Developing and evaluating the implementation of a complex intervention: using mixed methods to inform the design of a randomised controlled trial of an oral healthcare intervention after stroke.

BACKGROUND: Many interventions delivered within the stroke rehabilitation setting could be considered complex, though some are more complex than others. The degree of complexity might be based on the number of and interactions between levels, components and actions targeted within the intervention. The number of (and variation within) participant groups and the contexts in which it is delivered might also reflect the extent of complexity. Similarly, designing the evaluation of a complex intervention can be challenging. Considerations include the necessity for intervention standardisation, the multiplicity of outcome measures employed to capture the impact of a multifaceted intervention and the delivery of the intervention across different clinical settings operating within varying healthcare contexts. Our aim was to develop and evaluate the implementation of a complex, multidimensional oral health care (OHC) intervention for people in stroke rehabilitation settings which would inform the development of a randomised controlled trial. METHODS: After reviewing the evidence for the provision of OHC following stroke, multi-disciplinary experts informed the development of our intervention. Using both quantitative and qualitative methods we evaluated the implementation of the complex OHC intervention across patients, staff and service levels of care. We also adopted a pragmatic approach to patient recruitment, the completion of assessment tools and delivery of OHC, alongside an attention to the context in which it was delivered. RESULTS: We demonstrated the feasibility of implementing a complex OHC intervention across three levels of care. The complementary nature of the mixed methods approach to data gathering provided a complete picture of the implementation of the intervention and a detailed understanding of the variations within and interactions between the components of the intervention. Information on the feasibility of the outcome measures used to capture impact across a range of components was also collected, though some process orientated uncertainties including eligibility and recruitment rates remain to be further explored within a Phase II exploratory trial. CONCLUSIONS: Complex interventions can be captured and described in a manner which facilitates evaluation in the form of exploratory and subsequently definitive clinical trials. If effective, the evidence captured relating to the intervention context will facilitate translation into clinical practice.

Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria.

Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

Antiretrovirals as antimalarial agents.

Recent studies have indicated that antiretroviral protease inhibitors may affect outcome in malarial disease. We have investigated the antimalarial activities of 6 commonly used antiretroviral agents. Our data indicate that, in addition to the previously published effects on cytoadherence and phagocytosis, the human immunodeficiency virus (HIV)-1 protease inhibitors saquinavir, ritonavir, and indinavir directly inhibit the growth of Plasmodium falciparum in vitro at clinically relevant concentrations. These findings are particularly important in light of both the high rate of malaria and HIV-1 coinfection in sub-Saharan Africa and the effort to employ highly active antiretroviral therapy in these regions.

[Pheochromocytoma and paraganglioma]. / Feocromocitoma y paraganglioma.

Pheochromocytoma and paraganglioma are neoplasias of the chromaffin cells that manifest themselves in some 40-60% of cases by symptoms of episodic freeing of catecholamines. They are the cause of stable and malign HTA in some 0.1-1% of cases and must be discounted in a study of the same. They most frequently affect males and their incidence increases with age. The symptomatic episodes are basically characterised by high blood pressure, migraines, sweating and palpitations, although they can have other multiple manifestations and even take a silent form in upto 40-50% of cases. They are frequently associated (10%) with multiple endocrine neoplasias and other neuroectodermic syndromes. For their diagnosis it is essential to measure the catecholamines and their metabolites, both plasmatic and urinary, and to locate the tumour by means of image tests, especially magnetic resonance. In the handling of these tumours it must be born in mind that the carrying out of physical maneuvers on the tumour and the employment of drugs that free catecholamines can induce hypertensive crises. The treatment chosen is always surgical, curative in cases of benign pheochromocytoma or producing a reduction of the tumourous mass and associated symptoms in cases of malign pheochromocytoma (10%); in this latter case treatment is complemented with chemotherapy or drugs that control the tumourous symptoms. Untreated pheochromocytoma can be a mortal disease, hence the importance of its detection and early treatment.

The role of anti-herpes specific serum IgA levels as a marker in cervical oncogenesis.

In the last few years, a great effort has been made with the aim of discovering cervical cancer etiology factor(s). At present, both HSV and HPV have been demonstrated strictly associated with cervical premalignant and malignant lesions. Nevertheless problems do exist in achieving the definitive evidence of a causative role exerted by herpes virus and/or by papilloma virus. Starting from 1984, our group studied the humoral immune response against herpes virus type two, in patients affected with CIN and invasive cervical cancer, as well as with atypical metaplasia and papilloma virus cytopathic effect at pap test, giving in 1985, the first evidence that serum levels of specific anti-herpes IgA strictly correlates both with infections and viral shedding, even when asymptomatic, as with various stages in cervical oncogenesis. This study updates our previous reports showing that IgA serum levels may be a useful marker in herpes related human diseases. Finally, data show the preliminary evidence that IgA, when levels are determined in the male partners of patients, is also useful in the screening and detection of "high risk males". These data, if further confirmed, will be of great advantage in the clinical monitoring of cervical cancer treatments, as well as in management and follow-up of preinvasive epithelial lesions of the cervix.