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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 ***,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 *** primary outcome was a shift in scores on the modified Rankin scale(mRS)at day *** 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’*** were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWD)with 95%*** 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]***‘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 *** 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 *** IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those w

关键词： Glasgow nitrate random

Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease

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World Journal of Gastroenterology 2022年第36期28卷 5280-5299页

作者： jeffrey Barr Warner Steven Corrigan Guenthner Josiah Everett Hardesty craig James McClain Dennis Ray Warner Irina Andreyevna Kirpich Department of Medicine Division of GastroenterologyHepatology and NutritionUniversity of Louisville School of MedicineLouisvilleKY 40202United States Department of Pharmacology and Toxicology University of Louisville School of MedicineLouisvilleKY 40202United States Alcohol Research Center University of Louisville School of MedicineLouisvilleKY 40202United States Hepatobiology and Toxicology Center University of Louisville School of MedicineLouisvilleKY 40202United States Veterans Health Administration Robley Rex Veterans Medical CenterLouisvilleKY 40206United States Department of Microbiology and Immunology University of Louisville School of MedicineLouisvilleKY 40202United States

Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths *** its prevalence,there are few effective pharmacological options for the severe stages of this *** much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic *** means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among *** platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the *** many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in *** review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent *** also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.

关键词： Liver targeted delivery Nanoparticles Liposomes Polymeric nanoparticles Precision medicine Alcohol associated liver disease

Dietary fatty acids and bioactive fatty acid metabolites in alcoholic liver disease

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Liver Research 2019年第3期3卷 206-217页

作者： Kara H.Zirnheld Dennis R.Warner jeffrey B.Warner Josiah E.Hardesty craig J.McClain Irina A.Kirpich Division of Gastroenterology Hepatologyand NutritionDepartment of MedicineUniversity of Louisville School of MedicineLouisvilleKYUSA Department of Pharmacology and Toxicology University of Louisville School of MedicineLouisvilleKYUSA University of Louisville Alcohol Center University of Louisville School of MedicineLouisvilleKYUSA Robley Rex Veterans Medical Center LouisvilleKYUSA

Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and *** work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully *** rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA *** is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in *** that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this *** current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.

关键词： Dietary fatty acids Bioactive fatty acid metabolites Alcoholic liver disease(ALD) Omega-6 polyunsaturated fatty acids(n-6 PUFAs) Omega-3 polyunsaturated fatty acids(n-3 PUFAs)

Simultaneous expander and deep inferior epigastric perforator reconstruction:indications and alloderm sling technique for protecting the anastomosis

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Plastic and Aesthetic Research 2015年第1期2卷 63-68页

作者： Elizabeth Stirling craig Ajul Shah Sarah Persing jeffrey Salomon Stefano Fusi Department of Surgery Section of Plastic and Reconstructive SurgeryYale University School of MedicineNew HavenCT 06520USA

Aim:Autologous tissue is considered the“gold standard”for breast reconstruction ***,little is known about deep inferior epigastric perforator(DIEP)flap reconstruction in combination with tissue expander(TE)/*** authors describe a series of combined DIEP flap/TE reconstruction,including its indications and technique to ensure protection of the pedicle during the expansion ***:Between January 2009 and December 2012,patients undergoing immediate DIEP with TE reconstruction were retrospectively ***,comorbid conditions,intraoperative,postoperative expansion,complications,and technique data points were *** were taken postoperatively and patient’s satisfaction surveys were obtained to assess overall ***:Five patients underwent immediate DIEP flap/TE reconstruction utilizing our alloderm sling *** were no complications to the pedicle,flap,expander,or mastectomy skin perioperatively or *** patients describe being very satisfied,often with improved breast volume and projection as compared to their preoperative ***:The results of this study suggest that DIEP flap/TE reconstruction is safe,in particular when utilizing the alloderm sling technique,and should be considered in patients who lack sufficient abdominal tissue,have existing breast asymmetries,or do not desire the scar deformity of latissimus dorsi.

关键词： Alloderm autologous breast cancer breast reconstruction deep inferior epigastric perforator tissue expander

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions

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Neural Regeneration Research 2021年第5期16卷 851-855页

作者： jeffrey ALowell Kar Men Mah John LBixby Vance PLemmon Miami Project to Cure Paralysis University of MiamiMiamiFLUSA Department of Neurological Surgery University of MiamiMiamiFLUSA Department of Molecular and Cellular Pharmacology University of MiamiMiamiFLUSA

Adeno-associated virus(AAV)is an essential instrument in the neuroscientist’s toolkit,which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene *** the field of neural regeneration,the transduction of neurons enables the observation and regulation of axon growth and regeneration,and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system *** formulations of AAV preparations permit efficient viral transduction under physiologic conditions,but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic *** studied AAV transduction in the context of prior exposure of AAV serotype 8(AAV8)to environmental pH within the range encountered during endosomal endocytosis(pH 7.4 to pH 4.4),during which low pH-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus *** to the fundamental nature of these processes,we hypothesized that premature exposure of AAV8 particles to acidic pH would decrease viral transduction of HT1080 cells in vitro,as measured by fluorescent reporter gene expression using high-content imaging *** found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency,and that quantitative levels of reporter gene expression in transduced cells were similarly *** biggest decrease in transduction occurred between pH 7.4 and pH 6.4,suggesting the possible co-occurrence of a pH-associated event and viral inactivation within that *** together,these findings indicate that exposure of AAV8 to acidic pH for as little as 1 hour is deleterious to transduction *** studies are necessary to understand the pH-associated

关键词： adeno-associated virus autolytic capsid low pH protease proteolytic temperature trafficking transduction viral inactivation

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雷曼倒闭台前幕后

财经 2008年第21期 68-70页

作者： Carrick Mollenkamp Susanne craig jeffrey Mccracken Jon Hilsenrath 《华尔街日报》

在信贷危机期间，金融公司夹存于各种相互冲突的压力之间；既要将痛苦的真相告知公众。

关键词：倒闭金融公司危机期信贷

A Pilot Trial Testing the Feasibility of Using Molecular-Guided Therapy in Patients with Recurrent Neuroblastoma

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Journal of Cancer Therapy 2012年第5期3卷 602-612页

作者： Giselle L. Saulnier Sholler William Ferguson Genevieve Bergendahl Erika Currier Shannon R. Lenox jeffrey Bond Marni Slavik William Roberts Deanna Mitchell Don Eslin Jacqueline Kraveka Joel Kaplan Nehal Parikh Suman Malempati Gina Hanna Emily Eugster David Cherba Jeremy Miller craig Webb Cardinal Glennon Children’s Hospital Saint Louis University School of Medicine St. Louis University St. Louis USA Center for Cancer Genomics and Computational Biology Pediatric Oncology Translational Research Program at the Van Andel Research Institute in Grand Rapids Grand Rapids USA Center for Children’s Cancer and Blood Disorders Arnold Palmer Hospital for Children MD Anderson Cancer Center Orlando Orlando USA Department of Pediatric Oncology Helen DeVos Children’s Hospital Michigan State University Grand Rapids USA Department of Pediatric Oncology Oregon Health Science University Portland USA Division of Hematology/Oncology 2J Connecticut Children’s Medical Center Hartford USA Pediatric Hematology/Oncology Medical University of South Carolina Charleston USA Pediatric Oncology Levine Children’s Hospital Charlotte USA Rady Children’s Hospital San Diego University of California San Diego School of Medicine at the University of California San Diego San Diego USA Vermont Cancer Center Department of Medicine University of Vermont Burlington USA

Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of neuroblastoma with existing therapeutic agents may result in a rational, data-driven approach with potential to improve clinical outcomes. Methods: The primary objective of this pilot study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug predicttion report, molecular tumor board review yielding a formulated treatment plan, and independent medical monitor review within a 2-week period. Results: Five patients with multiply relapsed or refractory neuroblastoma were enrolled between April and June 2010. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-7 days), reports which linked this data into medically actionable drug candidates (1-5 days), molecular tumor board (1-3 days) and independent medical monitor review (1 day) were all completed in real-time. The average time was 10.5 days for all patients. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in less than 12 days. This warrants further testing in a Phase I study to determine safety of predicted treatments and evaluate whether the information obtained in these analyses would result in patient benefit.

关键词： Neuroblastoma Molecular Guided Therapy Predictive Therapies Molecular Profiling Genomic Profiling Pediatric Cancer

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他汀类药物治疗与癌症的患病危险汇总分析

美国医学会杂志（中文版） 2007年第5期26卷 271-277页

作者： Krista M. Dale craig I. Coleman Nickole N. Henyan jeffrey Kluger C. Michael White 仝其广（译）胡大一（校） University of Connecticut School of Pharmacy Storrs University of Connecticut School of Medicine Farmington University of Connecticut School of Medicine Farmington and Divisions of Cardiology University of Connecticut School of Medicine and Drug Information Hartford HospitalHartfordconn. 不详

背景：随机对照试验证实，他汀类降胆固醇药物能够预防心脏事件的发生。近来的回顾性分析提示，他汀类药物还可预防癌症。目的：观测他汀类药物治疗对癌症发生和癌症死亡的影响，分析他汀类药物对不同类型癌症的作用，探讨他汀亲脂性或... 详细信息

背景：随机对照试验证实，他汀类降胆固醇药物能够预防心脏事件的发生。近来的回顾性分析提示，他汀类药物还可预防癌症。目的：观测他汀类药物治疗对癌症发生和癌症死亡的影响，分析他汀类药物对不同类型癌症的作用，探讨他汀亲脂性或其来源的作用。数据来源：使用特定的检索词对2005年7月以前的MEDLINE、EMBASE、CLINAHL、Web of Science、CANCERLIT和Cochrane系统综述数据库进行系统文献检索。审查心脏病和癌症摘要，对论文参考文献亦进行人工审查。研究选择：在筛查的8943篇（n=86936）文献中，27篇符合入选标准。27篇论文共报道了26项他汀类药物随机对照试验。这些研究至少平均随访1年，每项研究至少入选100例患者。研究提供了癌症发生（n=20项研究）或癌症死亡（n=22项研究）数据。资料提取：3位研究者使用标准的资料提取工具独立地提取所有资料。应用随机效应模型（DerSimonian和Laird法），加权均值报告为优势比（odds ratios，ORs）和95％可信区间（confidence intervals，CIs）。应用Q统计评估统计学异质性。资料综合：汇总分析共包括6662例癌症和2407例癌症死亡。结果显示，他汀类药物并未降低癌症的发生（OR，1．02；95％CI，0．97～1．07）或癌症死亡（OR，1．01；95％CI，0．93～1．09），也未见任何类型癌症的减少。无论是亲水性他汀或亲脂性他汀、天然他汀或人工合成他汀都没有影响癌症的发生。结论：在随机对照试验中，他汀类药物对癌症发生和癌症死亡的危险呈中性效应。我们发现，癌症类型不受他汀类药物使用与否的影响，不同他汀类药物亚型（亲水或亲脂性、天然或人工合成）对癌症的危险亦无影响。

关键词：他汀类药物防癌症汇总分析药物治疗随机对照试验 CANCERLIT Cochrane MEDLINE

Phased,chromosome-scale genome assemblies of tetraploid potato reveal a complex genome,transcriptome,and predicted proteome landscape underpinning genetic diversity

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Molecular Plant 2022年第3期15卷 520-536页

作者： Genevieve Hoopes Xiaoxi Meng John P.Hamilton Sai Reddy Achakkagari Fernanda de Alves Freitas Guesdes Marie E.Bolger Joseph J.Coombs Danny Esselink Natalie R.Kaiser Linda Kodde Maria Kyriakidou Brian Lavrijssen Natascha van Lieshout Rachel Shereda Heather K.Tuttle Brieanne Vaillancourt Joshua C.Wood Jan Mde Boer Nolan Bornowski Peter Bourke David Douches Herman Jvan Eck Dave Ellis Max J.Feldman Kyle M.Gardner Johannes C.P.Hopman Jiming Jiang Walter S.De Jong Joseph C.Kuhl Richard G.Novy Stan Oome Vidyasagar Sathuvalli Ek Han Tan Remco A.Ursum M.Isabel Vales Kelly Vining Richard G.F.Visser Jack Vossen G.craig Yencho Noelle L.Anglin Christian W.B.Bachem jeffrey B.Endelman Laura M.Shannon Martina V.Stromvik Helen H.Tai Bjorn Usadel C.Robin Buell Richard Finkers Department of Plant Biology Michigan State UniversityEast LansingMI 48824USA Department of Horticultural Science University of MinnesotaSt.PaulMN 55108USA Department of Plant Science McGill UniversitySainte-Anne-de-BellevueQC H9X 3V9Canada Plant Breeding Wageningen University&ResearchPlant Breeding6708 PB Wageningenthe Netherlands IBG-4 Bioinformatics Forschungszentrum JülichWilhelm Johnen Str52428 JülichGermany Department of Plant Soiland Microbial SciencesMichigan State UniversityEast LansingMI 48824USA Bayer Crop Science WoodlandCA 95695USA Averis Seeds B.V. 9640 AA Veendamthe Netherlands International Potato Center 1895 Avenida La MolinaLimaPeru USDA-ARS ProsserWA 99350USA Agriculture and Agri-Food Canada Fredericton Research and Development Centre FrederictonNB E3B 4Z7Canada School of Integrative Plant Science Cornell UniversityIthacaNY 14853-1901USA Department of Plant Sciences University of IdahoMoscowID 83844USA USDA-ARS Small Grains and Potato Germplasm ResearchAberdeenID 83210USA HZPC Research B.V. Edisonweg 58501 XG Jourethe Netherlands Department of Crop and Soil Science Oregon State UniversityHermistonOR 97838USA School of Biology and Ecology University of Maine5735 Hitchner Hall OronoME 04469USA Department of Horticultural Sciences Texas A&M UniversityCollege StationTX 77843-2133USA Department of Horticulture Oregon State UniversityCorvallisOR 97331USA Department of Horticultural Science North Carolina State UniversityRaleighNC 27695-7609USA Department of Horticulture University of Wisconsin-MadisonMadisonWI 53706USA Department of Horticulture Michigan State UniversityEast LansingMI 48824USA Institute for Biological Data Science Heinrich Heine UniversityDusseldorf40225 DusseldorfGermany Plant Resilience Institute Michigan State UniversityEast LansingMI 48824USA Present address:GenNovation B.V. Wageningenthe Netherlands

Cultivated potato is a clonally propagated autotetraploid species with a highly heterogeneous *** assemblies of six cultivars including two chromosome-scale phased genome assemblies revealed extensive allelic diversity,including altered coding and transcript sequences,preferential allele expression,and structural variation that collectively result in a highly complex transcriptome and predicted proteome,which are distributed across the homologous *** species contribute to the extensive allelic diversity in tetraploid cultivars,demonstrating ancestral introgressions predating modern breeding *** a clonally propagated autotetraploid that undergoes limited meiosis,dysfunctional and deleterious alleles are not purged in tetraploid *** a quarter of the loci bore mutations are predicted to have a high negative impact on protein function,complicating breeder’s efforts to reduce genetic *** StCDF1 locus controls maturity,and analysis of six tetraploid genomes revealed that 12 allelic variants of StCDF1 are correlated with maturity in a dosage-dependent *** of the complexity of the tetraploid potato genome with its rampant structural variation and embedded deleterious and dysfunctional alleles will be key not only to implementing precision breeding of tetraploid cultivars but also to the construction of homozygous,diploid potato germplasm containing favorable alleles to capitalize on heterosis in F1 hybrids.

关键词： potato allele diversity phased assembly polyploid pan-genome wild introgressions