , Maruca Annalisa , Barreca Marilia , Juli Giada , Arbitrio Mariamena , Di Martino Maria Teresa , Caracciolo Daniele , Tagliaferri Pierosandro , Alcaro Stefano , Montalbano Alessandra , Barraja Paola , Tassone Pierfrancesco
Published: September 2022

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.
The Arrival of Gene Therapy for Patients with Hemophilia A
Authors: Castaman Giancarlo , Di Minno Giovanni , De Cristofaro Raimondo , Peyvandi Flora
Published: September 2022

Historically, the standard of care for hemophilia A has been intravenous administration of exogenous factor VIII (FVIII), either as prophylaxis or episodically. The development of emicizumab, a humanized bispecific monoclonal antibody mimicking activated FVIII, was a subsequent advance in treatment. However, both exogenous FVIII and emicizumab require repeated and lifelong administration, negatively impacting patient quality of life. A recent breakthrough has been the development of gene therapy. This allows a single intravenous treatment that could result in long-term expression of FVIII, maintenance of steady-state plasma concentrations, and minimization (or possibly elimination) of bleeding episodes for the recipient’s lifetime. Several gene therapies have been assessed in clinical trials, with positive outcomes. Valoctocogene roxaparvovec (an adeno-associated viral 5-based therapy encoding human B domain-deleted FVIII) is expected to be the first approved gene therapy in European countries, including Italy, in 2022. Some novel challenges exist including refining patient selection criteria, managing patient expectations, further elucidation of the durability and variability of transgene expression and long-term safety, and the development of standardized ‘hub and spoke’ centers to optimize and monitor this innovative treatment. Gene therapy represents a paradigm shift, and may become a new reference standard for treating patients with hemophilia A.
Exploring the Healthy Eye Microbiota Niche in a Multicenter Study
Authors: Borroni Davide , Paytuví-Gallart Andreu , Sanseverino Walter , Gómez-Huertas Carmen , Bonci Paola , Romano Vito , Giannaccare Giuseppe , Rechichi Miguel , Meduri Alessandro , Oliverio Giovanni William , Rocha-de-Lossada Carlos ,   on behalf of LUCY Consortium
Published: September 2022

Purpose: This study aims to explore and characterize healthy eye microbiota. Methods: Healthy subjects older than 18 years were selected for this descriptive cross-sectional study. Samples were collected with an eSwab with 1 mL of Liquid Amies Medium (Copan Brescia, Italy). Following DNA extraction, libraries preparation, and amplification, PCR products were purified and end-repaired for barcode ligation. Libraries were pooled to a final concentration of 26 pM. Template preparation was performed with Ion Chef according to Ion 510, Ion 520, and Ion 530 Kit-Chef protocol. Sequencing of the amplicon libraries was carried out on a 520 or 530 chip using the Ion Torrent S5 system (Thermo Fisher; Waltham, MA, USA). Raw reads were analyzed with GAIA (v 2.02). Results: Healthy eye microbiota is a low-diversity microbiome. The vast majority of the 137 analyzed samples were highly enriched with Staphylococcus, whereas only in a few of them, other genera such as Bacillus, Pseudomonas, and Corynebacterium predominate. We found an average of 88 genera with an average Shannon index of 0.65. Conclusion: We identified nine different ECSTs. A better understanding of healthy eye microbiota has the potential to improve disease diagnosis and personalized regimens to promote health.
Mucins and CFTR: Their Close Relationship
Authors: Okuda Kenichi , Shaffer Kendall M. , Ehre Camille
Published: September 2022

Mucociliary clearance is a critical defense mechanism for the lungs governed by regionally coordinated epithelial cellular activities, including mucin secretion, cilia beating, and transepithelial ion transport. Cystic fibrosis (CF), an autosomal genetic disorder caused by the dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, is characterized by failed mucociliary clearance due to abnormal mucus biophysical properties. In recent years, with the development of highly effective modulator therapies, the quality of life of a significant number of people living with CF has greatly improved; however, further understanding the cellular biology relevant to CFTR and airway mucus biochemical interactions are necessary to develop novel therapies aimed at restoring CFTR gene expression in the lungs. In this article, we discuss recent advances of transcriptome analysis at single-cell levels that revealed a heretofore unanticipated close relationship between secretory MUC5AC and MUC5B mucins and CFTR in the lungs. In addition, we review recent findings on airway mucus biochemical and biophysical properties, focusing on how mucin secretion and CFTR-mediated ion transport are integrated to maintain airway mucus homeostasis in health and how CFTR dysfunction and restoration of function affect mucus properties.
TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model
Authors: Versele Romain , Sevin Emmanuel , Gosselet Fabien , Fenart Laurence , Candela Pietra
Published: September 2022

The blood-brain barrier (BBB) is a selective barrier and a functional gatekeeper for the central nervous system (CNS), essential for maintaining brain homeostasis. The BBB is composed of specialized brain endothelial cells (BECs) lining the brain capillaries. The tight junctions formed by BECs regulate paracellular transport, whereas transcellular transport is regulated by specialized transporters, pumps and receptors. Cytokine-induced neuroinflammation, such as the tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), appear to play a role in BBB dysfunction and contribute to the progression of Alzheimer’s disease (AD) by contributing to amyloid-β (Aβ) peptide accumulation. Here, we investigated whether TNF-α and IL-1β modulate the permeability of the BBB and alter Aβ peptide transport across BECs. We used a human BBB in vitro model based on the use of brain-like endothelial cells (BLECs) obtained from endothelial cells derived from CD34+ stem cells cocultivated with brain pericytes. We demonstrated that TNF-α and IL-1β differentially induced changes in BLECs’ permeability by inducing alterations in the organization of junctional complexes as well as in transcelluar trafficking. Further, TNF-α and IL-1β act directly on BLECs by decreasing LRP1 and BCRP protein expression as well as the specific efflux of Aβ peptide. These results provide mechanisms by which CNS inflammation might modulate BBB permeability and promote Aβ peptide accumulation. A future therapeutic intervention targeting vascular inflammation at the BBB may have the therapeutic potential to slow down the progression of AD.
Recent Advances in Prion Inactivation by Plasma Sterilizer
Authors: Sakudo Akikazu , Yamashiro Risa , Onodera Takashi
Published: September 2022

Prions, which cause transmissible spongiform encephalopathies (TSEs), are a notorious group of infectious agents with possibly the highest resistance to complete inactivation. Although various gas plasma instruments have been developed, studies on prion inactivation using gas plasma instruments are limited. Among them, the hydrogen peroxide gas plasma instrument, STERRAD® (Advanced Sterilization Products; ASP, Johnson & Johnson, Irvine, CA, USA), is recommended for prion inactivation of heat-sensitive medical devices. However, STERRAD® is not a plasma sterilizer but a hydrogen peroxide gas sterilizer. In STERRAD®, plasma generated by radio frequency (RF) discharge removes excess hydrogen peroxide gas and does not contribute to sterilization. This is also supported by evidence that the instrument was not affected by the presence or absence of RF gas plasma. However, recent studies have shown that other gas plasma instruments derived from air, nitrogen, oxygen, Ar, and a mixture of gases using corona, dielectric barrier, microwave, and pulse discharges can inactivate scrapie prions. As inactivation studies on prions other than scrapie are limited, further accumulation of evidence on the effectiveness of gas plasma using human-derived prion samples is warranted for practical purposes.
The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme
Authors: Drongitis Denise , Verrillo Lucia , De Marinis Pasqualino , Orabona Pasquale , Caiola Agnese , Turitto Giacinto , Alfieri Alessandra , Bruscella Sara , Gentile Marisa , Moriello Vania , Sannino Ettore , Di Muccio Ines , Costa Valerio , Miano Maria Giuseppina , de Bellis Alberto
Published: September 2022

Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)—a negative KDM5C target—and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.
Decreased Platelet Specific Receptor Expression of P-Selectin and GPIIb/IIIa Predict Future Non-Surgical Bleeding in Patients after Left Ventricular Assist Device Implantation
Authors: Klaeske Kristin , Meyer Anna L. , Saeed Diyar , Eifert Sandra , Jawad Khalil , Sieg Franz , Haunschild Josephina , Borger Michael A. , Dieterlen Maja-Theresa
Published: September 2022

Non-surgical bleeding (NSB) is one of the major clinical complications in patients under continuous-flow left ventricular assist device (LVAD) support. The increased shear stress leads to an altered platelet receptor composition. Whether these changes increase the risk for NSB is unclear. Thus, we compared the platelet receptor composition of patients with (bleeder group, n = 18) and without NSB (non-bleeder group, n = 18) prior to LVAD implantation. Blood samples were obtained prior to LVAD implantation and after bleeding complications in the post-implant period. Platelet receptor expression of GPIbα, GPIIb/IIIa, P-selectin and CD63 as well as intra-platelet oxidative stress levels were quantified by flow cytometry. Bleeders and non-bleeders were comparable regarding clinical characteristics, von Willebrand factor diagnostics and the aggregation capacity before and after LVAD implantation (p > 0.05). LVAD patients in the bleeder group suffered from gastrointestinal bleeding (33%; n = 6), epistaxis (22%; n = 4), hematuria or hematoma (17%; n = 3, respectively) and cerebral bleeding (11%; n = 2). Prior to LVAD implantation, a restricted surface expression of the platelet receptors P-selectin and GPIIb/IIIa was observed in the bleeder group (P-selectin: 7.2 ± 2.6%; GPIIb/IIIa: 26,900 ± 13,608 U) compared to non-bleeders (P-selectin: 12.4 ± 8.1%, p = 0.02; GPIIb/IIIa: 36,259 ± 9914 U; p = 0.02). We hypothesized that the reduced platelet receptor expression of P-selectin and GPIIb/IIIa prior to LVAD implantation may be linked to LVAD-related NSB.
Implication of miR-155-5p and miR-143-3p in the Vascular Insulin Resistance and Instability of Human and Experimental Atherosclerotic Plaque
Authors: González-López Paula , Ares-Carral Carla , López-Pastor Andrea R. , Infante-Menéndez Jorge , González Illaness Tamara , Vega de Ceniga Melina , Esparza Leticia , Beneit Nuria , Martín-Ventura José Luis , Escribano Óscar , Gómez-Hernández Almudena
Published: September 2022

(1) Background: Cardiovascular diseases (CVDs) are the main cause of death in developed countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) modulate the expression of their targets and have emerged as key players in CVDs; (2) Methods: 18 miRNAs were selected (Pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from apolipoprotein E-deficient (ApoE−/−) mice. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE−/− mice were studied in human aortic and carotid samples; (3) Results: miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease in protein kinase B (AKT), target of miR-155-5p, and an increase in insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE−/− mice and in carotid plaques from patients with advanced carotid atherosclerosis (ACA). Finally, the overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells, while miR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells; (4) Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of atherosclerosis.
Gut Microbiota Functional Traits, Blood pH, and Anti-GAD Antibodies Concur in the Clinical Characterization of T1D at Onset
Authors: Del Chierico Federica , Conta Giorgia , Matteoli Maria Cristina , Fierabracci Alessandra , Reddel Sofia , Macari Gabriele , Gardini Simone , Guarrasi Valerio , Levi Mortera Stefano , Marzano Valeria , Vernocchi Pamela , Sciubba Fabio , Marini Federico , Deodati Annalisa , Rapini Novella , Cianfarani Stefano , Miccheli Alfredo , Putignani Lorenza
Published: September 2022

Alterations of gut microbiota have been identified before clinical manifestation of type 1 diabetes (T1D). To identify the associations amongst gut microbiome profile, metabolism and disease markers, the 16S rRNA-based microbiota profiling and 1H-NMR metabolomic analysis were performed on stool samples of 52 T1D patients at onset, 17 T1D siblings and 57 healthy subjects (CTRL). Univariate, multivariate analyses and classification models were applied to clinical and -omic integrated datasets. In T1D patients and their siblings, Clostridiales and Dorea were increased and Dialister and Akkermansia were decreased compared to CTRL, while in T1D, Lachnospiraceae were higher and Collinsella was lower, compared to siblings and CTRL. Higher levels of isobutyrate, malonate, Clostridium, Enterobacteriaceae, Clostridiales, Bacteroidales, were associated to T1D compared to CTRL. Patients with higher anti-GAD levels showed low abundances of Roseburia, Faecalibacterium and Alistipes and those with normal blood pH and low serum HbA1c levels showed high levels of purine and pyrimidine intermediates. We detected specific gut microbiota profiles linked to both T1D at the onset and to diabetes familiarity. The presence of specific microbial and metabolic profiles in gut linked to anti-GAD levels and to blood acidosis can be considered as predictive biomarker associated progression and severity of T1D.
Melatonin Inhibits hIAPP Oligomerization by Preventing β-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation
Authors: Wang Gang , Zhu Xinyi , Song Xiaona , Zhang Qingwen , Qian Zhenyu
Published: September 2022

The pathogenesis of type 2 diabetes (T2D) is highly related to the abnormal self-assembly of the human islet amyloid polypeptide (hIAPP) into amyloid aggregates. To inhibit hIAPP aggregation is considered a promising therapeutic strategy for T2D treatment. Melatonin (Mel) was reported to effectively impede the accumulation of hIAPP aggregates and dissolve preformed fibrils. However, the underlying mechanism at the atomic level remains elusive. Here, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the inhibitory effect of Mel on hIAPP oligomerization by using hIAPP20–29 octamer as templates. The conformational ensemble shows that Mel molecules can significantly prevent the β-sheet and backbone hydrogen bond formation of hIAPP20–29 octamer and remodel hIAPP oligomers and transform them into less compact conformations with more disordered contents. The interaction analysis shows that the binding behavior of Mel is dominated by hydrogen bonding with a peptide backbone and strengthened by aromatic stacking and CH–π interactions with peptide sidechains. The strong hIAPP–Mel interaction disrupts the hIAPP20–29 association, which is supposed to inhibit amyloid aggregation and cytotoxicity. We also performed conventional MD simulations to investigate the influence and binding affinity of Mel on the preformed hIAPP1–37 fibrillar octamer. Mel was found to preferentially bind to the amyloidogenic region hIAPP20–29, whereas it has a slight influence on the structural stability of the preformed fibrils. Our findings illustrate a possible pathway by which Mel alleviates diabetes symptoms from the perspective of Mel inhibiting amyloid deposits. This work reveals the inhibitory mechanism of Mel against hIAPP20–29 oligomerization, which provides useful clues for the development of efficient anti-amyloid agents.
Atherosclerosis Burdens in Diabetes Mellitus: Assessment by PET Imaging
Authors: Høilund-Carlsen Poul F. , Piri Reza , Madsen Per Lav , Revheim Mona-Elisabeth , Werner Thomas J. , Alavi Abass , Gerke Oke , Sturek Michael
Published: September 2022

Arteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated.