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Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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Stroke & Vascular Neurology 2024年第1期9卷 38-49,I0035-I0046页

作者： Jason Philip Appleton Lisa J Woodhouse Craig S Anderson Sandeep Ankolekar Lesley Cala mark Dixon Timothy J England Kailash Krishnan Grant mair Keith W muir John Potter Christopher I Price marc Randall Thompson G Robinson Christine Roffe Else C Sandset Jeffrey L Saver angela Shone Aloysius Niroshan Siriwardena Joanna m Wardlaw Nikola Sprigg Philip m Bath Stroke University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Applied HealthResearch University of Birmingham College of Medical and Dental SciencesBirminghamUK Stroke Trials Unit Mental Health and Clinical NeurosciencesUniversity of NottinghamNottinghamUK Faculty of medicine The George Institute for Global HealthSydneyNew South WalesAustralia The George Institute China at Peking University Health Science Center BeijingChina Neurology Royal Prince Alfred HospitalSydney Health PartnersSydneyNew South WalesAustralia Department of Neurology King's College Hospital NHS Foundation TrustLondonUK Faculty of Health and medical Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia East midlands Ambulance Service NHS Trust NottinghamUK Stroke Queen's Medical CentreNottingham University Hospitals NHS TrustNottinghamUK Centre for Clinical Brain Sciences Dementia Research InstituteUniveristy of EdinburghEdinburghUK Institute of Neurology and Psychology University of GlasgowGlasgowUK Bob Champion Research and Education Building University of East AngliaNorwichUK Institute of Neuroscience Newcastle UniversityNewcastle upon TyneUK Department of Neurology Leeds Teaching Hospitals NHS TrustLeedsUK Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUK Stroke Research in Stoke Institute for Science and Technology in MedicineKeele UniversityStoke-on TrentUK Department of Neurology Oslo University HospitalOsloNorway Research and Development Norwegian Air Ambulance FoundationOsloNorway Department of Neurology and Comprehensive Stroke Center David Geffen School of MedicineUCLALos AngelesCaliforniaUSA Research and Graduate Services University of NottinghamNottinghamUK Community and Health Research Unit University of LincolnLincolnUK

Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is unclear.Here,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of onset.The primary outcome was a shift in scores on the modified Rankin scale(mRS)at day 90.Secondary outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’markers.Data were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or mann-Whitney difference(mWD)with 95%CI.Results 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]min.Neuroimaging‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(mWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe stroke.Conclusions In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.WHAT IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those with acute stroke treated within 6hours of stroke

关键词： Glasgow nitrate random

A Golden Touch in the Design of multifunctional Porphyrin metallacages:Host-Guest Chemistry for Drug-Target Interactions

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CCS Chemistry 2024年第7期6卷 1662-1671页

作者： Tamara Rodríguez-Prieto Darren Wragg Nicole Heiduk mihyun Park Nicole Strittmatter Roland A.Fischer angela Casini Guillermo moreno-Alcántar Chair of medicinal and Bioinorganic Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München Professorship for Analytical Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München Chair of Inorganic and metalOrganic Chemistry Department of ChemistrySchool of Natural SciencesTechnical University of Munich85748 Garching b.München munich Data Science Institute(mDSI) Technical University of Munich85748 Garching b.München

The use of three-dimensional self-assembled metallacages(mCgs)as multimodal drug platforms holds great promise.However,the synthesis of mCgs with increased complexity and functionality is a great challenge since understanding of the interaction of mCgs with biological targets is still limited.In this context,this work reports on the integration of a gold(III)porphyrin scaffold into a prismatic mCg structure and explores its application for multimodal therapy of cancer in vitro,namely enabling both photodynamic therapy and chemotherapy.Combining experimental approaches with a state-of-the-art metadynamics theoretical study,we discovered that the gold cage shows unprecedented host-guest interaction-driven selective stabilization of guanine-quadruplex(G4)structures-validated anticancer drug targets-disclosing a new mechanism to pursue in the design of supramolecular drugs.

关键词： gold metallacages porphyrins G4stabili-zation host-guestchemistry anticanceragents

Dysfunction of the adhesion G protein-coupled receptor latrophilin 1(ADGRL1/LPHN1)increases the risk of obesity

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2298-2311页

作者： Heba ZabriTorsten Schöneberg AndréNguyen Dietzsch Hadi Al-Hasani Joachim Altschmied Katharina Bottermann Jana Brendler Judith Haendeler Susanne Horn Isabell Kaczmarek Antje Körner Kerstin Krause Kathrin Landgraf Diana Le Duc Laura Lehmann Stefan Lehr Stephanie Pick Albert Ricken Rene Schnorr angela Schulz martina Strnadová Akhil Velluva Heba Zabri Torsten Schöneberg Doreen Thor Simone Prömel Rudolf Schönheimer Institute of Biochemistry Medical FacultyLeipzig UniversityLeipzigGermany Institute for Clinical Biochemistry and Pathobiochemistry Medical FacultyGerman Diabetes CenterLeibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany German Center for Diabetes Research(DZD e.V.) Munich-NeuherbergGermany Cardiovascular Degeneration Clinical Chemistry and Laboratory DiagnosticsMedical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Cardiovascular Research Institute(CARID) Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Institute of Pharmacology Medical FacultyUniversity Hospital and Heinrich Heine University DüsseldorfDüsseldorfGermany Institute of Anatomy Medical FacultyLeipzig UniversityLeipzigGermany Center for Pediatric Research Hospital for Children and AdolescentsMedical FacultyLeipzig UniversityLeipzigGermany Helmholtz Institute for metabolic Obesity and Vascular Research(HI-MAG)of the Helmholtz Zentrum München at the University of Leipzig and University Hospital LeipzigLeipzigGermany Department of Endocrinology NephrologyRheumatologyLeipzig University Medical CenterLeipzigGermany Institute of Human Genetics Leipzig University Medical CenterLeipzigGermany Institute of Cell Biology Department of BiologyHeinrich Heine University DüsseldorfDüsseldorfGermany School of medicine University of Global Health EquityKigaliRwanda

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy balance.They,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from adipocytes.mutations in some GPCRs,such as the melanocortin receptor type 4(mC4R),have been associated with early-onset obesity.Here,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy balance.Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose homeostasis.Consistently,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity.Therefore,we propose that LPHN1 dysfunction is a risk factor for obesity development.

关键词： obesity metabolism intake

The role of emergency incident type in identifying first responders' health exposure risks

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Journal of Safety Science and Resilience 2023年第2期4卷 167-173页

作者： Emily J.haas Katherine N.Yoon Alexa Furek megan Casey Susan m.moore National Personal Protective Technology Laboratory(NPPTL) National Institute for Ocupational Safety and Health(NIOSH)PittsburghPA 15236United States National Personal Protective Technology Laboratory(NPPTL) National Institute forOccupational Safety and Health(NIOSH)MorgantownWV2605United States

Fire-based emergency management service(EmS)personnel are dispatched to various incidents daily,many of which have unique occupational risks.To fully understand the variability of incident types and how to best pre-pare and respond,an exploration of the U.S.coding system of incident types is necessary.This study uses potential exposure to SARS-CoV-2 as a case example to understand if and how coding categories for incident call types may be updated to improve data standardization and emergency response decision making.Researchers received emergency response incident data generated by three fire department computer-aided dispatch(CAD)systems between march and September 2020.Each incident was labeled EmS,Fire,or Other.Of the 162,766 incidents,approximately 8.1%(n=13,144)noted potential SARS-CoV-2 exposure within their narrative descriptions of which 86.3%were coded as EmS,9.9%as Fire,and 3.9%as Other.To assess coding variability across incident types,researchers used the original 3-incident type variable and a new 5-incident type variable reassigned by researchers into EmS,Fire,Other,Hazmat,and motor Vehicle.Logit regressions compared differences in potential exposure using the 3-and 5-incident type variables.When evaluating the 3-incident type variable,those respond-ing to a Fire versus an EmS incident were 84%less likely to be associated with potential exposure to SARS-Cov-2.For the 5-incident type variable,those responding to Fire incidents were 77%less likely to be associated with a potential exposure than those responding to EmS incidents.Changes in potential exposure between the 3-and 5-incident type models show the need to understand how incident types are assigned.This demonstrates the need for data standardization to accurately categorize incident types to improve emergency preparedness and response.Results have implications for incident type coding at fire department municipality and national levels.

关键词： Emergencymedical se Firefighter Incident type Surveillance Telecommunicator

Viscoelasticity and shear resistance at the aggregate scale of structured and organic carbon-free Chernozems

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Pedosphere 2023年第5期33卷 754-764页

作者： Christoph haas Rainer HORN Philipp SAGGAU Rainer DUTTmANN Institute for Plant Nutrition and Soil Science University of KielKiel 24118Germany Department of Geography Division of Landscape Ecology and Geoinformation SciencesUniversity of KielKiel 24118Germany

Soil rheology characterises the flow behaviour of soils at the particle-particle to aggregate scale.Amplitude sweep tests(ASTs)are often the method of choice for parameterizing soil flow properties,such as the shear strain values at the end of the linear viscoelastic range(i.e.,the deformation is mainly elastic)and at the yield point(i.e.,elastic equals plastic deformation).Samples from seven soil profiles and five soil depths of Chernozems,collected in the maidanetske study area,close to Uman City of Ukraine,were analysed to evaluate the effect of soil organic carbon(SOC)on the parameters related to soil microstructural stability derived from ASTs.Soil organic carbon was removed with H_(2)O_(2)to determine the soil texture-dependent values of soil rheological properties,which were compared to the values determined for samples with intact water-stable aggregates.The shear resistance-related parameters increased for aggregated soil samples compared to SOC-free soil samples,indicating an increase in soil stability due to SOC.In contrast,the values of the overall viscoelasticity and the shear strain were reduced for aggregated soil samples,indicating decreased soil stability.Pedotransfer functions were applied to predict the shear strain-dependent loss and storage moduli and shear stress values as a function of SOC depletion.Coarse particles(630–2000μm)and volumetric water content improved the models.We conclude that increased SOC content,through the gluing and cementing effects of SOC and altered aggregate shapes compared to SOC-free soil materials,contributes to higher microstructural strength.However,the increased water content in the SOC-containing soil samples reversed soil strengthening effect.This was due to the fact that a more rapid increase in positive water pressure under shear stress weakened the samples and the spherical aggregates began to rotate more easily,thus loosing energy,when compared to platy particles of the SOC-free soil materials.

关键词： aggregation rheology shear strain shear stress soil organic carbon depletion soil stability

Functional diversity in an Andean subparamo affected by wildfire in Colombia

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Plant Diversity 2023年第4期45卷 385-396页

作者： Korina Ocampo-Zuleta angela Parrado-Rosselli Instituto de Ciencias Ambientales y Evolutivas.Facultad de Ciencias.Universidad Austral de Chile.Campus Isla Teja 5090000 ValdiviaChile Programa de Doctorado en Ciencias mencion Ecología y Evolucion Escuela de GraduadosFacultad de CienciasUniversidad Austral de ChileValdiviaChile Jardín Botanico de Bogota Jose Celestino mutis Subdireccion CientíficaLínea de Investigacion en Restauracion Ecologica111071BogotaColombia Facultad del medio Ambiente y Recursos Naturales Universidad Distrital Francisco Jose de CaldasSede Vivero111711BogotaColombia

Recently,the Andean subparamo in Colombia has experienced severe wildfires,but little is known about the functional composition of recovering or not after a wildfire.Therefore,we examined the functional community composition subparamo affected byfire in 2016.We documented how functional traits changed 31 months after the disturbance and compared them with an unburned site.We sampled from one to two years after the fire every four months,then registered all recruits in 1655m plots.New individuals were classified into strategy functional groups based on the traits of persistence and dispersal.The first group was stem type and regeneration mechanism(seedling and resprout),and the second was fruit type and dispersal mode.We investigated the degree to which functional diversity changes plant communities over time(woody and non-woody),and we compared it with an unburned site.The most relevant results showed that resprouts and seed regenerated increased post-fire time and significant differences between sampling periods.The anemochory is the most relevant dispersal mode that indicates the community capacity to colonize the new gaps opened by the fire rapidly.We discuss how wildfire appears to be a triggering factor for persistence and dispersal strategy groups in subparamo burned given their characteristics of tolerance to stress.For this reason,a greater functional divergence between the ecosystems studied post-fire recovery has been related to higher levels of biodiversity at the landscape scale due to the high degree of endemism and significant differences in species composition between paramos.

关键词： Subparamo Cerro aguanoso Dispersal mode Functional traits Postfire regeneration

Near-field terahertz nonlinear optics with blue light

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Light(Science & Applications) 2023年第5期12卷 838-846页

作者： angela Pizzuto Pingchuan ma Daniel m.mittleman Department of Physics Brown UniversityProvidence RI 02912USA School of Engineering Brown UniversityProvidence RI 02912USA

The coupling of terahertz optical techniques to scattering-type scanning near-field microscopy(s-SNOm)has recently emerged as a valuable new paradigm for probing the properties of semiconductors and other materials on the nanoscale.Researchers have demonstrated a family of related techniques,including terahertz nanoscopy(elastic scattering,based on linear optics),time-resolved methods,and nanoscale terahertz emission spectroscopy.However,as with nearly all examples of s-SNOm since the technique’s inception in the mid-1990s,the wavelength of the optical source coupled to the near-field tip is long,usually at energies of 2.5 eV or less.Challenges in coupling of shorter wavelengths(i.e.,blue light)to the nanotip has greatly inhibited the study of nanoscale phenomena in wide bandgap materials such as Si and GaN.Here,we describe the first experimental demonstration of s-SNOm using blue light.With femtosecond pulses at 410 nm,we generate terahertz pulses directly from bulk silicon,spatially resolved with nanoscale resolution,and show that these signals provide spectroscopic information that cannot be obtained using near-infrared excitation.We develop a new theoretical framework to account for this nonlinear interaction,which enables accurate extraction of material parameters.This work establishes a new realm of possibilities for the study of technologically relevant wide-bandgap materials using s-SNOm methods.

关键词： scattering optics nonlinear

Kids gone wild–Alcohol use and patient characteristics in pediatric trauma during the coronavirus disease 2019 pandemic

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Pediatric Investigation 2023年第4期7卷 225-232页

作者： Neesha S Patel Brett H Waibel Bennett J Berning WT Hillman Terzian Charity H Evans angela m Hanna mark E Hamill Department of Surgery Division of AcuteCare SurgeryUniversity of Nebraska Medical CenterOmahaNebraskaUSA Department of Surgery Division of General and Thoracic Pediatric SugeryChildren’s Hospital and Medical CenterOmahaNebraskaUSA

Importance:Reported coronavirus disease 2019(COVID-19)pandemic effects on pediatric trauma have been variable.Objective:We investigated the characteristics of pediatric trauma including alcohol use during the pandemic at our urban trauma center.methods:The trauma database of our adult level 1 trauma center was queried for all pediatric(age≤18 years)patients presenting between march 1,2020,and October 30,2020.Data from 2017 to 2019 served as a control.Variables analyzed included demographics,mechanisms,injury severity,hospitalization characteristics,and positive blood alcohol.Results:Pandemic pediatric trauma volumes increased by 67.5%(330/year vs.197/year).Pandemic patients were younger(median age 13 vs.14 years,P=0.011),but similar in gender,ethnicity,severity,hospital length of stay,mortality,and rates of penetrating injury.Falls doubled(79/year vs.34/year)and shifted away from high falls>6 meters(0%vs.7.9%)to moderate falls 1–6 meters(58.2%vs.51.5%)(P=0.028).Transportation injury rates were similar however mechanisms shifted from motor vehicle crashes(−13.5%)towards recreational vehicles including motorcycles(+2.1%),all-terrain vehicles(+8.6%),and bicycles(+3.8%)(P=0.018).Pediatricpositive blood alcohol was significantly higher(11.2%vs.5.1%,Pma volumes during the COVID-19 pandemic increased.Pandemic patients had more recreational vehicle injuries and higher rates of positive blood alcohol.This suggests an increased need for alcohol assessment and targeted interventions in the pediatric population during pandemics or periods of school closures.

关键词： Alcohol COVID-19 Pediatric trauma Pediatrics

Small is beautiful–a glycolytic metabolite signals mTORC1 activation in cancer cell metabolism

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Signal Transduction and Targeted Therapy 2020年第1期5卷 299-300页

作者： angela m.Otto munich Institute of BioEngineering Technical University of Munich85748 GarchingGermany

Even though the mTOR complex has been known for decades as a nutrient sensor,being thus in focus for drug targeting in metabolic disease and cancer metabolism,it has remained puzzling how it is able to get a sense of glucose availability in cells.Now,a small metabolite of the glycolytic pathway,dihydroxyacetone phosphate,has been identified by Sabatini and his coworkers,who show how mTORC1-activity is regulated in glucose-starved and replenished cancer cells.

关键词： metabolism cancer mTORC1