影响体外受精-胚胎移植结局的职业、学历及居住地因素分析

目的探讨体外受精-胚胎移植（IVF-ET）结局与患者职业、学历及围孕期居住地的关系。方法回顾南方医院生殖中心
2010年1月~2014年6月首次IVF-ET助孕患者（n=3998）以及同期所有围产儿临床资料（n=3064）。了解不同IVF-ET结局与患
者职业、学历及居住地的关系。结果与本中心总体水平相比,女方务农患者早期流产风险升高（OR=4.319, P=0.047）。男女双
方职业与学历与IVF-ET异位妊娠存在相关性。围产儿出生缺陷发生率为2.1%。深圳市出生缺陷发生率较高（5.5%）,但与广
东省其他地区差异无统计学意义（P>0.05）。结论患者职业及学历对IVF-ET助孕结局有一定影响。积极开展卫生宣教和产前
检查十分必要。
     

Supporting individuals using medications for opioid use disorder in recovery residences: challenges and opportunities for addressing the opioid epidemic

ABSTRACT

Full and partial opioid agonists and opioid antagonist medications play an important role in containing the opioid epidemic. However, these medications have not been used to their full extent. Recovery support services, such as recovery residences (RRs), also play a key role. RRs may increase an individual’s recovery capital, facilitate social support for abstinence, and foster a sense of community among residents. These processes may be critical for individuals with opioid use disorder (OUD). In combination these two recovery pathways have the potential to enhance one another and improve outcomes among residents with OUD. Barriers to doing so have resulted in a limited supply of residences that can support residents using opioid agonist and antagonist medications. This perspective describes key interpersonal and structural barriers to medication use among individuals with an OUD seeking support from a recovery residence and discusses measures for reducing these barriers. These measures include workforce development to address stigma and attitudinal barriers and enhancing residence capability to ensure resident safety and reduce potential diversion. The perspective also highlights the need for additional research to facilitate the identification of best practices to improve outcomes among residents treated with medications living in recovery residences.     

喷淋塔内液滴运动及分布特性的研究

以工业规模喷淋吸收塔为研究对象,建立了塔内液滴运动数学模型,考察了液滴直径、液滴初速度、空塔气速、喷淋密度对塔内液滴运动及分布特性的影响。研究结果表明:液滴的临界粒径随空塔气速的增加而增大,终端沉降速度仅与液滴直径有关;增大气速或减小液滴直径可显著增大液滴在塔内的停留时间;塔内持液率及比表面积正比于喷淋密度,反比于液滴直径,提高空塔气速,粒径较小的液滴在塔内分布更为稠密,能显著提高传质面积。     

Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain,a novel recombinant single-chain factor VIII

Introduction

rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.

Materials and Methods

Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate^®) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl₃-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.

Results

rVIII-SingleChain displayed a high affinity for von Willebrand factor (K_D = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl₃-induced arterial occlusion model.

Conclusions

rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.     

A diffusion-diffusion model for percutaneous drug absorption

Several theories describing percutaneous drug absorption have been proposed, incorporating the mathematical solutions of differential equations describing percutaneous drug absorption processes where the vehicle and skin are regarded as simple diffusion membranes. By a solution derived from Laplace transforms, the mean residence time MRTand the variance of the residence time VRTin the vehicle are expressed as simple elementary functions of the following five pharmacokinetic parameters characterizing the percutaneous drug absorption: (1) k _d, which is defined as the normalized diffusion coefficient of the skin, (2) k_c, which is defined as the normalized skin-capillary boundary clearance, (3) the apparent length of diffusion of the skin l_d, (4) the effective length of the vehicle l_v, and (5) the diffusion coefficient of the vehicle D_v. All five parameters can be obtained by the methods proposed here. Results of numerical computation indicate that: (1) concentrationdistance curves in the vehicle and skin approximate two curves which are simply expressed using trigonometric functions when sufficient time elapses after an ointment application; (2) the most suitable condition for the assumption that the concentration of a drug in the uppermost epidermis can be considered unchanged is the case where the partition coefficient between vehicle and skin is small, and the constancy of drug concentration is even more valid when the effective length of the vehicle is large; and (3) the amount of a drug in the vehicle or skin and the flow rate of the drug from vehicle into skin or from skin into blood becomes linear on a semilogarithmic scale, and the slopes of those lines are small when D_v is small, when the partition coefficient between vehicle and skin is small, when l_v is large, or when k_c is small. A simple simulation method is also proposed using a biexponential for the concentration-time curve for the skin near the skin-capillary boundary, that is, the flow rate-time curve for drug passing from skin into blood.     

Moment analysis of drug disposition in kidney. V:In Vivo transepithelial transport ofp-aminohippurate in rat kidney

A new method that can assess the kinetics of in vivotransepithelial transport in rat kidney has been established. The method is based upon a multiple-indicator dilution experiment and the moment analysis theory. After simultaneous bolus injections of p-aminohippurate (PAH) and inulin into the right renal artery, blood samples were taken from the carotid artery and urine was separately collected from right and left ureters. The characteristic response for the first passage of drugs through the right kidney was evaluated by taking blood circulation into consideration. To determine the mean artery-tovein transit time and the extraction ratio in the kidney, an intravenous injection was also performed as a reference experiment for deconvolution. The urinary excretion curve corresponding to the first passage was obtained as the difference between both kidneys. The mean artery-tolumen transit time (mean transepithelial transit time, ¯T _cell )was computed by subtracting the mean urinary transit time of inulin from that of secreted PAH. Sinc transport across the luminal membrane into the lumen from tubular epithelial cells can influence the cellular residence time of drugs, ¯ T_cell and the single-pass mean residence time in epithelial cells (¯T _cell.sp )can be thought of describing luminal membrane transport. The value of ¯T _{cell obtained for 0. t mM PAH was 22 sec and it was prolonged to 61 sec in the presence of probenecid, suggesting an inhibitory effect on transport across the luminal membrane. On the other hand, antiluminal membrane transport into cells from blood is characterized by the volume of distribution in the kidney} (Vd _PAH ). Vd _{PAH was remarkably decreased by treatment with probenecid, indicating an inhibitory effect on antiluminal membrane transport. The effects of probenecid on both sides of epithelial cell membrane transport were first demonstrated} in vivo.The present method is useful for the analysis of in vivotransepithelial transport including antiluminal and luminal membrane transport for drugs excreted via tubular secretion.     

Mean residence time in peripheral tissue

The published methods for determining the mean residence time for drugs in peripheral tissue are reviewed in terms of assumptions involved, advantages and disadvantages. A method for determining mean transit time in peripheral tissue is proposed; this may be a more useful indicator of the tissue retention properties for drug compounds.     

Accuracy of noncompartmental pharmacokinetic parameters estimated from bolus injection and steady-state infusion data

A Monte Carlo simulation study was carried out to examine the accuracy of parameters derived from curve moments. Impulse response (IR) and washout (WO) concentration-time curves, based on a triexponential model, were analyzed by numerical integration and regression analysis. Both designs were tested according to their robustness to measurement error and model misspecification. Performance of the methods was judged using the median error (ME) and the median absolute error (MAE) of 1000 simulations. The WO design provided better estimates of mean disposition residence time and worse estimates of the normalized variance of disposition residence times (CV _d ² ) than its rival. At 20% measurement noise, theMAE ofCV _d ² was less than 13%. The WO design was much more robust to model misspecification. Numerical integration performed as good as, or better than, regression analysis. Both methods are very sensitive to tail-area error, meaning that special attention needs to be paid to this aspect of experimental design. This study demonstrates that it is possible to obtain good estimates of higher moment parameters in a well-designed experiment.