bluuebunny/crossref_metadata_2025 huggingface dataset:
Hand Areas Which Are Commonly Missed during Hand Disinfection by Nursing Students Who Completed a Basic Educational Course in Hand Hygiene
Authors: Gniadek Agnieszka , Ogórek-Tęcza Beata , Inglot Anna , Nowacka Anna , Micek Agnieszka
Published: March 2021

Background: Teaching nursing students how to correctly perform hand hygiene procedures may guarantee a reduction in transmitting pathogens through direct contact and, thus, it may lead to a decrease in the number of hospital infections. The aim of the study, which was conducted in low fidelity simulation conditions, was to assess the performance and the efficiency of a hand-rubbing disinfection technique among nursing students on the last day of their course. Materials and methods: The study was conducted in a group of 190 nursing students studying at the Jagiellonian University and it focused on the performed hand-rubbing disinfection procedure. The accuracy of the task performance was assessed by measuring the percentage of the amount of Fluo-Rub (B. Braun) fluorescent alcohol-based gel remaining on students’ hands after disinfection. The gel was rubbed into particular hand parts including four surfaces (left palm, right palm, left back and right back) divided into thirteen areas (I–XIII) and each surface was examined separately. The results were then dichotomized based on the cut-off point of 10% and two categories: “clean” and “dirty” were established. Additionally, the range of negligence in the disinfection procedure was assessed by counting the total number of the areas classified as “dirty”. The comparison of continuous and categorical variables was conducted by means of Friedman’s and Cochrane’s tests, respectively. Results: It was found out that the palm surfaces that were commonly missed during hand disinfection included the whole thumb (I and VI), the fingertip of the little finger (V) and the midpalm (XIII), whereas in the case of back surfaces (on both right and left hand) the most commonly missed areas were the fingertips and the whole thumb I–VI. Only 30 students (13%) had all 52 areas of both hands completely clean, whereas more than one third—66 students (33%)—failed to disinfect properly more than 10 areas out of all assessed ones on the surfaces of both hands. Conclusions: In the examined group of nursing students, a significant lack of compliance with hand disinfection procedures was observed and it was related mainly to thumbs and back parts of both hands. Therefore, it is essential to conduct systematic training sessions and assessment of hand hygiene procedures for nursing students at the end of every educational stage as it can lead to their developing these skills properly.
Multi-Drug Featurization and Deep Learning Improve Patient-Specific Predictions of Adverse Events
Authors: Anastopoulos Ioannis , Herczeg Chloe , Davis Kasey , Dixit Atray
Published: March 2021

While the clinical approval process is able to filter out medications whose utility does not offset their adverse drug reaction profile in humans, it is not well suited to characterizing lower frequency issues and idiosyncratic multi-drug interactions that can happen in real world diverse patient populations. With a growing abundance of real-world evidence databases containing hundreds of thousands of patient records, it is now feasible to build machine learning models that incorporate individual patient information to provide personalized adverse event predictions. In this study, we build models that integrate patient specific demographic, clinical, and genetic features (when available) with drug structure to predict adverse drug reactions. We develop an extensible graph convolutional approach to be able to integrate molecular effects from the variable number of medications a typical patient may be taking. Our model outperforms standard machine learning methods at the tasks of predicting hospitalization and death in the UK Biobank dataset yielding an R2 of 0.37 and an AUC of 0.90, respectively. We believe our model has potential for evaluating new therapeutic compounds for individualized toxicities in real world diverse populations. It can also be used to prioritize medications when there are multiple options being considered for treatment.
Influential Path of Social Risk Factors toward Suicidal Behavior—Evidence from Chinese Sina Weibo Users 2013–2018
Authors: Han Yujin , Li He , Xiao Yunyu , Li Ang , Zhu Tingshao
Published: March 2021

(1) Purpose: The purpose of this study was to determine suicidal risk factors, the relationship and the underlying mechanism between social variables and suicidal behavior. We hope to provide empirical support for the future suicide prevention of social media users at the social level. (2) Methods: The path analysis model with psychache as the mediate variable was constructed to analyze the relationship between suicidal behavior and selected social macro variables. The data for our research was taken from the Chinese Suicide Dictionary, Moral Foundation Dictionary, Cultural Value Dictionary and National Bureau of Statistics. (3) Results: The path analysis model was an adequate representation of the data. With the mediator psychache, higher authority vice, individualism, and disposable income of residents significantly predicted less suicidal behavior. Purity vice, collectivism, and proportion of the primary industry had positive significant effect on suicidal behavior via the mediator psychache. The coefficients of harm vice, fairness vice, ingroup vice, public transport and car for every 10,000 people, urban population density, gross domestic product (GDP), urban registered unemployment rate, and crude divorce rate were not significant. Furthermore, we applied the model to three major economic development belts in China. The model’s result meant different economic zones had no influence on the model designed in our study. (4) Conclusions: Our evidence informs population-based suicide prevention policymakers that incorporating some social factors like authority vice, individualism, etc. can help prevent suicidal ideation in China.
Digital Health Transition in Rheumatology: A Qualitative Study
Authors: Mühlensiepen Felix , Kurkowski Sandra , Krusche Martin , Mucke Johanna , Prill Robert , Heinze Martin , Welcker Martin , Schulze-Koops Hendrik , Vuillerme Nicolas , Schett Georg , Knitza Johannes
Published: March 2021

The global COVID-19 pandemic has led to drastic changes in the management of patients with rheumatic diseases. Due to the imminent risk of infection, monitoring intervals of rheumatic patients have prolonged. The aim of this study is to present insights from patients, rheumatologists, and digital product developers on the ongoing digital health transition in rheumatology. A qualitative and participatory semi-structured fishbowl approach was conducted to gain detailed insights from a total of 476 participants. The main findings show that digital health and remote care are generally welcomed by the participants. Five key themes emerged from the qualitative content analysis: (1) digital rheumatology use cases, (2) user descriptions, (3) adaptation to different environments of rheumatology care, and (4) potentials of and (5) barriers to digital rheumatology implementation. Codes were scaled by positive and negative ratings as well as on micro, meso, and macro levels. A main recommendation resulting from the insights is that both patients and rheumatologists need more information and education to successfully implement digital health tools into clinical routine.
Comparison of Interface Pressures and Subjective Comfort of Pressure-Relieving Overlays on the Operating Table for Healthy Volunteers
Authors: Han Min Jung , Ko Sangjin
Published: March 2021

(1) Background: Pressure ulcers in the hospital setting occurring within 72 h after surgery are called perioperative pressure injuries. The aim of this study was to provide data for the prevention of perioperative pressure injuries following the use of pressure-relieving overlays by measuring the interface pressures and subjective comfort. (2) Methods: This study is based on a repeated measures design. The subjects included 30 healthy volunteers aged 18 to 57 years. Interface pressures of the sacrum and both heels were measured in the supine position, and the subjective comfort was evaluated with visual analog scale after applying polyurethane foam, gel pad, and egg crate foam for relief. (3) Results: The pressures in the sacrum and both heels were the lowest with polyurethane foam, and the subjective comfort was the highest. (4) Conclusions: Inexpensive polyurethane foam with satisfactory pressure relief is recommended as an overlay for surgical patients.
Cultural Identity Conflict Informs Engagement with Self-Management Behaviours for South Asian Patients Living with Type-2 Diabetes: A Critical Interpretative Synthesis of Qualitative Research Studies
Authors: Patel Tasneem , Umeh Kanayo , Poole Helen , Vaja Ishfaq , Newson Lisa
Published: March 2021

The prevalence of type-2 diabetes (T2D) is increasing, particularly among South Asian (SA) communities. Previous research has highlighted the heterogeneous nature of SA ethnicity and the need to consider culture in SA patients’ self-management of T2D. We conducted a critical interpretative synthesis (CIS) which aimed to a) develop a new and comprehensive insight into the psychology which underpins SA patients’ T2D self-management behaviours and b) present a conceptual model to inform future T2D interventions. A systematic search of the literature retrieved 19 articles, including 536 participants. These were reviewed using established CIS procedures. Analysis identified seven constructs, from which an overarching synthesizing argument ‘Cultural Conflict’ was derived. Our findings suggest that patients reconstruct knowledge to manage their psychological, behavioural, and cultural conflicts, impacting decisional conflicts associated with T2D self-management and health professional advice (un)consciously. Those unable to resolve this conflict were more likely to default towards cultural identity, continue to align with cultural preferences rather than health professional guidance, and reduce engagement with self-management. Our synthesis and supporting model promote novel ideas for self-management of T2D care for SA patients. Specifically, health professionals should be trained and supported to explore and mitigate negative health beliefs to enable patients to manage social-cultural influences that impact their self-management behaviours.
An Evaluation of Street Dynamic Vitality and Its Influential Factors Based on Multi-Source Big Data
Authors: Guo Xin , Chen Hongfei , Yang Xiping
Published: March 2021

Urban vitality is an important indicator of urban development capacity. Streets’ metrics can depict intro-urban fabrics and physiognomy in detail, and thus street vitality affected by street metrics is a concrete manifestation of urban vitality. However, few studies have evaluated dynamic vitality or explored how it is influenced by land use. To bridge this gap, we fully evaluated street dynamic vitality and explored how to enhance the street dynamic vitality by changing the distribution and combination of land use. Specifically, we examined the street dynamic vitality and land use diversity in the main urban zone of Xining city in China using mobile communication and point of interest data, adopted optimized K-means clustering to identify street dynamic vitality types, evaluated the classification result based on vitality intensity and vitality stability, and explored the link between land use and dynamic vitality. Since vitality intensity limitations were found in describing street dynamic vitality, it was necessary to introduce vitality stability. We also found a positive correlation between the vitality intensity and land use density, there were outstanding traffic facilities in high-intensity vitality streets, and improving the abundance and uniformity of land use was beneficial to increase vitality stability. Overall, describing street vitality from a dynamic perspective can improve resource utilization efficiency and rationally plan layouts.
Targeted Delivery of Soluble Guanylate Cyclase (sGC) Activator Cinaciguat to Renal Mesangial Cells via Virus-Mimetic Nanoparticles Potentiates Anti-Fibrotic Effects by cGMP-Mediated Suppression of the TGF-β Pathway
Authors: Fleischmann Daniel , Harloff Manuela , Maslanka Figueroa Sara , Schlossmann Jens , Goepferich Achim
Published: March 2021

Diabetic nephropathy (DN) ranks among the most detrimental long-term effects of diabetes, affecting more than 30% of all patients. Within the diseased kidney, intraglomerular mesangial cells play a key role in facilitating the pro-fibrotic turnover of extracellular matrix components and a progredient glomerular hyperproliferation. These pathological effects are in part caused by an impaired functionality of soluble guanylate cyclase (sGC) and a consequentially reduced synthesis of anti-fibrotic messenger 3′,5′-cyclic guanosine monophosphate (cGMP). Bay 58-2667 (cinaciguat) is able to re-activate defective sGC; however, the drug suffers from poor bioavailability and its systemic administration is linked to adverse events such as severe hypotension, which can hamper the therapeutic effect. In this study, cinaciguat was therefore efficiently encapsulated into virus-mimetic nanoparticles (NPs) that are able to specifically target renal mesangial cells and therefore increase the intracellular drug accumulation. NP-assisted drug delivery thereby increased in vitro potency of cinaciguat-induced sGC stabilization and activation, as well as the related downstream signaling 4- to 5-fold. Additionally, administration of drug-loaded NPs provided a considerable suppression of the non-canonical transforming growth factor β (TGF-β) signaling pathway and the resulting pro-fibrotic remodeling by 50–100%, making the system a promising tool for a more refined therapy of DN and other related kidney pathologies.
Adverse Prognostic Impact of the KIT D816V Transcriptional Activity in Advanced Systemic Mastocytosis
Authors: Naumann Nicole , Lübke Johannes , Baumann Sofie , Schwaab Juliana , Hoffmann Oliver , Kreil Sebastian , Dangelo Vito , Reiter Lukas , Bugert Peter , Kristensen Thomas , Sotlar Karl , Haselmann Verena , Schneider Sven , Metzgeroth Georgia , Weiss Christel , Popp Henning D. , Fabarius Alice , Hofmann Wolf-Karsten , Cross Nicholas C. P. , Reiter Andreas , Jawhar Mohamad
Published: March 2021

In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the KIT D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), n = 40; advanced SM, AdvSM, n = 121) at referral and during follow-up for the KIT D816V variant allele frequency (VAF) at the DNA-level and the KIT D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation (r > 0.99, R2 > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM (r = 0.91, coefficient of determination, R2 = 0.84) but only to a lesser extent in AdvSM (r = 0.71; R2 = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; p = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 (p = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of KIT D816V may play an important role in the pathophysiology of SM.
Small Immunomodulatory Molecules as Potential Therapeutics in Experimental Murine Models of Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)
Authors: Shah Dilip , Das Pragnya , Acharya Suchismita , Agarwal Beamon , Christensen Dale J. , Robertson Stella M. , Bhandari Vineet
Published: March 2021

Background: Acute lung injury (ALI) or its most advanced form, acute respiratory distress syndrome (ARDS) is a severe inflammatory pulmonary process triggered by a variety of insults including sepsis, viral or bacterial pneumonia, and mechanical ventilator-induced trauma. Currently, there are no effective therapies available for ARDS. We have recently reported that a novel small molecule AVR-25 derived from chitin molecule (a long-chain polymer of N-acetylglucosamine) showed anti-inflammatory effects in the lungs. The goal of this study was to determine the efficacy of two chitin-derived compounds, AVR-25 and AVR-48, in multiple mouse models of ALI/ARDS. We further determined the safety and pharmacokinetic (PK) profile of the lead compound AVR-48 in rats. Methods: ALI in mice was induced by intratracheal instillation of a single dose of lipopolysaccharide (LPS; 100 µg) for 24 h or exposed to hyperoxia (100% oxygen) for 48 h or undergoing cecal ligation and puncture (CLP) procedure and observation for 10 days. Results: Both chitin derivatives, AVR-25 and AVR-48, showed decreased neutrophil recruitment and reduced inflammation in the lungs of ALI mice. Further, AVR-25 and AVR-48 mediated diminished lung inflammation was associated with reduced expression of lung adhesion molecules with improvement in pulmonary endothelial barrier function, pulmonary edema, and lung injury. Consistent with these results, CLP-induced sepsis mice treated with AVR-48 showed a significant increase in survival of the mice (80%) and improved lung histopathology in the treated CLP group. AVR-48, the lead chitin derivative compound, demonstrated a good safety profile. Conclusion: Both AVR-25 and AVR-48 demonstrate the potential to be developed as therapeutic agents to treat ALI/ARDS.
Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome
Authors: Pruett Jacob E. , Torres Fernandez Edgar D. , Everman Steven J. , Vinson Ruth M. , Davenport Kacey , Logan Madelyn K. , Ye Stephanie A. , Romero Damian G. , Yanes Cardozo Licy L.
Published: March 2021

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have a high prevalence of obesity, insulin resistance (IR), increased blood pressure (BP), and activation of the renin angiotensin system (RAS). Effective evidence-based therapeutics to ameliorate the cardiometabolic complications in PCOS are lacking. The sodium-glucose cotransporter-2 (SGLT2) inhibitor Empagliflozin (EMPA) reduces BP and hyperglycemia in type 2 diabetes mellitus. We hypothesized that hyperandrogenemia upregulates renal SGLT2 expression and that EMPA ameliorates cardiometabolic complications in a hyperandrogenemic PCOS model. Four-week-old female Sprague Dawley rats were treated with dihydrotestosterone (DHT) for 90 days, and EMPA was co-administered for the last three weeks. DHT upregulated renal SGLT2, SGLT4, and GLUT2, but downregulated SGLT3 mRNA expression. EMPA decreased DHT-mediated increases in fat mass, plasma leptin, and BP, but failed to decrease plasma insulin, HbA1c, or albuminuria. EMPA decreased DHT-mediated increase in renal angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), and angiotensin II type 1 receptor (AGT1R) mRNA and protein expression. In summary, SGLT2 inhibition proved beneficial in adiposity and BP reduction in a hyperandrogenemic PCOS model; however, additional therapies may be needed to improve IR and renal injury.
The “Hitchhiker’s Guide to the Galaxy” of Endothelial Dysfunction Markers in Human Fertility
Authors: Santi Daniele , Spaggiari Giorgia , Greco Carla , Lazzaretti Clara , Paradiso Elia , Casarini Livio , Potì Francesco , Brigante Giulia , Simoni Manuela
Published: March 2021

Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and represents the first step in the pathogenesis of cardiovascular diseases. The evaluation of endothelial health is fundamental in clinical practice and several direct and indirect markers have been suggested so far to identify any alterations in endothelial homeostasis. Alongside the known endothelial role on vascular health, several pieces of evidence have demonstrated that proper endothelial functioning plays a key role in human fertility and reproduction. Therefore, this state-of-the-art review updates the endothelial health markers discriminating between those available for clinical practice or for research purposes and their application in human fertility. Moreover, new molecules potentially helpful to clarify the link between endothelial and reproductive health are evaluated herein.
New Perspectives in the Study of Intestinal Inflammation: Focus on the Resolution of Inflammation
Authors: Camba-Gómez Miguel , Gualillo Oreste , Conde-Aranda Javier
Published: March 2021

Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.
Glycyrrhizin Attenuates Carcinogenesis by Inhibiting the Inflammatory Response in a Murine Model of Colorectal Cancer
Authors: Wang Guifeng , Hiramoto Keiichi , Ma Ning , Yoshikawa Nobuji , Ohnishi Shiho , Murata Mariko , Kawanishi Shosuke
Published: March 2021

Glycyrrhizin (GL), an important active ingredient of licorice root, which weakens the proinflammatory effects of high-mobility group box 1 (HMGB1) by blocking HMGB1 signaling. In this study, we investigated whether GL could suppress inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer. ICR mice were divided into four groups (n = 5, each)—control group, GL group, colon cancer (CC) group, and GL-treated CC (CC + GL) group, and sacrificed after 20 weeks. Plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using an enzyme-linked immunosorbent assay. The colonic tissue samples were immunohistochemically stained with DNA damage markers (8-nitroguanine and 8-oxo-7,8-dihydro-2′-deoxy-guanosine), inflammatory markers (COX-2 and HMGB1), and stem cell markers (YAP1 and SOX9). The average number of colonic tumors and the levels of IL-6 and TNF-α in the CC + GL group were significantly lower than those in the CC group. The levels of all inflammatory and cancer markers were significantly reduced in the CC + GL group. These results suggest that GL inhibits the inflammatory response by binding HMGB1, thereby inhibiting DNA damage and cancer stem cell proliferation and dedifferentiation. In conclusion, GL significantly attenuates the pathogenesis of AOM/DSS-induced colorectal cancer by inhibiting HMGB1-TLR4-NF-κB signaling.
Robust Detection of Somatic Mosaicism and Repeat Interruptions by Long-Read Targeted Sequencing in Myotonic Dystrophy Type 1
Authors: Mangin Antoine , de Pontual Laure , Tsai Yu-Chih , Monteil Laetitia , Nizon Mathilde , Boisseau Pierre , Mercier Sandra , Ziegle Janet , Harting John , Heiner Cheryl , Gourdon Geneviève , Tomé Stéphanie
Published: March 2021

Myotonic dystrophy type 1 (DM1) is the most complex and variable trinucleotide repeat disorder caused by an unstable CTG repeat expansion, reaching up to 4000 CTG in the most severe cases. The genetic and clinical variability of DM1 depend on the sex and age of the transmitting parent, but also on the CTG repeat number, presence of repeat interruptions and/or on the degree of somatic instability. Currently, it is difficult to simultaneously and accurately determine these contributing factors in DM1 patients due to the limitations of gold standard methods used in molecular diagnostics and research laboratories. Our study showed the efficiency of the latest PacBio long-read sequencing technology to sequence large CTG trinucleotides, detect multiple and single repeat interruptions and estimate the levels of somatic mosaicism in DM1 patients carrying complex CTG repeat expansions inaccessible to most methods. Using this innovative approach, we revealed the existence of de novo CCG interruptions associated with CTG stabilization/contraction across generations in a new DM1 family. We also demonstrated that our method is suitable to sequence the DM1 locus and measure somatic mosaicism in DM1 families carrying more than 1000 pure CTG repeats. Better characterization of expanded alleles in DM1 patients can significantly improve prognosis and genetic counseling, not only in DM1 but also for other tandem DNA repeat disorders.
Inflammatory Biomarkers in the Short-Term Prognosis of Venous Thromboembolism: A Narrative Review
Authors: Galeano-Valle Francisco , Ordieres-Ortega Lucía , Oblitas Crhistian Mario , del-Toro-Cervera Jorge , Alvarez-Sala-Walther Luis , Demelo-Rodríguez Pablo
Published: March 2021

The relationship between inflammation and venous thrombosis is not well understood. An inflammatory response may be both the cause and consequence of venous thromboembolism (VTE). In fact, several risk factors of VTE modulate thrombosis through inflammatory markers. Acute pulmonary embolism (PE) is burdened by a remarkable mortality rate, up to 34% in severely ill patients presenting with hemodynamic instability. Initial mortality risk stratification is based on hemodynamic instability. Patients with a situation of hemodynamic stability require immediate further risk assessment based on clinical, imaging, and circulating biomarkers, as well as the presence of comorbidities. Some inflammatory biomarkers have shown potential usefulness in the risk stratification of patients with VTE, especially acute PE. C-reactive protein on admission is associated with 30-day mortality and bleeding in VTE patients. P-selectin is associated with right ventricle dysfunction in PE patients and might be associated with VTE recurrences and the extension of thrombosis. Tissue factor microparticles are associated with VTE recurrence in cancer-associated thrombosis. Other inflammatory biomarkers present scarce evidence (inflammatory cytokines, erythrocyte sedimentation rate, fibrinogen, leukocyte count). In this manuscript, we will review the prognostic role of different inflammatory biomarkers available both for clinical practice and research in VTE patients.
Population-Predicted MHC Class II Epitope Presentation of SARS-CoV-2 Structural Proteins Correlates to the Case Fatality Rates of COVID-19 in Different Countries
Authors: Liang Chunguang , Bencurova Elena , Psota Eric , Neurgaonkar Priya , Prelog Martina , Scheller Carsten , Dandekar Thomas
Published: March 2021

We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.
Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases
Authors: Picchianti-Diamanti Andrea , Spinelli Francesca Romana , Rosado Maria Manuela , Conti Fabrizio , Laganà Bruno
Published: March 2021

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn’s disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.
Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions
Authors: de Oliveira dos Santos Ana Rita , de Oliveira Zanuso Bárbara , Miola Vitor Fernando Bordin , Barbalho Sandra Maria , Santos Bueno Patrícia C. , Flato Uri Adrian Prync , Detregiachi Claudia Rucco P. , Buchaim Daniela Vieira , Buchaim Rogério Leone , Tofano Ricardo José , Mendes Claudemir Gregório , Tofano Viviane Alessandra Capelluppi , dos Santos Haber Jesselina F.
Published: March 2021

Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, and hepatokines. These biomarkers can be harmful or beneficial to an organism and still perform crosstalk, acting through the endocrine, paracrine, and autocrine pathways. This study aims to review the crosstalk between adipokines, myokines, and hepatokines. Far beyond understanding the actions of each biomarker alone, it is important to underline that these cytokines act together in the body, resulting in a complex network of actions in different tissues, which may have beneficial or non-beneficial effects on the genesis of various physiological disorders and their respective outcomes, such as type 2 diabetes mellitus (DM2), obesity, metabolic syndrome, and cardiovascular diseases (CVD). Overweight individuals secrete more pro-inflammatory adipokines than those of a healthy weight, leading to an impaired immune response and greater susceptibility to inflammatory and infectious diseases. Myostatin is elevated in pro-inflammatory environments, sharing space with pro-inflammatory organokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), resistin, and chemerin. Fibroblast growth factor FGF21 acts as a beta-oxidation regulator and decreases lipogenesis in the liver. The crosstalk mentioned above can interfere with homeostatic disorders and can play a role as a potential therapeutic target that can assist in the methods of diagnosing metabolic syndrome and CVD.
The Editor’s Choice for Issue 4, Volume 6
Authors: Schielen Peter C. J. I.
Published: March 2021

The Editorial team (Ralph Fingerhut, Can Ficiccioglu, Dianne Webster, David Millington and I) is trying something new [...]
Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors
Authors: Indio Valentina , Schipani Angela , Nannini Margherita , Urbini Milena , Rizzo Alessandro , De Leo Antonio , Altimari Annalisa , Di Scioscio Valerio , Messelodi Daria , Tarantino Giuseppe , Astolfi Annalisa , Pantaleo Maria
Published: March 2021

Background: About 20–40% of gastrointestinal stromal tumors (GISTs) lacking KIT/PDGFRA mutations show defects in succinate dehydrogenase (SDH) complex. This study uncovers the gene expression profile (GEP) of SDH-deficient GIST in order to identify new signaling pathways or molecular events actionable for a tailored therapy. Methods: We analyzed 36 GIST tumor samples, either from formalin-fixed, paraffin-embedded by microarray or from fresh frozen tissue by RNA-seq, retrospectively collected among KIT-mutant and SDH-deficient GISTs. Pathway analysis was performed to highlight enriched and depleted transcriptional signatures. Tumor microenvironment and immune profile were also evaluated. Results: SDH-deficient GISTs showed a distinct GEP with respect to KIT-mutant GISTs. In particular, SDH-deficient GISTs were characterized by an increased expression of neural markers and by the activation of fibroblast growth factor receptor signaling and several biological pathways related to invasion and tumor progression. Among them, hypoxia and epithelial-to-mesenchymal transition emerged as features shared with SDH-deficient pheochromocytoma/paraganglioma. In addition, the study of immune landscape revealed the depletion of tumor microenvironment and inflammation gene signatures. Conclusions: This study provides an update of GEP in SDH-deficient GISTs, highlighting differences and similarities compared to KIT-mutant GISTs and to other neoplasm carrying the SDH loss of function. Our findings add a piece of knowledge in SDH-deficient GISTs, shedding light on their putative histology and on the dysregulated biological processes as targets of new therapeutic strategies.
Obesity, Abdominal Obesity and Chronic Kidney Disease in Young Adults: A Nationwide Population-Based Cohort Study
Authors: Bae Eun Hui , Lim Sang Yeob , Jung Jin-Hyung , Oh Tae Ryom , Choi Hong Sang , Kim Chang Seong , Ma Seong Kwon , Han Kyung-Do , Kim Soo Wan
Published: March 2021

Obesity has become a pandemic. It is one of the strongest risk-factors of new-onset chronic kidney disease (CKD). However, the effects of obesity and abdominal obesity on the risk of developing CKD in young adults has not been elucidated. From a nationwide health screening database, we included 3,030,884 young adults aged 20–39 years without CKD during a baseline examination in 2009–2010, who could follow up during 2013–2016. Patients were stratified into five levels based on their baseline body mass index (BMI) and six levels based on their waist circumference (WC; 5-cm increments). The primary outcome was the development of CKD. During the follow up, until 2016, 5853 (0.19%) participants developed CKD. Both BMI and WC showed a U-shaped relationship with CKD risk, identifying the cut-off values as a BMI of 21 and WC of 72 cm in young adults. The obesity group (odd ratio [OR] = 1.320, 95% confidence interval [CI]: 1.247–1.397) and abdominal obesity group (male WC ≥ 90, female WC ≥ 85) (OR = 1.208, 95%CI: 1.332–1.290) showed a higher CKD risk than the non-obesity or non-abdominal obesity groups after adjusting for covariates. In the CKD risk by obesity composite, the obesity displayed by the abdominal obesity group showed the highest CKD risk (OR = 1.502, 95%CI: 1.190–1.895), especially in those under 30 years old. During subgroup analysis, the diabetes mellitus (DM) group with obesity or abdominal obesity paradoxically showed a lower CKD risk compared with the non-obesity or non-abdominal obesity group. Obesity and abdominal obesity are associated with increased risk of developing CKD in young adults but a decreased risk in young adults with diabetes.
Clinical Management of Hypertension, Inflammation and Thrombosis in Hospitalized COVID-19 Patients: Impact on Survival and Concerns
Authors: Martínez-Botía Patricia , Bernardo Ángel , Acebes-Huerta Andrea , Caro Alberto , Leoz Blanca , Martínez-Carballeira Daniel , Palomo-Antequera Carmen , Soto Inmaculada , Gutiérrez Laura
Published: March 2021

The most severe clinical manifestations of the Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are due to an unbalanced immune response and a pro-thrombotic hemostatic disturbance, with arterial hypertension or diabetes as acknowledged risk factors. While waiting for a specific treatment, the clinical management of hospitalized patients is still a matter of debate, and the effectiveness of treatments to manage clinical manifestations and comorbidities has been questioned. In this study, we aim to assess the impact of the clinical management of arterial hypertension, inflammation and thrombosis on the survival of COVID-19 patients. The Spanish cohorts included in this observational retrospective study are from HM Hospitales (2035 patients) and from Hospital Universitario Central de Asturias (72 patients). Kaplan Meier survival curves, Cox regression and propensity score matching analyses were employed, considering demographic variables, comorbidities and treatment arms (when opportune) as covariates. The management of arterial hypertension with angiotensin-converting enzyme 2 (ACE2) inhibitors or angiotensin receptor blockers is not detrimental, as was initially reported, and neither was the use of non-steroidal anti-inflammatory drugs (NSAIDs). On the contrary, our analysis shows that the use on itself of corticosteroids is not beneficial. Importantly, the management of COVID-19 patients with low molecular weight heparin (LMWH) as an anticoagulant significantly improves the survival of hospitalized patients. These results delineate the current treatment options under debate, supporting the effectiveness of thrombosis prophylaxis on COVID-19 patients as a first-line treatment without the need for compromising the treatment of comorbidities, while suggesting cautiousness when administering corticosteroids.
A Randomized Clinical Trial Comparing Immediate Loading and Delayed Loading of Single-Tooth Implants: 5-Year Results
Authors: Gjelvold Björn , Kisch Jenö , Chrcanovic Bruno R.
Published: March 2021

The aim of this prospective randomized clinical study was to compare the clinical treatment outcome for single dental implants submitted to either immediate loading (IL) or delayed loading (DL) after 5 years of follow-up. Fifty patients with a missing maxillary tooth (15–25) were randomly allocated to either the IL or DL. The treatment procedures included implant installation in healed sites, temporary screw-retained crown and replacement with a permanent single implant crown. The two groups were evaluated with regard to implant survival, marginal bone level, papillae index, pink and white esthetic score (PES, WES). At the 5-year follow-up the implant survival rate was 100% and 95.8% for IL and DL, respectively. Implant success rate was 91.7% and 83.3% for IL and DL, respectively. The mean ± SD marginal bone loss for IL and DL was −0.50 ± 0.73 mm and −0.54 ± 0.65 mm, respectively. (p = 0.782). Statistically significant less marginal bone loss was found non-smokers (p = 0.021). No statistically significant differences were found for IL and DL concerning papillae index PES and WES after 5 years. This study suggests that implant-supported single crowns in the maxillary aesthetic zone can present similar results with respect to either IL or DL after 5 years.
Role of Baseline Computed-Tomography-Evaluated Body Composition in Predicting Outcome and Toxicity from First-Line Therapy in Advanced Gastric Cancer Patients
Authors: Catanese Silvia , Aringhieri Giacomo , Vivaldi Caterina , Salani Francesca , Vitali Saverio , Pecora Irene , Massa Valentina , Lencioni Monica , Vasile Enrico , Tintori Rachele , Balducci Francesco , Falcone Alfredo , Cappelli Carla , Fornaro Lorenzo
Published: March 2021

Sarcopenia is recognised as a predictor of toxicity and survival in localised and locally advanced gastric cancer (GC). Its prognostication power in advanced unresectable or metastatic GC (aGC) is debated. The survival impact of visceral and subcutaneous fat distribution (visceral fat area (VFA)/subcutaneous fat area (SFA)) is ambiguous. Our aim was to determine the influence of body composition parameters (BCp) on toxicity and survival in aGC patients undergoing palliative treatment. BCp were retrospectively assessed by baseline computed tomography for 78 aGC patients who received first-line chemotherapy from March 2010 to January 2017. Correlations between BCp and toxicity and survival were calculated by χ2-test and by log-rank-test and Cox-model, respectively. Sarcopenia fails to show association with progression-free survival (PFS) (p = 0.44) and overall survival (OS) (p = 0.88). However, sarcopenia influences the development of high-grade neutropenia (p = 0.048) and mucositis (p = 0.054). VFA/SFA (high vs. all the rest) results as a strong predictor of objective response (p = 0.02) and outcome (PFS, p = 0.001; OS, p = 0.02). At multivariate analysis for PFS, prognostic factors are VFA/SFA (p = 0.03) and a neutrophil–lymphocyte ratio >3. The same factors remain significant for OS (each p = 0.03) along with Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.008) and number of metastatic sites ≥2 (p < 0.001). In our cohort of aGC, VFA/SFA exhibit a robust impact on survival, with a higher sensitivity than sarcopenia.
Diagnosing Constipation Spectrum Disorders in a Primary Care Setting
Authors: Heidelbaugh Joel , Martinez de Andino Nicole , Pineles David , Poppers David M.
Published: March 2021

Understanding pathophysiological causes of constipation is worthwhile in directing therapy and improving symptoms. This review aims to identify and fill gaps in the understanding of the pathophysiology of constipation, understand its prevalence, review diagnostic tools available to primary care physicians (PCPs), and highlight patients’ expectations for the management of this common spectrum of disorders. Literature searches conducted via PubMed included terms related to constipation, diagnosis, and patient perceptions. Case studies were developed to highlight the differences between patients who may be appropriately managed in the primary care setting and those requiring specialty consultation. Myriad pathophysiological factors may contribute to constipation, including stool consistency, altered intestinal motility, gut microbiome, anorectal abnormalities, as well as behavioral and psychological factors. Common diagnoses of “primary constipation” include slow-transit constipation, defecation disorders, irritable bowel syndrome with constipation, and chronic idiopathic constipation. A detailed medical history should be conducted to exclude alarm features and PCPs should be familiar with pathophysiological factors that cause constipation, available diagnostic tools, alarm signs, and the various classification criteria for constipation subtypes in order to diagnose and treat patients accordingly. PCPs should understand when a referral to a gastroenterologist, anorectal specialist, pelvic floor physical therapist, and/or mental health specialist is appropriate.
Three-Dimensional Performance Analysis of a Radial-Inflow Turbine for Ocean Thermal Energy Conversion System
Authors: Chen Yun , Liu Yanjun , Zhang Li , Yang Xiaowei
Published: March 2021

Turbine is one of the key components of the ocean thermal energy conversion system (OTEC), and its aerodynamic performance and geometric dimension affect the performance of the system directly. This paper proposes a design method for the radial inflow turbine suitable for the ocean thermal energy conversion based on the parameter optimization of the ocean thermal energy conversion system. Aiming at the application characteristics of marine thermal energy conversion in a small temperature difference environment and the special thermophysical properties of the organic working fluid in this environment, one-dimensional design and three-dimensional CFD analysis of the turbine is separately done, of which the results were compared. At the same time, the performance of the turbine was verified by changing the inlet and outlet conditions of the radial turbine under the design conditions. The conclusion is that the three-dimensional CFD results of the turbine are in good agreement with the one-dimensional design, and the internal flow field of the turbine is stable, without obvious backflow and eddy current, which meets the application requirements of the ocean thermal energy conversion.
Effect of in Planta Treatment of ‘Cavendish’ Banana with Herbicides and Fungicides on the Colonisation and Sporulation by Fusarium oxysporum f.sp. cubense Subtropical Race 4
Authors: Anderson Jay , Aitken Elizabeth
Published: March 2021

Fusarium wilt caused by the soil-borne fungus Fusarium oxysporum f.sp. cubense (Foc) is a significant constraint to banana production worldwide, with the recent expansion of banana growing regions impacted by Foc Tropical Race 4 (TR4). The lack of commercially acceptable Cavendish cultivars with Foc resistance means the only current means of effective control is through strict quarantine and inoculum management. One method of control that is currently advocated includes the removal of infected plants which have been killed using herbicide injections. The aim of this work was to examine the effect of herbicide and fungicide treatments on sporulation of the fungus. In glasshouse studies using a green fluorescent transformed Foc Subtropical Race 4 isolate, we found treatments with herbicide hastened colonisation of the banana tissue and the production of micro- and macroconidia. The use of a fungicide did not prevent sporulation of the fungus in such tissue. This study demonstrates that herbicide treated plants are a source of potential inoculum for infection of nearby plants.