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How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

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World Journal of Gastroenterology 2015年第40期21卷 11331-11342页

作者： Mark G Ward peter M Irving miles p sparrow Department of Gastroenterology The Alfred Hospital Department of Gastroenterology Guy’s and St. Thomas’ NHS Foundation Trust

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. Similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.

关键词： Inflammatory bowel disease Thiopurines Drug monito

Experimental and numerical investigation of orbital atherectomy: absence of cavitation

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Journal of Biomedical Science and Engineering 2010年第11期3卷 1108-1116页

作者： Reza Ramazani-Rend Srikar Chelikani Ephraim M. sparrow John p. Abraham 不详

A definitive, quantitative investigation has been performed to determine whether orbital atherectomy gives rise to cavitation. The investigation encompassed a synergistic interaction between in vitro experimentation and numerical simulation. The experimentation was performed in two independent fluid environments: 1) a transparent tube having a diameter similar to that of the superficial femoral artery and 2) a large, fluid-filled, open-topped container. All of the experimental and simulation work was based on the geometric model of the Diamondback 360 atherectomy device (Cardiovascular Systems, Inc., St. paul, MN). Rotational speeds ranged from 80,000 to 214,000 rpm. The presence or absence of cavitation in the experiments was assessed by means of high-speed photography. The photographic images clearly display the fact that there was no cavitation. Flow visualization revealed the presence of fluid flows driven by pressure gradients created by the geometry of the rotating crown. The numerical simulations encompassed the fluid environments and the operating conditions of the experiments. The key result of the numerical simulation is that the minimum fluid pressure due to the rotational motion was approximately 50 times greater than the saturation vapor pressure of the fluid. Since the onset of cavitation requires that the fluid pressure falls below the saturation vapor pressure, the computational outcome strongly supports the experimental findings.

关键词： Orbital Atherectomy Cavitation Arterial Disease Numerical Simulation

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天文速览

作者： (英)Giles sparrow

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Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford

作者： (英)Giles sparrow

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World Journal of Gastroenterology 2020年第30期26卷 4428-4441页

作者： Samba Siva Reddy pulusu Ashish Srinivasan Krupa Krishnaprasad Daniel Cheng Jakob Begun CharlotteKeung Daniel Van Langenberg Lena Thin Tamara Mogilevski peter De Cruz Graham Radford-Smith Emma Flanagan Sally Bell Soleiman Kashkooli miles sparrow Simon Ghaly peter Bampton Elise Sawyer Susan Connor Quart-ul-ain Rizvi Jane M Andrews Gillian Mahy paola Chivers Simon Travis Ian Craig Lawrance Centre for Inflammatory Bowel Diseases St John of God HospitalSubiaco 6008Western AustraliaAustralia Translational Gastroenterology Unit NIHR Oxford Biomedical Research CentreOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxford OX39DUUnited Kingdom Inflammatory Bowel Disease Research Group Queensland institute of Medical ResearchHerston 4006QueenslandAustralia Department of Gastroenterology Mater HospitalBrisbane 4101QueenslandAustralia Department of Gastroenterology Mater HospitalSouth Brisbane 4101QueenslandAustralia of Gastroenterology Eastern HealthBox Hill 3128VictoriaAustralia Department of Gastroenterology Fiona Stanley HospitalMurdoch 6150Western AustraliaAustralia Department of Gastroenterology Austin HealthHeidelberg 3084VictoriaAustralia Department of Gastroenterology St Vincent’s HospitalFitzroy 3065VictoriaAustralia Department of Gastroenterology Northern HealthEpping 3076VictoriaAustralia Department of Gastroenterology The Alfred HospitalMelbourne 3004VictoriaAustralia Department of Gastroenterology St Vincent’s HospitalDarlinghurst 2010New South WalesAustralia Department of Gastroenterology Flinders Medical CentreBedford Park 5042South AustraliaAustralia Department of Gastroenterology Liverpool HospitalSydney 2170New South WalesAustralia Department of Gastroenterology Royal Adelaide Hospital&University of AdelaideAdelaide 5000South AustraliaAustralia Department of Gastroenterology Townsville HospitalDouglas 4814QueenslandAustralia Institute for Health Research University of Notre DameFremantle 6160Western AustraliaAustralia School of Medicine and pharmacology University of Western AustraliaCrawley 6009Western AustraliaAustralia

BACKGROUND Vedolizumab(VDZ),a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis(UC)*** To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving *** A retrospective review of Australian and Oxford,United Kingdom data for UC *** response at 3 mo,endoscopic remission at 6 mo and clinical remission at 3,6 and 12 mo were *** regression models and Kaplan Meier curves were performed to assess the time to remission,time to failure and the covariates influencing *** outcomes were *** Three hundred and three UC patients from 14 centres in Australia and United Kingdom,[60%n=182,anti-TNF naïve]were *** clinical response was 79%at 3 mo with more Australian patients achieving clinical response compared to Oxford(83%vs 70%p=0.01).Clinical remission for all patients was 56%,62%and 60%at 3,6 and 12 mo ***-TNF naive patients were more likely to achieve remission than exposed patients at all the time points(3 mo 66%vs 40%ppp=0.03).More Australian patients achieved endoscopic remission at 6 mo compared to Oxford(69%vs 43%p=0.01).On multi-variate analysis,anti-TNF naïve patients were 1.8(95%CI:1.3-2.3)times more likely to achieve remission than anti-TNF exposed(ppatients(11%)had colectomy by 12 *** VDZ was safe and effective with 60%of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.

关键词： Vedolizumab Ulcerative colitis Outcomes

Modulated-power Implantable Neuromodulation Devices and Their Impact on Surrounding Tissue Temperatures

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Journal of Biomedical Science and Engineering 2016年第12期9卷 545-562页

作者： John R. Stark Sergio R. Romero John M. Gorman John p. Abraham Ephraim M. sparrow Department of Mechanical Engineering The University of Kansas Lawrence KS USA School of Engineering University of St. Thomas St. Paul MN USA Department of Mechanical Engineering University of Minnesota Minneapolis MN USA

This project was intended to determine whether the preprogrammed time-varying recharge protocol for a battery incased in a neuromodulation implant can give rise to tissue temperatures that surpass a safe level or are otherwise benign. The study included the development of a highly accurate model of all the thermal processes that are activated by the recharging of the battery contained within the neuromodulation implant. The model was implemented by numerical simulations performed for several realistic operating conditions. The computed spatial and temporal tissue temperature distributions were employed to estimate possible tissue damage by making use of two independent methodologies. Independent calorimeter-based experiments were performed to provide validation for the calculated rates of heat generation in the coils of the implant. Spatial and temporal tissue temperature distributions extracted from the numerical simulations revealed the thermal effects associated with several realistic operating protocols. None of the operating protocols gave rise to temperatures above 42℃. Numerical values of thermal tissue damage metrics were determined and compared with accepted values which correspond to the absence and the presence of tissue damage. The experimentally determined rate of heat generation in the implant coils validated that from electrical measurements to within 2%. Both the tissue temperature results and the thermal damage metrics found no evidence of tissue injury when time-varying preprogrammed protocols are used in the recharging of neuromodulation implant-encased batteries.

关键词： Biological Heating Neurostimulation Neuromodulation Implant Recharge Thermal Injury Modulated-power Implant

Controlling the rate of penetration of a therapeutic drug into the wall of an artery by means of a pressurized balloon

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Journal of Biomedical Science and Engineering 2013年第5期6卷 527-532页

作者： John R. Stark John M. Gorman Ephraim M. sparrow John p. Abraham Rob E. Kohler Cardiovascular Systems Inc. St. Paul USA Department of Mechanical Engineering University of Minnesota Minneapolis USA School of Engineering University of St. Thomas St. Paul USA

The focus of this paper is to propose, model, and characterize a means of accelerating the rate of delivery of therapeutic drugs to human tissues. The investigated means is a pressurized, permeable-walled balloon filled with a homogeneous mixture of the drug and the carrier fluid. The fluid mixture, driven by pressure, traverses the thickness of the balloon wall through laser-drilled pores. The number and deployment of the pores can be controlled to a high degree of precision. As a consequence, the wall of the balloon can be regarded as a homogeneous porous medium, and the traversing fluid flow can be analyzed by means of porous media models. When the balloon is in intimate contact with the surface of a tissue bed, the therapeutic fluid flows in series as it passes through the balloon wall and penetrates the tissue. The flow rate can be controlled by proper selection of the balloon permeability, the viscosity of the flowing medium, and the pressure internal to the balloon. The delivered concentration of the drug was predicted by coupling the present balloon-focused theory with a previously developed tissue-bed model that includes both diffusion and advection processes. The tribologic interaction of the pressurized balloon with an artery wall was investigated experimentally to assess the possible formation of aneurysms.

关键词： Heart Disease plaque Treatment paclitaxel Drug Delivery

Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism

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World Journal of Nephrology 2017年第1期6卷 21-28页

作者： Simon JM Welham Alexander J sparrow David S Gardner Matthew J Elmes Division of Nutritional Sciences School of BiosciencesUniversity of NottinghamLoughborough School of Veterinary Medicine and Science University of NottinghamLoughborough

AIM To evaluate the effects of the non-selective, non-steroidal anti-infammatory drug （NSAID） acetylsalicylic acid （ASA）, on ex vivo embryonic kidney growth and *** pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA （0.04-0.4 mg/mL） for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 （pGE2） for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous （pTGS2-/- and pTGS2-/＋） embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal *** ASA concentration （0.1, 0.2 and 0.4 mg/mL） significantly inhibited metanephric growth （p 〈 0.05）. After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively （ p 〈 0.01）. Addition of 10 μmol/L pGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L pGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% （0.2 mg/mL; p 〈 0.05） and 47% （0.4 mg/mL; p 〈 0.01）. Finally, growth of pTGS2-/- and pTGS2＋/- kidneys in organ culture showed no differences, indicating that pTGS2 derived pGE2 may at best have a minor *** reduces early renal growth and development but the role of

关键词： Acetylsalicylic acid Nephrogenesis Kidney culture Non-steroidal anti-infammatory drug prostaglandins prostaglandin synthase 2

对采用Humphrey Matrix 24-2阈值方案的倍频技术视野检查法的临床评价

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世界核心医学期刊文摘（眼科学分册） 2005年第11期1卷 31-32页

作者： Spry p.G.D. Hussin H.M. sparrow J.M. 韩静 Bristol Eye Hospital Lower Maudlin Street Bristol BS1 2LX United Kingdom Dr.

Aims: To evaluate performance of frequency doubling technology (FDT) perimetry using the Humphrey Matrix 24-2 thresholding program in a hospital eye service (HES) glaucoma clinic. Methods: A random sample or individuals referred consecut ively to the HES for suspected glaucoma were examined with 24-2 threshold FDT i n addition to routine clinical tests. The discriminatory power of FDTand standar d automated perimetry (SAp) were assessed using glaucomatous optic nerve head ap pearance as the reference gold standard. Results: 48 of 62 eligible referred ind ividualswere recruited. Glaucoma prevalence was 31%. Median test duration per e ye was 5 minutes 16 seconds for FDT and 5 minutes 9 seconds for SAp. There was n o significant difference (p=0.184) between proportions of individuals with relia ble test results (FDT 75%, SAp 63%). Using a clinically appropriate binary criterion for abnormal visual field, sensitivity and specificity levels were 100%and 26%respectively for FDT and 80%and 52%f or SAp. Both tests had higher negative than positive predictive values with marg inal differences between tests. Criterion free receiver operator characteristic analysis revealed minimal discriminatory power differences. Conclusions: In a HE S glaucoma clinic in which new referrals are evaluated, threshold 24-2 FDT test ing with the Humphrey Matrix has performance characteristics similar to SAp. The se findings suggest threshold testing using the FDT Matrix and SAp is comparable when the 24-2 test pattern is used.

关键词：视野检查 Humphrey 眼保健检测模式阴性预测值阳性预测值金标准域值持续时间随机抽样