Epithelial ovarian carcinoma (EOC) is virtually insensitive to immune checkpoint inhibitors (ICIs). Recent findings from an innovative mouse model of EOC demonstrate that senescence induction underlies the increased sensitivity of homologous recombination-defective EOCs to platinum-based chemotherapy as it initiates tumor infiltration by immune effector cells coupled to restored sensitivity to ICIs.
Background This study aimed to provide reference values for body fat (BF) of basketball players considering sex, measurement method, and competitive level. Methods A systematic literature research was conducted using five electronic databases (PubMed, Web of Science, SPORTDiscus, CINAHL, Scopus). BF values were extracted, with analyses conducted using random-effects models and data reported as percentages with 95% confidence intervals (CI). Results After screening, 80 articles representing 4335 basketball players were selected. Pooled mean BF was 13.1% (95% CI 12.4–13.8%) for male players and 20.7% (95% CI 19.9–21.5%) for female players. Pooled mean BF was 21.4% (95% CI 18.4–24.3%) measured by dual-energy X-ray absorptiometry (DXA), 15.2% (95% CI 12.8–17.6%) via bioelectrical impedance analysis (BIA), 12.4% (95% CI 10.6–14.2%) via skinfolds and 20.0% (95% CI 13.4–26.6%) via air displacement plethysmography. Pooled mean BF across competitive levels were 13.5% (95% CI 11.6–15.3%) for international, 15.7% (95% CI 14.2–17.2%) for national and 15.1% (95% CI 13.5–16.7%) for regional-level players. As the meta-regression revealed significant effects of sex, measurement method and competitive level on BF, the meta-analysis was adjusted for these moderators. The final model revealed significant differences in BF between male and female players ( p < 0.001). BF measured by DXA was significantly higher than that measured by BIA or skinfolds ( p < 0.001). International-level players had significantly lower BF than national and regional-level players ( p < 0.05). Conclusions Despite the limitations of published data, this meta-analysis provides reference values for BF of basketball players. Sex, measurement method and competitive level influence BF values, and therefore must be taken into account when interpreting results.
Generating insights from a multimethod, multi-respondent qualitative study, we reveal the processes through which learning and development (L&D) signals the corporate brand and the heterogeneous responses of front-line employees (FLEs) in 4/5* hotels to these signalling efforts. Our insights reveal that L&D can play a key role in helping new employees reduce information asymmetry when it comes to the corporate brand and that employees do not respond to the signalling in a homogeneous way. Drawing on both signalling and construal level theories we conducted a sequential mixed method study across multiple respondents consisting of L&D professionals and FLEs in 30 4/5* hotels in Southeast Asia. We surfaced several important micro-foundations of the L&D signalling of corporate brand, including the use of multiple signal channels, different content elements, heterogeneous responses of FLEs to L&D signalling, and the importance of feedback. Our findings substantiate the key role that L&D plays as a signaller of corporate brand in 4/5*hotels and supports the view that FLEs will interpret these signals in different ways depending on their construal level. Our findings highlight important research implications and provide insights for managers and L&D professionals who wish to use L&D as part of corporate branding initiatives.
Chukrasia tabularis A.Juss. is a canopy tree widely distributed in Asia and commonly used for construction-grade timber. While the residues resulting from the timber exploration constitute the major source of waste, other parts of the plant remain underutilized. Therefore, aiming the valorisation of a major residue resulting from C. tabularis wood industry, the leaves were here investigated on their potential content in bioactive constituents, but also on their capacity to modulate mediators and enzymes engaged in metabolic disorders, particularly those involved on the development and progression of diabetes. HPLC–DAD–ESI/MSⁿ and UPLC-ESI-QTOF-MS² characterization of a methanol extract obtained from the leaves, allowed the identification of 25 phenolic constituents, quercetin-3-O-rhamnoside being identified as the main bioactive. The leaf extract and the major flavonoid (quercetin-3-O-rhamnoside) were investigated on their impact towards a series of targets involved in the physiopathology of diabetes. The extract displayed significant scavenging properties against nitric oxide and superoxide radicals, inhibiting also lipid peroxidation and aldose reductase activity. While no noteworthy effects were noted on pancreatic lipase and α-amylase activity, the extract strongly inhibited α-glucosidase (IC50 = 21.14 µg/mL) and proved to be ca. 5 times more effective than the benchmark drug, acarbose. Moreover, the leaf extract significantly inhibited also 5-lipoxygenase (5-LOX) (IC50 = 13.12 µg/mL). Kinetic studies on α-glucosidase and 5-LOX activity disclosed a mixed type inhibition. Furthermore, C. tabularis extract reduced LPS-induced overproduction of NO, L-citrulline and IL-6 in activated RAW 264.7 macrophages. When individually assayed, quercetin-3-O-rhamnoside significantly contributed to the antiradical properties and inhibitory effects of the extract upon the enzymatic targets, but other phenolic bioactives appear also to underlie the recorded anti-inflammatory effects. Taken together, our results demonstrate that the leaves of C. tabularis are rich in phenolic constituents with a great potential to improve metabolic disorders. The evidenced bioactivity of this industrial product might feed R&D programs for the development of new drugs that might simultaneously improve glycaemic, oxidative and inflammatory benchmarks in diabetic patients.
Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-L-Methionine (SAM) dependent 2-O’-ribose methyltransferase (2′-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2′-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2′-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2′-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and in silico ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery in silico. However, these LPs should be validated via in vitro and in vivo experimental models.
The methodological heterogeneity in paediatric foot studies does not entail a stable foundation on which to focus the diagnosis and treatment of the various childhood foot problems. For this reason, the use of highly reliable tests is essential to find relationships and to establish a basis to guide the following studies. The main objective proposed in this cross-sectional observational study protocol is to examine the relationship between hypermobility (Lower Limb Assessment Score and Beighton score) and ankle muscle strength in different types of feet. The second objective is to describe the relationship between physical activity tests in children, and to compare with foot type and ankle muscle strength. The Strengthening Reporting of Observational Studies in Epidemiology (STROBE) criteria will be followed. The hypermobility, posture, strength and physical condition tests will be analyzed through three stations, each one directed by a single specialist in paediatric podiatry. The study has been approved by the Ethics Committee of the Universidad Católica San Antonio de Murcia CE112104. The results will be disseminated regardless of the magnitude or direction of effect. Intra-examiner and inter-examiner reliability will be analyzed.
Many cities around the world are deploying wireless sensor networks to capture information on different environmental parameters. Noise, as one of the main pollutants with negative effects on health and economy, is monitored through sound pressure level. In this work, the application of unsupervised clustering to sound pressure level data from a wireless acoustic sensors network (WASN) is proposed. Data from a sensor network deployed in the city of Madrid are used to show the usefulness of performing a clustering process with the aim of detecting different patterns of behavior of noise levels. The preliminary results obtained have allowed us to divide the city into several acoustic zones, which help city managers to propose improvement plans.
Osteoarthritis is a source of chronic pain and disability. Dietary supplements have been shown to be a more secure option than NSAIDS. Particularly, the eggshell membrane has demonstrated efficacy in relieving joint pain and stiffness. A clinical trial was designed in which three groups were assigned to two different doses of this supplement and compared to a placebo control group. The primary outcome variable was knee pain, which was assessed using a visual analogue scale. Secondary outcome variables were knee functional ability, quadriceps muscle strength (assessed by isometric and isokinetic trials), and quality of sleep. All groups showed a significant decrease in pain perception, although maximum values were obtained in the high-dose group. Isokinetic and isometric trials showed a significant increase in strength in the high-dose group. Eggshell membrane showed the potential to reduce pain and stiffness symptomatology. Here, for the first time, two quantitative variables (mobility and strength of knee joint) were used to accurately evaluate changes in the quality of life of subjects affected by knee joint pain. The results of this study indicate a dose-dependent response, which should be taken into account for later use in therapeutics to establish the correct dosage.
Fish collagen has been widely used in tissue engineering (TE) applications as an implant, which is generally transplanted into target tissue with stem cells for better regeneration ability. In this case, the success rate of this research depends on the fundamental components of fish collagen such as amino acid composition, structural and rheological properties. Therefore, researchers have been trying to find an innovative raw material from marine origins for tissue engineering applications. Based on this concept, collagens such as acid-soluble (ASC) and pepsin-soluble (PSC) were extracted from a new type of cartilaginous fish, the blacktip reef shark, for the first time, and were further investigated for physicochemical, protein pattern, microstructural and peptide mapping. The study results confirmed that the extracted collagens resemble the protein pattern of type-I collagen comprising the α1, α2, β and γ chains. The hydrophobic amino acids were dominant in both collagens with glycine and hydroxyproline as major amino acids. From the FTIR spectra, α helix (27.72 and 26.32%), β-sheet (22.24 and 23.35%), β-turn (21.34 and 22.08%), triple helix (14.11 and 14.13%) and random coil (14.59 and 14.12%) structures of ASC and PSC were confirmed, respectively. Collagens retained their triple helical and secondary structure well. Both collagens had maximum solubility at 3% NaCl and pH 4, and had absorbance maxima at 234 nm, respectively. The peptide mapping was almost similar for ASC and PSC at pH 2, generating peptides ranging from 15 to 200 kDa, with 23 kDa as a major peptide fragment. The microstructural analysis confirmed the homogenous fibrillar nature of collagens with more interconnected networks. Overall, the preset study concluded that collagen can be extracted more efficiently without disturbing the secondary structure by pepsin treatment. Therefore, the blacktip reef shark skin could serve as a potential source for collagen extraction for the pharmaceutical and biomedical applications.
Introduction The gastrointestinal (GI) tract is a frequent site of bleeding in patients receiving anticoagulant therapy for venous thromboembolism (VTE). At-risk patients have not been consistently identified yet. Methods We used the RIETE registry to assess the clinical characteristics of patients developing major GI bleeding during the course of anticoagulation. Then, we built a predictive score based on multivariable analysis, aiming to identify patients at increased risk for major GI bleeding. Results We included 87,431 patients with acute VTE. During the course of anticoagulation, 778 (0.89%) suffered major GI bleeding, 815 (0.93%) non-major GI bleeding and 1462 (1.67%) had major bleeding outside the GI tract. During the first 30 days after major GI bleeding, 7.6% of patients re-bled, 3.9% had VTE recurrences and 33% died. On multivariable analysis, male sex, age ≥70 years, initial VTE presentation as pulmonary embolism, active cancer, prior VTE, recent major bleeding in the GI tract, esophageal varicosities, anemia, abnormal prothrombin time, renal insufficiency and use of corticosteroids were associated to an increased risk for major GI bleeding. Using the predictive score, 39,591 patients (45%) were at low risk; 36,602 (42%) at intermediate-risk; 9315 (11%) at high-risk; and 1923 (2.2%) at very high risk. Their rates of major GI bleeding were: 0.21%, 0.96%, 2.41% and 6.08%, respectively. The c-statistics was 0.771 (95%CI. 0.755–0.786). Conclusions We have developed a score which has the potential to identify patients at increased risk for GI bleeding, but needs to be externally validated.”
Importance Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs. Observations Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities. Conclusions and Relevance Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.
Introduction Population ageing poses a challenge for countries in preventing and detecting neurodegenerative disorders. The Montreal Cognitive Assessment (MoCA), a short, simple, valid, and reliable screening test, assesses general cognitive status, and is useful in public health contexts. This study aims to normalise and standardise the MoCA test for the Chilean population. Method We performed a descriptive, correlational validation study of the MoCA test, using a sample including 526 healthy individuals of both sexes, aged between 18 and 90 years, from the north, centre, and south of Chile. We analysed the effects of age, education level, and sex on MoCA performance. Results Age and education level had a significant impact on general cognitive performance, as determined by MoCA score. Age, education, and sex account for 1%-7% of variance. The mean (standard deviation) score for the total sample was 24.04 (3.22), whereas the normal range originally defined for the instrument is 26-30 points. Older adults with less formal education presented poorer results and lower cognitive performance. We propose a protocol for evaluating results by percentiles and scores for different age ranges, and an individual normalised scalar score. Discussion We present normative data for the MoCA test in the Chilean population, and propose cut-off points for different age ranges to discriminate normal cognitive performance from neurocognitive disorders; results are adjusted for education level. This proposal would assist in the use of the test and reduce the rate of false positives.
Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID-19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID-19 severity.
This paper examines the relationship between the perceived team climate for innovations and the experience of flow and worry and the moderating effect of team size. The research contains a multi-organization dataset with 323 software product development team members. The results show that the perceived climate for innovation is significantly positively related to the experience of flow and worry. However, the findings did not support the moderation with no differences in working in smaller or larger teams. This study indicates that the perceived climate for innovations positively relates to positive and negative individual effects without the importance of team size.
The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10'-Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.Communicated by Ramaswamy H. Sarma.
Hydrology teaching currently relies upon educators' background, requiring a change in training future professionals to manage water resources to address climate change, among other issues. In the teaching experience described in this paper, traditional lectures in a postgraduate civil engineering master's degree were replaced by the development and assessment of a lumped hydrological model implemented into an Excel spreadsheet. Although the primary activity evaluated the long‐term impacts of climate change on streamflow in a watershed, the students were required to address several specific issues such as calibration and validation processes, goodness‐of‐fit metrics, uncertainties of parameters, and sensitivity analysis. The learning experience's efficacy was assessed by conducting two surveys comparing the participants' knowledge before and after the exercise. The results revealed that 92.3% of the students considered that their hydrological skills had improved significantly following the exercise. Furthermore, the acquisition of hydrologi- cal modeling concepts was satisfactorily appreciated by all the participants, 97.6% of whom considered it useful or highly useful. Using a spreadsheet as a complementary tool in hydrology teaching increases student participation and motivation provided it is a contemporary and appealing issue, and the teacher clearly defines, monitors, and follows up on the class objectives.
Background: The influence of the microbiome on neurological diseases has been studied for years. Recent findings have shown a different composition of gut microbiota detected in patients with multiple sclerosis (MS). The role of this dysbiosis is still unknown. Objective: We analyzed the gut microbiota of 15 patients with active relapsing-remitting multiple sclerosis (RRMS), comparing with diet-matched healthy controls. Method: To determine the composition of the gut microbiota, we performed high-throughput sequencing of the 16S ribosomal RNA gene. The specific amplified sequences were in the V3 and V4 regions of the 16S ribosomal RNA gene. Results: The gut microbiota of RRMS patients differed from healthy controls in the levels of the Lachnospiraceae, Ezakiella, Ruminococcaceae, Hungatella, Roseburia, Clostridium, Shuttleworthia, Poephyromonas, and Bilophila genera. All these genera were included in a logistic regression analysis to determine the sensitivity and the specificity of the test. Finally, the ROC (receiver operating characteristic) and AUC with a 95% CI were calculated and best-matched for Ezakiella (AUC of 75.0 and CI from 60.6 to 89.4) and Bilophila (AUC of 70.2 and CI from 50.1 to 90.4). Conclusions: There is a dysbiosis in the gut microbiota of RRMS patients. An analysis of the components of the microbiota suggests the role of some genera as a predictive factor of RRMS prognosis and diagnosis.
The purpose of this article was to assess the effectiveness of ozone therapy as an adjunct to mechanical therapy in periodontitis patients. Thirty-two patients diagnosed with generalized periodontitis were selected, with a total of 655 teeth examined. Each patient’s mouth was divided into four quadrants (the split-mouth model) to be randomly treated with four sessions of gaseous ozone or air. The following clinical variables were recorded: the gingival index, the periodontal clinical attachment loss, the Miller’s mobility index and the clinical improvements, as assessed through the visual analog scale (VAS). In addition, the microorganisms were qualitatively compared. After four weeks of treatment, the teeth of the ozone-treated quadrants showed statistically significant reductions in the gingival index and an improvement in the clinical attachment (p < 0.0001). The same treatment also significantly improved mobility by between 70% and 86% compared to the control group (p < 0.0001). Statistically significant differences were also recorded for the VAS (p < 0.0001). In the qualitative study of the subgingival flora, significant differences were observed (p < 0.0001). The overall results of this trial support the view that ozone treatment is effective and well tolerated in cases of generalized chronic periodontitis.
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