Impact of pharmacogenomics on clinical practice in oncology

Multiple drug strategies for many cancer types are now readily available and there is a clear need for tools to inform decision making on therapy selection. Although there is still a long way to go before pharmacogenomics achieves the goal of individualized selection of cancer treatment, promising progress is being made. Genetic testing for thiopurine methyltransferase (TPMT) variant alleles in patients prior to mercaptopurine administration, and for UGT1A1*28 in patients prior to administration of irinotecan therapy, along with the instigation of genotype-guided clinical trials (e.g. TYMS) are important advances in cancer pharmacogenomics. Markers for the toxicity and efficacy of many oncology drugs remain unknown; however, the examples highlighted here suggest progress is being made towards the incorporation of pharmacogenomics into clinical practice in oncology.     

Accuracy of rapid tests for malaria and treatment outcomes for malaria and non-malaria cases among under-five children in rural Ghana

Background

WHO now recommends test-based management of malaria across all transmission settings. The accuracy of rapid diagnostic test (RDT) and the outcome of treatment based on the result of tests will influence acceptability of and adherence to the new guidelines.

Method

We conducted a study at the Kintampo hospital in rural Ghana to evaluate the performance of CareStart, a HRP-2 based RDT, using microscopy as reference. We applied IMCI treatment guidelines, restricted ACT to RDT-positive children and followed-up both RDT-positive (malaria) and RDT-negative (non-malaria) cases over 28 days.

Results

436 children were enrolled in the RDT evaluation and 391 (children with haemoglobin >8.0 gm/dl) were followed-up to assess treatment outcomes. Mean age was 25.4 months (s.d. 14.6). Sensitivity and specificity of the RDT were 100.0% and 73.0% respectively. Over the follow-up period, 32 (18.5%) RDT-negative children converted to positive, with 7 (4.0%) of them presenting with fever. More children in the non-malaria group made unscheduled visits than children in the malaria group (13.3% versus 7.7%) On all scheduled follow-up visits, proportion of children having a temperature higher than that recorded on day 0 was higher in the non-malaria group compared to the malaria group. Reports of unfavourable treatment outcomes by caregivers were higher among the non-malaria group than the malaria group.

Conclusions

The RDT had good sensitivity and specificity. However a minority of children who will not receive ACT based on RDT results may develop clinical malaria within a short period in high transmission settings. This could undermine caregivers'' and health workers'' confidence in the new guidelines. Improving the quality of management of non-malarial febrile illnesses should be a priority in the era of test-based management of malaria.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00832754","term_id":"NCT00832754"}}NCT00832754     

Dieldrin resistance in the malaria vector Anopheles gambiae in Ghana

Anopheles gambiae Giles s.s. (Diptera: Culicidae) is one of the principal vectors of malaria in the Ashanti region of central Ghana. High levels of resistance to dieldrin were recorded in a wild-caught sample from Obuasi (south of Kumasi) as well as a laboratory colony established using material from the wild population. Cytogenetic analysis of wild-caught and laboratory samples revealed chromosomal polymorphism for inversions 2La and 2Rb. Although inversion 2La has previously been shown to be associated with dieldrin resistance in certain other laboratory strains originating from West Africa, there was no obvious association between inversion karyotype assortment and the resistance phenotype in the Obuasi population. In addition, polymerase chain reaction analysis indicated the presence of the alanine296 to glycine mutation in the GABA (gamma amino-butyric acid) receptor (which has been mapped to a chromosomal position within inversion 2La). This mutation has previously been shown to be associated with dieldrin resistance in the same An. gambiae laboratory strains of West African origin. Our data show only a weak association between the dieldrin resistance phenotype and the presence of this mutation, suggesting that another dieldrin resistance mechanism is operational in the Obuasi population. Biochemical and synergist exposure assays suggest a metabolic component, probably mediated by monooxygenase P450 enzymes. We conclude that dieldrin resistance in the An. gambiae population of the Obuasi region occurs at a high level - most likely in the absence of selection - and that control of the resistance phenotype is polyfactorial and must include components other than mutations in the GABA receptor locus.     

Medical physics practice and training in Ghana

Medical physics has been an indispensable and strategic stakeholder in the delivery of radiological services to the healthcare system of Ghana. The practice has immensely supported radiation oncology and medical imaging facilities over the years, while the locally established training programme continues to produce human resource to feed these facilities. The training programme has grown to receive students from other African countries in addition to local students. Ghana has been recognised by the International Atomic Energy Agency as Regional Designated Centre for Academic Training of Medical Physicists in Africa. The Ghana Society for Medical Physics collaborates with the School of Nuclear and Allied Sciences of the University of Ghana to ensure that training offered to medical physicists meet international standards, making them clinically qualified. The Society has also worked together with other bodies for the passage of the Health Profession’s Regulatory Bodies Act, giving legal backing to the practice of medical physics and other allied health professions in Ghana. The country has participated in a number of International Atomic Energy Agency’s projects on medical physics and has benefited from its training courses, fellowships and workshops, as well as those of other agencies such as International Organization for Medical Physics. This has placed Ghana’s medical physicists in good position to practice competently and improve healthcare.     

Impact of chloroquine resistance on malaria mortality

Over 12 years, from 1984 to 1995, we conducted a prospective study of overall and malaria specific mortality among three rural populations in the Sahel, savanna and forest areas of Senegal. The emergence of chloroquine resistance has been associated with a dramatic increase in malaria mortality in each of the studied populations. After the emergence of chloroquine resistance, the risk of malaria death among children 0–9 years old in the three populations was multiplied by 2.1, 2.5 and 5.5, respectively. This is the first study to document malaria mortality at the community level in Africa before and after the emergence of chloroquine resistance. Findings suggest that the spread of chloroquine resistance has had a dramatic impact on the level of malaria mortality in most epidemiological contexts in tropical Africa.     

Impact of cocoa farming on vegetation in an agricultural landscape in Ghana

Cocoa production occurs almost wholly within areas identified as biodiversity hotspots in West Africa and it has been noted as a major contributor to deforestation at the forest‐agriculture interface. This study investigated the impact of cocoa farming on vegetation in relation to three land‐use types of increasing cocoa production intensity from remnant native forest through shaded to unshaded cocoa farmlands in Ghana. The study used transects and forty‐two 25 m × 25 m vegetation plots. The overall noncocoa plant species richness decreased significantly (95% CI) from the remnant native forest through shaded to the unshaded cocoa farmlands. Significant differences (P ≤ 0.05) were also found in the mean density and basal area of noncocoa plants per hectare with the remnant native forest recording the highest values and the unshaded cocoa farmlands the lowest. The relative density of about 44.7% out of the 41 most abundant plant species declined in cocoa farmlands. The results of this study showed that cocoa farming could result in a drastic forest plant species loss with subsequent recruitment of nonforest species, forest plant species population decline as well as changes in the structural characteristics of the vegetation. This impact increases with increasing cocoa production intensity.     

School-based participatory health education for malaria control in Ghana: engaging children as health messengers

Background

Infected humans make protective antibody responses to the PfEMP1 adhesion antigens exported by Plasmodium falciparum parasites to the erythrocyte membrane, but little is known about the kinetics of this antibody-receptor binding reaction or how the topology of PfEMP1 on the parasitized erythrocyte membrane influences antibody association with, and dissociation from, its antigenic target.

Methods

A Quartz Crystal Microbalance biosensor was used to measure the association and dissociation kinetics of VAR2CSA PfEMP1 binding to human monoclonal antibodies. Immuno-fluorescence microscopy was used to visualize antibody-mediated adhesion between the surfaces of live infected erythrocytes and atomic force microscopy was used to obtain higher resolution images of the membrane knobs on the infected erythrocyte to estimate knob surface areas and model VAR2CSA packing density on the knob.

Results

Kinetic analysis indicates that antibody dissociation from the VAR2CSA PfEMP1 antigen is extremely slow when there is a high avidity interaction. High avidity binding to PfEMP1 antigens on the surface of P. falciparum-infected erythrocytes in turn requires bivalent cross-linking of epitopes positioned within the distance that can be bridged by antibody. Calculations of the surface area of the knobs and the possible densities of PfEMP1 packing on the knobs indicate that high-avidity cross-linking antibody reactions are constrained by the architecture of the knobs and the large size of PfEMP1 molecules.

Conclusions

High avidity is required to achieve the strongest binding to VAR2CSA PfEMP1, but the structures that display PfEMP1 also tend to inhibit cross-linking between PfEMP1 antigens, by holding many binding epitopes at distances beyond the 15-18 nm sweep radius of an antibody. The large size of PfEMP1 will also constrain intra-knob cross-linking interactions. This analysis indicates that effective vaccines targeting the parasite's vulnerable adhesion receptors should primarily induce strongly adhering, high avidity antibodies whose association rate constant is less important than their dissociation rate constant.     

Impact of irrigation on malaria in Africa: paddies paradox

The high population growth rate of the African continent has led to an increased demand for food and is in danger of outstripping agricultural production. In order to meet this need, many governments have sought ways of improving food production by initiating large-scale irrigation projects, involving reclamation of arid and semi-arid areas for the cultivation of crops. Although crop irrigation promises one solution to alleviating hunger and encourages economic growth, irrigation has often been blamed for aggravating disease in local communities. Malaria is one of the major tropical diseases associated with irrigation schemes, and changes in the transmission pattern of this disease following irrigation development have been a perennial subject of debate. It has often been assumed that high numbers of malaria vector Anopheles mosquitoes (Diptera: Culicidae) resulting from irrigation schemes lead inevitably to increased malaria in local communities. However, recent studies in Africa have revealed a more complex picture. Increased numbers of vectors following irrigation can lead to increased malaria in areas of unstable transmission, where people have little or no immunity to malaria parasites, such as the African highlands and desert fringes. But for most of sub-Saharan Africa, where malaria is stable, the introduction of crop irrigation has little impact on malaria transmission. Indeed, there is growing evidence that for many sites there is less malaria in irrigated communities than surrounding areas. The explanation for this finding is still unresolved but, in some cases at least, can be attributed to displacement of the most endophilic and anthropophilic malaria vector Anopheles funestus Giles by An. arabiensis Patton with lower vectorial capacity, as the latter thrives more than the former in ricefields. Similarly, among members of the An. gambiae complex, some cytotypes of An. gambiae sensu stricto are more vectorial than others. For example, the Mopti form has high vectorial capacity and breeds perennially in irrigated sites, whereas the savanna form is often sympatric but more seasonal. Also we suggest that many communities near irrigation schemes benefit from the greater wealth created by these schemes. Consequently irrigation communities often have greater use of bednets, better access to improved healthcare and receive fewer infective bites compared with those outside such development schemes. Thus, in most cases, irrigation schemes in Africa do not appear to increase malaria risk, except in areas of unstable transmission. However, developers should take the opportunity to improve health-care facilities for local communities when planning irrigation schemes wherever they occur.     

Impact of commercial salt production on wetland quality and waterbirds on coastal lagoons in Ghana

A comparative study conducted on two saline coastal wetlands that have been developed into saltpans and two others (referred to as 'non-saltpans'), that are also saline but have no saltpans, describes the quality of lagoon water, benthic macroinvertebrates and waterbird communities characterising these wetlands. The wetlands were sampled monthly from September 2005–April 2006. Except for turbidity, which was significantly higher in the non-saltpans, (p < 0.05), all other physico-chemical parameters studied were not significantly different between the two wetland types (p > 0.05). The waterbird communities of the saltpans and non-saltpans, characterised by 48 and 50 species respectively, scored a Sorenson Index value of 0.88, indicating a high similarity. The population density of benthic macroinvertebrates in the saltpans and the non-saltpans was statistically similar (p > 0.05) but the population densities of waterbirds feeding exclusively on benthic macroinvertebrates were significantly higher in the non-saltpans (p < 0.05). Although the shallow ponds created for salt production might be providing more suitable feeding habitats for fish-eating birds, the development of these ponds has also reduced the exploitable area available to the birds feeding exclusively on invertebrates, requiring them to depend largely on the non-saltpans. Birds feeding exclusively on fish had significantly higher population densities in the saltpans (p < 0.05) than in non-saltpans. This was attributed to reduced efficiency of piscivory, due to the high turbidity associated with the non-saltpans. Waterbirds feeding on a wide range of food types showed no significant differences in their population densities (p > 0.05) in the two wetland types.     

Spatial analysis of land cover determinants of malaria incidence in the Ashanti Region, Ghana

Malaria belongs to the infectious diseases with the highest morbidity and mortality worldwide. As a vector-borne disease malaria distribution is strongly influenced by environmental factors. The aim of this study was to investigate the association between malaria risk and different land cover classes by using high-resolution multispectral Ikonos images and Poisson regression analyses. The association of malaria incidence with land cover around 12 villages in the Ashanti Region, Ghana, was assessed in 1,988 children <15 years of age. The median malaria incidence was 85.7 per 1,000 inhabitants and year (range 28.4–272.7). Swampy areas and banana/plantain production in the proximity of villages were strong predictors of a high malaria incidence. An increase of 10% of swampy area coverage in the 2 km radius around a village led to a 43% higher incidence (relative risk [RR] = 1.43, p<0.001). Each 10% increase of area with banana/plantain production around a village tripled the risk for malaria (RR = 3.25, p<0.001). An increase in forested area of 10% was associated with a 47% decrease of malaria incidence (RR = 0.53, p = 0.029).Distinct cultivation in the proximity of homesteads was associated with childhood malaria in a rural area in Ghana. The analyses demonstrate the usefulness of satellite images for the prediction of malaria endemicity. Thus, planning and monitoring of malaria control measures should be assisted by models based on geographic information systems.     

Early warning systems for malaria in Africa: from blueprint to practice

Although the development of early warning systems for malaria has been advocated by international agencies and academic researchers for many years, practical progress in this area has been relatively modest. In two recent articles, Thomson et al. provide new evidence that models of malaria incidence that incorporate monitored or predicted climate can provide early warnings of epidemics one to five months in advance in semi-arid areas. Although the potential benefits of these models in terms of improved management of epidemics are clear, several technical and practical hurdles still need to be overcome before the models can be widely integrated into routine malaria-control strategies.     

Evidence for over-dispersion in the distribution of clinical malaria episodes in children

Background

It may be assumed that patterns of clinical malaria in children of similar age under the same level of exposure would follow a Poisson distribution with no over-dispersion. Longitudinal studies that have been conducted over many years suggest that some children may experience more episodes of clinical malaria than would be expected. The aim of this study was to identify this group of children and investigate possible causes for this increased susceptibility.

Methodology and Principal Findings

Using Poisson regression, we chose a group of children whom we designated as ‘more susceptible’ to malaria from 373 children under 10 years of age who were followed up for between 3 to 5 years from 1998–2003. About 21% of the children were categorized as ‘more susceptible’ and although they contributed only 23% of the person-time of follow-up, they experienced 55% of total clinical malaria episodes. Children that were parasite negative at all cross-sectional survey were less likely to belong to this group [AOR = 0.09, (95% CI: 0.14–0.61), p = 0.001].

Conclusions and Significance

The pattern of clinical malaria episodes follows a negative binomial distribution. Use of lack of a clinical malaria episode in a certain time period as endpoints for intervention or immunological studies may not adequately distinguish groups who are more or less immune. It may be useful in such studies, in addition to the usual endpoint of the time to first episode, to include end points which take into account the total number of clinical episodes experienced per child.     

Two-year evaluation of Intermittent Preventive Treatment for Children (IPTc) combined with timely home treatment for malaria control in Ghana

Background

Intermittent preventive treatment (IPT) has recently been accepted as an important component of the malaria control strategy. Intermittent preventive treatment for children (IPTc) combined with timely treatment of malaria related febrile illness at home to reduce parasite prevalence and malaria morbidity in children aged between six and 60 months in a coastal community in Ghana. This paper reports persistence of reduced parasitaemia two years into the intervention. The baseline and year-one-evaluation findings were published earlier.

Objective

The main objective in the second year was to demonstrate whether the two interventions would further reduce parasite prevalence and malaria-related febrile illness in the study population.

Methods

This was an intervention study designed to compare baseline and evaluation findings without a control group. The study combined home-based delivery of intermittent preventive treatment for children (IPTc) aged 6 - 60 months and home treatment of suspected febrile malaria-related illness within 24 hours. All children aged 6 - 60 months received home-based delivery of intermittent preventive treatment using amodiaquine + artesunate, delivered at home by community assistants every four months (6 times in 24 months). Malaria parasite prevalence surveys were conducted before the first and after the third and sixth IPTc to the children. The evaluation surveys were done four months after the third and sixth IPTc was given.

Results

Parasite prevalence which reduced from 25% to 3.0% at year-one evaluation had reduced further from 3% to 1% at year-two-evaluation. At baseline, 13.8% of the children were febrile (axilary temperature of ≥37.5°C) compared to 2.2% at year-one-evaluation while 2.1% were febrile at year-two-evaluation.

Conclusion

The year-two-evaluation result indicates that IPTc given three times in a year (every four months) combined with timely treatment of febrile malaria illness, is effective to reduce malaria parasite prevalence in children aged 6 to 60 months in the study community. This must give hope to malaria control programme managers in sub-Saharan Africa where the burden of the disease is most debilitating.

     

Prescribing at the hospital-general practice interface. II: Impact of hospital outpatient dispensing policies in England on general practitioners and hospital consultants.

OBJECTIVE--To assess the impact on general practitioners and hospital consultants of hospital outpatient dispensing policies in England. DESIGN--Postal questionnaire and telephone interview survey of general practitioners and hospital consultants in January 1991. SETTING--94 selected major acute hospitals in England. PARTICIPANTS--20 general practitioners in the vicinity of each of 94 selected hospitals and eight consultants from each, selected by chief pharmacists. MAIN OUTCOME MEASURES--Proportions of general practitioners unable to assume responsibility for specialist drugs and of consultants wishing to retain responsibility; association between dispensing restrictions and the frequency of general practitioners being asked to prescribe hospital initiated treatments. RESULTS--Completed questionnaires were obtained from 1207 (64%) of 1887 general practitioners and 457 (63%) of 729 consultants. 570 (46%) general practitioners felt unable to take responsibility for certain treatments, principally because of difficulty in detecting side effects (367, 30%), uncertainty about explaining treatment to patients (332, 28%), and difficulty monitoring dosage (294, 24%). Among consultants 328 (72%) wished to retain responsibility, principally because of specialist need for monitoring (93, 20%), urgent need to commence treatment (64, 14%), and specialist need to initiate or stabilise treatment (63, 14%). The more restricted the drug supply to outpatients, the more frequently consultants asked general practitioners to prescribe (p less than 0.01) and complete a short course of treatment initiated by the hospital (p less than 0.001). CONCLUSIONS--Restrictive hospital outpatient dispensing shifts clinical responsibility on to general practitioners. Hospital doctors should be able to retain responsibility for prescribing when the general practitioner is unfamiliar with the drug or there is a specialist need to initiate, stabilise, or monitor treatment.     

Impact of changing drug treatment and malaria endemicity on the heritability of malaria phenotypes in a longitudinal family-based cohort study

Despite considerable success of genome wide association (GWA) studies in identifying causal variants for many human diseases, their success in unraveling the genetic basis to complex diseases has been more mitigated. Pathogen population structure may impact upon the infectious phenotype, especially with the intense short-term selective pressure that drug treatment exerts on pathogens. Rigorous analysis that accounts for repeated measures and disentangles the influence of genetic and environmental factors must be performed. Attempts should be made to consider whether pathogen diversity will impact upon host genetic responses to infection.We analyzed the heritability of two Plasmodium falciparum phenotypes, the number of clinical malaria episodes (PFA) and the proportion of these episodes positive for gametocytes (Pfgam), in a family-based cohort followed for 19 years, during which time there were four successive drug treatment regimes, with documented appearance of drug resistance. Repeated measures and variance components analyses were performed with fixed environmental, additive genetic, intra-individual and maternal effects for each drug period. Whilst there was a significant additive genetic effect underlying PFA during the first drug period of study, this was lost in subsequent periods. There was no additive genetic effect for Pfgam. The intra-individual effect increased significantly in the chloroquine period.The loss of an additive genetic effect following novel drug treatment may result in significant loss of power to detect genes in a GWA study. Prior genetic analysis must be a pre-requisite for more detailed GWA studies. The temporal changes in the individual genetic and the intra-individual estimates are consistent with those expected if there were specific host-parasite interactions. The complex basis to the human response to malaria parasite infection likely includes dominance/epistatic genetic effects encompassed within the intra-individual variance component. Evaluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort.