Validation of the Musculoskeletal Health Questionnaire in inflammatory arthritis: a psychometric evaluation.

Objectives: The Musculoskeletal Health Questionnaire (MSK-HQ) is a recently developed Patient Reported Outcome Measure for use across patients with musculoskeletal conditions. This study provides a validation of the MSK-HQ examining construct validity and reliability in inflammatory arthritis. Methods: 287 adults with inflammatory arthritis completed the MSK-HQ and other Patient Reported Outcome Measures at baseline and after 3 months. Construct validity was assessed using item response theory methods. Concurrent validity was considered in relation to the HAQ and EuroQol-5D in all patients, as well as the RA Impact of Disease (RAID), PsA Impact of Disease scales, and AS Quality of Life Questionnaire (ASQoL) in disease subtypes. Results: The MSK-HQ was approximately normally distributed with no evidence of floor or ceiling effects. A unidimensional structure was confirmed. Two items were less weakly related to the latent musculoskeletal health variable, providing some evidence of multidimensionality. Reliability was high (α = 0.93). The total score correlated highly with the HAQ (r = -0.81) and EuroQol-5D index (r = 0.80) in all patients, RAID in RA patients (r = -0.88), PsA Impact of Disease in PsA patients (r = -0.88), and ASQoL in AS patients (r = -0.86). Test-retest reliability was high (rICC = 0.73). Conclusion: This study provides evidence for the validity and reliability of the MSK-HQ in people with inflammatory arthritis. The major advantage of the MSK-HQ is that it is not disease specific and has high content validity in rheumatological conditions. The MSK-HQ score will be of value in clinical rheumatology practice, providing a measure that can be used across disease areas.

Tuberculosis and tuberculosis/HIV/AIDS-associated mortality in Africa: the urgent need to expand and invest in routine and research autopsies.

Frequently quoted statistics that tuberculosis and human immunodeficiency virus (HIV)/AIDS are the most important infectious causes of death in high-burden countries are based on clinical records, death certificates, and verbal autopsy studies. Causes of death ascertained through these methods are known to be grossly inaccurate. Most data from Africa on mortality and causes of death currently used by international agencies have come from verbal autopsy studies, which only provide inaccurate estimates of causes of death. Autopsy rates in most sub-Saharan African countries have declined over the years, and actual causes of deaths in the community and in hospitals in most sub-Saharan African countries remain unknown. The quality of cause-specific mortality statistics remains poor. The effect of various interventions to reduce mortality rates can only be evaluated accurately if cause-specific mortality data are available. Autopsy studies could have particular relevance to direct public health interventions, such as vaccination programs or preventive therapy, and could also allow for study of background levels of subclinical tuberculosis disease, Mycobacterium tuberculosis-HIV coinfection, and other infectious and noncommunicable diseases not yet clinically manifest. Autopsies performed soon after death may represent a unique opportunity to understand the pathogenesis of M. tuberculosis and the pathogenesis of early deaths after initiation of antiretroviral therapy. The few autopsies performed so far for research purposes have yielded invaluable information and insights into tuberculosis, HIV/AIDS, and other opportunistic infections. Accurate cause-specific mortality data are essential for prioritization of governmental and donor investments into health services to reduce morbidity and mortality from deadly infectious diseases such as tuberculosis and HIV/AIDS. There is an urgent need for reviving routine and research autopsies in sub-Saharan African countries.

Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities.

Tuberculosis is unique among the major infectious diseases in that it lacks accurate rapid point-of-care diagnostic tests. Failure to control the spread of tuberculosis is largely due to our inability to detect and treat all infectious cases of pulmonary tuberculosis in a timely fashion, allowing continued Mycobacterium tuberculosis transmission within communities. Currently recommended gold-standard diagnostic tests for tuberculosis are laboratory based, and multiple investigations may be necessary over a period of weeks or months before a diagnosis is made. Several new diagnostic tests have recently become available for detecting active tuberculosis disease, screening for latent M. tuberculosis infection, and identifying drug-resistant strains of M. tuberculosis. However, progress toward a robust point-of-care test has been limited, and novel biomarker discovery remains challenging. In the absence of effective prevention strategies, high rates of early case detection and subsequent cure are required for global tuberculosis control. Early case detection is dependent on test accuracy, accessibility, cost, and complexity, but also depends on the political will and funder investment to deliver optimal, sustainable care to those worst affected by the tuberculosis and human immunodeficiency virus epidemics. This review highlights unanswered questions, challenges, recent advances, unresolved operational and technical issues, needs, and opportunities related to tuberculosis diagnostics.

Trends of Zambia's tuberculosis burden over the past two decades.

OBJECTIVES: To study trends in Zambia's TB notification rates between 1990 and 2010 and to ascertain progress made towards TB control. METHODS: Retrospective review of TB notification returns and TB programme reports for the period from 1990 to 2010. RESULTS: Two distinct TB trend periods were identified: a period of rising trends up to a peak between 1990 and 2004 and a period of moderately declining trends between 2004 and 2010. Treatment outcomes improved over the two decades. Data on trends in paediatric TB, TB in prisoners and TB in pregnant women remain scanty and unreliable owing to poor diagnostic capability. There were no data available on trends on drug-resistant TB because of the lack of laboratory services to perform drug sensitivity testing. CONCLUSIONS: The period of increasing TB between 1990 and 2000 coincided with an increase in HIV/AIDS. The period of slightly decreasing TB between 2004 and 2010 can be attributed to improved TB care, sustained DOTS implementation and improvement in TB diagnostic services. Newer diagnostics technologies for the rapid diagnosis of active TB cases and for drug-resistant testing, recently endorsed by the WHO, need to be implemented into the national TB programmes to detect more cases and to provide epidemiological and surveillance data from which to obtain an evidence base for guided investments for TB control. Alignment of TB and HIV services is required to achieve improved management outcomes.

Identification of a major rif transcript common to gametocytes and sporozoites of Plasmodium falciparum.

BACKGROUND: The Plasmodium falciparum parasite is transmitted in its sexual gametocyte stage from man to mosquito and as asexual sporozoites from mosquito to man. Developing gametocytes sequester preferentially in the bone marrow, but mature stage gametocytes are released to the bloodstream. Sexual stage parasite surface proteins are of interest as candidate target antigens for transmission blocking vaccines. METHODS: In this study, the transcript profiles of rif and var genes, known to encode surface antigens in asexual blood stage parasites, were investigated at different stages of 3D7/NF54 gametocytogenesis and in sporozoites. RESULTS: Gametocytes exhibited a rif transcript profile unlinked to the rif and var transcript profile of the asexual progenitors. At stage V, mature gametocytes produced high levels of a single rif gene, PF13_0006, which also dominated the rif transcript profile of sporozoites. All var genes appeared to be silenced in sporozoites. CONCLUSIONS: The most prominent variant surface antigen transcribed in both gametocytes and sporozoites of 3D7/NF54 is a single variant of the RIFIN protein family. This discovery may lead to the identification of the parasites binding ligands responsible for the adhesion during sexual stages and potentially to novel vaccine candidates.

Promiscuous expression of α-tubulin II in maturing male and female Plasmodium falciparum gametocytes.

BACKGROUND: Antimalarial interventions designed to impact on the transmissible sexual stages of Plasmodium falciparum are evaluated by measurement of peripheral gametocyte carriage in vivo and infectivity to mosquitoes. Drug or vaccine-elicited effects may differentially affect the relative abundance of mature male and female sexual forms, and this can be measured by estimation of sex ratios before and after intervention in vivo and in vitro. Measuring the impact of anti-gametocyte drugs on sexual commitment of immature gametocyte stages in vitro is not currently possible as male and female parasites cannot be distinguished by morphology alone prior to stage IV. METHODOLOGY/PRINCIPAL FINDINGS: We have modified an existing immunofluorescence-based approach for distinguishing male and female gametocytes during development in vitro, by using highly synchronised magnetically-enriched gametocyte preparations at different stages of maturity. Antibodies recognising α-tubulin II (males) and Pfg377 (females) were used to attempt to discriminate the sexes. Transcription of these two proteins was not coordinated during in vitro development, with pfg377 transcripts accumulating only late in development, immediately prior to immunofluorescent signals from the PfG377 protein appearing in stage IV gametocytes. Contrary to previous descriptions of this protein as male-specific in P. falciparum, α-tubulin II recognised both male and female gametocytes at stages I to IV, but evidence of differential expression levels of this protein in late stage male and female gametocytes was found. Using antibodies recognising PfG377 as the primary marker and α-tubulin II as a secondary marker, robust estimates of sex ratio in in vitro cultures were obtained for gametocytes at stage IV or later, and validated by light microscopic counts. However, sex ratio estimation was not possible for early stage gametocytes due to the promiscuity of α-tubulin II protein expression, and the relatively late accumulation of PfG377 during the development process. CONCLUSIONS/SIGNIFICANCE: This approach is a feasible method for the evaluation of drug impacts on late-stage gametocyte sex ratio in in vitro studies. Additional sex-specific antigens need to be evaluated for sex ratio estimation in early stage gametocyte preparations.