Fungal infections in solid organ transplantation: An update on diagnosis and treatment

Invasive fungal infections constitute an important cause of morbidity and mortality in solid organ transplantation recipients. Since solid organ transplantation is an effective therapy for many patients with end-stage organ failure, prevention and treatment of fungal infections are of vital importance. Diagnosis and management of these infections, however, remain difficult due to the variety of clinical symptoms in addition to the lack of accurate diagnostic methods. The use of fungal biomarkers can lead to an increased diagnostic accuracy, resulting in improved clinical outcomes. The evidence for optimal prophylactic approaches remains inconclusive, which results in considerable variation in the administration of prophylaxis. The implementation of a standard protocol for prophylaxis remains difficult as previous treatment regimens, which can alter the distribution of different pathogens, affect the outcome of antifungal susceptibility testing. Furthermore, the increasing use of antifungals also contributes to incremental costs and the risk of development of drug resistance. This review will highlight risk factors, clinical manifestations and timing of fungal infections and will focus predominately on the current evidence for diagnosis and management of fungal infections.     

Development of the New Lung Allocation System in the United States

This article reviews the development of the new U.S. lung allocation system that took effect in spring 2005. In 1998, the Health Resources and Services Administration of the U.S. Department of Health and Human Services published the Organ Procurement and Transplantation Network (OPTN) Final Rule. Under the rule, which became effective in 2000, the OPTN had to demonstrate that existing allocation policies met certain conditions or change the policies to meet a range of criteria, including broader geographic sharing of organs, reducing the use of waiting time as an allocation criterion and creating equitable organ allocation systems using objective medical criteria and medical urgency to allocate donor organs for transplant. This mandate resulted in reviews of all organ allocation policies, and led to the creation of the Lung Allocation Subcommittee of the OPTN Thoracic Organ Transplantation Committee. This paper reviews the deliberations of the Subcommittee in identifying priorities for a new lung allocation system, the analyses undertaken by the OPTN and the Scientific Registry for Transplant Recipients and the evolution of a new lung allocation system that ranks candidates for lungs based on a Lung Allocation Score, incorporating waiting list and posttransplant survival probabilities.     

Modeling the biological response of normal human cells,including repair processes,to fractionated carbon beam irradiation

To understand the biological response of normal cells to fractionated carbon beam irradiation, the effects of potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) were both taken into account in a linear-quadratic (LQ) model. The model was verified by the results of a fractionated cell survival experiment with normal human fibroblast cells. Cells were irradiated with 200-kV X-rays and monoenergetic carbon ion beams (290 MeV/u) at two irradiation depths, corresponding to linear energy transfers (LETs) of approximately 13 keV/μm and 75 keV/μm, respectively, at the Heavy Ion Medical Accelerator in Chiba of the National Institute of Radiological Sciences. When we only took into account the repair factor of PLDR, γ, which was derived from the delayed assay, the cell survival response to fractionated carbon ion irradiation was not fully explained in some cases. When both the effects of SLDR and PLDR were taken into account in the LQ model, the cell survival response was well reproduced. The model analysis suggested that PLDR occurs in any type of radiation. The γ factors ranged from 0.36–0.93. In addition, SLD was perfectly repaired during the fraction interval for the lower LET irradiations but remained at about 30% for the high-LET irradiation.     

Weighted cumulative exposure models helped identify an association between early knee-pain consultations and future knee OA diagnosis

ObjectiveTo establish the association between prior knee-pain consultations and early diagnosis of knee osteoarthritis (OA) by weighted cumulative exposure (WCE) models.Study Design and SettingData were from an electronic health care record (EHR) database (Consultations in Primary Care Archive). WCE functions for modeling the cumulative effect of time-varying knee-pain consultations weighted by recency were derived as a predictive tool in a population-based case-control sample and validated in a prospective cohort sample. Two WCE functions ([i] weighting of the importance of past consultations determined a priori; [ii] flexible spline-based estimation) were comprehensively compared with two simpler models ([iii] time since most recent consultation; total number of past consultations) on model goodness of fit, discrimination, and calibration both in derivation and validation phases.ResultsPeople with the most recent and most frequent knee-pain consultations were more likely to have high WCE scores that were associated with increased risk of knee OA diagnosis both in derivation and validation phases. Better model goodness of fit, discrimination, and calibration were observed for flexible spline-based WCE models.ConclusionWCE functions can be used to model prediagnostic symptoms within routine EHR data and provide novel low-cost predictive tools contributing to early diagnosis.     

辛伐他汀和氨氯地平对实验性兔动脉粥样硬化进程中HO／CO系统的影响

目的探讨血红素加氧酶．一氧化碳系统在动脉粥样硬化中的变化、相互关系及辛伐他汀、氨氯地平对动脉粥样硬化进程中血红素加氧酶-一氧化碳的影响。方法家兔予以高胆固醇饮食（n=24）18周,8周后改用普通饮食并随机分为三组,模型组停用高胆固醇饮食,改普通饮食（n=8）;辛伐他汀组给予喂饲辛伐他汀进行药物干预8周,氨氯地平组给予喂饲氨氯地平进行药物干预8周（n=8）。同时设正常对照组（n=8）：给予普通饲料喂养16周。然后取静脉血分别用Chalmers A．H、硝酸还原酶法测定各实验组血中CO,取主动脉组织用免疫组织化学方法测定主动脉组织中HO-1的表达;并比较组间各项参数的差异。结果16周末模型组血脂水平、血浆一氧化碳水平、血红素加氧酶-1表达较对照组明显升高。辛伐他汀组血浆TC、TG、LDL下降明显,HDL升高;血浆一氧化碳水平及血红素加氧酶-1表达均明显降低。而氨氯地平组血脂无明显变化;血浆一氧化碳水平、血红素加氧酶-1表达亦明显降低。结论动脉粥样硬化进程中,辛伐他汀、氨氯地平均可以通过下调血红素加氧酶／一氧化碳系统而延缓动脉粥样硬化进程。     

SERCA抑制剂抑制人结肠癌SW480细胞生长的作用机制研究

目的探讨SERCA抑制剂抑制结肠癌细胞株SW480生长的作用机制,为结肠癌治疗提供实验依据。方法（1）应用Ca^2＋荧光指示剂Fura-2检测细胞内Ca^2＋的浓度。（2）MTT法检测细胞抑制率。结果毒胡萝卜素（Tg）可使SW480细胞内Ca^2＋水平由（133．26±5．17,197．46±4．62）明显升高到（436．63±5．21,766．41±3．12）,差异有统计学意义（P〈0．05）;毒胡萝卜素（Tg）对人结肠癌细胞株SW480的抑制率随浓度（10～50μmol／L）的提高而增高,由（10．67±5．28）％至（31．46±7．21）％,抑制率差异有统计学意义（P〈0．05）;毒胡萝卜素（Tg）与W7合用时,这种效应则受到抑制。结论随着毒胡萝卜紊（Tg）浓度的增大,细胞内钙浓度同步上升;同时毒胡萝卜素（Tg）对该细胞株的抑制率增高。但其所诱导的细胞抑制具体钙信号途径还有待进一步研究。     

rhBMP-2膜联合PDLLA-nano/HA夹板、螺钉固定促进兔下颌骨骨折愈合的实验研究

目的探讨rhBMP-2在可吸收PDLLA-nano/HA夹板、螺钉固定的骨折愈合中的作用效果。方法每只兔随机选取一侧下颌骨造成垂直于体部的完全骨折，分别采用PDLLA-nano/HA夹板固定组、PDLLA-nano/HA夹板固定后加入不含rhBMP-2的胶原膜组及用PDLLA-nano/HA夹板固定后加入含rhBMP-2的胶原膜组。分别于术后不同时段进行大体观察、X线检查和HE染色观察。结果各组动物伤口均Ⅰ期愈合，骨折无移位，咬合正常，X线显示由2周至12周，骨折线逐渐由清晰变为模糊最后消失，但加入rhBMP-2组比另2组在同一时间段骨折线密度更高。HE染色示在早期（2-4周）rhBMP-2组即有大量成骨细胞和成软骨细胞及新生骨样组织。12周rhBMP-2组骨折线不可见，骨小梁走向趋于规则，不含rhBMP-2的2组骨小梁呈网状，不如rhBMP-2组规则，骨折线模糊。结论PDLLA-nano/HA夹板是一种优良的骨折内固定材料，加入rhBMP-2后，骨折愈合得更快、更好。     

医疗卫生服务系统建模方法学研究

目的：构建医疗卫生服务系统（Health Delivery System,HDS）模型体系,实现宏观HDS的数字化描述、量化分析以及可视化模拟与干预实验,提供宏观卫生政策的试验研究平台（“模拟实验室”）.材料与方法：资料来源主要有国家3次卫生服务调查资料、国家及地方统计年鉴资料、对全国95个市县的抽样调查;HDS模型的构建和人群就医行为的模拟及干预用复杂系统动力学建模方法.结果：构建了（1＋n）二重维度HDS模型体系（“模拟实验室”）,对HDS进行定量模拟分析与政策干预试验,为宏观卫生政策制定提供不间断的“循证政策”研究工具与决策支持系统.     

Mortality predictions for Ireland, 2001–2015: cancers of the breast, ovary, and cervix and corpus uteri

Abstract.   O'Lorcain P, Comber H. Mortality predictions for Ireland, 2001–2015: cancers of the breast, ovary, cervix and corpus uteri. Int J Gynecol Cancer 2006; 16(Suppl. 1): 1–10.
Linear and log-linear Poisson regression models of Irish breast, ovarian, and cervical and corpus uterine cancer mortality data for the years 1953–2000 were used to predict European age standardized mortality rates (EASMRs) per 100,000 person years and numbers of deaths for the period 2001–2015. Rates for the whole population and for those under 65 are expected to fall from their current levels for breast and corpus uterine cancers but not for ovarian and cervical uterine cancers. EASMRs for postmenopausal women aged between 55 and 69 years are predicted to fall for breast, ovarian, and cervical and corpus uterine cancers. The continuing expansion of the Irish female population is the primary reason why the numbers of deaths arising from breast, ovarian, and cervical uterine cancer are predicted to increase in all of the above age groups. It is not exactly clear why the numbers of corpus uterine cancer deaths are expected to continue to decline, but it may be a matter of improvement in overall death-certificate coding or their diagnoses as cervical cancer deaths.     

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance.