Randomised controlled trial comparing problem solving treatment with amitriptyline and placebo for major depression in primary care.

OBJECTIVE--To determine whether, in the treatment of major depression in primary care, a brief psychological treatment (problem solving) was (a) as effective as antidepressant drugs and more effective than placebo; (b) feasible in practice; and (c) acceptable to patients. DESIGN--Randomised controlled trial of problem solving treatment, amitriptyline plus standard clinical management, and drug placebo plus standard clinical management. Each treatment was delivered in six sessions over 12 weeks. SETTING--Primary care in Oxfordshire. SUBJECTS--91 patients in primary care who had major depression. MAIN OUTCOME MEASURES--Observer and self reported measures of severity of depression, self reported measure of social outcome, and observer measure of psychological symptoms at six and 12 weeks; self reported measure of patient satisfaction at 12 weeks. Numbers of patients recovered at six and 12 weeks. RESULTS--At six and 12 weeks the difference in score on the Hamilton rating scale for depression between problem solving and placebo treatments was significant (5.3 (95% confidence interval 1.6 to 9.0) and 4.7 (0.4 to 9.0) respectively), but the difference between problem solving and amitriptyline was not significant (1.8 (-1.8 to 5.5) and 0.9 (-3.3 to 5.2) respectively). At 12 weeks 60% (18/30) of patients given problem solving treatment had recovered on the Hamilton scale compared with 52% (16/31) given amitriptyline and 27% (8/30) given placebo. Patients were satisfied with problem solving treatment; all patients who completed treatment (28/30) rated the treatment as helpful or very helpful. The six sessions of problem solving treatment totalled a mean therapy time of 3 1/2 hours. CONCLUSIONS--As a treatment for major depression in primary care, problem solving treatment is effective, feasible, and acceptable to patients.     

Comparing Trials with Multiple Outcomes: The Multivariate One-Sided Hypothesis with Unknown Covariances

The paper deals with a problem arising for tests in clinical trials. The outcomes of a standard and a new treatment to be compared are multivariate normally distributed with common but unknown covariance matrix. Under the null hypothesis the means of the outcomes are equal, under the alternative the new treatment is assumed to be superior, i.e. the means are larger without further quantification. For known covariance matrix there is a variety of tests for this problem. Some of these procedures can be extended to the case of unknown covariances if one is willing to accept a bias. There is, however, also an efficient unbiased test. The paper contains some numerical comparisons of these different procedures and takes a look on the minimax properties of the unbiased test.     

Estimating individualized treatment rules with risk constraint

Individualized treatment rules (ITRs) recommend treatments based on patient-specific characteristics in order to maximize the expected clinical outcome. At the same time, the risks caused by various adverse events cannot be ignored. In this paper, we propose a method to estimate an optimal ITR that maximizes clinical benefit while having the overall risk controlled at a desired level. Our method works for a general setting of multi-category treatment. The proposed procedure employs two shifted ramp losses to approximate the 0-1 loss in the objective function and constraint, respectively, and transforms the estimation problem into a difference of convex functions (DC) programming problem. A relaxed DC algorithm is used to solve the nonconvex constrained optimization problem. Simulations and a real data example are used to demonstrate the finite sample performance of the proposed method.     

Nested analysis of variance with autocorrelated errors

In this paper we consider the problem where there is a randomized experimental design with several successive time measurements on each experimental unit. One approach to the analysis of such data is to treat time as the subplot treatment and to use a split-plot analysis of variance. Alternatively, the problem may be considered in a more general multivariate framework. Here we recognize the time-induced correlations and apply an autoregressive time series modelling approach. Estimation and testing are addressed. Two examples are presented to illustrate the practicality of our procedure. Some extensions are also considered briefly.     

Exact significance testing to establish treatment equivalence with ordered categorical data

This communication concerns the problem of establishing the therapeutic equivalence of two treatments that are being compared on the basis of ordered categorical data. The problem is formulated as a significance test in which the null hypothesis specifies a treatment difference. An efficient numerical algorithm for computing the exact significance level is provided, along with a simple method for obtaining the asymptotic significance level. Both methods are applied to a clinical trial of a new agent versus an active control. Guidelines for when to use the exact procedure and when to rely on asymptotic theory are provided.     

Changes in bone mineral density in patients with prostate cancer treated with androgen deprivation therapy

Osteoporosis is a complication of permanent androgen deprivation in men with prostate carcinoma, following either bilateral orchiectomy or treatment with GnRH agonists. The present approach to the problem of osteoporosis includes prevention, adequate follow-up and appropriate treatment as an imperative of contemporary urological and endocrinological management of these patients. Bone densitometry was performed in 18 patients who were on GnRH agonists treatment during 1-3 years. The patients under therapy were followed clinically, PSA (prostate-specific antigen) values were determined and bone scintigraphy was performed. The bone mineral density values in 13 patients indicated osteopenia, whereas in one patient the finding was compatible with osteoporosis. Four patients had normal bone mineral density findings. Bone densitometry should be performed before initiation of treatment with GnRH agonists in order to quantify the therapy-related bone loss. Prevention of development of osteoporosis and its complications depends on the assessment of pharmacological treatment in this group of patients, including e.g. bisphosphonates and possible intermittent androgen deprivation.     

International guide to prescribing psychotropic medication for the management of problem behaviours in adults with intellectual disabilities

Psychotropic medications are used regularly to manage problem behaviours among people with intellectual disabilities. This causes concern because often these medications are used out of their licensed indications in this context. The WPA Section on Psychiatry of Intellectual Disability has recently developed an evidence and consensus-based international guide for practitioners for the use of psychotropic medications for problem behaviours among adults with intellectual disabilities. This guide advises on assessment of behaviours, producing a formulation, initiation of treatment, assessment of out-come and adverse effects, follow-up arrangements, and possibility of discontinuation of treatment.     

Nanomedicines in the treatment of patients with hepatitis C co-infected with HIV--focus on pegylated interferon-alpha

In immuno-competent individuals, the natural course of chronic hepatitis C virus (HCV) infection is highly variable and 5%-30% of patients develop cirrhosis over 20 years. Co-infection with HCV and human immunodeficiency virus (HIV) is an important prognostic factor and associated with more frequent and accelerated progression to cirrhosis. Until recently HIV/AIDS-related complications were life limiting in patients co-infected with HCV; the introduction of highly active antiretroviral treatment (HAART) and the better prognosis of HIV infection has made HCV-related complications an emerging health problem in HCV/HIV coinfected individuals. Treatment of chronic HCV infection has also evolved since the introduction of interferon-alpha. Recently, introduction of pegylated interferon-alpha (peginterferon-alpha) has resulted in an increase in sustained virus clearance rates of up to 80% in selected genotypes and patient populations. The safety and efficacy of modern anti HCV treatment regimens - based on peginterferon-alpha in combination with ribavirin - was evaluated in 4 controlled trials. Sustained clearance of hepatitis C virus can be achieved in up to 35% of patients with HIV/HCV co-infection, and novel HCV treatment regimens based on peginterferon-alpha have no negative effect on the control of HIV disease. In conclusion, if HIV infection is well controlled and CD4+ cell counts >100/mm3, treatment of chronic hepatitis C with peginterferon in combination with ribavirin is safe and should be given for 48 weeks regardless of the HCV genotype. Introduction of peginterferon-alpha has significantly improved adherence to treatment and treatment efficacy; in particular sustained virologic response in patients with HCV genotype 1 or 4 infection improved, but sustained viral clearance in only 7%-38% of patients infected with genotype I and 4 cannot be the final step in development of effective treatments in patients with HCV/HIV co-infection.     

On using Lehmann alternatives with nonresponders.

The problem of testing for treatment effect when some subjects in the treatment group may be unaffected by the treatment is considered. A form of the Lehmann alternative suggested by Conover and Salsburg is used that assumes that each control score has the same distribution as the minimum of the known number of responses in the treatment group. It is shown that the locally most powerful test leads to a test statistic that, under the hypothesis of no treatment effect, is the sum of independent pareto random variables whereas under the alternative hypothesis it is the sum of independent random variables from a mixture of two pareto distributions. The limiting distribution of the test statistic under both hypotheses is in the domain of attraction of a stable distribution whose indices are derived. The power of the test is given, and its properties are discussed. A set of data from clinical research involving development of a new drug is used to show application of the procedure and demonstrate its usefulness.     

Hypertension in pregnancy with special reference to its treatment]

Definition and classification of the arterial hypertension in pregnancy are discussed. An emphasis is on the problems of differential diagnosis between pre-eclampsia and other forms of hypertension. Use of hypotensive drugs in pregnant patients with particular reference to emergencies is also discussed. The treatment of pregnant women with hypertension is still a problem which require close co-operation of both an obstetrician and internist. Follow-up after labour is GP duty to find out if the patient remains hypertensive. If so, etiology of the disease should be again searched.     

On the Comparison of Umbrella Pattern Treatment Means with a Control Mean

This paper is concerned with comparing several increasing dose levels (treatments) with a zero dose control when the prior information about the umbrella pattern treatment means is available. The problem of testing whether there is at least one treatment which is better than the control is considered. Multiple test procedures are then proposed for deciding treatments (if any) which are better than the control. Some approximate criticial values of the proposed tests are reported. The results of a Monte Carlo power study are presented.     

Nonparametric comparison for panel count data with unequal observation processes

This article considers nonparametric comparison of several treatment groups based on panel count data, which often occur in, among others, medical follow-up studies and reliability experiments concerning recurrent events. For the problem, most of the existing procedures require that observation processes are identical across different treatment groups among other requirements. We propose a new class of nonparametric test procedures that allow different observation processes. The new test statistics are constructed based on the integrated weighted differences between the estimated mean functions of the underlying recurrent event processes. The asymptotic distributions of the proposed test statistics are established and their finite-sample properties are examined through Monte Carlo simulations, which indicate that the proposed approach works well for practical situations. An illustrative example is provided.     

Locally efficient estimation of the quality-adjusted lifetime distribution with right-censored data and covariates

Zhao and Tsiatis (1997) consider the problem of estimation of the distribution of the quality-adjusted lifetime when the chronological survival time is subject to right censoring. The quality-adjusted lifetime is typically defined as a weighted sum of the times spent in certain states up until death or some other failure time. They propose an estimator and establish the relevant asymptotics under the assumption of independent censoring. In this paper we extend the data structure with a covariate process observed until the end of follow-up and identify the optimal estimation problem. Because of the curse of dimensionality, no globally efficient nonparametric estimators, which have a good practical performance at moderate sample sizes, exist. Given a correctly specified model for the hazard of censoring conditional on the observed quality-of-life and covariate processes, we propose a closed-form one-step estimator of the distribution of the quality-adjusted lifetime whose asymptotic variance attains the efficiency bound if we can correctly specify a lower-dimensional working model for the conditional distribution of quality-adjusted lifetime given the observed quality-of-life and covariate processes. The estimator remains consistent and asymptotically normal even if this latter submodel is misspecified. The practical performance of the estimators is illustrated with a simulation study. We also extend our proposed one-step estimator to the case where treatment assignment is confounded by observed risk factors so that this estimator can be used to test a treatment effect in an observational study.     

The two-sample problem with induced dependent censorship

Induced dependent censorship is a general phenomenon in health service evaluation studies in which a measure such as quality-adjusted survival time or lifetime medical cost is of interest. We investigate the two-sample problem and propose two classes of nonparametric tests. Based on consistent estimation of the survival function for each sample, the two classes of test statistics examine the cumulative weighted difference in hazard functions and in survival functions. We derive a unified asymptotic null distribution theory and inference procedure. The tests are applied to trial V of the International Breast Cancer Study Group and show that long duration chemotherapy significantly improves time without symptoms of disease and toxicity of treatment as compared with the short duration treatment. Simulation studies demonstrate that the proposed tests, with a wide range of weight choices, perform well under moderate sample sizes.     

一种处理人体骨骼肌肉层各向异性导电性的数值方法

重点讨论了应用电磁场数值计算方法求解心电图正问题和逆问题中人体骨骼肌肉层的各向异性导电性的处理方法．文中应用有限元和边界元结合的方法,构造了一个包含不同的纤维方向组合的骨骼肌肉层的三维胸腔模型,并在此模型下引入了局部坐标内的各向异性导电率向整体坐标转换的方法．据此进行的模拟计算结果以图像的方式清晰地展示了各向异性导电性对体表电位图的影响．     

Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin

The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair.     

Effects of somatostatin in patients with portal hypertension

Portal hypertension is a common complication of chronic liver disease. Conventional therapy consists of surgery and palliative measures for the hemodynamic problem. It has been recently reported that somatostatin may reduce portal pressure without altering the systemic circulation and so reducing hepatic blood flow. This peptide also causes a significant fall in azygos circulation in patients with esophageal varices. The mechanism of this effect is unclear although suppression of intestinal vasodilating hormones and of glucagon have been claimed to play a role. Comparative clinical studies have shown somatostatin to be superior to the standard vasopressin treatment. Recent findings suggest that the efficacy of somatostatin can be increased by administering this peptide in repeated intravenous bolus injections. New derivatives, specially long-acting peptides, may eventually prove beneficial in the chronic treatment of this complication.     

Vagotomy; clinical results,with a note on temporary gastrostomy

Often in the treatment of chronic headache, both physical and emotional factors are entailed. Therefore, the results of therapy are limited by the potentialities of the patient in therapy, the pharmacologic actions of the medications used, and the physician's interest and orientation toward the problem. The treatment of choice is generally a combination of psychotherapy and drug therapy. Results in a large series of tests with these types of headaches indicate the effectiveness of treatment is greatly influenced by the patient's psychological reaction to the treatment situation in general and in particular to having received a remedy from the physician. Patients with migraine did not respond to placebos as well as did patients with tension headache, post-traumatic headache and headache associated with hypertension.     

Nonparametric Multiple Comparisons in Repeated Measures Designs for Data with Ties

We consider some multiple comparison problems in repeated measures designs for data with ties, particularly ordinal data; the methods are also applicable to continuous data, with or without ties. A unified asymptotic theory of rank tests of Brunner , Puri and Sen (1995) and Akritas and Brunner (1997) is utilized to derive large sample multiple comparison procedures (MCP's). First, we consider a single treatment and address the problem of comparing its time effects with respect to the baseline. Multiple sign tests and rank tests (and the corresponding simultaneous confidence intervals) are derived for this problem. Next, we consider two treatments and address the problem of testing for treatment × time interactions by comparing their time effects with respect to the baseline. Simulation studies are conducted to study the type I familywise error rates and powers of competing procedures under different distributional models. The data from a psychiatric study are analyzed using the above MCP's to answer the clinicians' questions.