Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children

<p>Abstract</p> <p>Background</p> <p>Malaria in Zambia remains a public health and developmental challenge, affecting mostly children under five and pregnant women. In 2002, the first-line treatment for uncomplicated malaria was changed to artemether-lumefantrine (AL) that has proved to be highly efficacious against multidrug resistant <it>Plasmodium falciparum</it>.</p> <p>Objective</p> <p>The study objective was to determine whether dihydroartemisinin-piperaquine (DHA/PQP) had similar efficacy, safety and tolerability as AL for the treatment of children with uncomplicated <it>P. falciparum </it>malaria in Ndola, Zambia.</p> <p>Methods</p> <p>Between 2005 and 2006, 304 children (6-59 months old) with uncomplicated <it>P. falciparum </it>were enrolled, randomized to AL (101) or DHA/PQP (203) and followed up for 42 days. Outcome of treatment was defined according to the standard WHO classification, i.e. early treatment failure (ETF), late clinical failure (LCF, late parasitological failure (LPF) and adequate clinical and parasitological response (ACPR). Recurrent infections were genotyped to distinguish between recrudescence and new infection.</p> <p>Results</p> <p>No ETF was observed. At day 28, PCR-uncorrected ACPR was 92% in the DHA/PQP and 74% in the AL arm (OR: 4.05; 95%CI: 1.89-8.74; p < 0.001). Most failure were new infections and PCR-corrected ACPR was similar in the two study arms (OR: 0.69; 95%CI: 0.22-2.26; p = 0.33). Similar results were observed for day 42, i.e. higher PCR-uncorrected ACPR for DHA/PQP, mainly due to the difference observed up to day 28, while the PCR-corrected ACPR was similar: DHA/PQP: 93% (179/192), AL: 93% (84/90), (OR: 0.92; 95%CI: 0.30-2.64; p = 0.85). Except for cough, more frequent in the DHA/PQP arm (p = 0.04), there were no differences between treatment arms in the occurrence of adverse events. Two serious adverse events were probably associated to AL treatment.</p> <p>Conclusion</p> <p>DHA/PQP was as efficacious, safe and well tolerated in treatment of uncomplicated malaria as AL, though in the latter group more new infections during the follow up were observed. DHA/PQP seems a potential candidate to be used as an alternative first-line or rescue treatment in Zambia.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN16263443">ISRCTN16263443</a>, at <url>http://www.controlled-trials.com/isrctn</url></p

Paediatric malaria case-management with artemether-lumefantrine in Zambia: a repeat cross-sectional study

BACKGROUND: Zambia was the first African country to change national antimalarial treatment policy to artemisinin-based combination therapy – artemether-lumefantrine. An evaluation during the early implementation phase revealed low readiness of health facilities and health workers to deliver artemether-lumefantrine, and worryingly suboptimal treatment practices. Improvements in the case-management of uncomplicated malaria two years after the initial evaluation and three years after the change of policy in Zambia are reported. METHODS: Data collected during the health facility surveys undertaken in 2004 and 2006 at all outpatient departments of government and mission facilities in four Zambian districts were analysed. The surveys were cross-sectional, using a range of quality of care assessment methods. The main outcome measures were changes in health facility and health worker readiness to deliver artemether-lumefantrine, and changes in case-management practices for children below five years of age presenting with uncomplicated malaria as defined by national guidelines. RESULTS: In 2004, 94 health facilities, 103 health workers and 944 consultations for children with uncomplicated malaria were evaluated. In 2006, 104 facilities, 135 health workers and 1125 consultations were evaluated using the same criteria of selection. Health facility and health worker readiness improved from 2004 to 2006: availability of artemether-lumefantrine from 51% (48/94) to 60% (62/104), presence of artemether-lumefantrine dosage wall charts from 20% (19/94) to 75% (78/104), possession of guidelines from 58% (60/103) to 92% (124/135), and provision of in-service training from 25% (26/103) to 41% (55/135). The proportions of children with uncomplicated malaria treated with artemether-lumefantrine also increased from 2004 to 2006: from 1% (6/527) to 27% (149/552) in children weighing 5 to 9 kg, and from 11% (42/394) to 42% (231/547) in children weighing 10 kg or more. In both weight groups and both years, 22% (441/2020) of children with uncomplicated malaria were not prescribed any antimalarial drug. CONCLUSION: Although significant improvements in malaria case-management have occurred over two years in Zambia, the quality of treatment provided at the point of care is not yet optimal. Strengthening weak health systems and improving the delivery of effective interventions should remain high priority in all countries implementing new treatment policies for malaria

From chloroquine to artemether-lumefantrine: the process of drug policy change in Zambia

<p>Abstract</p> <p>Background</p> <p>Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT).</p> <p>Methods</p> <p>All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy.</p> <p>Results</p> <p>A decision was made to change national drug policy to artemether-lumefantrine (AL) in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004.</p> <p>Conclusion</p> <p>Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires more effort and recognition that this becomes a health system and not a drug issue. This case study attempts to document the successful experience of change to ACT in Zambia and provides a realistic overview of some of the painful experiences and important lessons learnt.</p

Implementation of Internet-based preventive interventions for depression and anxiety: role of support? The design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Internet-based self-help is an effective preventive intervention for highly prevalent disorders, such as depression and anxiety. It is not clear, however, whether it is necessary to offer these interventions with professional support or if they work without any guidance. In case support is necessary, it is not clear which level of support is needed. This study examines whether an internet-based self-help intervention with a coach is more effective than the same intervention without a coach in terms of clinical outcomes, drop-out and economic costs. Moreover, we will investigate which level of support by a coach is more effective compared to other levels of support.</p> <p>Methods</p> <p>In this randomized controlled trial, a total of 500 subjects (18 year and older) from the general population with mild to moderate depression and/or anxiety will be assigned to one of five conditions: (1) web-based problem solving through the internet (self-examination therapy) without a coach; (2) the same as 1, but with the possibility to ask help from a coach on the initiative of the respondent (on demand, by email); (3) the same as 1, but with weekly scheduled contacts initiated by a coach (once per week, by email); (4) weekly scheduled contacts initiated by a coach, but no web-based intervention; (5) information only (through the internet). The interventions will consist of five weekly lessons. Primary outcome measures are symptoms of depression and anxiety. Secondary outcome measures are drop-out from the intervention, quality of life, and economic costs. Other secondary outcome measures that may predict outcome are also studied, e.g. client satisfaction and problem-solving skills. Measures are taken at baseline (pre-test), directly after the intervention (post-test, five weeks after baseline), 3 months later, and 12 months later. Analysis will be conducted on the intention-to-treat sample.</p> <p>Discussion</p> <p>This study aims to provide more insight into the clinical effectiveness, differences in drop-out rate and costs between interventions with and without support, and in particular different levels of support. This is important to know in relation to the dissemination of internet-based self-help interventions.</p> <p>Trial Registration</p> <p>Nederlands Trial Register (NTR): TC1355</p

Typology of adults diagnosed with mental disorders based on socio-demographics and clinical and service use characteristics

<p>Abstract</p> <p>Background</p> <p>Mental disorder is a leading cause of morbidity worldwide. Its cost and negative impact on productivity are substantial. Consequently, improving mental health-care system efficiency - especially service utilisation - is a priority. Few studies have explored the use of services by specific subgroups of persons with mental disorder; a better understanding of these individuals is key to improving service planning. This study develops a typology of individuals, diagnosed with mental disorder in a 12-month period, based on their individual characteristics and use of services within a Canadian urban catchment area of 258,000 persons served by a psychiatric hospital.</p> <p>Methods</p> <p>From among the 2,443 people who took part in the survey, 406 (17%) experienced at least one episode of mental disorder (as per the Composite International Diagnostic Interview (CIDI)) in the 12 months pre-interview. These individuals were selected for cluster analysis.</p> <p>Results</p> <p>Analysis yielded four user clusters: people who experienced mainly anxiety disorder; depressive disorder; alcohol and/or drug disorder; and multiple mental and dependence disorder. Two clusters were more closely associated with females and anxiety or depressive disorders. In the two other clusters, males were over-represented compared with the sample as a whole, namely, substance abuses with or without concomitant mental disorder. Clusters with the greatest number of mental disorders per subject used a greater number of mental health-care services. Conversely, clusters associated exclusively with dependence disorders used few services.</p> <p>Conclusion</p> <p>The study found considerable heterogeneity among socio-demographic characteristics, number of disorders, and number of health-care services used by individuals with mental or dependence disorders. Cluster analysis revealed important differences in service use with regard to gender and age. It reinforces the relevance of developing targeted programs for subgroups of individuals with mental and/or dependence disorders. Strategies aimed at changing low service users' attitude (youths and males) or instituting specialised programs for that particular clientele should be promoted. Finally, as concomitant disorders are frequent among individuals with mental disorder, psychological services and/or addiction programs must be prioritised as components of integrated services when planning treatment.</p

Uptake of health services for common mental disorders by first-generation Turkish and Moroccan migrants in the Netherlands

Abstract Background Migration and ethnic minority status have been associated with higher occurrence of common mental disorders (CMD), while mental health care utilisation by non-Western migrants has been reported to be low compared to the general population in Western host countries. Still, the evidence-base for this is poor. This study evaluates uptake of mental health services for CMD and psychological distress among first-generation non-Western migrants in Amsterdam, the Netherlands. Methods A population-based survey. First generation non-Western migrants and ethnic Dutch respondents (N = 580) participated in structured interviews in their own languages. The interview included the Composite International Diagnostic Interview (CIDI) and the Kessler psychological distress scale (K10). Uptake of services was measured by self-report. Data were analysed using weighting techniques and multivariate logistic regression. Results Of subjects with a CMD during six months preceding the interview, 50.9% reported care for mental problems in that period; 35.0% contacted specialised services. In relation to CMD, ethnic groups were equally likely to access specialised mental health services. In relation to psychological distress, however, Moroccan migrants reported less uptake of primary care services (OR = 0.37; 95% CI = 0.15 to 0.88). Conclusion About half of the ethnic Dutch, Turkish and Moroccan population in Amsterdam with CMD contact mental health services. Since the primary purpose of specialised mental health services is to treat "cases", this study provides strong indications for equal access to specialised care for these ethnic groups. The purpose of primary care services is however to treat psychological distress, so that access appears to be lower among Moroccan migrants

Professional Service Utilisation among Patients with Severe Mental Disorders

<p>Abstract</p> <p>Background</p> <p>Generally, patients with serious mental disorders (SMD) are frequent users of services who generate high care-related costs. Current reforms aim to increase service integration and primary care for improved patient care and health-care efficiency. This article identifies and compares variables associated with the use by patients with SMD of services offered by psychiatrists, case managers, and general practitioners (GPs). It also compares frequent and infrequent service use.</p> <p>Method</p> <p>One hundred forty patients with SMD from five regions in Quebec, Canada, were interviewed on their use of services in the previous year. Patients were also required to complete a questionnaire on needs-assessment. In addition, data were collected from clinical records. Descriptive, bivariate, and multivariate analyses were conducted.</p> <p>Results</p> <p>Most patients used services from psychiatrists and case managers, but no more than half consulted GPs. Most patients were followed at least by two professionals, chiefly psychiatrists and case managers. Care access, continuity of care, and total help received were the most important variables associated with the different types of professional consultation. These variables were also associated with frequent use of professional service, as compared with infrequent service use. In all, enabling factors rather than need factors were the core predictors of frequency of service utilisation by patients with SMD.</p> <p>Conclusion</p> <p>This study reveals that health care system organisation and professional practice - rather than patient need profiles - are the core predictors of professional consultation by patients with SMD. The homogeneity of our study population, i.e. mainly users with schizophrenia, recently discharged from hospital, may partly account for these results. Our findings also underscored the limited involvement of GPs in this patient population's care. As comorbidity is often associated with serious mental disorders, closer follow-up by GPs is needed. Globally, more effort should be directed at increasing shared-care initiatives, which would enhance coordination among psychiatrists, GPs, and psychosocial teams (including case managers). Finally, there is a need to increase awareness among health care providers, especially GPs, of the level of care required by patients with disabling and serious mental disorders.</p

Multiple Promoters and Alternative Splicing: Hoxa5 Transcriptional Complexity in the Mouse Embryo

The genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.We have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression

Identification of calcium-binding proteins associated with the human sperm plasma membrane

<p>Abstract</p> <p>Background</p> <p>The precise composition of the human sperm plasma membrane, the molecular interactions that define domain specific functions, and the regulation of membrane associated proteins during the capacitation process, still remain to be fully understood. Here, we investigated the repertoire of calcium-regulated proteins associated with the human sperm plasma membrane.</p> <p>Methods</p> <p>Surface specific radioiodination was combined with two-dimensional gel electrophoresis, a 45Ca-overlay assay, computer assisted image analysis and mass spectrometry to identify calcium-binding proteins exposed on the human sperm surface.</p> <p>Results</p> <p>Nine acidic 45Ca-binding sperm proteins were excised from stained preparative 2D gels and identified by mass spectrometry. Five of the calcium binding proteins; HSPA2 (HSP70-1), HSPA5 (Bip), HYOU1 (ORP150), serum amyloid P-component (SAP) and protein kinase C substrate 80K-H (80K-H) were found to be accessible to Iodo-Bead catalyzed 125I-labelling on the surface of intact human sperm. Agglutination and immunofluorescence analysis confirmed that SAP is situated on the plasma membrane of intact, motile sperm as well as permeabilized cells. Western blot analysis showed increased phosphorylation of human sperm 80K-H protein following in vitro capacitation. This is the first demonstration of the 80K-H protein in a mammalian sperm.</p> <p>Conclusion</p> <p>The presence of SAP on the surface of mature sperm implies that SAP has a physiological role in reproduction, which is thought to be in the removal of spermatozoa from the female genital tract via phagocytosis. Since 80K-H is a Ca2+-sensor recently implicated in the regulation of both inositol 1,4,5-trisphosphate receptor and transient receptor potential (TRP) cation channel activities, its detection in sperm represents the first direct signaling link between PKC and store-operated calcium channels identified in human sperm.</p