Development, validation and globalisation of a health status measure for evaluating patients with osteoarthritis

I developed a programme of research to develop, validate and globalise a valid, reliable and responsive standard of measurement (Western Ontario and McMaster Osteoarthritis Index - WOMAC Index) for osteoarthritis (OA) clinical trials. The initial phase (1982-1992) of WOMAC development involved development and validation. Specification of the item content was achieved through face-to-face interview of 100 patients with hip and/or knee OA. The resulting test index was composed of five subscales. Two independent validation studies, involving two different scaling formats, were designed and executed, one in an orthopaedic environment involving total joint arthroplasty, and the other in a rheumatology environment involving a double-blind randomised controlled clinical trial of two nonsteroidal anti-inflammatory drugs (NSAIDs). Four of the five subscales were successfully validated, of which three were retained in the final Index. The face, content and construct validity, reliability and responsiveness of the WOMAC Index were established. The end result of the aforementioned processes was the globalisation of the WOMAC Index, international consensus on core set domains for OA outcome measurement and specification of preferred measures, one of which was the WOMAC Index. Rapidly expanding utilisation of the WOMAC Index by academically-based and industry-based researchers, was shortly thereafter followed by a sharp increase in the number of studies reporting use of the WOMAC Index, such that by 1999 it was often the most commonly used health status questionnaire in osteoarthritis clinical research reported at major rheumatology conferences in Europe, N. America and Australasia. The late phase of development (2000-2005) has involved the further development of other language forms, other scaling formats, short forms and versions amenable to telephone administration and electronic data capture. This phase has also involved using WOMAC Index data to facilitate the development, by various research groups with whom I have collaborated, of definitions of responder criteria and state-attainment criteria. In particular, we have used WOMAC data, in whole or part, in the development of the following definitions of responder criteria: OARSI responder criteria, OMERACT- OARSI responder criteria, Minimum Perceptible Clinical Improvement (MPCI), Minimal Clinically Important Improvement (MCII), and in the development of the following definition of state-attainment criteria: Patient Acceptable Symptom State (PASS). The now fully developed WOMAC Index is a tri-dimensional, disease-specific, self-administered, health status measure. It probes clinically-important, patient-relevant symptoms in the areas of pain, stiffness and physical function in patients with OA of the hip and/or knee. The index consists of 24 questions (5 pain, 2 stiffness, 17 physical function) and can be completed in less than 5 minutes. It is available in Likert (WOMAC LK-series), Visual Analogue (WOMAC VA-series) and Numerical Rating (WOMAC NRS-series) scaled formats. WOMAC is valid, reliable, and sufficiently sensitive to detect clinically-important changes in health status following a variety of interventions (pharmacologic, surgical, physiotherapy, etc). It has been translated into many different languages and has been requested for use by more than 500 researchers in over 50 different countries. The WOMAC Index has become a global standard of measurement for clinical trials in hip and knee OA in rheumatology, is widely used in clinical research, and has been incorporated into several major regulatory and guidelines documents. The WOMAC Index has been important to the development of global harmonisation in outcome measurement, in formulating response and state attainment criteria, and in adjudicating the clinical benefit of new treatments for knee OA

In vitro studies on immunoregulation with special reference to rheumatoid arthritis

This thesis is based on studies conducted between 1979 and 1981 at the University of Western Ontario, London, Canada. Although considerable advance has been made in recent years in quantitation of various aspect of the immune response in rheumatoids, and in dissecting mechanisms by which the response is regulated in healthy individuals, there is a relative lack of information regarding immunoregulation in rheumatoid arthritis. A series of comparative studies were planned to examine quantitative and qualitative aspects of immunoregulation in patients with rheumatoid arthritis and normal healthy individuals. The introductory chapters of the thesis review certain aspects of rheumatoid arthritis and immunology, immunoregulation in normal individuals and the immunopathogenesis of rheumatoid arthritis. Subsequent chapters report the collection, standardization, modification and application of study methods and discuss the results of serial studies. For the functional studies, a modified reverse hemolytic plaque forming cell assay was used to measure immunoglobulin synthesis by B lymphocytes in cultures containing combinations of B and T lymphocytes. In this assay system responses (Studies 1-5) were shown to be related to culture duration, concentration and batch of pokeweed mitogen, source of foetal calf serum and the dose of irradiation used to manipulate the T cell help/suppression balance. In Study 6 immunoregulation was examined by selectively destroying T suppressor cells with optimal dose radiation prior to coculture with B cells, and in Study 7 by selectively removing T suppressor cells using a chicken rosette assay which depleted T cell suspensions of cells bearing Fc receptors for IgG (Tgamma cells) prior to coculture. In normal subjects, coculture of B cells with T cells enhanced the PFC (plaque forming cell) response, which was further increased when T cells were either irradiated at optimal dosages (T3200) depleted of Tgamma cells (T nongamma) prior to coculture - a response consistent with an effective reduction of suppressor T cell activity. In marked contrast, while rheumatoid T cells were capable of enhancing the response of rheumatoid B cells to an equivalent degree as in controls, the additional augmentation seen when B cells were co-cultured with T3200 or T nongamma cells was absent in almost all rheumatoids. These observations were interpreted as indicating a functional and/or numerical deficiency in one or several subsets of mononuclear cells, but were not consistent with a pure dysfunction or reduction in the number of suppressor T cells alone. While abnormalities in T suppression in rheumatoid arthritis have recently been reported, the co-existence of other immunoregulatory abnormalities has not been examined. It was also demonstrated that the controversial Tgamma cell population had suppressor activity and that the radiosensitive suppressor cell and the Tgamma cell were related. Finally, the restricted PFC response in rheumatoids was not found to be related to the number of Tgamma cells, which was normal. Prior to undertaking additional functional studies, lymphocyte suspensions were examined for their content of monocytes, Ia+ T cells and OKT4+, OKT5+ cells, since a numerical abnormality would have provided a simple explanation for the differences. (Abstract shortened by ProQuest.)

Inclusion of 'minor' trauma cases provides a better estimate of the total burden of injury: Queensland Trauma Registry provides a unique perspective

Introduction Injury is recognised as a frequent cause of preventable mortality and morbidity; however, incidence estimates focusing only on the extent of mortality and major trauma may seriously underestimate the magnitude of the total injury burden. There currently exists a paucity of information regarding minor trauma, and the aim of this study was to increase awareness of the contribution of minor trauma cases to the total burden of injury. Methods The demographics, injury details, acute care factors and outcomes of both minor trauma cases and major trauma cases were evaluated using data from the state-wide trauma registry in Queensland, Australia, from 2005 to 2010. The impact of changes in Abbreviated Injury Scale (AIS) versions on the classification of minor and major injury cases was also assessed. Results Over the 6-year period, minor cases [Injury Severity Score (ISS) ≤ 12] accounted for almost 90% of all trauma included on the Queensland Trauma Registry (QTR). These cases utilised more than half a million acute care bed days, underwent more than 66,500 operations, and accounted for more than 48,000 patient transport episodes via road ambulance, fixed wing aircraft, or helicopter. Furthermore, more than 5800 minor trauma cases utilised in-hospital rehabilitation services; almost 3000 were admitted to an ICU; and more than 20,000 were admitted to hospital for greater than one week. When using the contemporary criteria for classifying trauma (AIS 08), the proportion of cases classified as minor trauma (87.7%) and major trauma (12.3%) were similar to the proportion using the traditional criteria for AIS90 (87.9% and 12.1%, respectively). Conclusions This evaluation of minor trauma cases admitted to public hospitals in Queensland detected high levels of demand placed on trauma system resources in terms of acute care bed days, operations, ICU admissions, in-hospital rehabilitation services and patient transportation, and which are all associated with high cost. These data convincingly demonstrate the significant burden of injury imposed by minor trauma cases serious enough to be admitted to hospital

The dynamics of single spike-evoked adenosine release in the cerebellum

The purine adenosine is a potent neuromodulator in the brain, with roles in a number of diverse physiological and pathological processes. Modulators such as adenosine are difficult to study as once released they have a diffuse action (which can affect many neurones) and, unlike classical neurotransmitters, have no inotropic receptors. Thus rapid postsynaptic currents (PSCs) mediated by adenosine (equivalent to mPSCs) are not available for study. As a result the mechanisms and properties of adenosine release still remain relatively unclear. We have studied adenosine release evoked by stimulating the parallel fibres in the cerebellum. Using adenosine biosensors combined with deconvolution analysis and mathematical modelling, we have characterised the release dynamics and diffusion of adenosine in unprecedented detail. By partially blocking K+ channels, we were able to release adenosine in response to a single stimulus rather than a train of stimuli. This allowed reliable sub-second release of reproducible quantities of adenosine with stereotypic concentration waveforms that agreed well with predictions of a mathematical model of purine diffusion. We found no evidence for ATP release and thus suggest that adenosine is directly released in response to parallel fibre firing and does not arise from extracellular ATP metabolism. Adenosine release events showed novel short-term dynamics, including facilitated release with paired stimuli at millisecond stimulation intervals but depletion-recovery dynamics with paired stimuli delivered over minute time scales. These results demonstrate rich dynamics for adenosine release that are placed, for the first time, on a quantitative footing and show strong similarity with vesicular exocytosis

Intraarticular corticosteroid for treatment of osteorthritis of the knee

BACKGROUND: Osteoarthritis (OA) is a common joint disorder. In the knee, injections of corticosteroids into the joint (intra-articular (IA)) may relieve inflammation, and reduce pain and disability. OBJECTIVES: To evaluate the efficacy and safety of IA corticosteroids in treatment of OA of the knee. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE, EMBASE, PREMEDLINE (all to July 2003), and Current Contents (Sept 2000). Specialised journals, trial reference lists and review articles were handsearched. SELECTION CRITERIA: Randomised controlled trials of IA corticosteroids for patients with OA of the knee: single/double blind, placebo-based/comparative studies, reporting at least one core OMERACT III outcome measure. DATA COLLECTION AND ANALYSIS: Methodological quality of trials was assessed, and data were extracted in duplicate. Fixed effect and random effects models, giving weighted mean differences (WMD), were used for continuous variables. Dichotomous outcomes were analysed by relative risk (RR). MAIN RESULTS: Twenty-six trials (1721 participants) comparing IA corticosteroid against placebo, against IA hyaluronan/hylan (HA products), against joint lavage, and against other IA corticosteroids, were included.IA corticosteroid was more effective than IA placebo for pain reduction (WMD -17.79; 95% confidence interval (CI) -25.02 to -10.55) and patient global assessment (the RR was 1.44 (95% CI 1.13 to 1.82)) at one week post injection with an NNT of 3 to 4 for both, based on n=185 for pain on 100 mm visual analogue scale (VAS) and n=158 for patient global assessment. Data on function were sparse at one week post injection and neither statistically significant nor clinically important differences were detected.There was evidence of pain reduction between two weeks (the RR was 1.81 (95% CI 1.09 to 3.00)) to three weeks (the RR was 3.11 (95% CI 1.61 to 6.01), but a lack of evidence for efficacy in functional improvement.At four to 24 weeks post injection, there was lack of evidence of effect on pain and function (small studies showed benefits which did not reach statistical or clinical importance, i.e. less than 20% risk difference). For patient global, there were three studies which consistently showed lack of effect longer than one week post injection. However, all were fairly small sample sizes (less than 50 patients per group). This was supported by another study which did not find statistically significant differences, at any time point, on a continuous measure of patient global assessment (100 mm VAS).In comparisons of corticosteroids and HA products, no statistically significant differences were in general detected at one to four weeks post injection. Between five and 13 weeks post injection, HA products were more effective than corticosteroids for one or more of the following variables: WOMAC OA Index, Lequesne Index, pain, range of motion (flexion), and number of responders. One study showed a difference in function between 14 to 26 weeks, but no differences in efficacy were detected at 45 to 52 weeks. In general, the onset of effect was similar with IA corticosteroids, but was less durable than with HA products.Comparisons of IA corticosteroids showed triamcinolone hexacetonide was superior to betamethasone for number of patients reporting pain reduction up to four weeks post injection (the RR was 2.00 (95% CI 1.10 to 3.63). Comparisons between IA corticosteroid and joint lavage showed no differences in any of the efficacy or safety outcome measures. AUTHORS' CONCLUSIONS: The short-term benefit of IA corticosteroids in treatment of knee OA is well established, and few side effects have been reported. Longer term benefits have not been confirmed based on the RevMan analysis. The response to HA products appears more durable. In this review, some discrepancies were observed between the RevMan 4.1 analysis and the original publication. These are likely the result of using secondary rather than primary data and the statistical methods available in RevMan 4.1. Future trials should have standardised outcome measures and assessment times, run longer, investigate different patient subgroups, and clinical predictors of response (those associated with inflammation and structural damage)

AIDS-defining illnesses among patients with HIV in Singapore, 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS)

BACKGROUND: The objective was to describe the causes of initial and overall AIDS-defining disease episodes among HIV patients in Singapore. METHODS: A retrospective observational cohort study was performed of all adult patients seen at the national HIV referral center between 1985 and 2001. Data were extracted from the patients' records by ten trained healthcare workers. AIDS-defining conditions were established using predefined criteria. RESULTS: Among 1504 patients, 834 had experienced one or more AIDS-defining diseases. The most frequent causes of the initial AIDS-defining episode were Pneumocystis carinii pneumonia (35.7%), Mycobacterium tuberculosis (22.7%) and herpes simplex (7.4%). In total 1742 AIDS-defining episodes occurred. The most frequent causes were Pneumocystis carinii pneumonia (25.1%), Mycobacterium tuberculosis (16.2%) and cytomegalovirus retinitis (9.5%). CONCLUSIONS: The most frequent causes of AIDS-defining illnesses in Singapore are similar to those reported in the West, prior to the introduction of anti-retroviral therapy. Opportunistic infections remain the most frequent AIDS-defining illnesses

Leverage points for the uptake of organic food production and consumption in the United Kingdom

Organic food systems are recognised as an important component in meeting United Nations’ (UN) Sustainable Development Goals. A leverage points perspective can help to identify approaches which have the potential to facilitate transformative systemic change towards organic and sustainable farming. Using fuzzy cognitive maps developed from expert stakeholder opinions, we modelled a system of drivers of organic food production and consumption in the United Kingdom, according to the UN Sustainability Assessment of Food and Agriculture systems framework. The most influential concepts in the uptake of organic systems were related to system norms and values and social structures, such as short-term economic thinking, landowner engagement, and relationships with certification bodies. However, in a scenario analysis, organic stakeholders identified relatively shallower leverage points as more likely to change under a sustainable future, resulting in limited systemic change. This demonstrates the need for policies targeting system norms, values and social structures relating to food systems to facilitate the transition to organic and sustainable farming

Reflections on a crisis: political disenchantment, moral desolation, and political integrity

Declining levels of political trust and voter turnout, the shift towards populist politics marked by appeals to ‘the people’ and a rejection of ‘politics-as-usual’, are just some of the commonly cited manifestations of our culture of political disaffection. Democratic politics, it is argued, is in crisis. Whilst considerable energy has been expended on the task of lamenting the status of our politics and pondering over recommendations to tackle this perceived crisis, amid this raft of complaints and solutions lurks confusion. This paper seeks to explore the neglected question of what the precise nature of the crisis with which we are confronted involves, and, in so doing, to go some way towards untangling our confusion. Taking my cue from Machiavelli and his value-pluralist heirs, I argue that there is a rift between a morally admirable and a virtuous political life. Failure to appreciate this possibility causes narrations of crisis to misconstrue the moral messiness of politics in ways that lead us to misunderstand how we should respond to disenchantment. Specifically, I suggest that: (i) we think that there is a moral crisis in politics because we have an unsatisfactorily idealistic understanding of political integrity in the first place; and (ii) it is a mistake to imagine that the moral purification of politics is possible or desirable. Put simply, our crisis is not moral per se but primarily philosophical in nature: it relates to the very concepts we employ—the qualities of character and context we presuppose whilst pondering over political integrity