Costs and effectiveness--the impact of economic studies on TB control

This paper assesses the impact of economic studies on TB control during the period 1982-2002, with a focus on cost and cost-effectiveness studies. It begins by identifying broad categories of economic study relevant to TB control, and how economic studies can, theoretically, have an impact on TB control. The impact that economic studies of TB control have had in practice is then analysed through a systematic review of the literature on cost and cost-effectiveness studies related to TB control, and three case studies (one cost study and two cost-effectiveness studies). The results show that in the past 20 years, 66 cost-effectiveness studies and 31 cost studies have been done on a variety of important TB control topics, with a marked increase occurring after 1994. In terms of numbers, these studies have had most potential for impact in industrialized countries, and within industrialized countries are most likely to have had an impact on policy and practice related to screening and preventive therapy. In developing countries with a high burden of tuberculosis, far fewer studies have been undertaken. Here, the main impact of economic studies has been influencing policy and practice on the use of short-course chemotherapy, justifying the implementation of community-based care in Africa, and helping to mobilize funding for TB control based on the argument that short-course treatment for TB is one of the most cost-effective health interventions available. For the future, cost and cost-effectiveness studies will continue to be relevant, as will other types of economic study.     

Susceptibility genes and B-chronic lymphocytic leukaemia

Common genetic variants are thought to increase the risk of chronic lymphocytic leukaemia (CLL), and case-control studies provide an approach to detect these variants. There have been multiple candidate gene studies published to date, but relatively few disease pathway studies or large genomic association studies. We summarize the results of these previous studies, as well as present results from our recent large pathway study of 9412 single nucleotide polymorphisms from 1253 immunity and inflammation genes in a study of 126 CLL cases and 484 frequency-matched controls. Several promising genes have been identified as susceptibility genes for risk of CLL across all of these association studies. However, a number of candidate gene studies have not been replicated in follow-up studies, whereas the results from disease pathway and large genomic studies have yet to be replicated in an independent sample. The challenge of future studies of this type will be overcoming study design issues, including definition of CLL, sample size limitations and multiple testing issues.     

Between Candidate Genes and Whole Genomes: Time for Alternative Approaches in Blood Pressure Genetics

Blood pressure has a significant genetic component, but less than 3% of the observed variance has been attributed to genetic variants identified to date. Candidate gene studies of rare, monogenic hypertensive syndromes have conclusively implicated several genes altering renal sodium balance, and studies of essential hypertension have inconsistently implicated over 50 genes in pathways affecting renal sodium balance and other functions. Genome-wide linkage scans have replicated numerous quantitative trait loci throughout the genome, and over 50 single nucleotide polymorphisms (SNPs) have been replicated in multiple genome-wide association studies. These studies provide considerable evidence that epistasis and other interactions play a role in the genetic architecture of blood pressure regulation, but candidate gene studies have limited scope to test for epistasis, and genome-wide studies have low power for both main effects and interactions. This review summarizes the genetic findings to date for blood pressure, and it proposes focused, pathway-based approaches involving epistasis, gene-environment interactions, and next-generation sequencing to further the genetic dissection of blood pressure and hypertension.     

Novel therapeutic options for osteoporosis

Osteoporosis remains a significant clinical problem despite effective therapies. Many patients cannot or will not take currently available therapies. For this reason, research continues in search of more effective and more tolerable agents. Arzoxifene and TSE-424 are investigational selective estrogen receptor modulators that have been shown to be effective in animal studies and are now in clinical studies. Tibolone is a tissue-specific steroid that is currently used in Europe for the prevention and treatment of osteoporosis. Multiple studies have shown efficacy in improving bone mineral density, but no fracture studies have been conducted to date. Although studies of the effect of isoflavones on bone mineral density have been encouraging, a large multicenter study in Europe recently showed no effect of isoflavones on fractures. The investigational bisphosphonates ibandronate and zoledronic acid may offer the advantage of less frequent dosing. The newly described agent osteoprotegerin has been shown in early studies to inhibit bone turnover. Finally, the issue of efficacy of statins in bone continues to be debated with no prospective, randomized studies yet to confirm the suggestion of benefit seen in epidemiologic studies.     

Genetic determinants of bone mass

PURPOSE OF REVIEW: This review examines recent advances in the analysis of genetic determinants of bone mass. It addresses both human and animal linkage studies as well as genetic manipulations in animals, inbred mouse models, and candidate gene analyses. RECENT FINDINGS: Recent studies have implicated novel regulatory pathways in bone biology including both the neuroendocrine system and metabolic pathways linked to lipid metabolism. Variations in the lipoprotein receptor-related protein 5 (LRP5), part of the Wnt-frizzled pathway, were independently identified by linkage in high and low bone mass families. Subsequently, other high bone mass syndromes have been shown to have mutations in this gene. Neural studies have shown the skeletal regulatory activity of leptin and neuropeptide Y receptors via the hypothalamus. Subsequently, the beta-adrenergic pathway has been implicated, with important changes in bone mass. The lipoxygenase 12/15 pathway, identified through inbred mouse models and through pharmacologic studies with specific inhibitors, has also been shown to have important effects on bone mass. These studies exemplify the value of genetic models both to identify and then confirm pathways by mutational study and pharmacologic interventions. Continuing candidate gene studies often performed with multiple loci complement such discoveries. However, these studies have not focused on the clinical endpoint of fracture and few have included large enough groups to engender confidence in the associations reported, as such studies may require thousands of individuals. Interestingly, results often differ by ethnicity, age, or gender. A small proportion have examined whether relevant genes influence response to treatment. SUMMARY: The combinations of human and animal genetic linkage studies have advanced understanding of the regulation of bone mass. Studies ranging from linkage to pharmacology provide optimism for new targets and treatments for osteoporosis.     

The new genetics and chronic obstructive pulmonary disease

Epidemiological and family studies provide evidence for genetic factors contributing to chronic obstructive airways disease (COPD) susceptibility. Studies to date have focused on candidate genes implicated in the pathogenesis of the disease. In general, many of these studies have been underpowered or have not been extensive enough in investigating the full extent of genetic variation in these genes. This has resulted in conflicting data with potential false positives or findings that have not been replicated. More recently, larger studies and extensive coverage of candidate genes have implicated genetic variants that may contribute to the disease. The use of unbiased genome-wide association studies offer the prospect of identifying new genes involved in COPD susceptibility and genetic modifiers of disease phenotypes. There is cause for optimism as a number of major complex diseases have been successfully tackled in this way. The review will highlight what has been achieved by genetic studies to date, some of the related problems and the future impact of high throughput technologies such as genome-wide association studies on our understanding of the genetic basis of COPD.     

The role of non-HLA gene polymorphisms in graft-versus-host disease

A large number of reports have associated various non-HLA gene polymorphisms with the risk and severity of graft-versus-host disease (GVHD). To date, candidate gene studies and genome-wide association studies have been performed to investigate such non-HLA gene polymorphisms in relation to GVHD. Candidate gene studies are hypothesis-driven and cost-effective, whereas genome-wide association studies have the potential to discover new gene polymorphisms, including possible biomarkers and therapeutic targets. Some gene polymorphisms have the potential to affect protein function or gene expression, or to encode minor histocompatibility antigens. Non-HLA genotyping for genes influencing GVHD prior to transplantation should provide useful information that will facilitate choosing the donor, type of graft, conditioning treatment, and GVHD prophylaxis. However, attention should be paid to the need for validation studies and ethical issues.     

Psychosocial research and family planning services in Mexico

Psychosocial and service studies round out data from the demographic and contraceptive prevalence studies that have been conducted every 3 years since 1976 in Mexico. The studies can be formative, providing basic information for development of a program, or evaluative, indicating how well a program is performing. Among formative psychosocial studies in Mexico have been knowledge, attitude, and practice (KAP) studies, which are usually helpful in the initial stages of family planning program implementation. A 1964 study of knowledge and practice in 7 Mexican cities showed that attitudes toward family planning were more traditional and disapproving in Mexico City than in other areas, but that many women wanted no more children. About 1/4 of the population of Mexico City knew no contraceptive methods and about 1/2 knew only less effective traditional methods. By 1979, 72% of women knew at least 1 effective method. KAP studies have demonstrated differences in the family size desires of men and women and in the determinants of attitudes toward birth control. Formative studies of surgical contraception have been psychologically oriented, and have helped provide a rational basis for making the operation accessible to the public. Despite some passing problems, most women have adapted to sterilization and their libidos have normalized by 18 months postoperative. Studies of the knowledge and attitudes of physicians conducted in the early days of family planning programs have helped in the design of programs to inform them of the advantages and side affects of contraceptive methods. Other studies have helped identify traditional midwives with large practices in rural areas who could be trained to deliver family planning services and have demonstrated that they develop a good understanding of contraindications and side effects of oral contraceptives. Teaching materials for IEC programs have been evaluated with small samples, but minimal attention has been given to research on the best ways of providing family planning education for physicians, nurses, students, promoters, husbands, or other population groups. The greatest effort appears to have focused on development of educational materials for illiterates. Evaluative research on messages transmitted in IEC campaigns has however been abundant since the start of the programs. Careful studies of IEC c ampaigns in 1980-81 indicated that they improved knowledge of basic aspects of family planning considerably but had little effect on values and beliefs associated with family planning. Data on new acceptors in Mexico have come primarily from institutional registration systems, special studies, and as a subproduct of demographic surveys. Careful studies done by private organizations have provided information needed to reformulate commercial distribution programs and design supporting IEC campagns for their users and agents. Evaluative service studies have focuses on identifying factors in differential continuation rates for different methods and programs. Research on service delivery in rural areas has helped identify the most productive type of community worker and has uncovered causes of dissatisfaction and high turnover among workers which impairs their performance.     

The antiatherogenic effects of antihypertensive treatment: trials completed and ongoing

B-mode ultrasonography provides a reliable means of measuring carotid artery wall intima-media thickness. Because carotid intima-media thickness is correlated with blood pressure and is predictive of future cardiovascular events, it can be used as an endpoint in intervention trials. Inclusion of carotid bifurcation in the measurements appears necessary for inferences about atherosclerosis. Several intervention studies using antihypertensive agents have been completed and others are ongoing. Placebo-controlled studies have shown beneficial effects of calcium antagonists and ß-blockers, and contradictory responses with angiotensin converting enzyme inhibitors, but none of these studies have been performed in hypertensive patients. In hypertensive patients, three studies comparing different antihypertensive agents have been completed, with some evidence favoring calcium antagonists over diuretics. Two studies are ongoing, and should be completed and published soon.     

Recurrent ulcer after vagotomy and pyloroplasty: the X-ray appearances and their value in diagnosis

Barium meal studies have shown evidence of a recurrent ulcer or of stenosis in 12 out of 24 patients with recurrent dyspepsia after vagotomy and pyloroplasty. These 12 patients have been subsequently proved to have had recurrences and all but one are now cured by further surgery. Barium meals in 12 patients show no evidence of recurrence or stenosis, and follow-up clinical studies suggest that they do not have recurrent ulcer.Radiological studies appear to have great value in the interpretation of recurrent dyspeptic symptoms after vagotomy and pyloroplasty.     

Anaerobic bacteria and non-gonococcal urethritis

Anaerobic bacteria are frequent inhabitants of the urethra of both normal men and men with non-gonococcal urethritis. All microbiologically-based studies have shown them not to have a role in the aetiology of the condition. However, Bacteroides ureolyticus continues to be an enigma having been isolated more commonly from men with urethritis in some studies, not confirmed by others, as well as in treatment-based studies in which the organism has been implicated by some authors. Few studies related to anaerobic organisms in the male genital tract have been conducted during the last decade.     

Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies

Diabetic nephropathy is associated with an altered lipid profile characterized by elevated triglyceride rich lipoproteins, present even in the earlier stages of the renal disease. Although many experimental studies have demonstrated a significant deleterious role for hyperlipidemia in both the initiation and progression of renal injury, data remain more conflicting in humans. A few prospective studies, mostly in type 2 diabetes, have suggested an independent role for serum cholesterol level in the subsequent development of incipient or overt diabetic nephropathy. Furthermore, studies have reported in both types of diabetes an independent deleterious influence of serum total cholesterol on the decline in renal function and/or progression of albuminuria. However, the majority of these studies were post hoc analyses of previously controlled therapeutic trials with several observational studies not confirming these findings. It remains controversial whether apolipoprotein E gene polymorphism is an important factor in the development of diabetic nephropathy. Most of the interventional studies with lipid-lowering therapy in diabetic nephropathy have used HMG CoA reductase inhibitors and have been inconclusive. This may be due to a too short follow-up or insufficient number of patients. Further larger prospective studies are therefore required to better ascertain the role of lipids in the progression of diabetic nephropathy.     

Family studies in chronic lymphocytic leukaemia and other lymphoproliferative tumours

Families with multiple individuals affected with chronic lymphocytic leukaemia (CLL) and other related B-cell tumours have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions, including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in CLL families. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes but more studies are needed to verify these findings. The ability to conduct large scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate aetiological pathways.     

Economic issues with new rheumatologic therapeutics

PURPOSE OF REVIEW: Pharmacoeconomic evaluations are increasingly important in all aspects of medicine. In rheumatology, such studies have become all the more relevant following the introduction of highly effective biologic agents. Brought to the clinic initially for the treatment of rheumatoid arthritis, biologic agents have found expanded indication in other rheumatic diseases. RECENT FINDINGS: Building upon a long tradition in rheumatology, recent studies have updated and expanded upon the costs of various rheumatic diseases. These studies set the stage for determining the value of newer therapies. As a result of the chronic nature of rheumatic diseases, pharmacoeconomic evaluations must be carried out over sufficiently long time frames. Therefore, methodologic issues continue to be an area of ongoing discussion. Finally, ongoing studies have estimated the cost-effectiveness of novel rheumatologic therapies, in particular the inhibitors of tumor necrosis factor. These studies have shown that in several clinical circumstances, tumor necrosis factor inhibitors can indeed have an incremental cost-efficacy within the range of generally accepted medical interventions. While many of these studies focused on rheumatoid arthritis, there is growing interest in pharmacoeconomic evaluations in other rheumatic diseases. SUMMARY: Pharmacoeconomic evaluations are crucial to the optimal use of new therapies in rheumatology.     

Update on Parkinson disease

This Update reviews developments in the pathophysiology and treatment of Parkinson disease during the past several years. In the area of pathophysiology, studies have addressed the contribution of environmental factors such as caffeine and pesticides. Large-scale epidemiologic studies have also expanded the role genetic factors are thought to play. Detailed studies of kindreds with familial Parkinson disease due to alpha-synuclein and parkin have catalyzed basic science investigations into the pathologic mechanisms of the disease. These studies have led to the development of a pathophysiologic model of Parkinson disease that emphasizes abnormal protein aggregation. Studies of treatment have clarified the relative roles of l-dopa and dopamine agonists in early Parkinson disease and shown the potential for surgical interventions, particularly deep-brain stimulation, to relieve the symptoms of advanced, medically refractory disease.     

Genetics of human stature: Lessons from genome-wide association studies

Over the past 2 to 3 years, linkage disequilibrium mapping methods, or genome-wide association studies (GWAS), have made a seminal turn in the molecular genetic studies of complex human traits such as height, i.e., stature. Human stature is a highly heritable trait across populations and the phenotype for stature is easily measured and related to many other traits; therefore, it is available in most studies evaluating any phenotype. For this reason, it has become a beacon for large consortium genetic studies, during both the pre-GWAS and GWAS eras. Tens of thousands of genome-scanned individuals have been analysed together against their genome. Several loci have been implicated in association with stature (54 of these have been published), and most chromosomes have a locus linked to the trait in family studies. However, the prediction power of loci indentified by molecular genetic methods still remains inferior to clinical assessment of offspring stature using midparental height as a guide. Although the genomic methods provide important insights into heritability of stature, it will be a major challenge for molecular genetic studies to provide information that surpasses that of midparental height.     

Inherited thrombophilia and gestational vascular complications

The most common causes of inherited thrombophilia, the factor V Leiden and the factor II A20210 mutations, confer a higher risk of venous thromboembolism. Moreover, several studies have suggested that they can have a role in the occurrence of gestational vascular complications in otherwise unexplained recurrent fetal losses, hypertensive disorders of pregnancy and fetal growth restriction. Observational and case-control studies addressing these issues are available in literature. However, longitudinal, perspective studies are lacking. Mild hyperhomocysteinaemia can be due partly to inherited susceptibility--as the homozygous carriership of the T677 variant in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR). Case-control studies have been carried out on a possible association between unexplained fetal losses and mild hyperhomocysteinaemia. Although case-control and perspective studies are available on hyperhomocysteinaemia and other gestational vascular complications the data are conflicting.Intervention studies have been carried out to prevent adverse obstetric outcomes in women with factor V Leiden or factor II A20210 mutations and previous adverse outcomes. Although these are not randomized controlled trials, all have found significantly better outcomes in treated pregnancies compared to those of untreated pregnancies in the same women.     

Acupuncture in the treatment of heart failure

Few clinical studies evaluating the efficacy of acupuncture in heart failure have been performed. These studies have focused on the acupoint Neiguan (P6) in patients experiencing heart failure and have variably reported either an acute increase in ventricular contractility and/or relaxation or no effect on ventricular contractility and/or relaxation. To date, clinical studies have been hampered by small enrollment, inadequate controls, and unblinded design. Recent scientific studies of animal models of acupuncture support the concept that acupuncture produces release of endogenous opioids in the central nervous system, which in turn could inhibit central sympathetic outflow. Patients experiencing heart failure have markedly elevated sympathetic activity, and those with the greatest sympathetic activation have the worst survival. Preliminary data from our laboratory suggests that acupuncture could be sympatholytic in heart failure. We found that sympathetic activation during acute mental stress was virtually eliminated after acupuncture. More studies defining the efficacy of acupuncture, and its mechanisms, in the treatment of heart failure are warranted.     

Therapeutic alteration of the microbiota in rheumatic diseases: Hype or potential?

Multiple studies have demonstrated abnormalities in the contents of the fecal microbiota in patients with a variety of forms of arthritis. This has prompted interest in microbial-altering therapy as a therapeutic tool. While antibiotics as a long-term therapeutic tool have largely fallen out of favor, there have been multiple studies evaluating probiotics in rheumatoid arthritis, spondyloarthritis, or systemic sclerosis; a small number of studies have tested fecal microbial transplantation (FMT) in rheumatic diseases. Although probiotics were well tolerated, few studies detected meaningful clinical benefit regardless of indication. Likewise, one of the two randomized studies evaluating FMT showed minimal clinical benefit, while the other demonstrated worsening compared to sham treatment. In this review article, I summarize the literature on probiotics and FMT in rheumatic diseases, discuss potential reasons for the absence of demonstrable benefit, and suggest avenues of future direction of research.     

Childhood antecedents of adult respiratory disease

Abstract This review examines the relations between early childhood lower respiratory symptoms and adult respiratory disease. The problems associated with investigating potential associations between respiratory disease in children and adults are discussed. Some studies have limitations because they are retrospective and early childhood respiratory symptoms have not been accurately diagnosed. Therefore, in this review, particular attention is paid to longitudinal studies (some from birth) that have used strict diagnostic criteria for respiratory episodes. These studies provide unique insights into the risk factors for the development of childhood respiratory problems and for persistence of symptoms into adulthood. Although cross-sectional studies have indicated that early childhood respiratory disease is more frequent in adults with respiratory disease, evidence from longitudinal studies suggests that respiratory symptoms such as wheezing, are transient in the majority of infants and result from developmentally small airways. These longitudinal investigations have also indicated that persistence of symptoms into later childhood is associated with atopy. The important role of cigarette-smoke exposure as a risk factor for abnormal pulmonary development, persistence of respiratory disease and reduction in lung function is discussed. The discovery of genetic markers associated with respiratory syndromes such as asthma, should facilitate studies that investigate the childhood antecedents of adult respiratory disease. Future longitudinal studies using genetic markers, will allow relations between specific genotypes and phenotypic outcomes to be examined.