The case for a new system for oversight of research on human subjects

The increasing emphasis on evidence-based clinical practice has thrown into sharp focus multiple deficiencies in current systems of ethical review. This paper argues that a complete overhaul of systems for ethical oversight of studies involving human subjects is now required as developments in medical, epidemiological and genetic research have outstripped existing structures for ethical supervision. It shows that many problems are now evident and concludes that sequential and piecemeal amendments to present arrangements an inadequate to address these. Ar their core present systems of ethical review still rely on the integrity and judgement of individual investigators. One possible alternative is to train and license research investigators, make explicit their responsibilities and have ethics committees devote much more of their time to monitoring research activity in order to detect those infringing the rules.

Assessing perceived need for mental health care in a community survey: development of the Perceived Need for Care Questionnaire (PNCQ)

Background: The Perceived Need for Care Questionnaire (PNCQ) was designed for the Australian National Survey of Mental Health and Wellbeing. The PNCQ complemented collection of data on diagnosis and disability with the survey participants' perceptions of their needs for mental health care and the meeting of those needs. The four-stage design of the PNCQ mimics a conversational exploration of the topic of perceived needs. Five categories of perceived need are each assigned to one of four levels of perceived need (no need, unmet need, partially met need and met need). For unmet need and partially met need, information on barriers to care is collected, Methods: Inter-rater reliabilities of perceived needs assessed by the PNCQ were examined in a study of 145 anxiety clinic attenders. Construct validity of these items was tested, using a multi-trait multi-method approach and hypotheses regarding extreme groups, in a study with a sample of 51 general practice and community psychiatric service patients. Results: The instrument is brief to administer and has proved feasible for use in various settings. Inter-rater reliabilities for major categories, measured by the kappa statistic, exceeded 0.60 in most cases; for the summary category of all perceived needs, inter-rater reliability was 0.62. The multi-trait multi-method approach lent support to the construct validity of the instrument, as did findings in extreme groups. Conclusions: The PNCQ shows acceptable feasibility, reliability and validity, adding to the range of assessment tools available for epidemiological and health services research.

Passive smoking and lung cancer: a cumulative meta-analysis

Objective: To review the epidemiological evidence for the association between passive smoking and lung cancer. Method: Primary studies and meta-analyses examining the relationship between passive smoking and lung cancer were identified through a computerised literature search of Medline and Embase, secondary references, and experts in the field of passive smoking. Primary studies meeting the inclusion criteria were meta-analysed. Results From 1981 to the end of 1999 there have been 76 primary epidemiological studies of passive smoking and lung cancer, and 20 meta-analyses. There were 43 primary studies that met the inclusion criteria for this meta-analysis; more studies than previous assessments. The pooled relative risk (RR) for never-smoking women exposed to environmental tobacco smoke (ETS) from spouses, compared with unexposed never-smoking women was 1.29 (95% CI 1.17-1.43). Sequential cumulative meta-analysed results for each year from 1981 were calculated: since 1992 the RR has been greater than 1.25. For Western industrialised countries the RR for never-smoking women exposed to ETS compared with unexposed never-smoking women, was 1.21 (95% CI 1.10-1.33). Previously published international spousal meta-analyses have all produced statistically significant RRs greater than 1.17. Conclusions The abundance of evidence in this paper, and the consistency of findings across domestic and workplace primary studies, dosimetric extrapolations and meta-analyses, clearly indicates that non-smokers exposed to ETS are at increased risk of lung cancer. Implications: The recommended public health policy is for a total ban on smoking in enclosed public places and work sites.

Heroin overdose: causes and consequences

Over the past decade fatal opioid overdose has emerged as a major public health issue internationally. This paper examines the risk factors for overdose from a biomedical perspective. while significant risk factors for opioid overdose fatality are well recognized, the mechanism of fatal overdose remains unclear. Losses of tolerance and concomitant use of alcohol and other CNS depressants clearly play a major role in fatality; howeve, such risk factors do not account for the strong age and gender patterns observed consistently among victims of overdose. There is evidence that systemic disease may be more prevalent in users at greatest risk of overdose. We hypothesize that pulmonary and hepatic dysfunction resulting from such disease may increase susceptibility to both fatal and non-fatal overdose. Sequelae of non-fatal overdose are recognized in the clinical literature but few epidemiological data exist describing the burden of morbidity arising from such sequelae. The potential for overdose to cause persisting morbidity is reviewed.

Gender differences in the relationship between depression and suicidal ideation in young adolescents

Objective: This study examined the risk relationship between depressive symptomatology and suicidal ideation for young adolescent males and females. Method: A large cohort of students in their first year of high school completed the Center for Epidemiological Studies Depression Scale (CES-D) and the Adolescent Suicide Questionnaire. The risk relationship between depressive symptomatology and suicidal ideation was modelled using non-parametric kernel-smoothing techniques. Results: Suicidal ideation was more frequently reported by females compared with males which was partly explained by females having higher mean depression scores. At moderate levels of depression females also had a significantly higher risk of suicidal ideation compared with males and this increased risk contributed to the overall higher levels of female ideation. Conclusions: The risk relationship between depressive symptomatology and suicidal ideation is different for young adolescent males and females. The results indicate that moderate levels of depressive symptomatology can be associated with suicidal ideation (especially among young females) and that for these young people a suicide risk assessment is required.

Post-traumatic stress disorder: Findings from the Australian National Survey of Mental Health and Well-being

Background. We report on the epidemiology of post-traumatic stress disorder (PTSD) in the Australian community, including information on lifetime exposure to trauma, 12-month prevalence of PTSD, sociodemographic correlates and co-morbidity. Methods. Data were obtained from a stratified sample of 10641 participants as part of the Australian National Survey of Mental Health and Well-being. A modified version of the Composite International Diagnostic Interview was used to determine the presence of PTSD, as well as other DSM-IV anxiety, affective and substance use disorders. Results. The estimated 12-month prevalence of PTSD was 1.33%, which is considerably lower than that found in comparable North American studies. Although females were at greater risk than males within the subsample of those who had experienced trauma, the large gender differences noted in some recent epidemiological research were not replicated. Prevalence was elevated among the never married and previously married respondents, and was lower among those aged over 55. For both men and women, rape and sexual molestation were the traumatic events most likely to be associated with PTSD. A high level of Axis I co-morbidity was found among those persons with PTSD Conclusions. PTSD is a highly prevalent disorder in the Australian community and is routinely associated with high rates of anxiety, depression and substance disorders. Future research is needed to investigate rates among other populations outside the North American continent.

Perceived need for mental health care: influences of diagnosis, demography and disability

Background. Recent major epidemiological studies have adopted increasingly multidimensional approaches to assessment. Several of these have included some assessment of perceived need for mental health care. The Australian National Survey of Mental Health and Wellbeing, conducted in 1997, included a particularly detailed examination of this construct, with an instrument with demonstrated reliability and validity. Methods. A clustered probability sample of 10641 Australians responded to the field questionnaire for this survey, including questions on perceived need either where there had been service utilization, or where a disorder was detected by administration of sections of the Composite International Diagnostic Interview. The confidentialized unit record file generated from the survey was analysed for determinants of perceived need. Results. Perceived need is increased in females, in people in the middle years of adulthood, and in those who have affective disorders or co-morbidity. Effects of diagnosis and disability can account for most of the differences in gender specific rates. With correction for these effects through regression, there is less perceived need for social interventions and possibly more for counselling in females; disability is confirmed as strongly positively associated with perceived need, as are the presence of affective disorders or co-morbidity. Conclusions. The findings of this study underscore the imperative for mental health services to be attentive and responsive to consumer perceived need. The substantial majority of people who are significantly disabled by mental health problems are among those who see themselves as having such needs.

Adolescent depressive symptomatology: Improve schools or help students?

Despite the increasing interest in programs designed to improve the social ecology of schools, surprisingly little is known about whether differences between schools influence student mental health. This 3-year prospective, naturalistic study examines the school effect on adolescent depressive symptomatology (measured by the Center for Epidemiological Studies Depression Scale, CES-D) among 2,489 students from 25 Australian high schools. Multilevel modelling techniques (HLM) formed the basis of the statistical analyses, There were statistically significant school effects on students' depressive symptomatology; however, these were much smaller than expected. Nearly all of the variation in CES-D depression scores was found to be at the student level, indicating that the potential mental health gains from reducing risk factors in school social environments may be extremely limited and have little effect on student depressive symptomatology.

Bacterial dieback of pistachio in Australia

Xanthomonas bacteria have been found in association with dieback of pistachio trees in Australia. Identification of the bacterial species and/or pathovar and epidemiological studies are in progress.

The VITATOPS (vitamins to prevent stroke) Trial: Rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke

Background: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B-12 and vitamin B-6, it is not known whether lowering tHcy, by means of multivitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. Purpose: To determine whether vitamin supplements (folic acid 2 mg, B-6 25 Mg, B-12 500 mug) reduce the risk of stroke, and other serious vascular events, in patients with recent stroke or transient ischaemic attacks of the brain or eye (TIA). Methods: An international, multi-centre, randomised, double-blind, placebo-controlled clinical trial. Results: As of November 2001, more than 1,400 patients have been randomised from 10 countries in four continents. Conclusion: VITATOPS aims to recruit and follow up 8,000 patients between 2000 and 2004, and provide a reliable estimate of the safety and effectiveness of dietary supplementation with folic acid, vitamin B-12, and vitamin B-6 in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke. Copyright (C) 2002 S. Karger AG, Basel.

The incidence of schizophrenia: A systematic review

There has been a debate on whether or not the incidence of schizophrenia varies across time and place. In order to optimise the evidence upon which this debate is based, we have undertaken a systematicsystematic review of the literature. In this paper we provide an overview of the methods of the review and a preliminary analysis of the studies identified to date. Electronic databases (Medline, Psychlnfo, Embase, LILAC) were systematically searched for articles published between January 1965 and December 2001. The search terms were: (schizo* OR psycho*)AND (incidence OR prevalence). References were also identified from review articles, reference list and by writing to authors. To date we have identified 137 papers drawn from 33 nations. 37 papers in language other than English await translation. The currently included papers have generated 1413 different items of rate information data. In order to analyze these data we have undertaken several sequential filters in order to identify (a) non-overlapping data, (b) birth cohort study versus noncohort studies, (c) overall and sex-specific rates, (d) diagnostic criteria, (e) age ranges, (f) epoch of study, and (g) data on migrant or other special interest groups. In addition, we will examine the impact of urbanicity of site, age and/or sex standardization, and quality score on the incidence rates. The various discrete incidence rates will be presented graphically and the impact of various filters on these rates will be inspected using meta-analytic techniques. The use of meta-analysis may help elucidate the epidemiological landscape with respect to the incidence of schizophrenia and aid in the generation of new hypothesis. Acknowledgements: The Stanley Medical Research Institute supported project

Humans, dogs and parasitic zoonoses - Unravelling the relationships in a remote endemic community in Northeast India using molecular tools

Canine parasitic zoonoses pose a continuing public health problem, especially in developing countries and communities that are socioeconomically disadvantaged. Our study combined the use of conventional and molecular epidemic, logical tools to determine the role of dogs in transmission of gastrointestinal (GI) parasites such as hookworms, Giardia and Ascaris in a parasite endemic teagrowing community in northeast India. A highly sensitive and specific molecular tool was developed to detect and differentiate the zoonotic species of canine hookworm eggs directly from faeces. This allowed epidemiological screening of canine hookworm species in this community to be conducted with ease and accuracy. The zoonotic potential of canine Giardia was also investigated by characterising Giardia duodenalis recovered from humans and dogs living in the same locality and households at three different loci. Phylogenetic and epidemiological analysis provided compelling evidence to support the zoonotic transmission of canine Giardia. Molecular tools were also used to identify the species of Ascaris egg present in over 30% of dog faecal samples. The results demonstrated the role of dogs as a significant disseminator and environmental contaminator of Ascaris lumbricoides in communities where promiscuous defecation practices exist. Our study demonstrated the usefulness of combining conventional and molecular parasitological and epidemiological tools to help solve unresolved relationships with regards to parasitic zoonoses.

Assessing cost-effectiveness - Mental health: introduction to the study and methods

Objective: The Assessing Cost-Effectiveness - Mental Health (ACE-MH) study aims to assess from a health sector perspective, whether there are options for change that could improve the effectiveness and efficiency of Australia's current mental health services by directing available resources toward 'best practice' cost-effective services. Method: The use of standardized evaluation methods addresses the reservations expressed by many economists about the simplistic use of League Tables based on economic studies confounded by differences in methods, context and setting. The cost-effectiveness ratio for each intervention is calculated using economic and epidemiological data. This includes systematic reviews and randomised controlled trials for efficacy, the Australian Surveys of Mental Health and Wellbeing for current practice and a combination of trials and longitudinal studies for adherence. The cost-effectiveness ratios are presented as cost (A$) per disability-adjusted life year (DALY) saved with a 95% uncertainty interval based on Monte Carlo simulation modelling. An assessment of interventions on 'second filter' criteria ('equity', 'strength of evidence', 'feasibility' and 'acceptability to stakeholders') allows broader concepts of 'benefit' to be taken into account, as well as factors that might influence policy judgements in addition to cost-effectiveness ratios. Conclusions: The main limitation of the study is in the translation of the effect size from trials into a change in the DALY disability weight, which required the use of newly developed methods. While comparisons within disorders are valid, comparisons across disorders should be made with caution. A series of articles is planned to present the results.

Application of a species-specific PCR-RFLP to identify Ancylostoma eggs directly from canine faeces

Apart from their veterinary importance, the hookworms Ancylostoma caninum, Ancylostoma braziliense and Ancylostoma caninum are also capable of causing zoonotic disease in humans. A highly sensitive and species-specific PCR-RFLP technique was utilised to detect and differentiate the various canine Ancylostoma spp directly from eggs in faeces. This technique was utilised to screen 101 canine faecal samples from parasite endemic tea growing communities in Assam, India, as part as an ongoing epidemiological investigation into canine parasitic zoonoses. The prevalence of hookworms in dogs was found to be 98% using a combination of PCR and conventional microscopy. Overall, 36% of dogs were found positive for single hookworm infections with A. caninum, 24% positive for single infections with A. braziliense and 38% had mixed infections with both A. caninum and A. braziliense. No dogs were found positive for A. ceylanicum in the community under study. The high prevalence of A. caninum and A. braziliense in dogs in this community may account for the high incidence of cutaneous larva migrans (CLM) observed among the human population residing at the tea estates. The PCR-RFLP technique described herein allows epidemiological screening of canine hookworms to be conducted rapidly, with ease and accuracy, and has the potential to be applied to a number of different clinical, pharmacological and epidemiological situations. (C) 2004 Elsevier B.V. All rights reserved.

Low prenatal vitamin D alters morphology, cell density and gene expression in adult rat brain: Correlations with schizophrenia

Statement of the study: Based on data from ecological and analytic epidemiological studies, we have proposed that low prenatal vitamin D is a candidate risk-modifying factor for schizophrenia. Previously, we demonstrated that low prenatal vitamin D adversely affected brain development in neonatal rats (Eyles et al, 2003). Here we examine the impact of both prenatal and early life hypovitaminosis D on various outcomes in the adult rat brain. Methods: Female Sprague-Dawley rats were made vitamin D deficient via the use of a special diet (Dyets CA) and lighting conditions that excluded UVB radiation. Animals were kept under these conditions for 6 weeks then mated with males kept under normal conditions. Vitamin deplete dams were kept under these conditions during pregnancy. Offspring from two test groups were examined. Offspring were either reared with dams repleted with vitamin D at birth or remained under deplete conditions till weaning. Both test groups were weaned under normal vitamin D conditions and remained so till testing at adulthood. We compared the brains of adult offspring kept under both test conditions with animals from control environments. Summary of results: We found a significant persistent dose-related increase in lateral ventricle volume and alterations in anterior cingulate and prefrontal cortical cell densities (consistent with the known prodifferentiation properties of this steroid). In both test groups we observed a reduced expression of NGF as well as a down-regulation of transcripts coding for GABAA alpha 4 receptor and two neuronal structural elements; MAP2 and Neurofilament L. Conclusion: These findings provide further evidence that vitamin D is involved in brain development. An increase in prefrontal cortical cell density, a reduction neuronal structural elements and persistent ventriculomegaly are all common anatomical findings in the brains of patients with schizophrenia. The specific reduction in transcripts for neuronal structural proteins but not GFAP is also in accordance with the proposal that frontal cortical architecture in schizophrenia reflects a reduction in connectivity rather than a reduction in glial processes(Goldman-Rakic and Selemon, 1997). These findings confirm the biological plausibility of early life hypovitaminosis D as a risk factor for schizophrenia.