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4,200 |
Punishing pandemic encumbrance
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4,201 |
Dementia guidance please
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4,202 |
'Wearing ear-loop blue surgical masks is a fight to win'
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4,203 |
Scientific rigour
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4,204 |
Author Q&A: Adam Nulty
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4,205 |
PPE update
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4,206 |
Honours, awards, appointments
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4,207 |
RCSEd launches app and brand refresh
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4,208 |
Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model
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Oral carcinogenesis involves the progression of the normal mucosa into potentially malignant disorders and finally into cancer. Tumors are heterogeneous, with different clusters of cells expressing different genes and exhibiting different behaviors. 4-nitroquinoline 1-oxide (4-NQO) and arecoline were used to induce oral cancer in mice, and the main factors for gene expression influencing carcinogenesis were identified through single-cell RNA sequencing analysis. Male C57BL/6J mice were divided into two groups: a control group (receiving normal drinking water) and treatment group (receiving drinking water containing 4-NQO (200 mg/L) and arecoline (500 mg/L)) to induce the malignant development of oral cancer. Mice were sacrificed at 8, 16, 20, and 29 weeks. Except for mice sacrificed at 8 weeks, all mice were treated for 16 weeks and then either sacrificed or given normal drinking water for the remaining weeks. Tongue lesions were excised, and all cells obtained from mice in the 29- and 16-week treatment groups were clustered into 17 groups by using the Louvain algorithm. Cells in subtypes 7 (stem cells) and 9 (keratinocytes) were analyzed through gene set enrichment analysis. Results indicated that their genes were associated with the MYC_targets_v1 pathway, and this finding was confirmed by the presence of cisplatin-resistant nasopharyngeal carcinoma cell lines. These cell subtype biomarkers can be applied for the detection of patients with precancerous lesions, the identification of high-risk populations, and as a treatment target.
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4,209 |
Regulation of Male Fertility by the Renin-Angiotensin System
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The renin-angiotensin system (RAS) is a peptidic system known mainly for its roles in the maintenance of blood pressure and electrolyte and fluid homeostasis. However, several tissues and cells have been described to possess an intrinsic RAS that acts locally through different paracrine and autocrine mechanisms. In the male reproductive system, several components of this system have been observed in various organs and tissues, such as the testes, spermatozoa and seminal fluid. Some functions attributed to this local RAS are maintenance of seminal plasma electrolytes, regulation of steroidogenesis and spermatogenesis, and sperm functions. However, their specific actions in these locations are not fully understood. Therefore, a deep knowledge of the functions of the RAS at both the testicular and seminal levels could clarify its roles in male infertility and sperm physiology, and the different RAS elements could be used to design tools enabling the diagnosis and/or treatment of male infertility.
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4,210 |
Updated infection prevention and control guidance published
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4,211 |
British Society of Prosthodontics
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4,212 |
Long but Unreal Lockdowns in Latin America. Comment on Chen, Y.T.; Yen, Y.F.; Yu, S.H.; Su, E.C. An Examination on the Transmission of COVID-19 and the Effect of Response Strategies: A Comparative Analysis. Int. J. Environ. Res. Public Health 2020, 17, E5687
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Lockdowns have been important elements of epidemic control over time. During the COVID-19 pandemic, they have been implemented in many countries, at very different times, and accompanied by school or workplace closures, restrictions on mass gatherings, and public transport closure in different combinations. Recent evidence published in the International Journal of Environmental Research and Public Health suggests that SARS-CoV-19 transmission is diminished when strict lockdowns, contact tracing, and good public cooperation are implemented. However, in Latin America, not all lockdowns are real, and rapid increases in a few weeks in the number of infected, hospitalized, and deceased populations have been observed. In these cases, the effect of lockdowns is weakening of democracy.
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4,213 |
Molecular Drivers of Platelet Activation: Unraveling Novel Targets for Anti-Thrombotic and Anti-Thrombo-Inflammatory Therapy
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Cardiovascular diseases (CVDs) are the leading cause of death globally—partly a consequence of increased population size and ageing—and are major contributors to reduced quality of life. Platelets play a major role in hemostasis and thrombosis. While platelet activation and aggregation are essential for hemostasis at sites of vascular injury, uncontrolled platelet activation leads to pathological thrombus formation and provokes thrombosis leading to myocardial infarction or stroke. Platelet activation and thrombus formation is a multistage process with different signaling pathways involved to trigger platelet shape change, integrin activation, stable platelet adhesion, aggregation, and degranulation. Apart from thrombotic events, thrombo-inflammation contributes to organ damage and dysfunction in CVDs and is mediated by platelets and inflammatory cells. Therefore, in the past, many efforts have been made to investigate specific signaling pathways in platelets to identify innovative and promising approaches for novel antithrombotic and anti-thrombo-inflammatory strategies that do not interfere with hemostasis. In this review, we focus on some of the most recent data reported on different platelet receptors, including GPIb-vWF interactions, GPVI activation, platelet chemokine receptors, regulation of integrin signaling, and channel homeostasis of NMDAR and PANX1.
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4,214 |
Association of Short-Term Exposure to Meteorological Factors and Risk of Hand, Foot, and Mouth Disease: A Systematic Review and Meta-Analysis
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(1) Background: Inconsistencies were observed in studies on the relationship between short-term exposure to meteorological factors and the risk of hand, foot, and mouth disease (HFMD). This systematic review and meta-analysis was aimed to assess the overall effects of meteorological factors on the incidence of HFMD to help clarify these inconsistencies and serve as a piece of evidence for policy makers to determine relevant risk factors. (2) Methods: Articles published as of 24 October 2020, were searched in the four databases, namely, PubMed, Web of Science, Embase, and MEDLINE. We applied a meta-analysis to assess the impact of ambient temperature, relative humidity, rainfall, wind speed, and sunshine duration on the incidence of HFMD. We conducted subgroup analyses by exposure metrics, exposure time resolution, regional climate, national income level, gender, and age as a way to seek the source of heterogeneity. (3) Results: Screening by the given inclusion and exclusion criteria, a total of 28 studies were included in the analysis. We observed that the incidence of HFMD based on the single-day lag model is significantly associated with ambient temperature, relative humidity, rainfall, and wind speed. In the cumulative lag model, ambient temperature and relative humidity significantly increased the incidence of HFMD as well. Subgroup analysis showed that extremely high temperature and relative humidity significantly increased the risk of HFMD. Temperate regions, high-income countries, and children under five years old are major risk factors for HFMD. (4) Conclusions: Our results suggest that various meteorological factors can increase the incidence of HFMD. Therefore, the general public, especially susceptible populations, should pay close attention to weather changes and take protective measures in advance.
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4,215 |
“Follow the Whistle: Physical Activity Is Calling You”: Evaluation of Implementation and Impact of a Portuguese Nationwide Mass Media Campaign to Promote Physical Activity
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To raise perceived capability (C), opportunity (O) and motivation (M) for physical activity (PA) behaviour (B) among adults, the Portuguese Directorate-General of Health developed a mass media campaign named “Follow the Whistle”, based on behaviour change theory and social marketing principles. Comprehensive formative and process evaluation suggests this media-led campaign used best-practice principles. The campaign adopted a population-wide approach, had clear behavioural goals, and clear multi-strategy implementation. We assessed campaign awareness and initial impact using pre (n = 878, 57% women) and post-campaign (n = 1319, 58% women) independent adult population samples via an online questionnaire, comprising socio-demographic factors, campaign awareness and recall, and psychosocial and behavioural measures linked to the COM-B model. PA was assessed with IPAQ and the Activity Choice Index. The post-campaign recall was typical of levels following national campaigns (24%). Post-campaign measures were higher for key theory-based targets (all p < 0.05), namely self-efficacy, perceived opportunities to be more active and intrinsic motivation. The impact on social norms and self-efficacy was moderated by campaign awareness. Concerning PA, effects were found for vigorous activity (p < 0.01), but not for incidental activity. Overall the campaign impacted key theory-based intermediate outcomes, but did not influence incidental activity, which highlights the need for sustained and repeated campaign efforts.
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4,216 |
Verification of the Mediating Effect of Social Support on Physical Activity and Aging Anxiety of Korean Pre-Older Adults
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There is a lack of research on Korean prospective elderly persons. In particular, there is little research regarding whether social support has a mediating effect on the relationship between physical activity and aging anxiety. Accordingly, this study investigated how social support affected physical activity and aging anxiety in 778 prospective senior citizens (55 to 65 years old) out of a total of 1447 senior citizens who participated in the Embrain Panel Power and Panel Marketing Interactive. Participants completed the IPAQ (International Physical Activity Questionnaires), Social Support Scale, and Aging Anxiety Scale. Physical activity in these Korean pre-older adults affected aging anxiety (p < 0.001), with a fixed effect of physical activity on social support (p < 0.001). Further, social support affected aging anxiety (p < 0.001). Social support was also an important parameter in the relationship between physical activity and aging anxiety. In conclusion, high physical activity of pre-older Korean persons lowered their anxiety regarding aging. Social support acted as a mediator that lowered anxiety regarding aging in the most active pre-older persons.
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4,217 |
New Methods Used in Pharmacokinetics and Therapeutic Monitoring of the First and Newer Generations of Antiepileptic Drugs (AEDs)
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The review presents data from the last few years on bioanalytical methods used in therapeutic drug monitoring (TDM) of the 1st–3rd generation and the newest antiepileptic drug (AEDs) cenobamate in patients with various forms of seizures. Chemical classification, structure, mechanism of action, pharmacokinetic data and therapeutic ranges for total and free fractions and interactions were collected. The primary data on bioanalytical methods for AEDs determination included biological matrices, sample preparation, dried blood spot (DBS) analysis, column resolution, detection method, validation parameters, and clinical utility. In conclusion, the most frequently described method used in AED analysis is the LC-based technique (HPLC, UHPLC, USLC) combined with highly sensitive mass detection or fluorescence detection. However, less sensitive UV is also used. Capillary electrophoresis and gas chromatography have been rarely applied. Besides the precipitation of proteins or LLE, an automatic SPE is often a sample preparation method. Derivatization was also indicated to improve sensitivity and automate the analysis. The usefulness of the methods for TDM was also highlighted.
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4,218 |
Insightful Valorization of the Biological Activities of Pani Heloch Leaves through Experimental and Computer-Aided Mechanisms
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Pani heloch (Antidesma montanum) is traditionally used to treat innumerable diseases and is a source of wild vegetables for the management of different pathological conditions. The present study explored the qualitative phytochemicals; quantitative phenol and flavonoid contents; in vitro antioxidant, anti-inflammatory, and thrombolytic effects; and in vivo antipyretic and analgesic properties of the methanol extract of A. montanum leaves in different experimental models. The extract exhibited secondary metabolites including alkaloids, flavonoids, flavanols, phytosterols, cholesterols, phenols, terpenoids, glycosides, fixed oils, emodines, coumarins, resins, and tannins. Besides, Pani heloch showed strong antioxidant activity (IC(50) = 99.00 µg/mL), while a moderate percentage of clot lysis (31.56%) in human blood and significant anti-inflammatory activity (p < 0.001) was achieved with the standard. Moreover, the analgesic and antipyretic properties appeared to trigger a significant response (p < 0.001) relative to in the control group. Besides, an in silico study of carpusin revealed favorable protein-binding affinities. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity analysis and toxicological properties of all isolated compounds adopted Lipinski’s rule of five for drug-like potential and level of toxicity. Our research unveiled that the methanol extract of A. montanum leaves exhibited secondary metabolites that are a good source for managing inflammation, pyrexia, pain, and cellular toxicity. Computational approaches and further studies are required to identify the possible mechanism which responsible for the biological effects.
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4,219 |
Needle in a Haystack: The Naïve Repertoire as a Source of T Cell Receptors for Adoptive Therapy with Engineered T Cells
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T cell engineering with antigen-specific T cell receptors (TCRs) has allowed the generation of increasingly specific, reliable, and versatile T cell products with near-physiological features. However, a broad applicability of TCR-based therapies in cancer is still limited by the restricted number of TCRs, often also of suboptimal potency, available for clinical use. In addition, targeting of tumor neoantigens with TCR-engineered T cell therapy moves the field towards a highly personalized treatment, as tumor neoantigens derive from somatic mutations and are extremely patient-specific. Therefore, relevant TCRs have to be de novo identified for each patient and within a narrow time window. The naïve repertoire of healthy donors would represent a reliable source due to its huge diverse TCR repertoire, which theoretically entails T cells for any antigen specificity, including tumor neoantigens. As a challenge, antigen-specific naïve T cells are of extremely low frequency and mostly of low functionality, making the identification of highly functional TCRs finding a “needle in a haystack.” In this review, we present the technological advancements achieved in high-throughput mapping of patient-specific neoantigens and corresponding cognate TCRs and how these platforms can be used to interrogate the naïve repertoire for a fast and efficient identification of rare but therapeutically valuable TCRs for personalized adoptive T cell therapy.
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4,220 |
The Flame Retardancy of Polyethylene Composites: From Fundamental Concepts to Nanocomposites
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Polyethylene (PE) is one the most used plastics worldwide for a wide range of applications due to its good mechanical and chemical resistance, low density, cost efficiency, ease of processability, non-reactivity, low toxicity, good electric insulation, and good functionality. However, its high flammability and rapid flame spread pose dangers for certain applications. Therefore, different flame-retardant (FR) additives are incorporated into PE to increase its flame retardancy. In this review article, research papers from the past 10 years on the flame retardancy of PE systems are comprehensively reviewed and classified based on the additive sources. The FR additives are classified in well-known FR families, including phosphorous, melamine, nitrogen, inorganic hydroxides, boron, and silicon. The mechanism of fire retardance in each family is pinpointed. In addition to the efficiency of each FR in increasing the flame retardancy, its impact on the mechanical properties of the PE system is also discussed. Most of the FRs can decrease the heat release rate (HRR) of the PE products and simultaneously maintains the mechanical properties in appropriate ratios. Based on the literature, inorganic hydroxide seems to be used more in PE systems compared to other families. Finally, the role of nanotechnology for more efficient FR-PE systems is discussed and recommendations are given on implementing strategies that could help incorporate flame retardancy in the circular economy model.
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4,221 |
Synthesis and Antiviral Activity of a Series of 2′-C-Methyl-4′-thionucleoside Monophosphate Prodrugs
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The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4′-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom.
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4,222 |
Inactivation of Infectious Bacteria Using Nonthermal Biocompatible Plasma Cabinet Sterilizer
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Nonthermal, biocompatible plasma (NBP) is a promising unique state of matter that is effective against a wide range of pathogenic microorganisms. This study focused on a sterilization method for bacteria that used the dielectric barrier discharge (DBD) biocompatible plasma cabinet sterilizer as an ozone generator. Reactive oxygen species play a key role in inactivation when air or other oxygen-containing gases are used. Compared with the untreated control, Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Salmonella typhimurium (sepsis) were inhibited by approximately 99%, or were nondetectable following plasma treatment. Two kinds of plasma sterilizers containing six- or three-chamber cabinets were evaluated. There was no noticeable difference between the two configurations in the inactivation of microorganisms. Both cabinet configurations were shown to be able to reduce microbes dramatically, i.e., to the nondetectable range. Therefore, our data indicate that the biocompatible plasma cabinet sterilizer may prove to be an appropriate alternative sterilization procedure.
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4,223 |
The Accuracy of Self-Reported Body Weight Is High but Dependent on Recent Weight Change and Negative Affect in Teenage Girls
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Background: Research studies often rely on self-reported weight to calculate body mass index. The present study investigated how the accuracy of self-reported body weight in adolescent girls is affected by overweight/obesity, race/ethnicity, and mental health factors. Methods: In a cohort of girls who participated in the Trial of Activity for Adolescent Girls at ages 11 and 17 (n = 588), self-reported and measured weight were compared, and linear regression models were fitted to model the over- or underreporting. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to calculate depressive symptom subscales for negative affect, anhedonia and somatic symptoms. Results: Allowing 3% difference between self-reported and measured weight for the correct reporting of body weight, 59.2% of girls reported their weight correctly, 30.3% underreported (−5.8 ± 4.8 kg), and 10.5% overreported (4.3 ± 3.5 kg). The average difference between self-reported and measured body weight was −1.5 ± 4.3 kg (p < 0.001). Factors for misreporting body weight were overweight (β ± SE − 2.60 ± 0.66%), obesity (β ± SE − 2.41 ± 0.71%), weight change between ages 11 and 17 (β ± SE − 0.35 ± 0.04% for each kg), height change between ages 11 and 17 (β ± SE 0.29 ± 0.10% for each cm), and negative affect (β ± SE − 0.18 ± 0.08% for each score unit). Conclusions: The difference between self-reported and measured body weight in adolescent girls is relatively small. However, the accuracy of self-reported body weight may be lower in girls with overweight or obesity, recent weight and height change, and higher negative affect.
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4,224 |
Comparative Analysis of PM(2.5)-Bound Polycyclic Aromatic Hydrocarbons (PAHs), Nitro-PAHs (NPAHs), and Water-Soluble Inorganic Ions (WSIIs) at Two Background Sites in Japan
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Daily PM(2.5) (particulate matter with aerodynamic diameter ≤2.5 μm) samples were simultaneously collected at two background sites (Wajima Air Monitoring Station (WAMS) and Fukue-Jima Atmosphere and Aerosol Monitoring Station (FAMS)) in Japan in the East Asian winter and summer monsoon periods of 2017 and 2019, to compare the characteristics of air pollutants among different regions and to determine the possible variation during the long-range transport process. Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), and water-soluble inorganic ions (WSIIs) were analyzed. Despite the PM(2.5) concentrations at FAMS (8.90–78.5 µg/m(3)) being higher than those at WAMS (2.33–21.2 µg/m(3)) in the winter monsoon period, the average concentrations of ∑PAHs, ∑NPAHs, and ∑WSIIs were similar between the two sites. Diagnostic ratios indicated PAHs mainly originated from traffic emissions and mostly aged, whereas NPAHs were mostly secondarily formed during long-range transport. WSIIs at WAMS were mainly formed via the combustion process and secondary reactions, whereas those at FAMS mainly originated from sea salt and dust. Backward trajectories revealed the air masses could not only come from Asian continental coastal regions but also distant landlocked areas in the winter monsoon period, whereas most came from the ocean in the summer monsoon period. These findings can provide basic data for the establishment of prediction models of transboundary air pollutants in East Asia.
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4,225 |
The Influence of Maturity Status on Anthropometric Profile and Body Composition of Youth Goalkeepers
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The anthropometric profile assessment is an important aspect to consider during the growth stages of youth sport practitioners due to its usefulness in controlling maturity status and overall health. We performed an anthropometric profile evaluation in a sample of youth goalkeepers (n = 42) during a training camp, dividing them into three categories based on their years from peak height velocity (YPHV). We also checked if the selection of goalkeepers was associated with the birth quartile. The results showed that most of the participants’ anthropometric parameters followed the normal trend according to the maturation stages. However, several subjects showed an overweight/obese condition and/or high waist circumference. Non-optimal values were found, mostly in the group of goalkeepers around the PHV. In addition, no selection based on birth quartile was seen. Therefore, the anthropometric profile and body composition of youth goalkeepers are physiologically affected by maturity status. However, several subjects were found to be overweight/obese and at cardiometabolic risk, suggesting that children and adolescents, although practicing sport, should pay attention to potentially contributing factors such as the attainment of the recommended levels of physical activity, lowering sedentary time, and adopt a healthy lifestyle.
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4,226 |
In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors
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Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (2a–i) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds 2a–i on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1H-Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(6-ethoxybenzothiazol-2-yl)acetamide (2e) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC(50) values of 6.43 ± 0.72 μM, 9.62 ± 1.14 μM, and 8.07 ± 1.36 μM, respectively, when compared with erlotinib (IC(50) = 17.86 ± 3.22 μM, 19.41 ± 2.38 μM, and 23.81 ± 4.17 μM, respectively). Further mechanistic assays demonstrated that compound 2e enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC(50) value of 2.80 ± 0.52 μM when compared with erlotinib (IC(50) = 0.04 ± 0.01 μM). However, compound 2e did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound 2e emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound 2e is a promising EGFR inhibitor that warrants further clinical investigations.
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4,227 |
Antifibrotic and Regenerative Effects of Treamid in Pulmonary Fibrosis
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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by interstitial fibrosis and progressive respiratory failure. Pirfenidone and nintedanib slow down but do not stop the progression of IPF. Thus, new compounds with high antifibrotic activity and simultaneously regenerative activity are an unmet clinical need. Recently, we showed that Treamid can help restoring the pancreas and testicular tissue in mice with metabolic disorders. We hypothesized that Treamid may be effective in antifibrotic therapy and regeneration of damaged lung tissue in pulmonary fibrosis. In this study, experiments were performed on male C57BL/6 mice with bleomycin-induced pulmonary fibrosis. We applied histological and immunohistochemical methods, ELISA, and assessed the expression of markers of endothelial and epithelial cells in primary cultures of CD31(+) and CD326(+) lung cells. Finally, we evaluated esterase activity and apoptosis of lung cells in vitro. Our data indicate that Treamid exhibits antifibrotic activity in mice with pulmonary fibrosis and has a positive effect on capillaries of the lungs. Treamid also increases the number of endothelial progenitor cells in the lungs of animals with pulmonary fibrosis. Lastly, Treamid increases esterase activity and decreases apoptosis of CD31(+) lung cells in vitro. Based on these findings, we suggest that Treamid may represent a promising compound for the development of new antifibrotic agents, which are capable of stimulating regeneration of lung endothelium in IPF patients.
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4,228 |
Pre-clustering data sets using cluster4x improves the signal-to-noise ratio of high-throughput crystallography drug-screening analysis
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Drug and fragment screening at X-ray crystallography beamlines has been a huge success. However, it is inevitable that more high-profile biological drug targets will be identified for which high-quality, highly homogenous crystal systems cannot be found. With increasing heterogeneity in crystal systems, the application of current multi-data-set methods becomes ever less sensitive to bound ligands. In order to ease the bottleneck of finding a well behaved crystal system, pre-clustering of data sets can be carried out using cluster4x after data collection to separate data sets into smaller partitions in order to restore the sensitivity of multi-data-set methods. Here, the software cluster4x is introduced for this purpose and validated against published data sets using PanDDA, showing an improved total signal from existing ligands and identifying new hits in both highly heterogenous and less heterogenous multi-data sets. cluster4x provides the researcher with an interactive graphical user interface with which to explore multi-data set experiments.
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4,229 |
Archetypes of Gamification: Analysis of mHealth Apps
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BACKGROUND: Nowadays, numerous health-related mobile apps implement gamification in an attempt to draw on the motivational potential of video games and thereby increase user engagement or foster certain health behaviors. However, research on effective gamification is still in its infancy and researchers increasingly recognize methodological shortcomings of existing studies. What we actually know about the phenomenon today stems from fragmented pieces of knowledge, and a variety of different perspectives. Existing research primarily draws on conceptual knowledge that is gained from research prototypes, and isolated from industry best practices. We still lack knowledge on how gamification has been successfully designed and implemented within the industry and whether certain gamification approaches have shown to be particularly suitable for certain health behaviors. OBJECTIVE: We address this lack of knowledge concerning best practices in the design and implementation of gamification for health-related mobile apps by identifying archetypes of gamification approaches that have emerged in pertinent health-related mobile apps and analyzing to what extent those gamification approaches are influenced by the underlying desired health-related outcomes. METHODS: A 3-step research approach is employed. As a first step, a database of 143 pertinent gamified health-related mobile apps from the Apple App Store and Google Play Store is set up. Second, the gamification approach of each app within the database is classified based on an established taxonomy for gamification in health-related apps. Finally, a 2-step cluster analysis is conducted in order to identify archetypes of the most dominant gamification approaches in pertinent gamified health-related mobile apps. RESULTS: Eight archetypes of gamification emerged from the analysis of health-related mobile apps: (1) competition and collaboration, (2) pursuing self-set goals without rewards, (3) episodical compliance tracking, (4) inherent gamification for external goals, (5) internal rewards for self-set goals, (6) continuous assistance through positive reinforcement, (7) positive and negative reinforcement without rewards, and (8) progressive gamification for health professionals. The results indicate a close relationship between the identified archetypes and the actual health behavior that is being targeted. CONCLUSIONS: By unveiling salient best practices and discussing their relationship to targeted health behaviors, this study contributes to a more profound understanding of gamification in mobile health. The results can serve as a foundation for future research that advances the knowledge on how gamification may positively influence health behavior change and guide practitioners in the design and development of highly motivating and effective health-related mobile health apps.
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4,230 |
Smartphone App to Address Loneliness Among College Students: Pilot Randomized Controlled Trial
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BACKGROUND: Loneliness is a widespread and significant problem on college campuses. Prolonged loneliness in young adulthood is a risk factor for concurrent and future mental health problems and attrition, making college a critical time for support. Cognitive and behavioral interventions show promise for decreasing loneliness and can be widely disseminated through technology. OBJECTIVE: This pilot randomized controlled trial was conducted to examine the initial efficacy, feasibility, and desirability of a smartphone app, Nod, designed to deliver cognitive and behavioral skill-building exercises to reduce loneliness during the transition to college. METHODS: First-year college students (N=221, mean age 18.7 years, 59% female) were recruited online during incoming student orientation, and randomized to either receive immediate access to Nod (experimental group, n=100) or access after 4 weeks (control group, n=121). The app delivered skills via fully automated (1) “social challenges,” suggested activities designed to build social connections; (2) reflections, brief cognitive reframing exercises; and (3) student testimonials that encouraged a growth mindset toward social connection building. Main intention-to-treat analyses were used to compare the conditions on self-assessed loneliness, depressive symptoms, and other mental health and college adjustment outcomes at week 4, controlling for baseline values on those variables. Analyses were also performed to test the hypothesis that the treatment benefits would be particularly pronounced for participants with heightened psychological vulnerability at baseline (ie, higher baseline depressive symptoms and loneliness). RESULTS: Retention was 97% at week 4, and participants viewed an average 36.7 pages of app content. There were no significant condition differences in loneliness at week 4 (F(1, 211)=0.05, P=.82; η(p)(2) <.001). However, there was a significant condition-by-baseline depression interaction to predict week-4 loneliness (F(1,209)=9.65, P=.002; η(p)(2) =.04). Simple slope analyses indicated that baseline depression positively predicted week-4 loneliness among control participants (r=0.30, t(209)=3.81, P<.001), but not among experimental participants (r=–0.09, t(209)=–0.84, P=.40), suggesting that Nod buffered participants with high baseline depression scores from experiencing heightened midquarter loneliness. Similarly, there were no significant condition differences in other week-4 outcomes. However, moderation by baseline vulnerability was found for week-4 depressive symptoms, sleep quality, and indices of college adjustment (eg, perceived social support and campus belonging). CONCLUSIONS: Although Nod exposure did not impact outcomes for the full sample, these results provide initial evidence of its benefit for vulnerable students. The results of this trial suggest that cognitive and behavioral skills delivered via a mobile app can buffer psychologically vulnerable college students against heightened loneliness and depressive symptoms, as well as other negative college adjustment outcomes. Future work will aim to improve upon app engagement, and to address loneliness among other key populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT04164654; https://clinicaltrials.gov/ct2/show/NCT04164654
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4,231 |
The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever
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BACKGROUND: Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. METHODS: Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. RESULTS: The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age ≥60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). CONCLUSIONS: G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial.
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4,232 |
Transmission of SARS-COV-2 Infections in Households — Tennessee and Wisconsin, April–September 2020
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4,233 |
Dichloroacetate-induced metabolic reprogramming improves lifespan in a Drosophila model of surviving sepsis
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Sepsis is the leading cause of death in hospitalized patients and beyond the hospital stay and these long-term sequelae are due in part to unresolved inflammation. Metabolic shift from oxidative phosphorylation to aerobic glycolysis links metabolism to inflammation and such a shift is commonly observed in sepsis under normoxic conditions. By shifting the metabolic state from aerobic glycolysis to oxidative phosphorylation, we hypothesized it would reverse unresolved inflammation and subsequently improve outcome. We propose a shift from aerobic glycolysis to oxidative phosphorylation as a sepsis therapy by targeting the pathways involved in the conversion of pyruvate into acetyl-CoA via pyruvate dehydrogenase (PDH). Chemical manipulation of PDH using dichloroacetic acid (DCA) will promote oxidative phosphorylation over glycolysis and decrease inflammation. We tested our hypothesis in a Drosophila melanogaster model of surviving sepsis infected with Staphylococcus aureus. Drosophila were divided into 3 groups: unmanipulated, sham and sepsis survivors, all treated with linezolid; each group was either treated or not with DCA for one week following sepsis. We followed lifespan, measured gene expression of Toll, defensin, cecropin A, and drosomycin, and levels of lactate, pyruvate, acetyl-CoA as well as TCA metabolites. In our model, metabolic effects of sepsis are modified by DCA with normalized lactate, TCA metabolites, and was associated with improved lifespan of sepsis survivors, yet had no lifespan effects on unmanipulated and sham flies. While Drosomycin and cecropin A expression increased in sepsis survivors, DCA treatment decreased both and selectively increased defensin.
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Differences in structure and hibernation mechanism highlight diversification of the microsporidian ribosome
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Assembling and powering ribosomes are energy-intensive processes requiring fine-tuned cellular control mechanisms. In organisms operating under strict nutrient limitations, such as pathogenic microsporidia, conservation of energy via ribosomal hibernation and recycling is critical. The mechanisms by which hibernation is achieved in microsporidia, however, remain poorly understood. Here, we present the cryo–electron microscopy structure of the ribosome from Paranosema locustae spores, bound by the conserved eukaryotic hibernation and recycling factor Lso2. The microsporidian Lso2 homolog adopts a V-shaped conformation to bridge the mRNA decoding site and the large subunit tRNA binding sites, providing a reversible ribosome inactivation mechanism. Although microsporidian ribosomes are highly compacted, the P. locustae ribosome retains several rRNA segments absent in other microsporidia, and represents an intermediate state of rRNA reduction. In one case, the near complete reduction of an expansion segment has resulted in a single bound nucleotide, which may act as an architectural co-factor to stabilize a protein–protein interface. The presented structure highlights the reductive evolution in these emerging pathogens and sheds light on a conserved mechanism for eukaryotic ribosome hibernation.
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New Beginnings
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Isolation of monoclonal antibodies from anti-synthetase syndrome patients and affinity maturation by recombination of independent somatic variants
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The autoimmune disease known as Jo-1 positive anti-synthetase syndrome (ASS) is characterized by circulating antibody titers to histidyl-tRNA synthetase (HARS), which may play a role in modulating the non-canonical functions of HARS. Monoclonal antibodies to HARS were isolated by single-cell screening and sequencing from three Jo-1 positive ASS patients and shown to be of high affinity, covering diverse epitope space. The immune response was further characterized by repertoire sequencing from the most productive of the donor samples. In line with previous studies of autoimmune repertoires, these antibodies tended to have long complementarity-determining region H3 sequences with more positive-charged residues than average. Clones of interest were clustered into groups with related sequences, allowing us to observe different somatic mutations in related clones. We postulated that these had found alternate structural solutions for high affinity binding, but that mutations might be transferable between clones to further enhance binding affinity. Transfer of somatic mutations between antibodies within the same clonal group was able to enhance binding affinity in a number of cases, including beneficial transfer of a mutation from a lower affinity clone into one of higher affinity. Affinity enhancement was seen with mutation transfer both between related single-cell clones, and directly from related repertoire sequences. To our knowledge, this is the first demonstration of somatic hypermutation transfer from repertoire sequences to further mature in vivo derived antibodies, and represents an additional tool to aid in affinity maturation for the development of antibodies.
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An atlas of immune cell exhaustion in HIV-infected individuals revealed by single-cell transcriptomics
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Chronic infection with human immunodeficiency virus (HIV) can cause progressive loss of immune cell function, or exhaustion, which impairs control of virus replication. However, little is known about the development and maintenance, as well as heterogeneity of immune cell exhaustion. Here, we investigated the effects of HIV infection on immune cell exhaustion at the transcriptomic level by analyzing single-cell RNA sequencing of peripheral blood mononuclear cells from four healthy subjects (37,847 cells) and six HIV-infected donors (28,610 cells). We identified nine immune cell clusters and eight T cell subclusters, and three of these (exhausted CD4(+) and CD8(+) T cells and interferon-responsive CD8(+) T cells) were detected only in samples from HIV-infected donors. An inhibitory receptor KLRG1 was identified in a HIV-1 specific exhausted CD8(+) T cell population expressing KLRG1, TIGIT, and T-bet(dim)Eomes(hi) markers. Ex-vivo antibody blockade of KLRG1 restored the function of HIV-specific exhausted CD8(+) T cells demonstrating the contribution of KLRG1(+) population to T cell exhaustion and providing an immunotherapy target to treat HIV chronic infection. These data provide a comprehensive analysis of gene signatures associated with immune cell exhaustion during HIV infection, which could be useful in understanding exhaustion mechanisms and developing new cure therapies.
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Something Big that Matters: The American Society of Tropical Medicine and Hygiene’s Commitment to Combat Climate Change
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Design and Evaluation of Risk Assessment Tools to Identify Pediatric Tuberculosis Infection in Bohol, the Philippines, a Low–HIV- and High–TB-Burden Setting
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Identifying children with, or at substantial risk of, Mycobacterium tuberculosis infection (TBI) and providing TB preventive therapy (TPT) represent an important, yet challenging, strategy in curbing the global burden of childhood TB. Risk assessment scoring tools, which quantify risks associated with unique factors characterizing an individual, could act as a surrogate measure of TBI risk and guide effective and efficient TPT delivery. We assessed important risk factors of childhood TBI and created risk assessment tools through secondary analysis of data from a large, community-based childhood TB prevalence study in the island province of Bohol in the Philippines, a low–HIV- and high–TB-burden, post-disaster setting. We identified four factors that were statistically associated with acquiring TBI—being 5 years or older, having a known TB contact, having a known TB contact who was either the mother or another primary caregiver, and living in a high–TB-burden municipality. We created 2-item, 4-item, and 9-item scores intended to identify child TBI in this low-resource, low–HIV-, and high–TB-burden setting. In addition to the design, evaluation, and impact analysis of these generalizable and valuable risk assessment tools, our study findings emphasize the necessity of targeting both household and community-associated transmissions of childhood TBI to achieve the global goal to end TB.
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p53 promotes ZDHHC1-mediated IFITM3 palmitoylation to inhibit Japanese encephalitis virus replication
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The tumor suppressor p53 as an innate antiviral regulator contributes to restricting Japanese encephalitis virus (JEV) replication, but the mechanism is still unclear. The interferon-induced transmembrane protein 3 (IFITM3) is an intrinsic barrier to a range of virus infection, whether IFITM3 is responsible for the p53-mediated anti-JEV response remains elusive. Here, we found that IFITM3 significantly inhibited JEV replication in a protein-palmitoylation-dependent manner and incorporated into JEV virions to diminish the infectivity of progeny viruses. Palmitoylation was also indispensible for keeping IFITM3 from lysosomal degradation to maintain its protein stability. p53 up-regulated IFITM3 expression at the protein level via enhancing IFITM3 palmitoylation. Screening of palmitoyltransferases revealed that zinc finger DHHC domain-containing protein 1 (ZDHHC1) was transcriptionally up-regulated by p53, and consequently ZDHHC1 interacted with IFITM3 to promote its palmitoylation and stability. Knockdown of IFITM3 significantly impaired the inhibitory role of ZDHHC1 on JEV replication. Meanwhile, knockdown of either ZDHHC1 or IFITM3 expression also compromised the p53-mediated anti-JEV effect. Interestingly, JEV reduced p53 expression to impair ZDHHC1 mediated IFITM3 palmitoylation for viral evasion. Our data suggest the existence of a previously unrecognized p53-ZDHHC1-IFITM3 regulatory pathway with an essential role in restricting JEV infection and provide a novel insight into JEV-host interaction.
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Perspectives and practices of healthcare providers and caregivers on healthcare-associated infections in the neonatal intensive care units of two hospitals in Ghana
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Healthcare-associated infections (HAIs) remain a serious threat to patient safety worldwide, particularly in low- and middle-income countries. Reducing the burden of HAIs through the observation and enforcement of infection prevention and control (IPC) practices remains a priority. Despite growing emphasis on HAI prevention in low- and middle-income countries, limited evidence is available to improve IPC practices to reduce HAIs. This study examined the perspectives of healthcare providers (HPs) and mothers in the neonatal intensive care unit on HAIs and determined the major barriers and facilitators to promoting standard IPC practices. This study draws on data from an ethnographic study using 38 in-depth interviews, four focus group discussions and participant observation conducted among HPs and mothers in neonatal intensive care units of a secondary- and tertiary-level hospital in Ghana. The qualitative data were analysed using a grounded theory approach, and NVivo 12 to facilitate coding. HPs and mothers demonstrated a modest level of understanding about HAIs. Personal, interpersonal, community, organizational and policy-level factors interacted in complex ways to influence IPC practices. HPs sometimes considered HAI concerns to be secondary in the face of a heavy clinical workload, a lack of structured systems and the quest to protect professional authority. The positive attitudes of some HPs, and peer interactions promoted standard IPC practices. Mothers expressed interest in participation in IPC activities. It however requires systematic efforts by HPs to partner with mothers in IPC. Training and capacity building of HPs, provision of adequate resources and improving communication between HPs and mothers were recommended to improve standard IPC practices. We conclude that there is a need for institutionalizing IPC policies and strengthening strategies that acknowledge and value mothers’ roles as caregivers and partners in IPC. To ensure this, HPs should be better equipped to prioritize communication and collaboration with mothers to reduce the burden of HAIs.
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Protocol for a prospective descriptive prevalence study of catatonia in an acute mental health unit in urban South Africa
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INTRODUCTION: Catatonia arises from serious mental, medical, neurological or toxic conditions. The prevalence range depends on the setting and the range is anything from 7% to 63% in other countries. South African prevalence rates are currently unknown. The proposed study is a quantitative descriptive study using the Bush Francis Catatonia Screening Instrument as a screening tool with a data capturing information sheet to extract clinical information from patient folders. The study will investigate: (1) prevalence of catatonia, (2) clinical and demographic correlates associated with catatonia, (3) predictors of catatonia, (4) response to treatment and (5) subjective experience of catatonia. METHODS AND ANALYSIS: The setting is an acute mental health unit (MHU) within a regional, general medical hospital in Nelson Mandela Bay, South Africa, which accepts referrals from within the hospital and from outlying clinics. Participants will be recruited from inpatients in the MHU from beginning of September 2020 to end of August 2021. Most admissions are involuntarily, under the Mental Health Care Act of 2002 with an age range of 13 to over 65 years. Participants who screen positive for catatonia will be followed up after discharge for 3 months to measure outcomes. Primary outcomes will include the 12-month prevalence rate of catatonia, descriptive and other data on presentation and assessment of catatonia in the MHU. Secondary outcomes will include data on treatment response, participants’ report of their subjective experience of catatonia and predictors of catatonia. Descriptive statistics, multivariate binomial logistic regression and univariate analyses will be conducted to evaluate associations between catatonia and clinical or demographic data which could be predictors of catatonia. Survival analysis will be used to examine the time to recovery after diagnosis and initiation of treatment. The 95% CI will be used to demonstrate the precision of estimates. The level of significance will be p≤0.05. ETHICS AND DISSEMINATION: The study has received ethical approval from the Research and Ethics Committees of the Eastern Cape Department of Health, Walter Sisulu University and Nelson Mandela University. The results will be disseminated as follows: at various presentations and feedback sessions; as part of a PhD thesis in Psychology at Nelson Mandela University; and in a manuscript that will be submitted to a peer-reviewed journal.
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The Copenhagen test and treat hepatitis C in a mobile clinic study: a protocol for an intervention study to enhance the HCV cascade of care for people who inject drugs (T’N’T HepC)
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INTRODUCTION: Injecting drug use is the primary driver of hepatitis C virus (HCV) infection in Europe. Despite the need for more engagement with care, people who inject drugs (PWID) are hard to reach with HCV testing and treatment. We initiated a study to evaluate the efficacy for testing and linkage to care among PWID consulting peer-based testing at a mobile clinic in Copenhagen, Denmark. METHODS AND ANALYSIS: In this intervention study, we will recruit participants at a single community-based, peer-run mobile clinic. In a single visit, we will first offer participants a point-of-care HCV antibody test, and if they test positive, then they will receive an HCV RNA test. If they are HCV-RNA+, we will administer facilitated referrals to designated ‘fast-track’ clinics at a hospital or an addiction centre for treatment. The primary outcomes for this study are the number of tested and treated individuals. Secondary outcomes include individuals lost at each step in the care cascade. ETHICS AND DISSEMINATION: The results of this study could provide a model for targeting PWID for HCV testing and treatment in Demark and other settings, which could help achieve WHO HCV elimination targets. The Health Research Ethics Committee of Denmark and the Danish Data Protection Agency confirmed (December 2018/January 2019) that this study did not require their approval. Study findings will be disseminated through peer-reviewed publications, conference presentations and social media.
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Cytoplasmic sharing through apical membrane remodeling
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Multiple nuclei sharing a common cytoplasm are found in diverse tissues, organisms, and diseases. Yet, multinucleation remains a poorly understood biological property. Cytoplasm sharing invariably involves plasma membrane breaches. In contrast, we discovered cytoplasm sharing without membrane breaching in highly resorptive Drosophila rectal papillae. During a six-hour developmental window, 100 individual papillar cells assemble a multinucleate cytoplasm, allowing passage of proteins of at least 62 kDa throughout papillar tissue. Papillar cytoplasm sharing does not employ canonical mechanisms such as incomplete cytokinesis or muscle fusion pore regulators. Instead, sharing requires gap junction proteins (normally associated with transport of molecules < 1 kDa), which are positioned by membrane remodeling GTPases. Our work reveals a new role for apical membrane remodeling in converting a multicellular epithelium into a giant multinucleate cytoplasm.
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SAVI, in silico generation of billions of easily synthesizable compounds through expert-system type rules
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We have made available a database of over 1 billion compounds predicted to be easily synthesizable, called Synthetically Accessible Virtual Inventory (SAVI). They have been created by a set of transforms based on an adaptation and extension of the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from the LHASA project. The chemoinformatics toolkit CACTVS was used to apply a total of 53 transforms to about 150,000 readily available building blocks (enamine.net). Only single-step, two-reactant syntheses were calculated for this database even though the technology can execute multi-step reactions. The possibility to incorporate scoring systems in CHMTRN allowed us to subdivide the database of 1.75 billion compounds in sets according to their predicted synthesizability, with the most-synthesizable class comprising 1.09 billion synthetic products. Properties calculated for all SAVI products show that the database should be well-suited for drug discovery. It is being made publicly available for free download from https://doi.org/10.35115/37n9-5738.
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The birth of a bacterial tRNA gene by large-scale, tandem duplication events
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Organisms differ in the types and numbers of tRNA genes that they carry. While the evolutionary mechanisms behind tRNA gene set evolution have been investigated theoretically and computationally, direct observations of tRNA gene set evolution remain rare. Here, we report the evolution of a tRNA gene set in laboratory populations of the bacterium Pseudomonas fluorescens SBW25. The growth defect caused by deleting the single-copy tRNA gene, serCGA, is rapidly compensated by large-scale (45–290 kb) duplications in the chromosome. Each duplication encompasses a second, compensatory tRNA gene (serTGA) and is associated with a rise in tRNA-Ser(UGA) in the mature tRNA pool. We postulate that tRNA-Ser(CGA) elimination increases the translational demand for tRNA-Ser(UGA), a pressure relieved by increasing serTGA copy number. This work demonstrates that tRNA gene sets can evolve through duplication of existing tRNA genes, a phenomenon that may contribute to the presence of multiple, identical tRNA gene copies within genomes.
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4,247 |
Soluble PD-L1 is associated with local and systemic inflammation markers in primary and secondary brain tumours
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BACKGROUND: Immune-modulatory treatments have so far shown limited clinical activity in primary brain tumours. We aimed to investigate soluble programmed death receptor ligand 1 (sPD-L1) as systemic inflammation parameter in patients with brain tumour. METHODS: EDTA plasma was collected from 81 glioma (55 glioblastoma (GBM), 26 lower-grade glioma (LGG)), 17 meningioma and 44 brain metastasis (BM) patients and 24 controls. sPD-L1 concentrations were determined by ELISA. Correlations with the local tumour microenvironment were assessed by immunohistochemical analysis for PD-L1, CD3 and CD8. RESULTS: sPD-L1 was detected in 62 out of 166 (37.7%) patients (glioma: 41/81, 50.6%; meningioma: 5/17, 29.4%; BM: 7/44, 15.9%; controls: 9/24, 37.5%; p=0.002). sPD-L1 concentrations were lower in BM than in LGG (p=0.003) or GBM (p<0.001). Membranous PD-L1 expression on tumour cells was not associated with sPD-L1 concentrations (p=0.953). sPD-L1 concentration was inversely correlated with the density of CD8+ (r=−0.713, p=0.001) and CD3+ (r=−0.484, p=0.042) tumour-infiltrating lymphocytes in LGG. sPD-L1 is correlated with neutrophil counts (r=−0.318, p=0.045) and C reactive protein levels (r=−0.363, p=0.008) in GBM. sPD-L1+ patients had longer overall survival in GBM (p=0.006) and worse OS in LGG (p=0.028). CONCLUSIONS: sPD-L1 is detectable in a fraction of patients with brain tumour. Although it is not correlated with tissue PD-L1 expression, correlations with other local and systemic inflammation parameters could be detected in LGG and GBM.
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Of gratitude and hope in trying times
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Requirement of a prompt solution to address infection and mortality due to COVID-19 among Peruvian physicians
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The Stages of CS: Clinical and Translational Update
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PURPOSE OF REVIEW: With improvements in cardiovascular care, and routine percutaneous coronary intervention for ST elevation myocardial infarction, more patients are surviving following acute coronary syndromes. However, a minority of patients develop cardiogenic shock which results in approximately 50% 30-day mortality. There are various ways to classify cardiogenic shock, and much has been written about this topic in recent years. This review will examine recent developments and put them in context. RECENT FINDINGS: The large randomized trials of cardiogenic shock treatments such as the IABP-SHOCK II trial used a clinical definition of shock including hypotension (systolic blood pressure of 90 mmHg or less, or requirement of vasopressors to maintain such a blood pressure), as well as hypoperfusion. However, while this defines a minimum standard to define cardiogenic shock, it does not distinguish between a patient on a single vasoconstrictor and one who is on multiple high dose infusions or one on extracorporeal membrane oxygenation. The Society for Cardiac Angiography and Intervention recently published an expert consensus statement defining stages of cardiogenic shock, from at risk to beginning, classic, deteriorating, and extremis cardiogenic shock stages. The simple framework has been validated rapidly in multiple populations including the intensive care unit, a post-myocardial infarction population, an out of hospital cardiac arrest population, and most recently in a multicenter shock collaborative, SUMMARY: Classification is fundamental to understanding a disease state, and crafting solutions to improve outcomes. The last 20 years has witnessed an explosion of percutaneous mechanical circulatory support devices of increasing sophistication and capability, and yet there has been little progress in improving outcomes of cardiogenic shock. Hopefully, the next 20 years will see massive advances in understanding of the complexities of the various stages of cardiogenic shock. With such knowledge, it is likely that targeted treatments will be developed and the mortality of this disease will finally plummet.
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Continuing professional development module: An updated introduction to electroencephalogram-based brain monitoring during intended general anesthesia
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The electroencephalogram (EEG) provides a reliable reflection of the brain’s electrical state, so it can reassure us that the anesthetic agents are actually reaching the patient’s brain, and are having the desired effect. In most patients, the EEG changes somewhat predictably in response to propofol and volatile agents, so a frontal EEG channel can guide avoidance of insufficient and excessive administration of general anesthesia. Persistent alpha-spindles (around 10 Hz) phase-amplitude coupled with slow delta waves (around 1 Hz) are commonly seen during an “appropriate hypnotic state of general anesthesia”. Such patterns can be appreciated from the EEG waveform or from the spectrogram (a colour-coded display of how the power in the various EEG frequencies changes with time). Nevertheless, there are exceptions to this. For example, administration of ketamine and nitrous oxide is generally not associated with the aforementioned alpha-spindle coupled with delta wave pattern. Also, some patients, including older adults and those with neurodegenerative disorders, are less predisposed to generate a strong electroencephalographic “alpha-spindle” pattern during general anesthesia. There might also be some rare instances when the frontal EEG shows a pattern suggestive of general anesthesia, while the patient has some awareness and is able to follow simple commands, albeit this is typically without obvious distress or memory formation. Thus, the frontal EEG alone, as currently analyzed, is an imperfect but clinically useful mirror, and more scientific insights will be needed before we can claim to have a reliable readout of brain “function” during general anesthesia.
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Digitoxigenin presents an effective and selective antileishmanial action against Leishmania infantum and is a potential therapeutic agent for visceral leishmaniasis
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Treatment for visceral leishmaniasis (VL) is hampered mainly by drug toxicity, their high cost, and parasite resistance. Drug development is a long and pricey process, and therefore, drug repositioning may be an alternative worth pursuing. Cardenolides are used to treat cardiac diseases, especially those obtained from Digitalis species. In the present study, cardenolide digitoxigenin (DIGI) obtained from a methanolic extract of Digitalis lanata leaves was tested for its antileishmanial activity against Leishmania infantum species. Results showed that 50% Leishmania and murine macrophage inhibitory concentrations (IC(50) and CC(50), respectively) were of 6.9 ± 1.5 and 295.3 ± 14.5 μg/mL, respectively. With amphotericin B (AmpB) deoxycholate, used as a control drug, values of 0.13 ± 0.02 and 0.79 ± 0.12 μg/mL, respectively, were observed. Selectivity index (SI) values were of 42.8 and 6.1 for DIGI and AmpB, respectively. Preliminary studies suggested that the mechanism of action for DIGI is to cause alterations in the mitochondrial membrane potential, to increase the levels of reactive oxygen species and induce accumulation of lipid bodies in the parasites. DIGI was incorporated into Pluronic® F127-based polymeric micelles, and the formula (DIGI/Mic) was used to treat L. infantum–infected mice. Miltefosine was used as a control drug. Results showed that animals treated with either miltefosine, DIGI, or DIGI/Mic presented significant reductions in the parasite load in their spleens, livers, bone marrows, and draining lymph nodes, as well as the development of a specific Th1-type response, when compared with the controls. Results obtained 1 day after treatment were corroborated with data corresponding to 15 days after therapy. Importantly, treatment with DIGI/Mic induced better parasitological and immunological responses when compared with miltefosine- and DIGI-treated mice. In conclusion, DIGI/Mic has the potential to be used as a therapeutic agent to protect against L. infantum infection, and it is therefore worth of consideration in future studies addressing VL treatment.
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A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity
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Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Inhibitors of the dengue proteinase NS2B/3, the dengue capsid, and the host autophagy pathway were used as query compounds. Three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity, and display strong antiviral activity in cultured cells were selected for further analysis. Pyrimethamine (50% inhibitory concentration [IC(50)] = 1.2 μM), like the dengue proteinase inhibitor ARDP0006 to which it shows structural similarity, inhibited intramolecular NS2B/3 cleavage. Lack of toxicity early in infection allowed testing in mice, in which pyrimethamine also reduced viral loads. Niclosamide (IC(50) = 0.28 μM), like dengue core inhibitor ST-148, affected structural components of the virion and inhibited early processes during infection. Vandetanib (IC(50) = 1.6 μM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo. Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening.
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Reply to Yaroshetskiy et al.: Acute Respiratory Distress Syndrome in COVID-19: Do All These Patients Definitely Require Intubation and Mechanical Ventilation?
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Bedside Evaluation of Pulmonary Embolism by Saline Contrast Electrical Impedance Tomography Method: A Prospective Observational Study
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4,256 |
A Step Forward toward a Bedside and Timely Monitoring of Regional [Formula: see text] / [Formula: see text] Matching
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4,257 |
Reducing Moral Distress in the Setting of a Public Health Crisis
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4,258 |
Tuning Proton Transfer Thermodynamics in SARS-Cov-2 Main Protease: Implications for Catalysis and Inhibitor Design
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In this comutational work a hybrid quantum mechanics/molecular mechanics approach, the MD-PMM approach, is used to investigate the proton transfer reaction the activates the catalytic activity of SARS-CoV-2 main protease. The proton transfer thermodynamics is investigated for the apo ensyme (i.e., without any bound substrate or inhibitor) and in the presence of a inhibitor, N3, which was previously shown to covalently bind SARS-CoV-2 main protease.
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A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), has spread rapidly across the globe, creating an unparalleled global health burden and spurring a deepening economic crisis. As of July 7th, 2020, almost seven months into the outbreak, there are no approved vaccines and few treatments available. Developing drugs that target multiple points in the viral life cycle could serve as a strategy to tackle the current as well as future coronavirus pandemics. Here we leverage the power of our recently developed in silico screening platform, VirtualFlow, to identify inhibitors that target SARS-CoV-2. VirtualFlow is able to efficiently harness the power of computing clusters and cloud-based computing platforms to carry out ultra-large scale virtual screens. In this unprecedented structure-based multi-target virtual screening campaign, we have used VirtualFlow to screen an average of approximately 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets in the cloud. In addition to targeting the active sites of viral enzymes, we also target critical auxiliary sites such as functionally important protein-protein interaction interfaces. This multi-target approach not only increases the likelihood of finding a potent inhibitor, but could also help identify a collection of anti-coronavirus drugs that would retain efficacy in the face of viral mutation. Drugs belonging to different regimen classes could be combined to develop possible combination therapies, and top hits that bind at highly conserved sites would be potential candidates for further development as coronavirus drugs. Here, we present the top 200 in silico hits for each target site. While in-house experimental validation of some of these compounds is currently underway, we want to make this array of potential inhibitor candidates available to researchers worldwide in consideration of the pressing need for fast-tracked drug development.
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Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19
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We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.
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Copper(II) Inhibition of the SARS-CoV-2 Main Protease
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In an analysis of the structural stability of the coronavirus main protease (Mpro), we identified regions of the protein that could be disabled by cobalt(III)-cation binding to histidines and cysteines [1]. Here we have extended our work to include copper(II) chelates, which we have docked to HIS 41 and CYS 145 in the Mpro active-site region. We have found stable docked structures where Cu(II) could readily bond to the CYS 145 thiolate, which would be lethal to the enzyme. We also started studying the Spike Protein, PDB ID: 6VXX and the region around the D614G mutant.
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REDIAL-2020: A Suite of Machine Learning Models to Estimate Anti-SARS-CoV-2 Activities
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Strategies for drug discovery and repositioning are an urgent need with respect to COVID-19. We developed "REDIAL-2020", a suite of machine learning models for estimating small molecule activity from molecular structure, for a range of SARS-CoV-2 related assays. Each classifier is based on three distinct types of descriptors (fingerprint, physicochemical, and pharmacophore) for parallel model development. These models were trained using high throughput screening data from the NCATS COVID19 portal (https://opendata.ncats.nih.gov/covid19/index.html), with multiple categorical machine learning algorithms. The “best models” are combined in an ensemble consensus predictor that outperforms single models where external validation is available. This suite of machine learning models is available through the DrugCentral web portal (http://drugcentral.org/Redial). Acceptable input formats are: drug name, PubChem CID, or SMILES; the output is an estimate of anti-SARS-CoV-2 activities. The web application reports estimated activity across three areas (viral entry, viral replication, and live virus infectivity) spanning six independent models, followed by a similarity search that displays the most similar molecules to the query among experimentally determined data. The ML models have 60% to 74% external predictivity, based on three separate datasets. Complementing the NCATS COVID19 portal, REDIAL-2020 can serve as a rapid online tool for identifying active molecules for COVID-19 treatment. The source code and specific models are available through Github (https://github.com/sirimullalab/redial-2020), or via Docker Hub (https://hub.docker.com/r/sirimullalab/redial-2020) for users preferring a containerized version.
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Periarteriolar stroma cells guide T cells from the red to the white pulp in the spleen
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While both the spleen and lymph nodes are called secondary lymphoid tissues, how lymphocytes enter these tissues are quite different from each other. This is because the architecture of the two types of organs and the mode of lymphocyte migration into these organs are quite distinct. In the spleen, T cells are passively released in the blood flow from the arterioles in the red pulp and marginal zone area. In contrast, T cells in the blood are actively captured on high endothelial venules in lymph nodes by the coordinated actions of CCR7 and several adhesion molecules. A recent finding indicates that T cells, released in the red pulp and marginal zone areas, actively find their way to the white zone by utilizing the migration track created by periarteriolar stromal cells. This finding adds one more piece to our understanding of lymphocyte migration for effective adaptive immune responses in the spleen.
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The other side of the innate immune system: humoral arms favoring cancer
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Cancer cells take advantage of NETosis to escape host immune surveillance and mediate metastasis. The pharmacological targeting of NETosis may prove beneficial in maximizing the response to cancer immunotherapy.
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Progranulin deficiency confers resistance to autoimmune encephalomyelitis in mice
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Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing, pathogen removal, and autoimmunity. We showed that patients with multiple sclerosis (MS) have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis (EAE). However, unexpectedly, progranulin-deficient mice (Grn(−/−)) were resistant to EAE, and this resistance was fully restored by wild-type bone marrow transplantation. FACS analyses revealed a loss of MHC-II-positive antigen-presenting cells in Grn(−/−) mice and a reduction in the number of CD8+ and CD4+ T-cells along with a strong increase in the number of scavenger receptor class B (CD36+) phagocytes, suggesting defects in antigen presentation along with a compensatory increase in phagocytosis. Indeed, bone marrow-derived dendritic cells from Grn(−/−) mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation. An increase in the number of CD36+ phagocytes was associated with increased local inflammation at the site of immunization, stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes, an increase in the phagocytosis of E. coli particles and latex beads and defects in the clearance of the material. Hence, the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation, and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
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Geostatistical analysis and mapping of malaria risk in children of Mozambique
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Malaria remains one of the most prevalent infectious diseases in the tropics and subtropics, and Mozambique is not an exception. To design geographically targeted and effective intervention mechanisms of malaria, an up-to-date map that shows the spatial distribution of malaria is needed. This study analyzed 2018 Mozambique Malaria Indicator Survey using geostatistical methods to: i) explore individual, household, and community-level determinants of malaria in under-five children, ii) prepare a malaria prevalence map in Mozambique, and iii) produce prediction prevalence maps and exceedence probability across the country. The results show the overall weighted prevalence of malaria was 38.9% (N = 4347, with 95% CI: 36.9%–40.8%). Across different provinces of Mozambique, the prevalence of malaria ranges from 1% in Maputo city to 57.3% in Cabo Delgado province. Malaria prevalence was found to be higher in rural areas, increased with child’s age, and decreased with household wealth index and mother’s level of education. Given the high prevalence of childhood malaria observed in Mozambique there is an urgent need for effective public health interventions in malaria hot spot areas. The household determinants of malaria infection that are identified in this study as well as the maps of parasitaemia risk could be used by malaria control program implementers to define priority intervention areas.
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Violence prevention accelerators for children and adolescents in South Africa: A path analysis using two pooled cohorts
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BACKGROUND: The INSPIRE framework was developed by 10 global agencies as the first global package for preventing and responding to violence against children. The framework includes seven complementary strategies. Delivering all seven strategies is a challenge in resource-limited contexts. Consequently, governments are requesting additional evidence to inform which ‘accelerator’ provisions can simultaneously reduce multiple types of violence against children. METHODS AND FINDINGS: We pooled data from two prospective South African adolescent cohorts including Young Carers (2010–2012) and Mzantsi Wakho (2014–2017). The combined sample size was 5,034 adolescents. Each cohort measured six self-reported violence outcomes (sexual abuse, transactional sexual exploitation, physical abuse, emotional abuse, community violence victimisation, and youth lawbreaking) and seven self-reported INSPIRE-aligned protective factors (positive parenting, parental monitoring and supervision, food security at home, basic economic security at home, free schooling, free school meals, and abuse response services). Associations between hypothesised protective factors and violence outcomes were estimated jointly in a sex-stratified multivariate path model, controlling for baseline outcomes and socio-demographics and correcting for multiple-hypothesis testing using the Benjamini-Hochberg procedure. We calculated adjusted probability estimates conditional on the presence of no, one, or all protective factors significantly associated with reduced odds of at least three forms of violence in the path model. Adjusted risk differences (ARDs) and adjusted risk ratios (ARRs) with 95% confidence intervals (CIs) were also calculated. The sample mean age was 13.54 years, and 56.62% were female. There was 4% loss to follow-up. Positive parenting, parental monitoring and supervision, and food security at home were each associated with lower odds of three or more violence outcomes (p < 0.05). For girls, the adjusted probability of violence outcomes was estimated to be lower if all three of these factors were present, as compared to none of them: sexual abuse, 5.38% and 1.64% (ARD: −3.74% points, 95% CI −5.31 to −2.16, p < 0.001); transactional sexual exploitation, 10.07% and 4.84% (ARD: −5.23% points, 95% CI −7.26 to −3.20, p < 0.001); physical abuse, 38.58% and 23.85% (ARD: −14.72% points, 95% CI −19.11 to −10.33, p < 0.001); emotional abuse, 25.39% and 12.98% (ARD: −12.41% points, 95% CI −16.00 to −8.83, p < 0.001); community violence victimisation, 36.25% and 28.37% (ARD: −7.87% points, 95% CI −11.98 to −3.76, p < 0.001); and youth lawbreaking, 18.90% and 11.61% (ARD: −7.30% points, 95% CI −10.50 to −4.09, p < 0.001). For boys, the adjusted probability of violence outcomes was also estimated to be lower if all three factors were present, as compared to none of them: sexual abuse, 2.39% to 1.80% (ARD: −0.59% points, 95% CI −2.24 to 1.05, p = 0.482); transactional sexual exploitation, 6.97% to 4.55% (ARD: −2.42% points, 95% CI −4.77 to −0.08, p = 0.043); physical abuse from 37.19% to 25.44% (ARD: −11.74% points, 95% CI −16.91 to −6.58, p < 0.001); emotional abuse from 23.72% to 10.72% (ARD: −13.00% points, 95% CI −17.04 to −8.95, p < 0.001); community violence victimisation from 41.28% to 35.41% (ARD: −5.87% points, 95% CI −10.98 to −0.75, p = 0.025); and youth lawbreaking from 22.44% to 14.98% (ARD −7.46% points, 95% CI −11.57 to −3.35, p < 0.001). Key limitations were risk of residual confounding and not having information on protective factors related to all seven INSPIRE strategies. CONCLUSION: In this cohort study, we found that positive and supervisory caregiving and food security at home are associated with reduced risk of multiple forms of violence against children. The presence of all three of these factors may be linked to greater risk reduction as compared to the presence of one or none of these factors. Policies promoting action on positive and supervisory caregiving and food security at home are likely to support further efficiencies in the delivery of INSPIRE.
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The acceptance of zinc biofortified rice in Latin America: A consumer sensory study and grain quality characterization
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Zinc deficiency is a major public health problem in vulnerable populations of Latin America and the Caribbean. Biofortification of rice (Oryza sativa L.) with zinc has the potential to alleviate zinc deficiencies. However, as plant breeding processes can alter grain culinary quality and favorable sensory attributes, grain quality and consumer acceptability need to be assessed prior to releasing a variety to the public. A grain quality characterization and a sensory acceptability analysis were carried out with two varieties of zinc biofortified rice and a local control both in Bolivia and Colombia. The aim of this study was to evaluate the physicochemical parameters that are significant in consumer acceptance and to determine the acceptability of zinc biofortified rice by consumers. Results of physicochemical parameters were analyzed using ANOVA. The sensory acceptability was evaluated in 243 adults utilizing a 7-point hedonic scale and a Wilcoxon’s signed rank test was used to determine the overall acceptability of the varieties. Biofortified rice variety T2-11 and MAC-18 -control 1- were equally accepted by consumers in Bolivia with no significant differences (p<0.05). The grain quality analysis reported that both presented long and slender rice grains (L>7.5 mm and L/B>3), an intermediate to high amylose content (>25%) and a similar level of chalkiness. In Colombia, the biofortified variety 035 presented a higher score in overall acceptance in comparison to biofortified variety 021 and the local variety CICA4 -control 2-. However, no significant differences were observed (p<0.05). Conversely to the other two varieties, the biofortified variety 035 presented the largest size grain (L/B = 2.97), a lower chalkiness and an amylose content above 25%. This study shows that the grain quality properties of rice have an influence on acceptability and that zinc biofortified rice varieties are accepted by consumers.
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RNA structure prediction using positive and negative evolutionary information
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Knowing the structure of conserved structural RNAs is important to elucidate their function and mechanism of action. However, predicting a conserved RNA structure remains unreliable, even when using a combination of thermodynamic stability and evolutionary covariation information. Here we present a method to predict a conserved RNA structure that combines the following three features. First, it uses significant covariation due to RNA structure and removes spurious covariation due to phylogeny. Second, it uses negative evolutionary information: basepairs that have variation but no significant covariation are prevented from occurring. Lastly, it uses a battery of probabilistic folding algorithms that incorporate all positive covariation into one structure. The method, named CaCoFold (Cascade variation/covariation Constrained Folding algorithm), predicts a nested structure guided by a maximal subset of positive basepairs, and recursively incorporates all remaining positive basepairs into alternative helices. The alternative helices can be compatible with the nested structure such as pseudoknots, or overlapping such as competing structures, base triplets, or other 3D non-antiparallel interactions. We present evidence that CaCoFold predictions are consistent with structures modeled from crystallography.
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Sample pooling methods for efficient pathogen screening: Practical implications
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Due to the large number of negative tests, individually screening large populations for rare pathogens can be wasteful and expensive. Sample pooling methods improve the efficiency of large-scale pathogen screening campaigns by reducing the number of tests and reagents required to accurately categorize positive and negative individuals. Such methods rely on group testing theory which mainly focuses on minimizing the total number of tests; however, many other practical concerns and tradeoffs must be considered when choosing an appropriate method for a given set of circumstances. Here we use computational simulations to determine how several theoretical approaches compare in terms of (a) the number of tests, to minimize costs and save reagents, (b) the number of sequential steps, to reduce the time it takes to complete the assay, (c) the number of samples per pool, to avoid the limits of detection, (d) simplicity, to reduce the risk of human error, and (e) robustness, to poor estimates of the number of positive samples. We found that established methods often perform very well in one area but very poorly in others. Therefore, we introduce and validate a new method which performs fairly well across each of the above criteria making it a good general use approach.
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A mathematical model and inference method for bacterial colonization in hospital units applied to active surveillance data for carbapenem-resistant enterobacteriaceae
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Widespread use of antibiotics has resulted in an increase in antimicrobial-resistant microorganisms. Although not all bacterial contact results in infection, patients can become asymptomatically colonized, increasing the risk of infection and pathogen transmission. Consequently, many institutions have begun active surveillance, but in non-research settings, the resulting data are often incomplete and may include non-random testing, making conventional epidemiological analysis problematic. We describe a mathematical model and inference method for in-hospital bacterial colonization and transmission of carbapenem-resistant Enterobacteriaceae that is tailored for analysis of active surveillance data with incomplete observations. The model and inference method make use of the full detailed state of the hospital unit, which takes into account the colonization status of each individual in the unit and not only the number of colonized patients at any given time. The inference method computes the exact likelihood of all possible histories consistent with partial observations (despite the exponential increase in possible states that can make likelihood calculation intractable for large hospital units), includes techniques to improve computational efficiency, is tested by computer simulation, and is applied to active surveillance data from a 13-bed rehabilitation unit in New York City. The inference method for exact likelihood calculation is applicable to other Markov models incorporating incomplete observations. The parameters that we identify are the patient–patient transmission rate, pre-existing colonization probability, and prior-to-new-patient transmission probability. Besides identifying the parameters, we predict the effects on the total prevalence (0.07 of the total colonized patient-days) of changing the parameters and estimate the increase in total prevalence attributable to patient–patient transmission (0.02) above the baseline pre-existing colonization (0.05). Simulations with a colonized versus uncolonized long-stay patient had 44% higher total prevalence, suggesting that the long-stay patient may have been a reservoir of transmission. High-priority interventions may include isolation of incoming colonized patients and repeated screening of long-stay patients.
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Photovoltaic modules evaluation and dry-season energy yield prediction model for NEM in Malaysia
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This study analyzes the performance of two PV modules, amorphous silicon (a-Si) and crystalline silicon (c-Si) and predicts energy yield, which can be seen as facilitation to achieve the target of 35% reduction of greenhouse gases emission by 2030. Malaysia Energy Commission recommends crystalline PV modules for net energy metering (NEM), but the climate regime is a concern for output power and efficiency. Based on rainfall and irradiance data, this study aims to categorize the climate of peninsular Malaysia into rainy and dry seasons; and then the performance of the two modules are evaluated under the dry season. A new mathematical model is developed to predict energy yield and the results are validated through experimental and systematic error analysis. The parameters are collected using a self-developed ZigBeePRO-based wireless system with the rate of 3 samples/min over a period of five days. The results unveil that efficiency is inversely proportional to the irradiance due to negative temperature coefficient for crystalline modules. For this phenomenon, efficiency of c-Si (9.8%) is found always higher than a-Si (3.5%). However, a-Si shows better shadow tolerance compared to c-Si, observed from a lesser decrease rate in efficiency of the former with the increase in irradiance. Due to better spectrum response and temperature coefficient, a-Si shows greater performance on output power efficiency (OPE), performance ratio (PR), and yield factor. From the regression analysis, it is found that the coefficient of determination (R(2)) is between 0.7179 and 0.9611. The energy from the proposed model indicates that a-Si yields 15.07% higher kWh than c-Si when luminance for recorded days is 70% medium and 30% high. This study is important to determine the highest percentage of energy yield and to get faster NEM payback period, where as of now, there is no such model to indicate seasonal energy yield in Malaysia.
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Erratum: Vol. 69, No. 43
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Progress Toward Regional Measles Elimination — Worldwide, 2000–2019
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Erratum: Vol. 69, No. 43
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Note from the editors: Eurosurveillance contributor survey results
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Anesthesiology airway-related medicolegal cases from the Canadian Medical Protection Association
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PURPOSE: We analyzed closed civil legal cases in 2007-2016 from the Canadian Medical Protective Association (CMPA) involving specialist anesthesiologists where airway management was the central concern. METHODS: We included all airway-related civil legal cases involving specialist anesthesiologists that closed from 2007 to 2016. The following variables were abstracted by CMPA medical analysts: clinical context, peer expert opinions of contributing factors, and patient and legal outcomes. RESULTS: We found 46 of the 406 (11%) closed cases involving anesthesiologists to be airway-related. Twenty-six cases (57%) involved elective surgery and 31 patients (67%) were categorized as American Society of Anesthesiologists physical status III. Twenty-five cases (54%) occurred outside the operating room (e.g., postanesthesia care unit, intensive care unit, or other satellite locations). In 19 (42%) cases, there was at least one predictor of a difficult airway. Peer experts identified judgement failures in 30 cases (65%), most commonly inadequate airway evaluation. In 30 cases (65%), the patient died or had a permanent brain injury. The medicolegal outcome favoured the patient in 27 (59%) cases, with a median [interquartile range] payment of 422,845 [257,637-935,673] CAD. CONCLUSIONS: Severe patient harm is common when airway management is the focus of a CMPA medicolegal complaint involving anesthesiologists. Patients were otherwise typically low risk cases presenting for elective surgery. Failure to assess or to change management based on the airway exam or encountered difficulty were the most common errors. Our findings support the continued need for adoption, adherence, and practice of guidelines for anticipated and unanticipated difficult airway management for every patient encounter.
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Point-of-care diagnostic tests for influenza in the emergency department: A cost-effectiveness analysis in a high-risk population from a Canadian perspective
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BACKGROUND: Our objective was to assess the cost-effectiveness of novel rapid diagnostic tests: rapid influenza diagnostic tests (RIDT), digital immunoassays (DIA), rapid nucleic acid amplification tests (NAAT), and other treatment algorithms for influenza in high-risk patients presenting to hospital with influenza-like illness (ILI). METHODS: We developed a decision-analytic model to assess the cost-effectiveness of diagnostic test strategies (RIDT, DIA, NAAT, clinical judgement, batch polymerase chain reaction) preceding treatment; no diagnostic testing and treating everyone; and not treating anyone. We modeled high-risk 65-year old patients from a health payer perspective and accrued outcomes over a patient’s lifetime. We reported health outcomes, quality-adjusted life years (QALYs), healthcare costs, and net health benefit (NHB) to measure cost-effectiveness per cohort of 100,000 patients. RESULTS: Treating everyone with no prior testing was the most cost-effective strategy, at a cost-effectiveness threshold of $50,000/QALY, in over 85% of simulations. This strategy yielded the highest NHB of 15.0344 QALYs, but inappropriately treats all patients without influenza. Of the novel rapid diagnostics, NAAT resulted in the highest NHB (15.0277 QALYs), and the least number of deaths (1,571 per 100,000). Sensitivity analyses determined that results were most impacted by the pretest probability of ILI being influenza, diagnostic test sensitivity, and treatment effectiveness. CONCLUSIONS: Based on our model, treating high-risk patients presenting to hospital with influenza-like illness, without performing a novel rapid diagnostic test, resulted in the highest NHB and was most cost-effective. However, consideration of whether treatment is appropriate in the absence of diagnostic confirmation should be taken into account for decision-making by clinicians and policymakers.
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Right Here, Right Now, on Purpose
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Cytotoxic T cells swarm by homotypic chemokine signalling
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Cytotoxic T lymphocytes (CTLs) are thought to arrive at target sites either via random search or following signals by other leukocytes. Here, we reveal independent emergent behaviour in CTL populations attacking tumour masses. Primary murine CTLs coordinate their migration in a process reminiscent of the swarming observed in neutrophils. CTLs engaging cognate targets accelerate the recruitment of distant T cells through long-range homotypic signalling, in part mediated via the diffusion of chemokines CCL3 and CCL4. Newly arriving CTLs augment the chemotactic signal, further accelerating mass recruitment in a positive feedback loop. Activated effector human T cells and chimeric antigen receptor (CAR) T cells similarly employ intra-population signalling to drive rapid convergence. Thus, CTLs recognising a cognate target can induce a localised mass response by amplifying the direct recruitment of additional T cells independently of other leukocytes.
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Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonia, is a progressive, irreversible, and typically lethal disease characterized by an abnormal fibrotic response involving vast areas of the lungs. Given the poor knowledge of the mechanisms underpinning IPF onset and progression, a better understanding of the cellular processes and molecular pathways involved is essential for the development of effective therapies, currently lacking. Besides a number of established IPF-associated risk factors, such as cigarette smoking, environmental factors, comorbidities, and viral infections, several other processes have been linked with this devastating disease. Apoptosis, senescence, epithelial-mesenchymal transition, endothelial-mesenchymal transition, and epithelial cell migration have been shown to play a key role in IPF-associated tissue remodeling. Moreover, molecules, such as chemokines, cytokines, growth factors, adenosine, glycosaminoglycans, non-coding RNAs, and cellular processes including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, hypoxia, and alternative polyadenylation have been linked with IPF development. Importantly, strategies targeting these processes have been investigated to modulate abnormal cellular phenotypes and maintain tissue homeostasis in the lung. This review provides an update regarding the emerging cellular and molecular mechanisms involved in the onset and progression of IPF.
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Mitteilungen der Deutschen Gesellschaft für Pathologie
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Application of antigenic biomarkers for Mycobacterium tuberculosis
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The study and characterization of biomolecules involved in the interaction between mycobacteria and their hosts are crucial to determine their roles in the invasion process and provide basic knowledge about the biology and pathogenesis of disease. Promising new biomarkers for diagnosis and immunotherapy have emerged recently. My-cobacterium is an ancient pathogen that has developed complex strategies for its persistence in the host and environment, likely based on the complexity of the network of interactions between the molecules involved in infection. Several biomarkers have received recent attention in the process of developing rapid and reliable detection techniques for tuberculosis. Among the most widely investigated antigens are CFP-10 (10-kDa culture filtrate protein), ESAT-6 (6-kDa early secretory antigenic target), Ag85A, Ag85B, CFP-7, and PPE18. Some of these antigens have been proposed as biomarkers to assess the key elements of the response to infection of both the pathogen and host. The design of novel and accurate diagnostic methods is essential for the control of tuberculosis worldwide. Presently, the diagnostic methods are based on the identification of molecules in the humoral response in infected individuals. Therefore, these tests depend on the capacity of the host to develop an immune response, which usually is heterogeneous. In the last 20 years, special attention has been given to the design of multiantigenic diagnostic methods to improve the levels of sensitivity and specificity. In this review, we summarize the state of the art in the study and use of mycobacterium biomolecules with the potential to support novel tuberculosis control strategies.
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Update Thoraxpathologie 2020: Bericht der Arbeitsgemeinschaft
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The impact of per diem senior pediatric radiologists in an academic setting
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The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline
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PURPOSE: High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings. METHODS: We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions. RESULTS: The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty). CONCLUSIONS: This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00134-020-06312-y) contains supplementary material, which is available to authorized users.
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Association between pet ownership and physical activity levels, atopic conditions, and mental health in Singapore: a propensity score-matched analysis
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Although existing literature increasingly suggests a positive influence of pet ownership on human physical activity levels, results from many European, American, and Japanese studies have been inconsistent. How pet ownership impacts mental health and atopy is likewise controversial and whether distinct demographic subgroups experience differential effects is unclear. This cross-sectional study surveyed participants (n = 823) via a self-administered online questionnaire. Comparisons of outcomes between pet owners and non-pet owners with subgroup analyses were performed within a propensity score-matched subset (n = 566) of respondents. There were no differences in physical activity levels or mental health scores between pet owners and non-pet owners. In subgroup analyses, compared to non-pet owners, main pet caregivers reported 14.1 (95% CI 2.79–25.3) and 19.0 (95% CI 4.70–33.3) more minutes per week of moderate- and vigorous-intensity physical activity respectively and higher SF-36 emotional well-being (β = 2.7, 95% CI 0.100–5.32) and energy scores (β = 3.8, 95% CI 0.410–7.27). Age was a significant effect modifier of the association between pet ownership and emotional well-being, energy and social functioning scores, with greater scores above the ages of 39, 35 and 39 years old respectively (interaction p = 0.043, 0.044, 0.042). Finally, pet acquisition was associated with worsening of allergic rhinitis, while pet ownership cessation was associated with improvement of allergic rhinitis and eczema symptoms. To our knowledge, this is the first study addressing the public health impact of pet ownership in Southeast Asia and its findings add contextual nuance to suggest potential benefits derived from pet ownership.
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4,288 |
Wechselwirkungen von radikaler Prostatovesikulektomie und Diagnostik des Prostatakarzinoms: Eine medizinhistorische Bestandsaufnahme anlässlich 20 Jahre robotisch assistierter Therapie
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The question of what came first—in this case the diagnosis of prostate cancer or its therapy—seems absurd at first glance and is reminiscent of the classic metaphor-like problem that preoccupied the Greek writer Plutarch (45–125). Today it is a matter of course that a reliable diagnosis is made before treating a disease, but this must be viewed as inconsistent in medical history. The beginnings of radical prostatectomy for the treatment of prostate cancer, like the first surgical therapies for kidney and bladder tumors, can be located in the pioneering period of organ surgery in the German Empire (1871–1918). The establishment of this procedure in its current form with larger numbers of cases is in turn thanks to the Nestor of American urology, Hugh Hampton Young, who carried out the first perineal prostatovesiculectomy, which from today’s perspective can be described as complete. Although the indication has remained largely unchanged since then, this intervention has undergone extensive changes in recent decades. But how has the diagnosis of prostate cancer developed in this period? Of course, much more dynamic. While the procedure prostatovesiculectomy was already established, development of prostate cancer diagnosis began first slowly in the course of the 20th century, then more dynamically. The following article uses medical (historical) original sources to present not only the basics and further developments of the established and, at the same time, subject to constant intervention in urology, but also the essential developments in the environment of neighboring medical disciplines, for example, think of laboratory medicine, radiology, nuclear medicine or rehabilitation medicine, but especially pathology. Incidentally, it was only these developments that created the basis for the correct setting of indications and the identification of alternatives to radical prostatovesiculectomy.
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Evaluation of an unconditional cash transfer program targeting children’s first-1,000–days linear growth in rural Togo: A cluster-randomized controlled trial
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BACKGROUND: In 2014, the government of Togo implemented a pilot unconditional cash transfer (UCT) program in rural villages that aimed at improving children’s nutrition, health, and protection. It combined monthly UCTs (approximately US$8.40 /month) with a package of community activities (including behavior change communication [BCC] sessions, home visits, and integrated community case management of childhood illnesses and acute malnutrition [ICCM-Nut]) delivered to mother–child pairs during the first “1,000 days” of life. We primarily investigated program impact at population level on children’s height-for-age z-scores (HAZs) and secondarily on stunting (HAZ < −2) and intermediary outcomes including household’s food insecurity, mother–child pairs’ diet and health, delivery in a health facility and low birth weight (LBW), women’s knowledge, and physical intimate partner violence (IPV). METHODS AND FINDINGS: We implemented a parallel-cluster–randomized controlled trial, in which 162 villages were randomized into either an intervention arm (UCTs + package of community activities, n = 82) or a control arm (package of community activities only, n = 80). Two different representative samples of children aged 6–29 months and their mothers were surveyed in each arm, one before the intervention in 2014 (control: n = 1,301, intervention: n = 1,357), the other 2 years afterwards in 2016 (control: n = 996, intervention: n = 1,035). Difference-in-differences (DD) estimates of impact were calculated, adjusting for clustering. Children’s average age was 17.4 (± 0.24 SE) months in the control arm and 17.6 (± 0.19 SE) months in the intervention arm at baseline. UCTs had a protective effect on HAZ (DD = +0.25 z-scores, 95% confidence interval [CI]: 0.01–0.50, p = 0.039), which deteriorated in the control arm while remaining stable in the intervention arm, but had no impact on stunting (DD = −6.2 percentage points [pp], relative odds ratio [ROR]: 0.74, 95% CI: 0.51–1.06, p = 0.097). UCTs positively impacted both mothers’ and children’s (18–23 months) consumption of animal source foods (ASFs) (respectively, DD = +4.5 pp, ROR: 2.24, 95% CI: 1.09–4.61, p = 0.029 and DD = +9.1 pp, ROR: 2.65, 95% CI: 1.01–6.98, p = 0.048) and household food insecurity (DD = −10.7 pp, ROR: 0.63, 95% CI: 0.43–0.91, p = 0.016). UCTs did not impact on reported child morbidity 2 week’s prior to report (DD = −3.5 pp, ROR: 0.80, 95% CI: 0.56–1.14, p = 0.214) but reduced the financial barrier to seeking healthcare for sick children (DD = −26.4 pp, ROR: 0.23, 95% CI: 0.08–0.66, p = 0.006). Women who received cash had higher odds of delivering in a health facility (DD = +10.6 pp, ROR: 1.53, 95% CI: 1.10–2.13, p = 0.012) and lower odds of giving birth to babies with birth weights (BWs) <2,500 g (DD = −11.8, ROR: 0.29, 95% CI: 0.10–0.82, p = 0.020). Positive effects were also found on women’s knowledge (DD = +14.8, ROR: 1.86, 95% CI: 1.32–2.62, p < 0.001) and physical IPV (DD = −7.9 pp, ROR: 0.60, 95% CI: 0.36–0.99, p = 0.048). Study limitations included the short evaluation period (24 months) and the low coverage of UCTs, which might have reduced the program’s impact. CONCLUSIONS: UCTs targeting the first “1,000 days” had a protective effect on child’s linear growth in rural areas of Togo. Their simultaneous positive effects on various immediate, underlying, and basic causes of malnutrition certainly contributed to this ultimate impact. The positive impacts observed on pregnancy- and birth-related outcomes call for further attention to the conception period in nutrition-sensitive programs. TRIAL REGISTRATION: ISRCTN Registry ISRCTN83330970.
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Development, Application, and Quality Control of Serology Assays Used for Diagnostic Monitoring of Laboratory Nonhuman Primates
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The careful development, validation, and implementation of serodiagnostic assays can provide reliable results that make them a valuable tool in microbial quality control for nonhuman primates. This article includes identification and description of the components of assay development, including formulas for calculating the number of positive serum samples needed for assay validation and methods for calculating their diagnostic sensitivity and specificity. To ensure that assays are performing within predetermined specifications, there must be a quality control system that includes appropriate system and sample suitability controls as well as mechanisms to track assay performance over time. The section on quality assurance includes definitions of precision and accuracy in assay performance, and how to interpret these two factors using the Levey-Jennings chart, Westgard's rules, and other monitoring methods. Because all serologic assays are prone to false positive and false negative results, it is essential to interpret all diagnostic test results using both the expected prevalence of disease in the population and the population-specific assay performance characteristics that are determined during assay validation. The discussion on interpreting diagnostic test results also includes guidelines for calculating the positive and negative predictive values of an assay and for interpreting results based on the disease prevalence of the test population. A glossary provides definitions of commonly used terms.
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Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection
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Antibodies against viral pathogens represent promising therapeutic agents for the control of infection, and their antiviral efficacy has been shown to require the coordinated function of both the Fab and Fc domains(1). The Fc domain engages a wide spectrum of receptors on discrete cells of the immune system to trigger the clearance of viruses and subsequent killing of infected cells(1–4). Here we report that Fc engineering of anti-influenza IgG monoclonal antibodies for selective binding to the activating Fcγ receptor FcγRIIa results in enhanced ability to prevent or treat lethal viral respiratory infection in mice, with increased maturation of dendritic cells and the induction of protective CD8(+) T cell responses. These findings highlight the capacity for IgG antibodies to induce protective adaptive immunity to viral infection when they selectively activate a dendritic cell and T cell pathway, with important implications for the development of therapeutic antibodies with improved antiviral efficacy against viral respiratory pathogens.
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4,292 |
Not yet 90-90-90: A quality improvement approach to human immunodeficiency virus viral suppression in paediatric patients in the rural Eastern Cape, South Africa
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BACKGROUND: A strategy implemented by the South African Department of Health to manage the high burden of human immunodeficiency virus (HIV) has been to task-shift services to primary health care clinics. Outcomes of paediatric patients with HIV are poorer than those of adults, particularly in rural areas. Viral suppression in paediatric patients at the feeder clinics of a rural South African hospital was anecdotally far below the aim of the Joint United Nations Programme on HIV/AIDS (UNAIDS) of 90%. METHODS: A quality improvement approach was used to conduct a baseline assessment of HIV viral suppression in paediatric patients and other process measures, implement a clinical mentorship intervention and evaluate its effectiveness. RESULTS: An initial audit of 235 clinical folders of paediatric patients with HIV revealed a viral suppression of 55.3%. Other poor measures included prescription accuracy, viral loads performed within schedule and response to successive high viral loads. A clinical mentorship intervention using dedicated doctor outreach was implemented and the audit repeated after 12 months (263 folders). Viral suppression improved to 67.4%, as did most other process measures. CONCLUSION: The quality improvement approach regarding the aim to significantly improve viral suppression in paediatric patients through the implementation of clinical mentorship was successful.
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4,293 |
Innovations: Innovating together while social distancing
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4,294 |
Correction: Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer
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4,295 |
A novel ACT-based video game to support mental health through embedded learning: a mixed-methods feasibility study protocol
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INTRODUCTION: In recent years, serious video games have been used to promote emotional regulation in individuals with mental health issues. Although these therapeutic strategies are innovative, they are limited with respect to scope of treatment, often focusing on specific cognitive skills, to help remediate a specific mental health disorder. OBJECTIVE: Here, we propose a protocol for assessing the feasibility of a novel acceptance and commitment therapy (ACT)-based video game for young adults. METHODS AND ANALYSIS: The Medical Research Council (MRC) framework will be used for developing a complex intervention to design and test the feasibility of an ACT-based video game intervention using a mixed-methods approach involving qualitative and quantitative data. The primary outcomes will include feasibility testing of recruitment processes and the acceptability of the intervention through qualitative interviews, attendance and rates of attrition. Secondary outcomes will involve a series of quantitative questionnaires to obtain effect sizes for power analysis, allowing for the ideal sample size for an appropriately powered, randomised controlled trial to be determined. ETHICS AND DISSEMINATION: This study has been approved by the Psychology Department Research Ethics Committee (2020-4929-3923) at Swansea University in the UK. Dissemination activities will involve publications in peer-reviewed journals, presentations at local and national conferences and promotion through social media. TRIAL REGISTRATION NUMBER: NCT04566042.
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4,296 |
Development of a double monoclonal antibody–based sandwich enzyme-linked immunosorbent assay for detecting canine distemper virus
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ABSTRACT: Canine distemper virus (CDV) infection causes mass mortality in diverse carnivore species. For effective virus surveillance, rapid and sensitive assays are needed to detect CDV in field samples. In this study, after BABL/c mice were immunized with recombinant CDV-fusion (F) protein, monoclonal antibodies (mAbs) against recombinant CDV-F protein (designated 1A5, 1A6, and 7D5) were produced using traditional hybridoma cell technology. Next, capture antibody (1A6, 800 ng/well) and horseradish peroxidase (HRP)–conjugated detection antibody (HRP-7D5, 1:100, 500 ng/well) were used in a double monoclonal antibody–based sandwich enzyme-linked immunosorbent assay (ELISA) for CDV detection after optimization of both mAb amounts per well using a checkerboard titration test. Based on sandwich ELISA test results for 120 known CDV-negative samples, the cutoff value for a positive result was set to an OD(450 nm) value ≥ 0.196. As compared with test results obtained from commercial immune colloidal gold test strips, the low limits of detection for the two assays were revealed to be 100 TCID(50) per 100 μL. In addition, the sandwich ELISA agreed 100% and 96.4% with commercial immune colloidal gold test strips when testing serum and stool samples. The sandwich ELISA assay provided statistically similar CDV detection. Thus, the sandwich ELISA developed here to detect CDV in fecal and serum samples provided good sensitivity, high specificity, and good reproducibility and should serve as an ideal method for large-scale surveillance of CDV infections in carnivores. KEY POINTS: • Three CDV mAbs that recognized different epitopes and bound to virion were generated. • The sandwich ELISA based mAbs to detect CDV in fecal and serum samples was developed. • The sandwich ELISA is an ideal method for detecting CDV infections in the field.
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4,297 |
Methamphetamine induces cardiomyopathy by Sigmar1 inhibition-dependent impairment of mitochondrial dynamics and function
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Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.
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4,298 |
Escalation therapy in severe traumatic brain injury: how long is intracranial pressure monitoring necessary?
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Traumatic brain injury frequently causes an elevation of intracranial pressure (ICP) that could lead to reduction of cerebral perfusion pressure and cause brain ischemia. Invasive ICP monitoring is recommended by international guidelines, in order to reduce the incidence of secondary brain injury; although rare, the complications related to ICP probes could be dependent on the duration of monitoring. The aim of this manuscript is to clarify the appropriate timing for removal and management of invasive ICP monitoring, in order to reduce the risk of related complications and guarantee adequate cerebral autoregulatory control. There is no universal consensus concerning the duration of invasive ICP monitoring and its related complications, although the pertinent literature seems to show that the longer is the monitoring maintenance, the higher is the risk of technical issues. Besides, upon 72 h of normal ICP values or less than 72 h if the first computed tomography scan is normal (none or minimal signs of injury) and the neurological exam is available (allowing to observe variations and possible occurrence of new-onset pathological response), the removal of invasive ICP monitoring can be justified. The availability of non-invasive monitoring systems should be considered to follow up patients’ clinical course after invasive ICP probe removal or for substituting the invasive monitoring in case of contraindication to its placement. Recently, optic nerve sheath diameter and straight sinus systolic flow velocity evaluation through ultrasound methods showed a good correlation with ICP values, demonstrating their potential role in place of invasive monitoring or in the early weaning phase from the invasive ICP monitoring.
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4,299 |
Biography: Christine Stier, M.D.
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