bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening for prostate cancer: protocol for updating multiple systematic reviews to inform a Canadian Task Force on Preventive Health Care guideline update
Authors: Bennett Alexandria , Beck Andrew , Shaver Nicole , Grad Roland , Leblanc Allana , Limburg Heather , Gray Casey , Abou-Setta Ahmed , Klarenbach Scott , Persaud Navindra , Thériault Guylène , Thombs Brett D. , Todd Keith J , Bell Neil , Dahm Philipp , Loblaw Andrew , Giudice Lisa Del , Xiaomei Yao , Skidmore Becky , Harris Elizabeth , Brouwers Melissa , Little Julian , Moher David
Published: May 2022

Purpose: To inform updated recommendations by the Canadian Task Force on Preventive Health Care on screening for prostate cancer in adults aged 18 years and older in primary care. This protocol outlines the planned scope and methods for a series of systematic reviews.Methods: Updates of two systematic reviews and a de novo review will be conducted to synthesize the evidence on the benefits and harms of screening for prostate cancer with prostate specific antigen (PSA) and/or digital rectal examination (DRE) (with or without additional information) and patient values and preferences. Outcomes for the benefits of screening include reduced prostate cancer mortality, all-cause mortality, and incidence of metastatic prostate cancer. Outcomes for the harms of screening include false positive screening tests, overdiagnosis, complications due to biopsy, and complications of treatment including incontinence (urinary or bowel), and erectile dysfunction. Quality of life or functioning (overall and disease-specific) and psychological effects outcomes are considered as a possible benefit or harm. Outcomes for the values and preferences review include quantitative or qualitative information regarding choice to screen or intention to undergo screening. For the reviews on benefits or harms, we will search for randomized controlled trials, quasi-randomised, and controlled studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. For the review on values and preferences, we will search for experimental or observational studies in MEDLINE, Embase, and PsycInfo. For all reviews, we will also search websites of relevant organizations, grey literature, and reference lists of included studies. Title and abstract screening, full-text review, data extraction, and risk of bias assessments will be completed independently by pairs of reviewers with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be used to assess the certainty of the evidence for each outcome.Discussion: The series of systematic reviews will be used by the Canadian Task Force on Preventive Health Care to update their 2014 guideline on screening for prostate cancer in adults aged 18 years and older.Systematic review registration: This review has been registered with PROSPERO (ref# pending) and is available on the Open Science Framework (osf.io/dm32k).
Field test and numerical modeling of the practicability of sonic crystal acoustic barriers
Authors: Qin Xiao-chun , NI An-chen , CHEN Zheng-Hao , FANG Meng-Jie , LI Yan-hua
Published: May 2022

The rapid development of highway traffic has gradually deteriorated the acoustic environment along highways. Sonic crystal theory provides new ideas for traffic noise control. However, current road noise reduction methods based on sonic crystals are still at the theoretical analysis stage, and the lack of reliable calculation models and field test verifications has restricted the promotion and application of sonic crystal acoustic barriers (SCABs). Based on the acoustic performance design of SCABs, in this study, a field test was conducted to study the noise reduction characteristics of SCABs; the corresponding 3D finite element method (FEM) model was established and validated; and three types of optimization measures for noise reduction performance were explored. The main conclusions were as follows: Compared with traditional acoustic barriers along highways, SCABs are more targeted for noise reduction, and the noise reduction performance in the band gap is improved by 0.3-8.8 dB(A). Moreover, as the distance increases behind the acoustic barriers, the noise reduction effect decreases more slowly. The 3D FEM model can accurately describe the spatial characteristics of the sound field and shows agreement with the field test results, with an error of less than 3 dB(A). Compared with the 2D FEM model, the 3D FEM model can accurately calculate the noise reduction performance of an SCAB with resonant elements. Additionally, the gradient combination of scatterers, the filling of porous sound-absorbing materials and the use of microperforated plates can effectively improve the SCAB noise reduction performance. The results provide scientific and reliable experimental support and design guidance for the popularization and application of SCABs in traffic noise control.
Topographic attributes to map land use capability of soils derived from basalt
Authors: Oliveira Jairo Calderari , Mucha Nadia Mariane , Rodrigues Miriam Fernanda , Pellegrini André , Souza Luiz Claudio Paula
Published: May 2022

Subtropical soils derived from basalt covers an area of 1.5 x 106 km2 intensively used for agriculture in South America. There is little information about such soils on a scale compatible with the planning of watersheds. This study has the aim to use topographic attributes to generate soil maps on a semi-detailed scale and elaborate land suitability maps. The study was carried out in a watershed in southern Brazil under a subtropical climate, and soils derived from basalt. A total of 129 points were morphologically described and 17 representative soil class profiles were sampled for laboratory analysis. Areas that should be destined for conservation had the lowest mean for AACN index indicating the proximity of the water table to the surface and the mean MrVBF value above 2. The TWI value higher than 10 was associated with Gleysol. The Regosol were situated in step relief, with the highest mean of LS Factor. Ferralsol and Nitisol were separated with 10 < AACN > 20 and MrRTF > 0.5, associated to flatter and higher areas. Nitisol was the predominant class, occupying 60.78% of the total area, while in previous maps it was identified in 14.94% of the watershed area. Land use beyond its capacity was identified in 31.15% of the Regosol while for the Gleysol this occurs in 38.10%. The farmers use areas of low suitability or with high potential for degradation for agricultural activities, being 2647.29 ha used above the land use capacity in the Lontra river watershed.
Voltage Regulation of DC-DC Boost Converter With Input Filter Hybrid and Embedded PWM Control Approaches
Authors: Sinafar Behzad , Badamchizadeh Mohammad Ali
Published: May 2022

In this paper, two different active control approaches are proposed for a cascaded interconnection of a boost converter and input filter. Designing stabilizing controller in the presence of input filter is a challenging problem. For this reason, a continuous embedded Pulse Width Modulation (PWM) control approach based on the averaged dynamics of the system and duty-cycle manipulation of fixed-frequency PWM control block is proposed and nonlinear controller with a simple structure is developed. Then, as a secondary approach, the system is presented in the hybrid dynamical system framework and hybrid control is developed in a time-triggered scheme. The hybrid dynamical model avoids any approximation or use of PWM block, hence control policy is applied via direct switching control resulting in variable-frequency switching signal. Stability analysis and performance investigation are studied for both of the proposed controllers for the required conditions, and control design procedure are extracted. Finally, a comprehensive numerical simulation is evaluated and results are discussed in full detail.
Antipodal seismic observation locates liquid region on the Earth’s Inner Core
Authors: Tsuboi Seiji , Butler Rhett
Published: May 2022

The Earth's inner core is thought to have been formed by the precipitation of iron from the fluid outer core1. It is considered that a part of the inner core surface where iron in the fluid outer core is precipitated may be melted and formed a mushy region2-4, but its position is not well understood seismologically. We recently analyzed seismic waveforms observed at the antipodal station of the seismic source and showed that there may be a clear precursor of lower reflections at the inner core boundary5. It has been found that this precursor wave can be successfully modeled as a reflection under the liquid / solid interface at a depth of 100 km below the inner core boundary. In this study, we use these precursor waves of the lower reflection at the inner core boundary observed at the antipodal station (> 179°). The sensitivity kernel for the shear wave velocity structure on the inner core surface was calculated by the adjoint method corresponding to these precursor waves, using theoretical seismic waveforms. The location of the fluid region was identified using the obtained sensitivity kernel. Our results show two regions of the inner core surface where the shear wave velocity is close to zero and is considered fluid. These regions are consistent with the westward shifts of geomagnetic anomalies observed on the Earth's surface and the regions of upwellings expected from geomagnetic dynamo simulations in the outer core3. These results may provide a seismological evidence that the inner core is locked to the mantle through the geodynamic motion in the outer core and provide new insights to the origin of the earth's magnetic field.
Integrated cognitive behavioral treatment for substance use and depressive symptoms: A homeless case series and feasibility study
Authors: Molander Olof , Bjureberg Johan , Sahlin Hanna , Beijer Ulla , Gumpert Clara , Ljótsson Brjánn
Published: May 2022

BackgroundHomelessness is associated with high prevalence of psychiatric disorders such as substance use disorders, including alcohol use disorder, and depression. MethodsThis case series and feasibility trial evaluated a novel integrated cognitive behavioral treatment (ICBT), which was adapted specifically for homeless individuals and developed to treat substance use and depressive symptoms simultaneously. The ICBT was delivered among four homeless individuals enrolled in the Treatment First program (a social services program where treatment is offered in conjunction with temporary transitional housing), who had access to stable and sober housing milieus. ResultsThe ICBT was rated high in expectancy of improvement, credibility, and satisfaction, with few treatment-related adverse events, and fairly high treatment retention. At twelve months follow up, three of four participants were not homeless anymore. All treatment participants experienced short term reductions in substance use and/or depressive symptoms. ConclusionsThe study provided preliminary support that the ICBT is a feasible and potentially effective treatment for homeless individuals with substance use and/or depressive symptoms. However, the delivery format within the Treatment First program was not feasible due to treatment workload. The ICBT could be offered within the social services Housing First program instead (where permanent housing is offered before treatment), or to non-homeless individuals.Trial registrationThe study was registered retrospectively at Clinical trials.gov (NCT05329181).
Designing a generic, adaptive protocol resource for the measurement of health impact in cash transfer trials
Authors: Johnson Elliott Aidan , Johnson Matthew Thomas , Kypridemos Christodoulos , Villadsen Aase , Pickett Kate E
Published: May 2022

IntroductionIn the context of the COVID-19 pandemic, upstream interventions that tackle social determinants of health inequalities have never been more important. Evaluations of upstream cash transfer trials have failed to capture comprehensively the impacts that such systems might have on population health through inadequate design of the interventions themselves and failure to implement consistent, thorough research measures that can be used in microsimulations to model long-term impact. In this article, we describe the process of developing a generic, adaptive protocol resource to address this issue and the challenges involved in that process.MethodsWe outline two types of prospective intervention based on trials currently under discussion. In developing the remainder of the resource, we establish six key principles, implement a modular approach based on types of measure and their prospective resource intensity, and source (validated where possible) measures and baseline data primarily from routine collection and large, longitudinal cohort studies. Through these measures, we seek to cover all areas of health impact identified in our theoretical model.ResultsWe find that, in general, self-reported measures alongside routinely collected linked respondent data may provide data capable of demonstrating comprehensive health impact. However, we also suggest that, where possible, physiological measures should be included to elucidate underlying biological effects that may not be accurately captured through self-reporting alone and can enable modelling of long-term health outcomes.DiscussionWe suggest that while Open Access evaluation instruments are available and usable to measure most constructs of interest, there remain some areas for which further development is necessary. This includes self-reported wellbeing measures that require paid licences but are used in a range of nationally important longitudinal studies instead of Open Access alternatives.
Multivariable prediction models of caries increment: a systematic review and critical appraisal
Authors: Havsed Kristian , Petersson Gunnel Hänsel , Isberg Per-Erik , Pigg Maria , Svensäter Gunnel , Rohlin Madeleine
Published: May 2022

Background Multivariable prediction models are used in oral health care to identify individuals with an increased likelihood of caries increment. The outcomes of the models should help to manage individualized interventions and to determine the periodicity of service. The objective was to review and critically appraise studies of multivariable prediction models of caries increment. Methods Longitudinal studies that developed or validated prediction models of caries and expressed caries increment as a function of at least 3 predictors were included. PubMed, Cochrane Library, and Web of Science supplemented with reference lists of included studies were searched. Two reviewers independently extracted data using CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies) and assessed risk of bias and concern regarding applicability using PROBAST (Prediction model Risk Of Bias ASessment Tool). Predictors were analysed and model performance was recalculated as estimated positive (LR+) and negative likelihood ratios (LR-) based on sensitivity and specificity presented in the studies included. Results Among the 765 reports identified, 21 studies providing 66 prediction models fulfilled the inclusion criteria. Over 150 candidate predictors were considered, and 31 predictors remained in studies of final developmental models: caries experience, mutans streptococci in saliva, fluoride supplements, and visible dental plaque being the most common predictors. Predictive performances varied, providing LR+ and LR- ranges of 0.78 –10.3 and 0.0 – 1.1, respectively. Only four models of coronal caries and one root caries model scored LR+ values of at least 5. All studies were assessed as having high risk of bias, generally due to insufficient number of outcomes in relation to candidate predictors and considerable uncertainty regarding predictor thresholds and measurements. Concern regarding applicability was low overall. Conclusions The review calls attention to several methodological deficiencies and the significant heterogeneity observed across the studies ruled out meta-analyses. The high risk of bias affects the predictive performance and thereby the clinical applicability of the studied prediction models. The modest performance of most models implies that alternative predictors should be considered, such as bacteria with acid tolerant properties. Systematic review registration PROSPERO CRD#152467 April 28, 2020
Adsorption of a thione derivative On Carbon, AlN, and BN Nanotubes: A Detailed DFT and MD Investigation
Authors: Al-Otaibi Jamelah S , Shabeer Muhammad , Mary Y.Sheena , Mary Y.Shyma , Thomas Renjith
Published: May 2022

The performance of nanotubes (NT) of carbon (CC), aluminum-nitrogen (AlN), and boron-nitrogen (BN) as a sensor and nanocarrier for mercaptopurine (MCP) was investigated by means of a theoretical approach. The calculated negative values of adsorption energy showed the interaction and adsorption of MCP. HOMO and LUMO distributions were only found on the NT counter portion of the drug-nanotube not on MCP for AlN-NT and BN-NT while HOMO is over MCP and LUMO are over NT for CC-NT. The polarizability of MCP-NTs is greater than that of MCP. Raman wavenumbers of MCP are enhanced in NTs and hence NTs can act as a sensor for the detection of MCP. Solvent dependency on adsorption behavior is also presented in the manuscript, where we found that the AlN nanotube showed exceptionally high free energy of adsorption over other nanotubes in all solvent mediums. Solvation-free energies were also reported. Noncovalent interaction scattered plot also showed significant intermolecular interaction between AlN nanotubes and the mercaptopurine when compared to other nanotubes under study. To find the antiviral activity of MCP and MCP-NTs against antiviral activities, docking and molecular dynamics simulations were performed with 1HMP PDB. Recovery times show that MCP desorption occurs quickly. The MD simulations and docking results show that BN and CC-NTs with MCP show good activity as drug carriers.
Phosphohistidine signaling promotes FAK-RB1 interaction and growth factor-independent proliferation of esophageal squamous cell carcinoma
Authors: Hochwald Steven , Zhang Jianliang , Gelman Irwin , Qu Jun
Published: May 2022

Current clinical therapies targeting receptor tyrosine kinases including focal adhesion kinase (FAK) have had limited or no effect on esophageal squamous cell carcinoma (ESCC). Unlike esophageal adenocarcinomas, ESCC acquire glucose in excess of their anabolic need. We recently reported that glucose-induced growth factor-independent proliferation requires the phosphorylation of FAKHis58. Here, we confirm His58 phosphorylation in FAK immunoprecipitates of glucose-stimulated, serum-starved ESCC cells using antibodies specific for 3-phosphohistidine and mass spectrometry. We also confirm a role for the histidine kinase, NME1, in glucose-induced FAKpoHis58 and ESCC cell proliferation, correlating with increased levels of NME1 in ESCC tumors versus normal esophageal tissues. Unbiased screening identified glucose-induced RB1 binding to FAK, mediated through a “LxCxE” RB1-binding motif in FAK’s FERM domain. Importantly, in the absence of growth factors, glucose increased FAK scaffolding of RB1 in the cytoplasm, correlating with increased ESCC G1àS phase transition. Our data strongly suggest that this glucose-mediated mitogenic pathway represents a unique targetable opportunity in ESCC.
Subdividing ART Patients and Analyzing the Medical Burden by Modeling of CD4 Cell Count
Authors: Li Min , Wang Qunwei , Shen Yinzhong
Published: May 2022

Objective To subdivide the antiretroviral therapy (ART) HIV/AIDS patients by modeling the CD4 cell count variable, aiming to reduce the medical burden from life-long ART.Methods The data of outpatients at the research unit between August 2009 and December 2020 were exported and mined. A recency-frequency (RF) model was established for data subdivision, and data of Non-churn ART patients were preserved. Common factor analysis (CFA) was conducted on the three indicators of the baseline/mean/last CD4 cell counts to obtain critical variables, then k-means modeling was used to subdivide ART patients, and their medical burden was analyzed.Results A total of 12,106 samples of Non-churn ART patients were preserved by RF modeling. The baseline/mean/last CD4 cell counts served as important variables employed for modeling. The patients were divided into 15 types, including two types with poor compliance and poor immune reconstitution, two types with good compliance but poor immune reconstitution, four types with poor compliance but good immune reconstitution and seven types with good compliance and good immune reconstitution: the frequency of visits was 5.25-9.95 visits/person/year, and the percentage of examination fees was 44.24-59.05%, with a medical burden of 4,114.24-12,676.66 yuan/person/year, of which 42.62-70.09% was reduced.Conclusion The CD4 cell count is not only an important indicator for judging post-ART immune recovery, but also a major modeling variable in subdividing ART patients with varying medical burdens. Poor compliance and poor immune reconstitution lead to excessive visits and frequent examination, which were the leading causes of the heavy medical burden of ART.
Species-specific plastid SSR markers reveal evidence of cultivar misassignments in Brazilian pecan orchards
Authors: Nagel Jordana , Poletto Tales , Muniz Marlove , Poletto Igor , Oliveira Joana , Stefenon Valdir Marcos
Published: May 2022

Pecan is an important perennial species introduced in southern Brazil more than 80 years ago with cultivars originating from the USA. The expansion of planted areas in Brazil is limited due to poor performance of some cultivars in regions climatically different from the original distribution area of the species. The development of cultivars adapted to the Brazilian edaphoclimatic conditions is, therefore, needed. As the correct identification of registered cultivars is essential for the development of pecan breeding programs, this study aimed at using a novel set of plastid SSR markers for identifying possible misassignments in Pecan cultivars from southern Brazilian orchards. Twenty-four plants of eight commercial cultivars and three plants from open-pollinated origin were genotyped using ten plastid SSR markers. These markers were developed from the plastid genome of the pecan cultivar Imperial. The plastid markers, which have maternal inheritance in pecan, clearly represented the parental relationship among cultivars Shawnee, Jackson, Success, and Barton. The low genetic differentiation between cultivars Shawnee and Jackson reflected the close relationship of half-sibs since both have cultivar Schley as maternal parent. The samples of cultivar Barton formed a single clade in the UPGMA cluster analysis. On the other hand, there was no consistent grouping of plants identified as Imperial, Melhorada, Mahan, Jackson, Shawnee, Success, as well as those from open-pollinated origin. Thus, samples named Barton have the same genetic patterns, while some samples named Imperial, Melhorada, Mahan, Jackson, Shawnee, Success are likely misassigned. The plastid microsatellite markers used in this study are relevant tools for advancing breeding programs of pecan, through the selection of genotypes, characterization of genetic diversity and identification of genitors.
Meiosis Conversion of Centrioles
Authors: Ubani Solomon I.
Published: May 2022

Research was to study meiosis a kind of cell division by reproductive organism. The research question involved can two processes of division result in four cells with only a particular replicate. The method involved study of complex DNA found in eukaryotic cells. This consisted of research of its function and density of structures. The results showed the reproductive cells were past due were converted in motile cells. The resultant was less regular and contained a Golgi apparatus, centrioles and mitochondria. The location was confirmed by microscopy of different Golgi indicators. The phases contained a constant number of Golgi dispersed in the cytoplasm. It concluded before division, genetic material from the reproductive each crossed other creating a combination of cells. The fertilization of the haploid cells produced by meiosis produced a cell with two copies.
Effect of traction direction and pressure load on the palatal plate on retentive force
Authors: Yamane Kunihito , Sato Yuji , Furuya Junichi , Kitagawa Noboru , Ikemura Naoya , Shimodaira Osamu
Published: May 2022

Background: Recently, denture stabilizers that are easy to clean and contain moisturizing ingredients have been developed for patients with dry mouth. Although the retentive force produced by conventional denture stabilizers and oral moisturizers have been compared on models, no study has reported their comparison in the oral cavity. In this study, we aimed to clarify the effects of different directions of traction and loads at the time of pressure contact on the retentive force on a palatal plate made from a dentulous jaw model.Methods: A palatal plate was fabricated with thermoplastic resin on a dentulous jaw model, and a loop-shaped traction device was attached to the centre of the palate. The test samples were a cream-type denture adhesive, a denture adhesive for dry mouth, an oral moisturizer, and a denture moisturizer. The specimens were applied to the inner surface of the plate, which was then mounted under vertical pressure. Then, the retentive force was measured, using a digital force gauge, while the plate was pulled in different directions and with different loads.Results: No significant difference in retentive force was observed in any of the test samples when the direction of traction was between 45° and 60°. The retentive force of the denture adhesive for dry mouth was significantly higher with a direction of traction of 90° than that of 45° or 60°. The retentive force when oral moisturizer was used was significantly higher in the 90° traction direction than in the 45° direction. There was no significant difference between a force of 4.0 kgf or 5.5 kgf when using a denture adhesive for dry mouth. Comparing the four load size conditions, the larger the load, the higher was the retentive force. Similar results were obtained for the cream-type denture adhesive and denture moisturizer. Significantly higher retentive force was observed for larger loads when oral moisturizer was used.Conclusions The results suggest that the direction of traction and the pressure load affect the retentive force on a palatal plate.
Immunohistochemical Analysis of Tn Neoantigen Expression in Colorectal Adenocarcinoma and Precursor Lesions
Authors: Dombek Gabrielle E. , Ore Ana Sofia , Cheng Jane , Matsumoto Yasuyuki , Glickman Jonathan N. , Fleishman Aaron , Heimburg-Molinaro Jamie , Poylin Vitaliy Y. , Fabrizio Anne , Cataldo Thomas , Messaris Evangelos , Cummings Richard D.
Published: May 2022

Background
The Tn neoantigen (CD175) is an O-glycan expressed in various types of human adenocarcinomas, including colorectal cancer (CRC), though prior studies have relied heavily upon poorly characterized in-house generated antibodies and lectins. In this study, we explored Tn expression in CRC using ReBaGs6, a well-characterized recombinant murine antibody with high specificity for clustered Tn antigen.
Methods
Using well-defined monoclonal antibodies, expression patterns of Tn and sialylated Tn (STn) antigens were characterized by immunostaining in CRC, in matched peritumoral [transitional margin (TM)] mucosa, and in normal colonic mucosa distant from the tumor, as well as in adenomas. Vicia villosa agglutinin lectin was used to detect terminal GalNAc expression. Histo-scoring (H scoring) of staining was carried out, and pairwise comparisons of staining levels between tissue types were performed using paired samples Wilcoxon rank sum tests, with statistical significance set at 0.05.
Results
While minimal intracellular Tn staining was seen in normal mucosa, significantly higher expression was observed in both TM mucosa (p < 0.001) and adenocarcinoma (p < 0.001). This pattern was reflected to a lesser degree by STn expression in these tissue types. Interestingly, TM mucosa demonstrates a Tn expression level even higher than that of the adenocarcinoma itself (p = 0.019). Colorectal adenomas demonstrated greater Tn and STn expression relative to normal mucosa (p < 0.001 and p = 0.012, respectively).
Conclusions
In summary, CRC is characterized by alterations in Tn/STn antigen expression in neoplastic epithelium as well as peritumoral benign mucosa. Tn/STn antigens are seldom expressed in normal mucosa. This suggests that TM mucosa, in addition to CRC itself, represents a source of glycoproteins rich in Tn that may offer future biomarker targets.
Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with Covid-19: an open-label randomized controlled trial
Authors: De Leeuw Elisabeth , Damme Karel F.A. Van , Declercq Jozefien , Bosteels Cedric , Maes Bastiaan , Tavernier Simon J. , Detalle Laurent , Smart Trevor , Glatt Sophie , Debeuf Nincy , Deckers Julie , Lameire Sahine , Vandecasteele Stefaan J , De Neve Nikolaas , Demedts Ingel K. , Govaerts Elke , Knoop Christiane , Vanhove Karolien , Moutschen Michel , Terryn Wim , Depuydt Pieter , Braeckel Eva Van , Haerynck Filomeen , Hendrickx Tine C.J. , Parrein Vanessa , Lalla Marianna , Brittain Claire , Lambrecht Bart N.
Published: May 2022

Background: The efficacy and safety of complement inhibition in Covid-19 patients is unclear.Methods: A multicenter randomized controlled, open-label trial. Hospitalized Covid-19 patients with signs of hyperinflammation and hypoxemia (PaO2/FiO2 below 350 mHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.Results: 81 patients were randomly assigned to zilucoplan (n=55) or the control group (n=26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56·4 mmHg in the zilucoplan group and 20·6 mmHg in the control group (mean difference +35.8; 95% confidence interval (CI) -9.4 to 80.9; p=0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0·4; 95% CI 0·1 to 1·5) At long-term follow up, the distance walked in a 6 min test was 539·7 m in zilucoplan and 490·6 m in the control group (p=0·18). Zilucoplan lowered serum C5b-9 (p<0·001) and interleukin-8 (p=0·03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.Conclusion: Administration of zilucoplan to Covid-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function and clinical outcome suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.(Funded by UCB and Ghent University Special Research Fund for COVID-19 Research; ClinicalTrials.gov, NCT04382755 – May 11, 2020; EudraCT, 2020-002130-33 – May 6, 2020)
Multi-omics analysis revealed the association of human gut microbiota composition and metabolic functions with the daily diet of the additive Ficus hirta Vahl
Authors: Lin Ying , Xiao Ruiming , Luo Guangjuan , Liao Wanci , Chen Shuting , Han Shuangyan , Liang Shuli
Published: May 2022

Ficus hirta Vahl (FHV), a traditional herbal ingredient of the tonic diet, receives increasing popularity in southern China. However, it is largely unknown that how a FHV diet (FHVD) affects the human gut microbiome. A total of 43 healthy individuals were randomized into the FHVD (n=25) and Control (n=18) groups to receive diet intervention for 8 weeks. 16S rRNA sequencing, metagenomic sequencing and metabolic profile of participants were measured to assess the association between FHV diet and gut microbiome. A preservation effect of Faecalibacterium and enrichment of Dialister, Veillonella, Clostridium, and Lachnospiraceae were found during the FHVD. Accordingly, the pathway of amino acid synthesis, citrate cycle, coenzyme synthesis, and partial B vitamin synthesis were found to be more abundant in the FHVD. In addition, serine, glutamine, gamma-aminobutyric acid, tryptamine, and short-chain fatty acids (SCFAs) were higher after the FHVD. The conjoint analysis of FHV components and in-vitro fermentation confirmed that the improved SCFAs concentration was collectively contributed by the increasing abundance of key enzyme genes and available substrates. In conclusion, the muti-omics analysis showed that the FHVD optimized the structure of the gut microbial community and its metabolic profile, leading to a healthy tendency, with a small cluster of bacteria driving the variation rather than a single taxon.
ATPase Thorase Deficiency Causes α-synucleinopathy and Parkinson’s Disease-Like Behavior by Impairing PINK1/Parkin-Mediated Mitophagy
Authors: Zhang Jianmin , Gao Fei , Yang Jia , Cai Menghua , Yang Qi , Zhang Han , Li Chao , Wang Huaishan , Fu Yi , Wang Dongdong , Xu Yi , Chen Hui , Hu Yu , He Wei
Published: May 2022

Mitophagy is essential for the maintenance of mitochondrial quality control (MQC) and neuronal survival. Defects in mitophagy have been implicated in the onset and progression of Parkinson’s disease (PD). However, the underlying mechanisms of mitophagy in the pathogenesis of PD remains unclear. Here, the AAA+ ATPase Thorase was identified being essential for mitophagy. Mice lacking Thorase exhibited PD-like behavior and α-synucleinopathy in the brains. Genetic deletion of Thorase exacerbated phenotypes of α-synucleinopathy in a familial PD-like A53T mouse model, whereas overexpression of Thorase prevented α-syn accumulation in vivo. Thorase regulates the balance of mitochondrial fusion/fission.Thorase deficiency resulted in more fragmented mitochondria and the blockage of dysfunctional mitochondrion degradation through PINK1/Parkin-mediated mitophagy. Thorase directly interacted with α-syn and regulated ubiquitinated α-syn degradation through mitophagy. The discoveries in this study place Thorase as a novel druggable target for pharmaceutical intervention of PD.
The maximum standardized uptake value in patients with recurrent or persistent prostate cancer after radical prostatectomy and PSMA-PET-guided salvage radiotherapy–a multicenter retrospective analysis
Authors: Spohn Simon , Farolfi Andrea , Schandeler Sarah , Vogel Marco M.E. , Ruf Juri , Mix Michael , Kirste Simon , Ceci Francesco , Fanti Stefano , Lanzafame Helena , Serani Francesca , Gratzke Christian , Sigle August , Combs Stephanie E. , Bernhardt Denise , Gschwend Juergen E. , Buchner Josef A. , Trapp Christian , Belka Claus , Bartenstein Peter , Eiber Matthias , Nekolla Stephan G. , Schiller Kilian , Grosu Anca L. , Schmidt-Hegemann Nina-Sophie , Zamboglou Constantinos , Peeken Jan C.
Published: May 2022

Purpose:
This study aims to evaluate the association of the maximum standardized uptake value (SUVmax) in positron-emission tomography targeting prostate-specific-membrane-antigen (PSMA-PET) prior to savage radiotherapy (sRT) on biochemical recurrence free survival (BRFS) in a large multicenter cohort.
Methods:
Patients who underwent 68Ga-PSMA11-PET prior to sRT were enrolled in four high-volume centers in this retrospective multicenter study. Only patients with PET-positive local recurrence (LR) and/or nodal recurrence (NR) within the pelvis were included. Patients were treated with intensity-modulated-sRT to the prostatic fossa and elective lymphatics in case of nodal disease. Dose escalation was delivered to PET-positive LR and NR. Androgen deprivation therapy was administered at the discretion of the treating physician. LR and NR were manually delineated using and SUVmax was extracted for LR and NR. Cox-regression was performed to analyze the impact of clinical parameters and the SUVmax-derived values on BRFS.
Results:
235 patients with a median follow up (FU) of 24 months were included in the final cohort. 2-years and 4-years BRFS for all patients were 68% and 56%. The presence of LR was associated with favorable BRFS (p = 0.016). Presence of NR was associated with unfavorable BRFS (p = 0.007). While there was a trend for SUVmax values ≥ median (p = 0.071), SUVmax values ≥ 75%quartile in LR were significantly associated with unfavorable BRFS (p = 0.022, HR: 2.1, 95%CI 1.1–4.6). SUVmax value in NR was not significantly associated with BRFS. SUVmax in LR stayed significant in multivariate analysis (p = 0.030). Sensitivity analysis with patients for who had a FU of > 12 months (n = 197) and only LR confirmed these results.
Conclusion
The non-invasive biomarker SUVmax can prognosticate outcome in patients undergoing sRT and recurrence confined to the prostatic fossa in PSMA-PET. Its addition might contribute to improve risk-stratification of patients with recurrent PCa and to guide personalized treatment decisions in terms of treatment intensity adaption.
2-hydroxyethyl methacrylate-derived reactive oxygen species stimulate ATP release via TRPA1 in human dental pulp cells
Authors: Orimoto Ai , Kitamura Chiaki , Ono Kentaro
Published: May 2022

Extracellular ATP (adenosine triphosphate) and transient receptor potential ankyrin 1 (TRPA1) channels are involved in calcium signaling in odontoblasts and dental pain. The resin monomer 2-hydroxyethyl methacrylate (HEMA), used in dental restorative procedures, is related to apoptotic cell death via oxidative stress. Although the TRPA1 channel is highly sensitive to reactive oxygen species (ROS), the effect of HEMA-induced ROS on ATP release to the extracellular space and the TRPA1 channel has not been clarified in human dental pulp. In this study, we investigated the extracellular ATP signaling and TRPA1 activation by HEMA-derived ROS in immortalized human dental pulp cells (hDPSC-K4DT). Among the ROS-sensitive TRP channels, TRPA1 expression was highest in undifferentiated hDPSC-K4DT cells, and its expression levels were further enhanced by osteogenic differentiation. In differentiated hDPSC-K4DT cells, 30 mM HEMA increased intracellular ROS production and ATP release, although 3 mM HEMA had no effect. Pretreatment with the free radical scavenger PBN (N-tert-butyl-α-phenylnitrone) or TRPA1 antagonist HC-030031 suppressed HEMA-induced responses. These results suggest that ROS production induced by a higher dose of HEMA activates the TRPA1 channel in human dental pulp cells, leading to ATP release. These findings may contribute to the understanding of the molecular and cellular pathogenesis of tertiary dentin formation and pain in response to dental biomaterials.
Isotopic profile and functioning of hyperseasonal savannas threatened by Australian acacia invasion
Authors: Meira-Neto João Augusto Alves , Villa Pedro Manuel , Silva Nathália , Silva Maria Carolina Nunes Alves , Tolentino Glaucia Soares , Buttschardt Tillmann , Ulm Florian , Máguas Cristina
Published: May 2022

The hyperseasonal savanna experiences regular flooding, drought stresses and is a neotropical vegetation type threatened by global change including Acacia spp. invasion. To deepen the understanding of hyperseasonal savannas after Acacia invasion in a climate change scenario, we aimed to answer whether: i) the plants are separated into different metabolic groups of plants; ii) Acacia invasion can change the functioning for different metabolic groups of plants; iii) invasive Acacia uptake water differently from native species; iv) there are different threats of Acacia invasion on different metabolic groups of plants. We detected both C3 and C4 metabolic groups of plants. Two C3 species are possibly CAM facultative. The functioning of C3 plants as a functional group was not affected by the Acacia invasion, but this result does not exclude an expected species turnover between C3 herbs and C3 trees. The C4 plants of invaded Mussununga lost their response of increasing water use efficiency to the increasing Leaf N%. Plants depend on the same water source as the soil water from recent rains. There are differences in d18O among species possibly because some grow mostly during the rainy season with the 18O-enriched water meanwhile the invader Acacia mangium grows throughout the year whenever it rains. C3 plants largely dominate these ecosystems. There is a possible threat to C4 plants. Hyperseasonal savannas should be considered critically endangered by global change, especially after Acacia invasions. Initiatives for conservation of hyperseasonal savannas should be considered for effective conservation of these ecosystems.
SS-31 Modification Inhibits Pro-inflammatory Effect of Macrophages Induced by Superparamagnetic Iron Oxide Nanoparticles
Authors: Lu Qizheng , Liu Haibo , Zheng Hao , Zhang Youming , Ou Jinbo , You Jieyun , Zhang Qi , Pi Jingjiang , Yao Xiaobo , Xu Jing , Wang Xingxu , Wang Yunkai , Pei Ning , Shen Yunli
Published: May 2022

Superparamagnetic iron oxide nanoparticles (SPION) could induce macrophage polarization into the pro-inflammatory M1-like subtype. The adverse effect is very likely to restrict the diagnostic or therapeutic applications of SPION in the cardiovascular field. To inhibit the pro-inflammatory effect, a mitochondrial targeted antioxidant peptide SS-31 modifying SPION (SPION@SS-31) was constructed. The macrophages (RAW 264.7) were incubated with SPION or SPION@SS-31 at the concentration of 50 µg Fe3O4/mL for 24 hours. Compared to the SPION group, the SPION@SS-31 group demonstrated significantly reduced macrophage damage, evidenced by maintained cell viability, a decrease of early cells apoptosis and reactive oxygen species (ROS) production. Moreover, the pro-inflammatory factor TNF-α and M1-like cell surface markers CD86 and CD80 were significantly down-regulated in the SPION@SS-31 group. Notably, higher levels of anti-inflammatory factors IL-10 and TGF-β and M2-like cell surface marker CD163 were detected in the SPION@SS-31 group by enzyme-linked immunosorbent assay (ELISA) and flow cytometric analysis. Besides, severe disruption of mitochondrial microstructure was observed by transmission electron microscope (TEM) in the SPION group, but less in the SPION@SS-31 group. Co-loading mitochondria-targeted antioxidant peptide SS-31 could significantly mitigate the pro-inflammatory effect of macrophages induced by SPION, indicating that the modification strategy has the potential to promote macrophages M2-like polarization in vitro study.
Cofactors in food allergy: a retrospective study on a cohort of Sardinian patients sensitized to Omega-5 gliadin and Pru p 3
Authors: Costanzo Giulia , Matolo Annalisa , Saderi Laura , Messina Maria Rita , Firinu Davide , Barca Maria Pina , Serra Paolo , Corso Nicoletta , Sotgiu Giovanni , Giacco Stefano Del
Published: May 2022

Purpose: Aim of this study is to clarify the impact of cofactors on allergic reactions in patients sensitized to LTP and ω-5-gliadin.Materials and methods: We retrospectively examined the charts of our outpatients from January 2015 to July 2019 and identified 157 patients seen for urticaria/angioedema or anaphylaxis after a meal, in presence or absence of cofactors and sensitized to LTPs (Pru p 3 and/or Tri a 14) and/or ω-5-gliadin (Tri a 19). Results: we compared LTPs-positive patients and those sensitized to Tri a 19 in order to assess the difference in cofactors involved and in frequency of clinical presentation. Our data show that exercise is the most frequent cofactor in FDEIAn and the involvement of exercise, alcohol and multiple cofactors was more frequently found in males than in females. We found that exercise, pollen counts peaks and multiple cofactors were more often related to anaphylaxis than mild reactions. Finally, we performed a comparison between LTPs+ patients and Tri a 19+ patients that showed, in this latter group, a lower frequency of allergic comorbidities, a higher median age at the onset of symptoms and frequency of alcohol exposure.Conclusions:Our data show that the search for possible cofactors involved in food allergy is essential not only for diagnostic purposes, but also for risk assessment strategies.
Profiles of GPs with High and Low Physician Empathy: Personal, Professional, and Antibiotic Prescribing Characteristics
Authors: Kristensen Troels , Ejersted Charlotte , Ahnfeldt-Mollerup Peder , Søndergaard Jens , Charles Justin
Published: May 2022

Background
General Practitioner’s (GPs) professional empathy has been hypothesized to have substantial impact on their delivered healthcare and use of medicine. This study compares profiles of personal, professional, and antibiotic prescribing characteristics of GPs with high and low empathy.
Methods
We apply an extreme group design and a unique combined set of survey and drug register data. The survey was sent to a stratified sample of 1,196 GPs comprising 30% of the Danish GP population and 464 GPs responded(38,8%). GPs in the top and bottom decile of empathy levels were identified. The applied Jefferson Scale of Empathy for Health Professionals includes 20 items that fall into three factors: perspective taking, compassionate care, walking in patient’s shoes. Total scores, factor scores, and individual item scores were calculated to disentangle the differences between the profiles. All intra- and inter-profile descriptive statistics and differences were bootstrapped to estimate the variability and related confidence intervals (CIs).
Results
61% of GPs in the top decile of the empathy score were female. GPs in this group reported the following person-centered factors as more important for their job satisfaction than the bottom decile: The Patient-physician relationship, interaction with colleagues, and intellectual stimulation. High-empathy scoring GPs prescribed significantly less penicillin than the low-empathy GPs. This was true for most penicillin subcategories. There were no significant differences in age, practice setting (urban vs. rural), practice type (partnership vs. single-handed), overall job satisfaction, or GP’s value of prestige and economic profit for their job satisfaction. The intra profile variation index and CIs show less prescribing uncertainty among GPs with high empathy.
Conclusions
This study reveals that high empathy GPs may have different personal, professional, and antibiotic prescribing characteristics than low empathy GPs and have less variable empathy levels as a group. Furthermore, person-centered high empathy GPs on average seem to prescribe less penicillins than low empathy GPs.