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Periodontal diseases, primarily gingivitis and periodontitis, are characterised by progressive inflammation and tissue destruction. However, they are unusual in that they are not also accompanied by the pain commonly seen in other inflammatory conditions. This suggests that interactions between periodontal bacteria and host cells create a unique environment in which the pro-algesic effects of inflammatory mediators and factors released during tissue damage are directly or indirectly inhibited. In this review, we summarise the evidence that periodontal disease is characterised by an accumulation of classically pro-algesic factors from bacteria and host cells. We then discuss several mechanisms by which inflammatory sensitisation of nociceptive fibres could be prevented through inactivation or inhibition of these factors. Further studies are necessary to fully understand the molecular processes underlying the endogenous localised hypoalgesia in human periodontal disease. This knowledge might provide a rational basis to develop future therapeutic interventions, such as host modulation therapies, against a wide variety of other human pain conditions. [ABSTRACT FROM AUTHOR]

Rationale: Gold miners in South Africa undergo annual radiological screening for tuberculosis in an occupational health center of a gold mining company, but the optimal screening algorithm is unclear.Objectives: To evaluate methods for active case detection of tuberculosis.Methods: A sequential sample of miners attending annual medical examination was screened for tuberculosis using a symptom questionnaire, chest radiograph, and two sputum specimens for microscopy and culture.Measurements and Main Results: There were 1,955 miners included in this study; all were male with a median age of 41 years (range, 20-61 yr). Presence of at least one of a trio of symptoms (new or worsening cough, night sweats, or weight loss) had similar sensitivity (29.4%) to either chest radiograph (25.5%) or sputum smear (25.5%). These sensitivities did not differ by HIV status. Presence of one or more elements of the symptom trio and/or new radiological abnormality substantially increased sensitivity to 49.0%. Specificity of the symptom trio was higher in HIV-uninfected (91.8%) than in HIV-infected persons (88.2%; P = 0.018). Specificity of chest radiography and smear were similar (98.7% and 99.0%, respectively) and did not differ by HIV status (both P values > 0.8).Conclusions: In a population of gold miners who undergo regular radiological screening, the addition of chest radiography to symptom screening substantially improved the sensitivity and positive predictive value. HIV infection did not alter the sensitivity of the screening tool. [ABSTRACT FROM AUTHOR]

In 1999 the Enhanced Tuberculosis Surveillance (ETS) system was introduced in the United Kingdom to strengthen surveillance of tuberculosis (TB). The aim of this study was to assess the use of record-linkage and capture-recapture methodology for estimating the completeness of TB reporting in England between 1999 and 2002. Due to the size of the TB data sources sophisticated record-linkage software was required and the proportion of false-positive cases among unlinked hospital-derived TB records was estimated through a population mixture model. This study showed that record-linkage of TB data sources and cross-validation with additional TB-related datasets improved data quality as well as case ascertainment. Since the introduction of ETS observed completeness of notification in England has increased and the results were consistent with expected levels of under-notification. Completeness of notification estimated by a log-linear capture-recapture model was highly inconsistent with prior estimates and the validity of this methodology was further examined. [ABSTRACT FROM AUTHOR]

Truncated models are indirect methods to estimate the size of a hidden population which, in contrast to the capture-recapture method, can be used on a single information source. We estimated the coverage of a tuberculosis screening programme among illicit drug users and homeless persons with a mobile digital X-ray unit between 1 January 2003 and 31 December 2005 in Rotterdam, The Netherlands, using truncated models. The screening programme reached about two-third of the estimated target population at least once annually. The intended coverage (at least two chest X-rays per person per year) was about 23%. We conclude that simple truncated models can be used relatively easily on available single-source routine data to estimate the size of a population of illicit drug users and homeless persons. We assumed that the most likely overall bias in this study would be overestimation and therefore the coverage of the targeted mobile tuberculosis screening programme would be higher. [ABSTRACT FROM AUTHOR]

Capture-recapture analysis has been used to evaluate infectious disease surveillance. Violation of the underlying assumptions can jeopardize the validity of the capture-recapture estimates and a tool is needed for cross-validation. We re-examined 19 datasets of log-linear model capture-recapture studies on infectious disease incidence using three truncated models for incomplete count data as alternative population estimators. The truncated models yield comparable estimates to independent log-linear capture-recapture models and to parsimonious log-linear models when the number of patients is limited, or the ratio between patients registered once and twice is between 0.5 and 1.5. Compared to saturated log-linear models the truncated models produce considerably lower and often more plausible estimates. We conclude that for estimating infectious disease incidence independent and parsimonious three-source log-linear capture-recapture models are preferable but truncated models can be used as a heuristic tool to identify possible failure in log-linear models, especially when saturated log-linear models are selected. [ABSTRACT FROM AUTHOR]

Background: Although failure of tuberculosis (TB) control in sub-Saharan Africa is attributed to the HIV epidemic, it is unclear why the directly observed therapy short-course (DOTS) strategy is insufficient in this setting. We conducted a cross-sectional survey of pulmonary TB (PTB) and HIV infection in a community of 13,000 with high HIV prevalence and high TB notification rate and a well-functioning DOTS TB control program.Methods: Active case finding for PTB was performed in 762 adults using sputum microscopy and Mycobacterium tuberculosis culture, testing for HIV, and a symptom and risk factor questionnaire. Survey findings were correlated with notification data extracted from the TB treatment register.Results: Of those surveyed, 174 (23%) tested HIV positive, 11 (7 HIV positive) were receiving TB therapy, 6 (5 HIV positive) had previously undiagnosed smear-positive PTB, and 6 (4 HIV positive) had smear-negative/culture-positive PTB. Symptoms were not a useful screen for PTB. Among HIV-positive and -negative individuals, prevalence of notified smear-positive PTB was 1,563/100,000 and 352/100,000, undiagnosed smear-positive PTB prevalence was 2,837/100,000 and 175/100,000, and case-finding proportions were 37 and 67%, respectively. Estimated duration of infectiousness was similar for HIV-positive and HIV-negative individuals. However, 87% of total person-years of undiagnosed smear-positive TB in the community were among HIV-infected individuals.Conclusions: PTB was identified in 9% of HIV-infected individuals, with 5% being previously undiagnosed. Lack of symptoms suggestive of PTB may contribute to low case-finding rates. DOTS strategy based on passive case finding should be supplemented by active case finding targeting HIV-infected individuals. [ABSTRACT FROM AUTHOR]

We hypothesized that rapid presentation may be a general feature of tuberculosis (TB) associated with human immunodeficiency virus (HIV) that limits the impact of HIV on the point prevalence of TB. To investigate this, we performed a cross-sectional HIV and TB disease survey with retrospective and prospective follow-up. HIV prevalence among 1,773 systematically recruited miners was 27%. TB incidence was much more strongly HIV associated (incidence rate ratio, 5.5; 95% confidence interval [CI], 3.5-8.6) than the point prevalence of undiagnosed TB disease (odds ratio, 1.7; 95% CI, 0.9-3.3). For smear-positive TB, 7 of 9 (78%) prevalent cases were HIV negative, and point prevalence was nonsignificantly lower in miners who were HIV positive (odds ratio, 0.8; 95% CI, 0.1-4.2). The calculated mean duration of smear positivity before diagnosis (point prevalence/incidence) was substantially shorter for HIV-positive than HIV-negative TB patients (0.17 and 1.15 years, respectively; ratio, 0.15; 95% CI, 0.00-0.73). HIV has considerably less impact on the point prevalence of TB disease than on TB incidence, probably because rapid disease progression increases presentation and case-finding rates. The difference in mean duration of smear positivity was particularly marked and, if generalizable, will have major implications for TB control prospects in high HIV prevalence areas. [ABSTRACT FROM AUTHOR]

The recovery of whale populations from centuries of exploitation will have important management and ecological implications due to greater exposure to anthropogenic activities and increasing prey consumption. Here, a Bayesian population model integrates catch data, estimates of abundance, and information on genetics and biology to assess the recovery of western South Atlantic (WSA) humpback whales (Megaptera novaeangliae). Modelling scenarios evaluated the sensitivity of model outputs resulting from the use of different data, different model assumptions and uncertainty in catch allocation and in accounting for whales killed but not landed. A long period of exploitation drove WSA humpback whales to the brink of extinction. They declined from nearly 27 000 (95% PI = 22 800–33 000) individuals in 1830 to only 450 (95% PI = 200–1400) whales in the mid-1950s. Protection led to a strong recovery and the current population is estimated to be at 93% (95% PI = 73–100%) of its pre-exploitation size. The recovery of WSA humpback whales may result in large removals of their primary prey, the Antarctic krill (Euphausia superba), and has the potential to modify the community structure in their feeding grounds. Continued monitoring is needed to understand how these whales will respond to modern threats and to climate-driven changes to their habitats.

A case study design was used to describe an integrated occupational and physical therapy approach for the treatment of an infant with severe arthrogryposis. The patient was evaluated and treated as an outpatient from 4-11 weeks of age, treated as an inpatient from 11-15 weeks of age, and was re-assessed at 15 weeks of age. Therapeutic intervention included parental instruction, passive range of motion, facilitation of active movement, fabrication of positioning equipment, splinting, and developmental activities. Improvements were found in parental management skills, passive range of motion, active movement, postural alignment, and developmental maturation. [ABSTRACT FROM AUTHOR]

Abstract Background Patients undergoing major elective or urgent surgery are at high risk of death or significant morbidity. Measures to reduce this morbidity and mortality include pre-operative optimisation and use of higher levels of dependency care after surgery. We propose a pragmatic multi-centre randomised controlled trial of level of dependency and pre-operative fluid therapy in high-risk surgical patients undergoing major elective surgery. Methods/Design A multi-centre randomised controlled trial with a 2 * 2 factorial design. The first randomisation is to pre-operative fluid therapy or standard regimen and the second randomisation is to routine intensive care versus high dependency care during the early post-operative period. We intend to recruit 204 patients undergoing major elective and urgent abdominal and thoraco-abdominal surgery who fulfil high-risk surgical criteria. The primary outcome for the comparison of level of care is cost-effectiveness at six months and for the comparison of fluid optimisation is the number of hospital days after surgery. Discussion We believe that the results of this study will be invaluable in determining the future care and clinical resource utilisation for this group of patients and thus will have a major impact on clinical practice. Trial Registration Trial registration number - ISRCTN32188676

Abstract Background Publicly funded clinical trials require a substantial commitment of time and money. To ensure that sufficient numbers of patients are recruited it is essential that they address important questions in a rigorous manner and are managed well, adopting effective marketing strategies. Methods Using methods of analysis drawn from management studies, this paper presents a structured assessment framework or reference model, derived from a case analysis of the MRC's CRASH trial, of 12 factors that may affect the success of the marketing and sales activities associated with clinical trials. Results The case study demonstrates that trials need various categories of people to buy in – hence, to be successful, trialists must embrace marketing strategies to some extent. Conclusion The performance of future clinical trials could be enhanced if trialists routinely considered these factors.

Abstract Background Securing and managing finances for multicentre randomised controlled trials is a highly complex activity which is rarely considered in the research literature. This paper describes the process of financial negotiation and the impact of financial considerations in four UK multicentre trials. These trials had met, or were on schedule to meet, recruitment targets agreed with their public-sector funders. The trials were considered within a larger study examining factors which might be associated with trial recruitment (STEPS). Methods In-depth semi-structured telephone interviews were conducted in 2003–04 with 45 individuals with various responsibilities to one of the four trials. Interviewees were recruited through purposive and then snowball sampling. Interview transcripts were analysed with the assistance of the qualitative package Atlas-ti. Results The data suggest that the UK system of dividing funds into research, treatment and NHS support costs brought the trial teams into complicated negotiations with multiple funders. The divisions were somewhat malleable and the funding system was used differently in each trial. The fact that all funders had the potential to influence and shape the trials considered here was an important issue as the perspectives of applicants and funders could diverge. The extent and range of industry involvement in non-industry-led trials was striking. Three broad periods of financial work (foundation, maintenance, and resourcing completion) were identified. From development to completion of a trial, the trialists had to be resourceful and flexible, adapting to changing internal and external circumstances. In each period, trialists and collaborators could face changing costs and challenges. Each trial extended the recruitment period; three required funding extensions from MRC or HTA. Conclusion This study highlights complex financial aspects of planning and conducting trials, especially where multiple funders are involved. Recognition of the importance of financial stability and of the need for appropriate training in this area should be paralleled by further similar research with a broader range of trials, aimed at understanding and facilitating the conduct of clinical research.

Abstract Background A commonly reported problem with the conduct of multicentre randomised controlled trials (RCTs) is that recruitment is often slower or more difficult than expected, with many trials failing to reach their planned sample size within the timescale and funding originally envisaged. The aim of this study was to explore factors that may have been associated with good and poor recruitment in a cohort of multicentre trials funded by two public bodies: the UK Medical Research Council (MRC) and the Health Technology Assessment (HTA) Programme. Methods The cohort of trials was identified from the administrative databases held by the two funding bodies. 114 trials that recruited participants between 1994 and 2002 met the inclusion criteria. The full scientific applications and subsequent trial reports submitted by the trial teams to the funders provided the principal data sources. Associations between trial characteristics and recruitment success were tested using the Chi-squared test, or Fisher's exact test where appropriate. Results Less than a third (31%) of the trials achieved their original recruitment target and half (53%) were awarded an extension. The proportion achieving targets did not appear to improve over time. The overall start to recruitment was delayed in 47 (41%) trials and early recruitment problems were identified in 77 (63%) trials. The inter-relationship between trial features and recruitment success was complex. A variety of strategies were employed to try to increase recruitment, but their success could not be assessed. Conclusion Recruitment problems are complex and challenging. Many of the trials in the cohort experienced recruitment difficulties. Trials often required extended recruitment periods (sometimes supported by additional funds). While this is of continuing concern, success in addressing the trial question may be more important than recruitment alone.

Abstract Background Conventional total hip replacement (THR) may be felt to carry too high a risk of failure over a patient's lifetime, especially in young people. There is increasing interest in metal on metal hip resurfacing arthroplasty (MoM) as this offers a bone-conserving option for treating those patients who are not considered eligible for THR. We aim to evaluate the effectiveness of MoM for treatment of hip disease, and compare it with alternative treatments for hip disease offered within the UK. Methods A systematic review was carried out to identify the relevant literature on MoM published before 2002. As watchful waiting and total hip replacement are alternative methods commonly used to alleviate the symptoms of degenerative joint disease of the hip, we compared MoM with these. Results The data on the effectiveness of MoM are scarce, as it is a relatively new technique and at present only short-term results are available. Conclusion It is not possible to make any firm conclusions about the effectiveness of MoM based on these early results. While the short-term results are promising, it is unclear if such results would be replicated in more rigorous studies, and what the long-term performance might be. Further research is needed which ideally should involve long-term randomised comparisons of MoM with alternative approaches to the clinical management of hip disease.

Abstract Background Economic evaluations alongside clinical trials are becoming increasingly common. Cost data are often collected through the use of postal questionnaires; however, the accuracy of this method is uncertain. We compared postal questionnaires with hospital records for collecting data on physiotherapy service use. Methods As part of a randomised trial of orthopaedic medicine compared with orthopaedic surgery we collected physiotherapy use data on a group of patients from retrospective postal questionnaires and from hospital records. Results 315 patients were referred for physiotherapy. Hospital data on attendances was available for 30% (n = 96), compared with 48% (n = 150) of patients completing questionnaire data (95% Cl for difference = 10% to 24%); 19% (n = 59) had data available from both sources. The two methods produced an intraclass correlation coefficient of 0.54 (95% Cl 0.31 to 0.70). However, the two methods produced significantly different estimates of resource use with patient self report recalling a mean of 1.3 extra visits (95% Cl 0.4 to 2.2) compared with hospital records. Conclusions Using questionnaires in this study produced data on a greater number of patients compared with examination of hospital records. However, the two data sources did differ in the quantity of physiotherapy used and this should be taken into account in any analysis.

Background: As ART programmes in African settings expand beyond the pilot stages, adherence to treatment may become an increasing challenge. This qualitative study examines potential barriers to, and facilitators of, adherence to ART in a workplace programme in South Africa.Methods: We conducted key informant interviews with 12 participants: six ART patients, five health service providers (HSPs) and one human resources manager.Results: The main reported barriers were denial of existence of HIV or of one's own positive status, use of traditional medicines, speaking a different language from the HSP, alcohol use, being away from home, perceived severity of side-effects, feeling better on treatment and long waiting times at the clinic. The key facilitators were social support, belief in the value of treatment, belief in the importance of one's own life to the survival of one's family, and the ability to fit ART into daily life schedules.Conclusion: Given the reported uncertainty about the existence of HIV disease and the use of traditional medicines while on ART, despite a programme emphasising ART counselling, there is a need to find effective ways to support adherence to ART even if the individual does not accept biomedical concepts of HIV disease or decides to use traditional medicines. Additionally, providers should identify ways to minimize barriers in communication with patients with whom they have no common language. Finally, dissatisfaction with clinical services, due to long waiting times, should be addressed. [ABSTRACT FROM AUTHOR]

Background: There is a high incidence of opportunistic infection among HIV-1-infected patients with tuberculosis in Africa and, consequently, high mortality. We assessed the safety and efficacy of trimethoprim-sulphamethoxazole 800 mg/160 mg (co-trimoxazole) prophylaxis in prevention of such infections and in decrease of morbidity and mortality.Methods: Between October, 1995, and April, 1998, we enrolled 771 HIV-1 seropositive and HIV-1 and HIV-2 dually seroreactive patients who had sputum-smear-positive pulmonary tuberculosis (median age 32 years [range 18-64], median CD4-cell count 317 cells/microL) attending Abidjan's four largest outpatient tuberculosis treatment centres. Patients were randomly assigned one daily tablet of co-trimoxazole (n=386) or placebo (n=385) 1 month after the start of a standard 6-month tuberculosis regimen. We assessed adherence to study drug and tolerance monthly for 5 months and every 3 months thereafter, as well as rates of admission to hospital.Findings: Rates of laboratory and clinical adverse events were similar in the two groups. 51 patients in the co-trimoxazole group (13.8/100 person-years) and 86 in the placebo group (25.4/100 person-years) died (decrease In risk 46% [95% CI 23-62], p<0.001). 29 patients on co-trimoxazole (8.2/100 person-years) and 47 on placebo (15.0/100 person-years) were admitted to hospital at least once after randomisation (decrease 43% [10-64]), p=0.02). There were significantly fewer admissions for septicaemia and enteritis in the co-trimoxazole group than in the placebo group.Interpretation: In HIV-1-infected patients with tuberculosis, daily co-trimoxazole prophylaxis was well tolerated and significantly decreased mortality and hospital admission rates. Our findings may have important implications for improvement of clinical care for such patients in Africa. [ABSTRACT FROM AUTHOR]