Quantifying the risks and benefits of efavirenz use in HIV‐infected women of childbearing age in the USA

Objectives

The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz‐related teratogenicity) associated with using efavirenz in HIV‐infected women of childbearing age in the USA.

Methods

We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz‐based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor‐based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100 000 women, we incorporated literature‐based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women.

Results

Survival for HIV‐infected women who received an efavirenz‐based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non‐efavirenz‐based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100 000 exposed women, compared with 72.46/100 000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS‐related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz‐exposed women.

Conclusions

Use of non‐efavirenz‐based initial ART in HIV‐infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision‐making regarding efavirenz use presents a trade‐off between these two risks; this study can inform discussions between patients and health care providers.     

Adherence to highly active antiretroviral therapy assessed by pharmacy claims predicts survival in HIV-infected South African adults

It is unclear how adherence to highly active antiretroviral therapy (HAART) may best be monitored in large HIV programs in sub-Saharan Africa where it is being scaled up. We aimed to evaluate the association between HAART adherence, as estimated by pharmacy claims, and survival in HIV-1-infected South African adults enrolled in a private-sector AIDS management program. Of the 6288 patients who began HAART between January 1999 and August 2004, 3805 (61%) were female and 6094 (97%) were black African. HAART adherence was >or=80% for 3298 patients (52%) and 100% for 1916 patients (30%). Women were significantly more likely to have adherence>or=80% than men (54% vs 49%, P<0.001). The median (interquartile range) follow-up time was 1.8 (1.37-2.5) years. As of 1 September 2004, 222 patients had died-a crude mortality rate of 3.5%. In a multivariate Cox regression model, adherence<80% was associated with lower survival (relative hazard 3.23; 95% confidence interval: 2.37-4.39). When medication adherence was divided into 5 strata with a width of 20% each, each stratum had lower survival rates than the adjacent, higher-adherence stratum. Among other variables tested, only baseline CD4+ T-cell count was significantly associated with decreased survival in multivariate analysis (relative hazard 5.13; 95% confidence interval: 3.42-7.72, for CD4+ T-cell count200 cells/microL). Pharmacy-based records may be a simple and effective population-level tool for monitoring adherence as HAART programs in Africa are scaled up.     

Preclinical characterization of WAY-211612: a dual 5-HT uptake inhibitor and 5-HT1A receptor antagonist and potential novel antidepressant

Background and purpose

As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT_1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT_1A receptor antagonist activities, was evaluated in preclinical models.

Experimental approach

Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.

Key results

WAY-211612 inhibited 5-HT reuptake (K_i = 1.5 nmol·L⁻¹; K_B = 17.7 nmol·L⁻¹) and exhibited full 5-HT_1A receptor antagonist activity (K_i = 1.2 nmol·L⁻¹; K_B = 6.3 nmol·L⁻¹; I_max 100% in adenyl cyclase assays; K_B = 19.8 nmol·L⁻¹; I_max 100% in GTPγS). WAY-211612 (3 and 30 mg·kg⁻¹, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT_1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg⁻¹, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg⁻¹, s.c.) and a 5-HT_1A antagonist (WAY-100635; 0.3 mg·kg⁻¹, s.c). WAY-211612 (3.3–30 mg·kg⁻¹, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg⁻¹, i.p. and 10–56 mg·kg⁻¹, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg⁻¹, i.p.) in the rat scheduled-induced polydipsia model.

Conclusions and implications

These findings suggest that WAY-211612 may represent a novel antidepressant.     

精神卫生防治机构医务人员工作现状及满意度调查分析

目的了解精神卫生防治机构医务人员的工作现状、满意度水平以及对精神卫生防治工作的建议,分析影响满意度的主要因素,为针对性的制定相关政策和采取相应措施提供科学依据。方法1成立调研组：2抽取两所县级精神卫生机构的医务人员代表召开座谈会;3发放无记名调查问卷,使用SPSSI1．5统计软件进行数据处理。结果调查结果显示：医务人员对工作现状满意程度不高,特别是在工作压力、社会地位、工作待遇、工作环境等方面满意度较低,且满意度与学历、职称、岗位及工龄有关,其差异有统计学意义。结论应根据医务人员对工作的满意度情况,分别采取针对性的管理措施及激励机制,提高他们的工作积极性,从而提高医疗服务质量,促进精神卫生事业的健康发展。     

Causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study

OBJECTIVE: To ascertain the immediate and underlying causes of death in adults who died in hospital with a premortem diagnosis of tuberculosis. DESIGN: Causes of death were assessed independently by internists and pathologists in 50 adults admitted to two Soweto hospitals who died 24 h or more after admission. Detailed record reviews and complete autopsies, including HIV tests when not performed premortem, were performed. In addition, a variety of postmortem microbiological tests were performed. RESULTS: Forty-seven patients had HIV infection; all were antiretroviral naive. Their median age was 34.5 years, median CD4 cell count was 48 cells/microl and median length of hospitalization before death was 6 days. Autopsy confirmed the premortem diagnosis of tuberculosis in 37 HIV-infected patients (79%), whereas 10 (21%) did not demonstrate tuberculosis. Bronchopneumonia and cytomegalovirus pneumonitis were the leading pathologies in these 10 patients. In 47 HIV-infected cadavers immediate or contributory causes of death were: extensive pulmonary tuberculosis, 32 (68%); disseminated tuberculosis, 28 (60%); bacterial pneumonia, 13 (26%); cytomegalovirus pneumonitis in seven (15%); cytomegalovirus DNA was found in 31 (66%) and Pneumocystis pneumonia was found in five cadavers (11%). The lung, followed by lymph nodes, liver and kidney, were the commonest sites of tuberculosis. Mycobacterium tuberculosis was cultured from 19 spleens, one of which was multidrug resistant, and Salmonella spp. was cultured from 11 splenic specimens. CONCLUSION: We demonstrated disseminated, extensive tuberculosis associated with advanced HIV disease. Severe bacterial infections, including salmonellosis, were the leading co-morbidity, suggesting that hospitalized HIV-infected adults in whom tuberculosis is suspected may benefit from broad-spectrum antibiotic therapy.     

同期胰肾联合移植12例报告--德国埃森大学的经验

目的总结同期胰肾联合移植(SPK)术的治疗效果和经验。方法自2002年1月至2003年9月,以SPK术治疗胰岛素依赖型糖尿病(IDDM)合并终末期肾病(ESRD)患者12例。每例受者接受来自同一供者的胰腺和肾脏,移植肾以经典方法植入左侧盆腔,胰腺植于右下腹。1例移植胰腺静脉与受者门静脉系统吻合,11例与体静脉系统吻合。胰腺外分泌引流方法为:3例移植物十二指肠段与受者十二指肠吻合,9例与空肠上段吻合。术前应用甲泼尼龙及抗胸腺细胞球蛋白作为免疫诱导,术后以他克莫司、霉酚酸酯和泼尼松三联抗排斥药物维持。结果术后平均随访时间23个月,受者、移植胰腺和移植肾的存活率分别为100%、91.7%和91.7%。1例再次行SPK术的受者,术后出现了超急性排斥反应,且未能逆转,于术后13d切除移植物;其余11例首次行SPK术的受者中,3例(28.3%)出现急性排斥,均获成功纠治。2例受者术后移植肾功能延迟恢复,行过渡性透析。11例首次行SPK术的移植胰腺术后立即发挥了功能,分别于术后1~5d内停用胰岛素。结论同期胰肾联合移植是胰岛素依赖型糖尿病合并终末期肾病患者的一种安全而有效的治疗方法。     

Deep white matter infarction: correlation of MR imaging and histopathologic findings

Focal and confluent areas of periventricular hyperintensity have been reported on magnetic resonance (MR) images in 30% of patients over 60 years of age. In order to better understand the pathologic basis of these lesions, the authors studied 14 formalin-fixed brains with MR imaging. Multiple focal areas of hyperintensity were identified in the periventricular white matter in three of the 14 brains studied (21%). Subsequent gross and microscopic pathologic examination of both hyperintense and normal-intensity areas was performed on 87 tissue sections. The larger lesions were characterized centrally by necrosis, axonal loss, and demyelination and therefore represent true infarcts. Reactive astrocytes oriented along the degenerated axons were identified at distances of up to several centimeters from the central infarct. This is called isomorphic gliosis and is associated with increased intensity on T2-weighted images that increases the apparent size of the central lesion.