Evaluation of hypothesis testing for comparing two populations using NONMEM analysis

In a simulation study of inference on population pharmacokinetic parameters, two methods of performing tests of hypotheses comparing two populations using NONMEM were evaluated. These two methods are the test based upon 95% confidence intervals and the likelihood ratio test. Data were simulated according to a monoexponential model and, in that context, power curves for each test were generated for (i)the ratio of mean clearance and (ii)the ratio of the population standard deviations of clearance. To generate the power curves, a range of these parameters was employed; other pharmacokinetic parameters were selected to reflect the variability typically present in a Phase II clinical trial. For tests comparing the means, the confidence interval tests had approximately the same power as the likelihood ratio tests and were consistently more faithful to the nominal level of significance. For comparison of the standard deviations, and when the volume of information available was relatively small, however, the likelihood ratio test was more able to detect differences between the two groups. These results were then compared to results on parameter estimation in order to gain insight into the question of power. As an example, the nonnormality of estimates of the ratio of standard deviations plays an important role in explaining the low power for the confidence interval tests. We conclude that, except for the situation of modeling standard deviations with only sparse information, NONMEM produces tests of significance that are effective at detecting clinically significant differences between two populations.Partial support from the Upjohn Company, NIH-BRSG SO RR 07066, and the Burroughs Wellcome Foundation.     

瑞波西汀与多虑平治疗老年抑郁症对照研究

目的观察瑞波西汀治疗老年抑郁症的疗效和安全性。方法随机将60例年龄≥60岁的老年抑郁症患者分为多虑平组（30例）和瑞波西汀组（30例），疗程6周，采用汉密尔顿抑郁量表（HAMD）和副反应量表（TESS）在治疗前和治疗后1、2、4、6周末评定药物疗效和副反应。结果两组疗效无显著差异，HAMD总分反各因子分从疗后2周至6周均较治疗前显著降低，两组间比较无显著性差异；治疗结束时TESS评分瑞波西汀组显著低于多虑平组。结论瑞波西汀适合于老年抑郁症患者的治疗，服用方便、安全，可首选使用。     

Guardians of health: The dimensions of elder caregiving among women in a Mexico City neighborhood

Little is known about the family care of older adults in Mexico and the role of women in this process. To begin to fill this knowledge gap, this paper describes how a small sample of low-income women in one Mexico City neighborhood conceptualized the caregiver role and identified the forms of assistance they gave to their older relatives on a daily basis. A grounded theory approach was used to collect and analyze the data. Forty-one semi-structured qualitative interviews were conducted with female caregivers. The age of participants was between 19 and 83 years, and care recipients between 56 and 92 years. The relationship of caregiver to care recipient was wife, daughter, daughter-in-law, granddaughter, sibling, and other relative. The mean length of time providing care was 5 years. Most participants were not employed outside the home, and the median monthly household income was 2000 pesos. We found that caregiving was a life-changing event, with 27 of 41 participants viewing themselves as guardians. Caregivers' emphasis was on care recipients' emotional needs in order to provide “the most precious gift” of “time and attention.” Two forms of assistance were ‘keeping company’ and ‘watching out’ as safeguards against poor health or further decline in health. These findings increase the cultural understanding of caregiving in Mexico. Further research is needed to test the caregiving concepts identified in this study.     

Amputation of a crossover 2nd toe in the presence of hallux valgus

Background: There are many surgical procedures for the correction of hallux valgus and crossover 2nd toe deformity. Amputation of a crossover 2nd toe is often performed as a salvage procedure if the primary 2nd toe corrective procedure fails.Aims: To assess the outcomes of amputating a crossover 2nd toe in the presence of hallux valgus in elderly patients above 70 years old; as a primary procedure.Materials and methods: Seven patients (8 ft) underwent amputation of their crossover 2nd toe. A disease specific questionnaire using a Visual Analogue Scale (VAS) was implemented measuring pain, deformity, discomfort, and walking distance.Results: The mean age of the patients was 82 years old, range 74–89 years old. Amputation of the 2nd toe significantly reduces pain, discomfort and the appearance of deformity, there was no difference in the patient’s walking distance after surgery.Conclusion: We recommend this type of surgery as a primary procedure in elderly patients above 70 years old, if the first ray is not causing symptoms.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

老年人腹腔镜胆囊切除术172例报告

目的 :探讨老年人腹腔镜胆囊切除术的安全性、可行性及注意点。方法 :对 172例老年人胆囊良性病变进行腹腔镜胆囊切除术。其中伴有并存病 96例 (5 5 .81% )。结果 :172例病人均恢复良好 ,无并发症发生 ,无中转开腹病例。结论 :只要做好围手术处理 ,老年人行腹腔镜胆囊切除术是安全可行的。     

A Study of Fluoxetine in Obese Elderly Patients with Type 2 Diabetes

In order to establish the safety and efficacy of fluoxetine in subjects over 60 years of age with Type 2 diabetes, a randomized, double-blind, parallel study of 30 obese subjects was undertaken, comparing the use of fluoxetine 60 mg daily with placebo. Subjects were diet controlled with an HbA₁ < 14% (reference range 6–9%) and BMI > 29 kg m². Those taking fluoxetine had a median weight loss of 2.6 kg at 3 months (p < 0.001) and 3.9 kg at 6 months (p < 0–02), compared with weight loss in the placebo group of 0.1 kg and 0.0 kg at 3 and 6 months, respectively. Improved glycaemic control was also demonstrated in the fluoxetine group compared with placebo, initial HbA₁ levels of 8.0% vs 8.7% (NS) falling at 4 months by 0.9% (p < 0.02) and at six months by 0.9% (p < 0.02). No sustained improvement in fasting blood glucose levels was demonstrated. Reporting of adverse events was similar in both groups. Fluoxetine in the short term aids weight loss and improves glycaemic control without a significant increase in adverse events in elderly Type 2 diabetic subjects.     

HLA-B44 subtyping in a Spanish population: further evidence of Caucasian population diversity

HLA-B44 is the most frequent HLA-B allele in Caucasian populations. Several B44 subtypes, B*4402-B*4406, have been identified in individuals with this ethnic origin. Mismatches among B44 subtypes have been described as major targets for allogeneic responses in bone marrow transplantation. We have developed a PCR-SSO method, based on a B12- specific DNA amplification of exon 2 through exon 3 and subsequent non radioactive hybridization with eight probes, which allow us to discriminate all B12 homozygous combinations. We applied this method to determine the frequency of B44 subtypes in a Spanish population, as well as their HLA-A.-C.-DRB1,-DRB3/DRB4/DRB5.-DQA1 and -DQB1 associated haplotypes. A total of 141 healthy unrelated Spanish individuals and 31 B44-bearing haplotypes were investigated. Four B44 alleles were identified, B*4402 (33%), B*4403 (66%), B*4404 (0.7%), and B*4405 (0.7%). Haplotype analysis showed a clear differentiated distribution pattern for the two major B44 subtypes. B*4402 is associated with Cw5 (11/13) and A2 antigens (10/13). In contrast, B*4403 is mainly found together with DRB1*0701 (14/16). An inverted B*4402/B*4403 frequency in comparison with other European and North American Caucasian populations, revealed the existence of an extended haplotype diversity between populations of the same ethnic origin. Apart from anthropological studies, high resolution typing for HLA class I antigens presenting molecular polymorphism will be of great relevance in unrelated bone marrow transplantation.