bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease
Authors: Ramanathan Raghu , Ali Ahmad Hassan , Ibdah Jamal A.
Published: July 2022

Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.
Multifunctional Analysis of Chia Seed (Salvia hispanica L.) Bioactive Peptides Using Peptidomics and Molecular Dynamics Simulations Approaches
Authors: Aguilar-Toalá José E. , Vidal-Limon Abraham , Liceaga Andrea M.
Published: July 2022

Chia seed peptides (CSP) can be a source of multifunctional biopeptides to treat non-communicable diseases. However, interactions and binding affinity involved in targeting specific receptors remains unexplored. In this study, molecular simulation techniques were used as virtual screening of CSP to determine drug-like candidates using a multi-target-directed ligand approach. CSP fraction with the best bioactivities in vitro was sequenced. Then, a prediction model was built using physicochemical descriptors (hydrophobicity, hydrophilicity, intestinal stability, antiangiogenic, antihypertensive, and anti-inflammatory) to calculate potential scores and rank possible biopeptides. Furthermore, molecular dynamics simulations (MDS) and ensemble molecular docking analysis were carried out using four human protein targets (ACE, angiotensin converting enzyme; VEGF, vascular endothelial growth factor; GLUC, glucocorticoid and MINC, mineralocorticoid receptors). Five known-sequence peptides (NNVFYPF, FNIVFPG, SRPWPIDY, QLQRWFR, GSRFDWTR) and five de novo peptides (DFKF, DLRF, FKAF, FRSF, QFRF) had the lowest energy score and higher affinity for ACE and VEGF. The therapeutic effects of these selected peptides can be related to the inhibition of the enzymes involved in angiogenesis and hypertension, due to formation of stable complexes with VEGF and ACE binding sites, respectively. The application of MDS is a good resource for identifying bioactive peptides for future experimental validation.
Interaction of CYP3A4 with Rationally Designed Ritonavir Analogues: Impact of Steric Constraints Imposed on the Heme-Ligating Group and the End-Pyridine Attachment
Authors: Samuels Eric R. , Sevrioukova Irina F.
Published: July 2022

Controlled inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) is utilized to boost bioavailability of anti-viral and immunosuppressant pharmaceuticals. We investigate structure–activity relationships (SARs) in analogues of ritonavir, a potent CYP3A4 inhibitor marketed as pharmacoenhancer, to determine structural elements required for potent inhibition and whether the inhibitory potency can be further improved via a rational structure-based design. This study investigated eight (series VI) inhibitors differing in head- and end-moieties and their respective linkers. SAR analysis revealed the multifactorial regulation of inhibitory strength, with steric constraints imposed on the tethered heme-ligating moiety being a key factor. Minimization of these constraints by changing the linkers’ length/flexibility and N-heteroatom position strengthened heme coordination and markedly improved binding and/or inhibitory strength. Impact of the end-pyridine attachment was not uniform due to influence of other determinants controlling the ligand-binding mode. This interplay between pharmacophoric determinants and the end-group enlargement can be used for further inhibitor optimization.
Molecular Mechanisms of Parthanatos and Its Role in Diverse Diseases
Authors: Huang Ping , Chen Guangwei , Jin Weifeng , Mao Kunjun , Wan Haitong , He Yu
Published: July 2022

Differential evolution of apoptosis, programmed necrosis, and autophagy, parthanatos is a form of cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1), which is caused by DNA damage. PARP1 hyper-activation stimulates apoptosis-inducing factor (AIF) nucleus translocation, and accelerates nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP) depletion, leading to DNA fragmentation. The mechanisms of parthanatos mainly include DNA damage, PARP1 hyper-activation, PAR accumulation, NAD+ and ATP depletion, and AIF nucleus translocation. Now, it is reported that parthanatos widely exists in different diseases (tumors, retinal diseases, neurological diseases, diabetes, renal diseases, cardiovascular diseases, ischemia-reperfusion injury...). Excessive or defective parthanatos contributes to pathological cell damage; therefore, parthanatos is critical in the therapy and prevention of many diseases. In this work, the hallmarks and molecular mechanisms of parthanatos and its related disorders are summarized. The questions raised by the recent findings are also presented. Further understanding of parthanatos will provide a new treatment option for associated conditions.
Substance GP-2250 as a New Therapeutic Agent for Malignant Peritoneal Mesothelioma—A 3-D In Vitro Study
Authors: Baron Claudia , Buchholz Marie , Majchrzak-Stiller Britta , Peters Ilka , Fein Daniel , Müller Thomas , Uhl Waldemar , Höhn Philipp , Strotmann Johanna , Braumann Chris
Published: July 2022

Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis remains poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects. GP-2250 is a novel antineoplastic agent, currently under clinical investigation. This in vitro study aims to investigate effects of GP-2250 including combinations with CP and MMC on malignant mesothelioma. JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP, MMC and combination therapies of GP-2250 + CP/MMC. Microscopic effects were documented, and a flow-cytometric apoptosis/necrosis assay was performed. Synergistic and antagonistic effects were analyzed by computing the combination index by Chou-Talalay. GP-2250 showed an antiadhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cultured cells, inducing apoptosis and necrosis. Combination treatments of GP-2250 with MMC and CP led to significant reductions of the effective doses of CP/MMC. Synergistic and additive effects were observed. GP-2250 showed promising antineoplastic effects on malignant mesothelioma cells in vitro especially in combination with CP/MMC. This forms the basis for further in vivo and clinical investigations in order to broaden treatment options.
Effects of Ethanol on Expression of Coding and Noncoding RNAs in Murine Neuroblastoma Neuro2a Cells
Authors: Choi Mi Ran , Cho Sinyoung , Kim Dai-Jin , Choi Jung-Seok , Jin Yeung-Bae , Kim Miran , Chang Hye Jin , Jeon Seong Ho , Yang Young Duk , Lee Sang-Rae
Published: July 2022

Excessive use of alcohol can induce neurobiological and neuropathological alterations in the brain, including the hippocampus and forebrain, through changes in neurotransmitter systems, hormonal systems, and neuroimmune processes. We aimed to investigate the effects of ethanol on the expression of coding and noncoding RNAs in a brain-derived cell line exposed to ethanol. After exposing Neuro2a cells, a neuroblastoma cell line, to ethanol for 24 and 72 h, we observed cell proliferation and analyzed up- and downregulated mRNAs and long noncoding RNAs (lncRNAs) using total RNA-Seq technology. We validated the differential expression of some mRNAs and lncRNAs by RT-qPCR and analyzed the expression of Cebpd and Rnu3a through knock-down of Cebpd. Cell proliferation was significantly reduced in cells exposed to 100 mM ethanol for 72 h, with 1773 transcripts up- or downregulated by greater than three-fold in ethanol-treated cells compared to controls. Of these, 514 were identified as lncRNAs. Differentially expressed mRNAs and lncRNAs were mainly observed in cells exposed to ethanol for 72 h, in which Atm and Cnr1 decreased, but Trib3, Cebpd, and Spdef increased. On the other hand, lncRNAs Kcnq1ot1, Tug1, and Xist were changed by ethanol, and Rnu3a in particular was greatly increased by chronic ethanol treatment through inhibition of Cebpd. Our results increase the understanding of cellular and molecular mechanisms related to coding and noncoding RNAs in an in vitro model of acute and chronic exposure to ethanol.
Connexin and Pannexin Large-Pore Channels in Microcirculation and Neurovascular Coupling Function
Authors: Burboa Pía C. , Puebla Mariela , Gaete Pablo S. , Durán Walter N. , Lillo Mauricio A.
Published: July 2022

Microcirculation homeostasis depends on several channels permeable to ions and/or small molecules that facilitate the regulation of the vasomotor tone, hyperpermeability, the blood–brain barrier, and the neurovascular coupling function. Connexin (Cxs) and Pannexin (Panxs) large-pore channel proteins are implicated in several aspects of vascular physiology. The permeation of ions (i.e., Ca2+) and key metabolites (ATP, prostaglandins, D-serine, etc.) through Cxs (i.e., gap junction channels or hemichannels) and Panxs proteins plays a vital role in intercellular communication and maintaining vascular homeostasis. Therefore, dysregulation or genetic pathologies associated with these channels promote deleterious tissue consequences. This review provides an overview of current knowledge concerning the physiological role of these large-pore molecule channels in microcirculation (arterioles, capillaries, venules) and in the neurovascular coupling function.
Tau as a Biomarker of Neurodegeneration
Authors: Holper Sarah , Watson Rosie , Yassi Nawaf
Published: July 2022

Less than 50 years since tau was first isolated from a porcine brain, its detection in femtolitre concentrations in biological fluids is revolutionizing the diagnosis of neurodegenerative diseases. This review highlights the molecular and technological advances that have catapulted tau from obscurity to the forefront of biomarker diagnostics. Comprehensive updates are provided describing the burgeoning clinical applications of tau as a biomarker of neurodegeneration. For the clinician, tau not only enhances diagnostic accuracy, but holds promise as a predictor of clinical progression, phenotype, and response to drug therapy. For patients living with neurodegenerative disorders, characterization of tau dysregulation could provide much-needed clarity to a notoriously murky diagnostic landscape.
Naturally Occurring Osteoarthritis Features and Treatments: Systematic Review on the Aged Guinea Pig Model
Authors: Veronesi Francesca , Salamanna Francesca , Martini Lucia , Fini Milena
Published: July 2022

To date, several in vivo models have been used to reproduce the onset and monitor the progression of osteoarthritis (OA), and guinea pigs represent a standard model for studying naturally occurring, age-related OA. This systematic review aims to characterize the guinea pig for its employment in in vivo, naturally occurring OA studies and for the evaluation of specific disease-modifying agents. The search was performed in PubMed, Scopus, and Web of Knowledge in the last 10 years. Of the 233 records screened, 49 studies were included. Results showed that within a relatively short period of time, this model develops specific OA aspects, including cartilage degeneration, marginal osteophytes formation, and subchondral bone alterations. Disease severity increases with age, beginning at 3 months with mild OA and reaching moderate–severe OA at 18 months. Among the different strains, Dunkin Hartley develops OA at a relatively early age. Thus, disease-modifying agents have mainly been evaluated for this strain. As summarized herein, spontaneous development of OA in guinea pigs represents an excellent model for studying disease pathogenesis and for evaluating therapeutic interventions. In an ongoing effort at standardization, a detailed characterization of specific OA models is necessary, even considering the main purpose of these models, i.e., translatability to human OA.
Improved Generation of Human Induced Pluripotent Stem Cell-Derived Cardiac Pacemaker Cells Using Novel Differentiation Protocols
Authors: Darche Fabrice F. , Ullrich Nina D. , Huang Ziqiang , Koenen Michael , Rivinius Rasmus , Frey Norbert , Schweizer Patrick A.
Published: July 2022

Current protocols for the differentiation of human-induced pluripotent stem cells (hiPSC) into cardiomyocytes only generate a small amount of cardiac pacemaker cells. In previous work, we reported the generation of high amounts of cardiac pacemaker cells by co-culturing hiPSC with mouse visceral endoderm-like (END2) cells. However, potential medical applications of cardiac pacemaker cells generated according to this protocol, comprise an incalculable xenogeneic risk. We thus aimed to establish novel protocols maintaining the differentiation efficiency of the END2 cell-based protocol, yet eliminating the use of END2 cells. Three protocols were based on the activation and inhibition of the Wingless/Integrated (Wnt) signaling pathway, supplemented either with retinoic acid and the Wnt activator CHIR99021 (protocol B) or with the NODAL inhibitor SB431542 (protocol C) or with a combination of all three components (protocol D). An additional fourth protocol (protocol E) was used, which was originally developed by the manufacturer STEMCELL Technologies for the differentiation of hiPSC or hESC into atrial cardiomyocytes. All protocols (B, C, D, E) were compared to the END2 cell-based protocol A, serving as reference, in terms of their ability to differentiate hiPSC into cardiac pacemaker cells. Our analysis revealed that protocol E induced upregulation of 12 out of 15 cardiac pacemaker-specific genes. For comparison, reference protocol A upregulated 11, while protocols B, C and D upregulated 9, 10 and 8 cardiac pacemaker-specific genes, respectively. Cells differentiated according to protocol E displayed intense fluorescence signals of cardiac pacemaker-specific markers and showed excellent rate responsiveness to adrenergic and cholinergic stimulation. In conclusion, we characterized four novel and END2 cell-independent protocols for the differentiation of hiPSC into cardiac pacemaker cells, of which protocol E was the most efficient.
I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice
Authors: Mota Bibiana C. , Ashburner Nathan , Abelleira-Hervas Laura , Liu Liyueyue , Aleksynas Robertas , Rovati Lucio Claudio , Caselli Gianfranco , Sastre Magdalena
Published: July 2022

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.
Bioenergetics and Reactive Nitrogen Species in Bacteria
Authors: Borisov Vitaliy B. , Forte Elena
Published: July 2022

The production of reactive nitrogen species (RNS) by the innate immune system is part of the host’s defense against invading pathogenic bacteria. In this review, we summarize recent studies on the molecular basis of the effects of nitric oxide and peroxynitrite on microbial respiration and energy conservation. We discuss possible molecular mechanisms underlying RNS resistance in bacteria mediated by unique respiratory oxygen reductases, the mycobacterial bcc-aa3 supercomplex, and bd-type cytochromes. A complete picture of the impact of RNS on microbial bioenergetics is not yet available. However, this research area is developing very rapidly, and the knowledge gained should help us develop new methods of treating infectious diseases.
Epigenetic and Transcriptomic Programming of HSC Quiescence Signaling in Large for Gestational Age Neonates
Authors: Pelletier Alexandre , Carrier Arnaud , Zhao Yongmei , Canouil Mickaël , Derhourhi Mehdi , Durand Emmanuelle , Berberian-Ferrato Lionel , Greally John , Hughes Francine , Froguel Philippe , Bonnefond Amélie , Delahaye Fabien
Published: July 2022

Excessive fetal growth is associated with DNA methylation alterations in human hematopoietic stem and progenitor cells (HSPC), but their functional impact remains elusive. We implemented an integrative analysis combining single-cell epigenomics, single-cell transcriptomics, and in vitro analyses to functionally link DNA methylation changes to putative alterations of HSPC functions. We showed in hematopoietic stem cells (HSC) from large for gestational age neonates that both DNA hypermethylation and chromatin rearrangements target a specific network of transcription factors known to sustain stem cell quiescence. In parallel, we found a decreased expression of key genes regulating HSC differentiation including EGR1, KLF2, SOCS3, and JUNB. Our functional analyses showed that this epigenetic programming was associated with a decreased ability for HSCs to remain quiescent. Taken together, our multimodal approach using single-cell (epi)genomics showed that human fetal overgrowth affects hematopoietic stem cells’ quiescence signaling via epigenetic programming.
Comprehensive Identification of Human Cell Type Chromatin Activity-Specific and Cell Type Expression-Specific MicroRNAs
Authors: Han Yu , Zhou Yuan
Published: July 2022

MicroRNAs (miRNAs) regulate multiple transcripts and thus shape the expression landscape of a cell. Information about miRNA expression and distribution across cell types is crucial for the understanding of miRNAs’ functions and their translational applications as biomarkers or therapeutic targets. In this study, we identify cell-type-specific miRNAs by combining multiple correspondence analysis and Gini coefficients to dissect miRNAs’ expression profiles and chromatin activity score profiles, which results in collections of chromatin activity-specific miRNAs in 91 cell types and expression-specific miRNAs in 124 cell types. Moreover, we find that cell-type-specific miRNAs are closely associated with disease miRNAs, such as T-cell-specific miRNAs, which are closely associated with cancer prognosis. Finally, we constructed mirCellType, an online tool based on cell-type-specific miRNA signatures, to dissect the cell type composition of complex samples with miRNA expression profiles.
Next-Generation Grade and Survival Expression Biomarkers of Human Gliomas Based on Algorithmically Reconstructed Molecular Pathways
Authors: Zolotovskaia Marianna A. , Kovalenko Max A. , Tkachev Victor S. , Simonov Alexander M. , Sorokin Maxim I. , Kim Ella , Kuzmin Denis V. , Karademir-Yilmaz Betul , Buzdin Anton A.
Published: July 2022

In gliomas, expression of certain marker genes is strongly associated with survival and tumor type and often exceeds histological assessments. Using a human interactome model, we algorithmically reconstructed 7494 new-type molecular pathways that are centered each on an individual protein. Each single-gene expression and gene-centric pathway activation was tested as a survival and tumor grade biomarker in gliomas and their diagnostic subgroups (IDH mutant or wild type, IDH mutant with 1p/19q co-deletion, MGMT promoter methylated or unmethylated), including the three major molecular subtypes of glioblastoma (proneural, mesenchymal, classical). We used three datasets from The Cancer Genome Atlas and the Chinese Glioma Genome Atlas, which in total include 527 glioblastoma and 1097 low grade glioma profiles. We identified 2724 such gene and 2418 pathway survival biomarkers out of total 17,717 genes and 7494 pathways analyzed. We then assessed tumor grade and molecular subtype biomarkers and with the threshold of AUC > 0.7 identified 1322/982 gene biomarkers and 472/537 pathway biomarkers. This suggests roughly two times greater efficacy of the reconstructed pathway approach compared to gene biomarkers. Thus, we conclude that activation levels of algorithmically reconstructed gene-centric pathways are a potent class of new-generation diagnostic and prognostic biomarkers for gliomas.
Pivotal Role of Phytohormones and Their Responsive Genes in Plant Growth and Their Signaling and Transduction Pathway under Salt Stress in Cotton
Authors: Ahmad Irshad , Zhu Guanglong , Zhou Guisheng , Song Xudong , Hussein Ibrahim Muhi Eldeen , Ibrahim Salih Ebtehal Gabralla , Hussain Shahid , Younas Muhammad Usama
Published: July 2022

The presence of phyto-hormones in plants at relatively low concentrations plays an indispensable role in regulating crop growth and yield. Salt stress is one of the major abiotic stresses limiting cotton production. It has been reported that exogenous phyto-hormones are involved in various plant defense systems against salt stress. Recently, different studies revealed the pivotal performance of hormones in regulating cotton growth and yield. However, a comprehensive understanding of these exogenous hormones, which regulate cotton growth and yield under salt stress, is lacking. In this review, we focused on new advances in elucidating the roles of exogenous hormones (gibberellin (GA) and salicylic acid (SA)) and their signaling and transduction pathways and the cross-talk between GA and SA in regulating crop growth and development under salt stress. In this review, we not only focused on the role of phyto-hormones but also identified the roles of GA and SA responsive genes to salt stress. Our aim is to provide a comprehensive review of the performance of GA and SA and their responsive genes under salt stress, assisting in the further elucidation of the mechanism that plant hormones use to regulate growth and yield under salt stress.
The Calcium-Dependent Protein Kinase TaCDPK27 Positively Regulates Salt Tolerance in Wheat
Authors: Yue Jie-Yu , Jiao Jin-Lan , Wang Wen-Wen , Wang Hua-Zhong
Published: July 2022

As essential calcium ion (Ca2+) sensors in plants, calcium-dependent protein kinases (CDPKs) function in regulating the environmental adaptation of plants. However, the response mechanism of CDPKs to salt stress is not well understood. In the current study, the wheat salt-responsive gene TaCDPK27 was identified. The open reading frame (ORF) of TaCDPK27 was 1875 bp, coding 624 amino acids. The predicted molecular weight and isoelectric point were 68.905 kDa and 5.6, respectively. TaCDPK27 has the closest relationship with subgroup III members of the CDPK family of rice. Increased expression of TaCDPK27 in wheat seedling roots and leaves was triggered by 150 mM NaCl treatment. TaCDPK27 was mainly located in the cytoplasm. After NaCl treatment, some of this protein was transferred to the membrane. The inhibitory effect of TaCDPK27 silencing on the growth of wheat seedlings was slight. After exposure to 150 mM NaCl for 6 days, the NaCl stress tolerance of TaCDPK27-silenced wheat seedlings was reduced, with shorter lengths of both roots and leaves compared with those of the control seedlings. Moreover, silencing of TaCDPK27 further promoted the generation of reactive oxygen species (ROS); reduced the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT); aggravated the injury to photosystem II (PS II); and increased programmed cell death (PCD) in wheat leaves under NaCl treatment, confirming that the TaCDPK27-silenced seedlings exhibited more NaCl injury than control seedlings. Taken together, the decrease in NaCl tolerance in TaCDPK27-silenced seedlings was due to excessive ROS accumulation and subsequent aggravation of the NaCl-induced PCD. TaCDPK27 may be essential for positively regulating salt tolerance in wheat seedlings.
Incorporating a Machine Learning Model into a Web-Based Administrative Decision Support Tool for Predicting Workplace Absenteeism
Authors: Nath Gopal , Wang Yawei , Coursey Austin , Saha Krishna K. , Prabhu Srikanth , Sengupta Saptarshi
Published: July 2022

Productivity losses caused by absenteeism at work cost U.S. employers billions of dollars each year. In addition, employers typically spend a considerable amount of time managing employees who perform poorly. By using predictive analytics and machine learning algorithms, organizations can make better decisions, thereby increasing organizational productivity, reducing costs, and improving efficiency. Thus, in this paper we propose hybrid optimization methods in order to find the most parsimonious model for absenteeism classification. We utilized data from a Brazilian courier company. In order to categorize absenteeism classes, we preprocessed the data, selected the attributes via multiple methods, balanced the dataset using the synthetic minority over-sampling method, and then employed four methods of machine learning classification: Support Vector Machine (SVM), Multinomial Logistic Regression (MLR), Artificial Neural Network (ANN), and Random Forest (RF). We selected the best model based on several validation scores, and compared its performance against the existing model. Furthermore, project managers may lack experience in machine learning, or may not have the time to spend developing machine learning algorithms. Thus, we propose a web-based interactive tool supported by cognitive analytics management (CAM) theory. The web-based decision tool enables managers to make more informed decisions, and can be used without any prior knowledge of machine learning. Understanding absenteeism patterns can assist managers in revising policies or creating new arrangements to reduce absences in the workplace, financial losses, and the probability of economic insolvency.
Octogenarians Are the New Sexagenarians: Cruciate-Retaining Total Knee Arthroplasty Is Not Inferior to Posterior-Stabilized Arthroplasty in Octogenarian Patients
Authors: D’Ambrosi Riccardo , Menon Prem Haridas , Salunke Abhijeet , Mariani Ilaria , Palminteri Giovanni , Basile Giuseppe , Ursino Nicola , Mangiavini Laura , Hantes Michael
Published: July 2022

Purpose: The primary goal of this study was to compare survivorship and functional results in individuals aged 80 and over who underwent total knee arthroplasty (TKA) with cruciate-retaining (CR) or posterior-stabilized (PS) implants. Methods: We prospectively analyzed the clinical records of two consecutive cohorts for a total of 96 implants in patients aged 80 years or over. The first cohort consisted of 59 consecutive cemented PS cases, while the second cohort comprised 37 consecutive cemented CR cases. The decision to either perform a PS or CR arthroplasty was taken based on preoperative magnetic resonance imaging and intraoperative findings. The clinical evaluation entailed evaluating each patient’s visual analogue scale for pain (VAS), range of motion (flexion and extension), Knee Society Score (KSS), and Oxford Knee Score (OKS). Each patient was clinically evaluated the day before surgery (T0) and at two consecutive follow-ups at least 1 (T1) and 2 (T2) years after surgery. Implant survival was calculated using the Kaplan–Meier method. Results: Both groups showed statistically significant improvements at each follow-up compared with the preoperative values (p < 0.05). The CR group showed a higher flexion degree at T1 than the PS group (116.14 ± 5.57° versus 113.16 ± 7.66°; p = 0.048). No differences were found between the two groups regarding survival rate (chi-squared test p-value = 0.789). Three failures were noted in the CR group, while there were four in the PS group. Conclusions: This prospective clinical study demonstrates that CR and PS TKA had similar clinical outcomes in octogenarians with regard to knee function, postoperative knee pain, and other complications. Prosthesis survivorship for CR and PS TKA were both satisfactory, and in selected octogenarian patients, CR TKA should always be considered because of the reduced surgical time.
Continuous Renal Replacement Therapy after Liver Transplantation: Peri-Operative Associated Factors and Impact on Survival
Authors: Martucci Gennaro , Rossetti Matteo , Li Petri Sergio , Alduino Rossella , Volpes Riccardo , Panarello Giovanna , Gruttadauria Salvatore , Burgio Gaetano , Arcadipane Antonio
Published: July 2022

Continuous renal replacement therapy (CRRT) following orthotopic liver transplantation (OLT) is usually started for multifactorial reasons, with variable incidence among series. This paper presents a single-center retrospective observational study on the early use (within one week) of CRRT after consecutive cadaveric OLT from January 2008 to December 2016. Preoperative patient characteristics and intraoperative data were collected, and patients were divided into two groups (CRRT and no CRRT) to explore the factors associated with the use of CRRT. Repeated measurements of postoperative creatinine were analyzed with generalized estimating equation (GEE) models. Among 528 OLT patients, 75 (14.2%) were treated with CRRT at least once in the first week. Patients treated with CRRT showed lower survival in a Kaplan–Meier curve (log-rank p value < 0.01). Patients treated with CRRT had a more severe preoperative profile, with a significantly higher age, MELD, BUN, creatinine, and total bilirubin, as well as a longer surgery time and a higher number of transfusions of red blood cells, plasma, and platelets (all p values < 0.05). In a stepwise multiple analysis, the following characteristics remained independently associated with the use of CRRT: the MELD score OR 1.12 (95% CL: 1.07–1.16), p value < 0.001, and the preoperative value for blood urea nitrogen OR 1.016 (95% CL: 1.010–1.023), p value < 0.001. The early use of CRRT after OLT occurred at a low rate in this large cohort; however, it was associated with worse outcomes. Apart from the preoperative severity, repeated intraoperative hypotension episodes, which were likely modifiable or preventable, were associated with the increased use of CRRT and higher postoperative creatinine.
Volume-Outcome Relationship in Surgical and Cardiac Transcatheter Interventions with a Focus on Transcatheter Aortic Valve Implantation
Authors: Mauler-Wittwer Sarah , Noble Stephane
Published: July 2022

“Practice makes perfect” is an old saying that can be true for complex interventions. There is a strong and persistent relationship between high volume and better outcomes with more than 300 studies being reported on the subject. The more complex the procedure, the greater the volume-outcome relationship is. Failure to rescue was shown to be one of the factors explaining higher mortality rates post complex surgery. High-volume centers provide a better safety net, thanks to the structure and better protocols, and low-volume operators have better results at high-volume centers than at low-volume centers. Finally, effort should be made to regroup complex procedures in high-volume centers, but without compromising patient access to the procedures. Adaptation to local and geographic constraints is important.
Characteristics and Outcomes of Patients Consulted by a Multidisciplinary Pulmonary Embolism Response Team: 5-Year Experience
Authors: Pietrasik Arkadiusz , Gąsecka Aleksandra , Kurzyna Paweł , Wrona Katarzyna , Darocha Szymon , Banaszkiewicz Marta , Zieliński Dariusz , Zajkowska Dominika , Smyk Julia Maria , Rymaszewska Dominika , Jasińska Karolina , Wasilewski Marcin , Wolański Rafał , Procyk Grzegorz , Szwed Piotr , Florczyk Michał , Wróbel Krzysztof , Grabowski Marcin , Torbicki Adam , Kurzyna Marcin
Published: July 2022

(1) Background: Pulmonary embolism (PE) is the third most frequent acute cardiovascular condition worldwide. PE response teams (PERTs) have been created to facilitate treatment implementation in PE patients. Here, we report on the 5-year experience of PERT operating in Warsaw, Poland, with regard to the characteristics and outcomes of the consulted patients. (2) Methods: Patients diagnosed with PE between September 2017 and December 2021 were included in the study. Clinical and treatment data were obtained from medical records. Patient outcomes were assessed in-hospital, at a 1- and 12-month follow-up. (3) Results: There were 235 PERT activations. The risk of early mortality was low in 51 patients (21.8%), intermediate–low in 83 (35.3%), intermediate–high in 80 (34.0%) and high in 21 (8.9%) patients. Anticoagulation alone was the most frequently administered treatment in all patient subgroups (altogether 84.7%). Systemic thrombolysis (47.6%) and interventional therapy (52%) were the prevailing treatment options in high-risk patients. The in-hospital mortality was 6.4%. The adverse events during 1-year follow-up included five deaths, two recurrent VTE and two minor bleeding events. (4) Conclusions: Our initial 5-year experience showed that the activity of the local PERT facilitated patient-tailored decision making and the access to advanced therapies, with subsequent low overall mortality and treatment complication rates, confirming the benefits of PERT implementation.
Itch in Hidradenitis Suppurativa/Acne Inversa: A Systematic Review
Authors: Agarwal Puneet , Lunge Snehal Balvant , Shetty Nandini Sundar , Karagaiah Priyanka , Daveluy Steven , Ortega-Loayza Alex G. , Tzellos Thrasyvoulos , Szepietowski Jacek C. , Zouboulis Christos C. , Grabbe Stephan , Goldust Mohamad
Published: July 2022

Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory disease of the pilosebaceous unit leading to formation of painful, inflammatory nodules, abscesses and tunnels in apocrine gland-bearing areas of the skin. Pain and drainage are the most important symptoms associated with reduction of quality of life in HS. On the other hand, an overlooked symptom in quality of life studies is itch, despite the fact that several studies have reported its importance. Various theories have tried to explain the pathogenesis of itch in HS, such as the presence of mast cells in the cell infiltrates and elevated Ig E levels in the lesional skin. Smoking and advanced stage of disease have been found to be associated with increased intensity of itch. A PUBMED search was conducted to perform a systematic literature review using the term “hidradenitis suppurativa” [all fields], the keywords “pruritus”, “itching”, “itch” [all fields] and with “AND” as operator. Mast cells and mTor signaling were found to be raised in both lesional and perilesional skin. Itch as a presenting symptom has been found in 35–82.6% of patients across multiple studies. It often co-presents with pain and may be misinterpreted as burning, stinging, tickling, tweaking, prickling, etc. The presence of itch is associated with reduced quality of life, depression and impairment of social life. Brodalumab, a monoclonal antibody against IL-17A receptor, produced significant improvements in itch, pain, QoL and depression in patients with moderate to severe HS. Statins have shown some reduction in itch intensity score. Further studies are required to gain a better understanding of the etiopathogenesis and optimal therapeutic modalities for itch in HS that will allow clinicians to better address issue and reduce its impact on quality of life.
Prevalence and Clinical Conditions Related to Sarcopaenia among Older Persons Living in the Community
Authors: Blanco-Reina Encarnación , Ocaña-Riola Ricardo , Ariza-Zafra Gabriel , García-Merino María Rosa , Aguilar-Cano Lorena , Valdellós Jenifer , Torres-Blanco Claudia , Bellido-Estévez Inmaculada
Published: July 2022

(1) Background: In health care and in society at large, sarcopaenia is a disorder of major importance that can lead to disability and other negative health-related events. Our study aim is to determine the prevalence of sarcopaenia among older people attended in primary care and to analyse the factors associated with this age-related clinical condition; (2) Methods: A multicentre cross-sectional study was conducted of 333 community-dwelling Spanish adults aged 65 years or more. Sociodemographic, clinical, functional, anthropometric, and pharmacological data were collected. Sarcopaenia was defined following European Working Group on Sarcopaenia in Older People (EWGSOP) criteria; (3) Results: Sarcopaenia was present in 20.4% of the study sample, and to a severe degree in 6%. The intensity of the association between sarcopaenia and frailty was weak-moderate (Cramer V = 0.45). According to the multinomial logistic regression model performed, sarcopaenia was positively associated with age and with the presence of psychopathology (OR = 2.72; 95% CI = 1.30–5.70) and was inversely correlated with body mass index (OR = 0.73, 95% CI = 0.67–0.80; (4) Conclusions: Sarcopaenia commonly affects community-dwelling older persons and may be associated with age, body mass index, and psychopathology. The latter factor may be modifiable or treatable and is therefore a possible target for intervention.
Practical Application of Augmented/Mixed Reality Technologies in Surgery of Abdominal Cancer Patients
Authors: Ivanov Vladimir M. , Krivtsov Anton M. , Strelkov Sergey V. , Smirnov Anton Yu. , Shipov Roman Yu. , Grebenkov Vladimir G. , Rumyantsev Valery N. , Gheleznyak Igor S. , Surov Dmitry A. , Korzhuk Michail S. , Koskin Valery S.
Published: July 2022

The technology of augmented and mixed reality (AR/MR) is useful in various areas of modern surgery. We considered the use of augmented and mixed reality technologies as a method of preoperative planning and intraoperative navigation in abdominal cancer patients. Practical use of AM/MR raises a range questions, which demand suitable solutions. The difficulties and obstacles we encountered in the practical use of AR/MR are presented, along with the ways we chose to overcome them. The most demonstrative case is covered in detail. The three-dimensional anatomical model obtained from the CT scan needed to be rigidly attached to the patient’s body, and therefore an invasive approach was developed, using an orthopedic pin fixed to the pelvic bones. The pin is used both similarly to an X-ray contrast marker and as a marker for augmented reality. This solution made it possible, not only to visualize the anatomical structures of the patient and the border zone of the tumor, but also to change the position of the patient during the operation. In addition, a noninvasive (skin-based) marking method was developed that allows the application of mixed and augmented reality during operation. Both techniques were used (8 clinical cases) for preoperative planning and intraoperative navigation, which allowed surgeons to verify the radicality of the operation, to have visual control of all anatomical structures near the zone of interest, and to reduce the time of surgical intervention, thereby reducing the complication rate and improving the rehabilitation period.
Multi-Omics Analysis of Low-Temperature Fruiting Highlights the Promising Cultivation Application of the Nutrients Accumulation in Hypsizygus marmoreus
Authors: Gong Ming , Huang Tianyu , Li Yan , Li Jinxin , Tang Lihua , Su Erzheng , Zou Gen , Bao Dapeng
Published: July 2022

Hypsizygus marmoreus is a representative edible mushroom with low-temperature fruiting after a long postripening (LFLP). Clarifying the mechanism of LFLP and applying a rigorous low-temperature-limited process will optimize the mushroom cultivation process. This study performed an integrative multi-omics analysis of the molecular mechanism of LFLP in combination with genetic, physiological, and cultivation confirmation. The results showed that the amino acid content was increased during LFLP, mainly arginine. pH analysis showed acidification in the postripening stage and alkalization in the substrates of the reproductive growth stage. An enzyme activity test confirmed the increased enzyme activity of arginase and citrate synthase in the postripening stage. Weighted gene coexpression network analysis of the transcriptome and metabolomics indicated that pH variation is correlated mainly with changes in citrate and arginine. Multi-omics reveals a straightforward way of providing enriched materials for amino acid biosynthesis, namely, synergistically elevating citric acid and arginine through enhanced activity of the arginine synthesis branch pathway in the citrate cycle. Our study confirmed that GCN2 mediated metabolic adaptation by enhancing protein translation, highlighting its regulatory role during LFLP. Exogenously added citric acid and arginine shortened the postripening period by 10 days and increased the fruiting body yield by 10.2~15.5%. This research sheds light on the molecular mechanism of LFLP in H. marmoreus and highlights the promising application of nutrient accumulation in high-efficiency cultivation.
Effects of Volatile Organic Compounds Produced by Pseudomonas aurantiaca ST-TJ4 against Verticillium dahliae
Authors: Ni Hang , Kong Wei-Liang , Zhang Yu , Wu Xiao-Qin
Published: July 2022

Verticillium dahliae is one of the most destructive fungal pathogens, causing substantial economic losses in agriculture and forestry. The use of plant growth-promoting rhizobacteria (PGPR) is an effective and environmentally friendly strategy for controlling diseases caused by V. dahliae. In this study, 90 mm in diameter Petri plates were used to test the effect of volatile organic compounds (VOCs) produced by different concentrations of Pseudomonasaurantiaca ST-TJ4 cells suspension on V. dahliae mycelia radial growth and biomass. The mycelial morphology was observed by using scanning electron microscopy. The conidia germination and microsclerotia formation of V. dahliae were evaluated. The VOCs with antifungal activity were collected by headspace solid-phase microextraction (SPME), and their components were analyzed by gas chromatography-mass spectrometry (GC-MS). The VOCs produced by strain ST-TJ4 significantly inhibited the growth of mycelium of V. dahliae. The morphology of the hyphae was rough and wrinkled when exposed to VOCs. The VOCs of strain ST-TJ4 have a significant inhibitory effect on V. dahliae conidia germination and microsclerotia formation. At the same time, the VOCs also reduce the expression of genes related to melanin synthesis in V. dahliae. In particular, the expression of the hydrophobin gene (VDAG-02273) was down-regulated the most, about 67-fold. The VOCs effectively alleviate the severity of cotton root disease. In the volatile profile of strain ST-TJ4, 2-undecanone and 1-nonanol assayed in the range 10–200 µL per plate revealed a significant inhibitory effect on V. dahliae mycelial radial growth. These compounds may be useful to devise new control strategies for control of Verticillium wilt disease caused by V. dahliae.
Exploring the Association between Vitamin D and Changes in Cognitive Function in Chilean Older Adults: Evidence from the ALEXANDROS Cohort Study
Authors: Márquez Carlos , Angel Bárbara , Lera Lydia , Bendayan Rebecca , Sánchez Hugo , Albala Cecilia
Published: July 2022

Background: The increasing aging of the population with the consequent increase of age-associated cognitive disorders pose the challenge of controlling its preventable risk factors, among which vitamin D deficit is a putative factor. Thus, our objective is to explore the association between vitamin D and cognitive performance in a cohort study of community-dwelling Chilean older people. Material and Methods: Cohort study of 955 (69.7% female), community-dwelling older Chileans free of cognitive impairment from the Alexandros cohorts, with 25(OH)D measurement at baseline. Cognitive Function was evaluated with the Mini Mental State Examination (MMSE) short-form questionnaire. Plasma levels of 25(OH)D were classified as Normal > 30 ng/mL Insufficiency 20–29 ng/mL, Deficiency 20–12 ng/mL and Severe Deficiency < 12 ng/mL. Penalized regressions models were made to assess associations. Results: Mean age of the sample was 66.6 + 4.5 years, with 8.5 + 4.7 years of education. After a mean follow-up of 9.6 years, 54 new cases of Mild Cognitive Impairment (MCI)were identified (Incidence density rate = 5.9 per 1000 person/years). Mean vitamin D plasma levels were lower in people with MCI than in the normal cognitive ones (23.0 + 12.75 vs. 28.35 + 15.17 ng/mL, p < 0.01). In the fully adjusted model only severe deficiency of vitamin D was associated with MCI (RR = 2.33; 95% CI: (1.03–5.26). Conclusions: In this longitudinal study, our results confirm that low Vitamin D is a risk factor for MCI, and that people with severe deficiency have more than double the risk of MCI people with normal Vitamin D levels. Considering the high frequency of vitamin D deficiency in older people, and its preventability, these results are very valuable for future public health programmes.
Qualitative Interview Study of Gynecologic Oncologist Utilization of Recommended Same-Day Discharge Following Minimally Invasive Hysterectomy
Authors: Bunde Sophia , Adambekov Shalkar , Glikson Ella , Linkov Faina
Published: July 2022

Recent investigations have supported the safety and benefits of discharging women on the same day following a minimally invasive hysterectomy (MIH) for both benign and malignant indications. Not all eligible candidates for same-day discharge (SDD) are discharged the same day, and patients undergoing an MIH for malignant indications have decreased the odds of receiving SDD despite established safety. The objective of this study was to use qualitative interviews to explore physician decision making regarding SDD after an MIH for malignant indications. Six qualitative interviews of gynecologic oncologists were analyzed using recurrent theme analysis for distinct themes in physician decision making regarding SDD. Results suggest that physician-perceived barriers to SDD include patient health characteristics, patient social characteristics, and hospital-system factors. Cited factors influencing SDD include patient travel, social support, practice setting (urban vs. rural) and staff comfort with the recommendation. Obstructive sleep apnea and post-surgical oxygenation appear to be a recurring reason for unplanned admission. The utilization of SDD after an MIH in the gynecologic oncology patient population is influenced by patient, physician, and system factors. Addressing the physician’s perceived barriers to SDD and catering recommendations to the gynecologic oncology population may increase utilization.