Timothy M. E. Davis

Reappraisal of known malaria resistance loci in a large multicenter study

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10−4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Common infections in diabetes: pathogenesis, management and relationship to glycaemic control.

Specific defects in innate and adaptive immune function have been identified in diabetic patients in a range of in vitro studies. However, the relevance of these findings to the integrated response to infection in vivo remains unclear, especially in patients with good glycaemic control. Vaccine efficacy seems adequate in most diabetic patients, but those with type 1 diabetes and high glycosylated haemoglobin levels are most likely to exhibit hypo‐responsiveness. While particular infections are closely associated with diabetes, this is usually in the context of extreme metabolic disturbances such as ketoacidosis. The link between glycaemic control and the risk of common community‐acquired infections is less well established but could be clarified if infection data from large community‐based observational or intervention studies were available. The relationship between hospital‐acquired infections and diabetes is well recognized, particularly among post‐operative cardiac and critically ill surgical patients in whom intensive insulin therapy improves clinical outcome independent of glycaemia. Nevertheless, further research is needed to improve our understanding of the role of diabetes and glycaemic control in the pathogenesis and management of community‐ and hospital‐acquired infections. Copyright

Clinical and Laboratory Features of Human Plasmodium knowlesi Infection

BACKGROUND Plasmodium knowlesi is increasingly recognized as a cause of human malaria in Southeast Asia but there are no detailed prospective clinical studies of naturally acquired infections. METHODS In a systematic study of the presentation and course of patients with acute P. knowlesi infection, clinical and laboratory data were collected from previously untreated, nonpregnant adults admitted to the hospital with polymerase chain reaction-confirmed acute malaria at Kapit Hospital (Sarawak, Malaysia) from July 2006 through February 2008. RESULTS Of 152 patients recruited, 107 (70%) had P. knowlesi infection, 24 (16%) had Plasmodium falciparum infection, and 21 (14%) had Plasmodium vivax. Patients with P. knowlesi infection presented with a nonspecific febrile illness, had a baseline median parasitemia value at hospital admission of 1387 parasites/microL (interquartile range, 6-222,570 parasites/microL), and all were thrombocytopenic at hospital admission or on the following day. Most (93.5%) of the patients with P. knowlesi infection had uncomplicated malaria that responded to chloroquine and primaquine treatment. Based on World Health Organization criteria for falciparum malaria, 7 patients with P. knowlesi infection (6.5%) had severe infections at hospital admission. The most frequent complication was respiratory distress, which was present at hospital admission in 4 patients and developed after admission in an additional 3 patients. P. knowlesi parasitemia at hospital admission was an independent determinant of respiratory distress, as were serum creatinine level, serum bilirubin, and platelet count at admission (p < .002 for each). Two patients with knowlesi malaria died, representing a case fatality rate of 1.8% (95% confidence interval, 0.2%-6.6%). CONCLUSIONS Knowlesi malaria causes a wide spectrum of disease. Most cases are uncomplicated and respond promptly to treatment, but approximately 1 in 10 patients develop potentially fatal complications.

Piperaquine: a resurgent antimalarial drug.

Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria, but no pharmacokinetic characterisation was undertaken. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4 (CV4): dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate), which was followed by CV8 (the same components as CV4 but in increased quantities), Artecom (in which primaquine was omitted) and Artekin or Duo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates >95%), and have demonstrated that currently recommended regimens are not associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state/bioavailability, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of an ACT.

A trial of combination antimalarial therapies in children from Papua New Guinea.

BACKGROUND Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species, such as in Papua New Guinea. METHODS Between April 2005 and July 2007, we conducted an open-label, randomized, parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria. The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum, after correction for reinfections identified through polymerase-chain-reaction (PCR) genotyping of polymorphic loci in parasite DNA. Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping. RESULTS Of 2802 febrile children screened, 482 with falciparum malaria and 195 with vivax malaria were included. The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group (95.2%), as compared with 81.5% in the chloroquine-sulfadoxine-pyrimethamine group (P=0.003), 85.4% in the artesunate-sulfadoxine-pyrimethamine group (P=0.02), and 88.0% in the dihydroartemisinin-piperaquine group (P=0.06). The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group (69.4%) was more than twice that in each of the other three treatment groups. The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50% correlated significantly (P<0.001). Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine (P=0.004 for both comparisons). CONCLUSIONS The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax. The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine. (Australian New Zealand Clinical Trials Registry number, ACTRN12605000550606.)

Efficacy and safety of dihydroartemisinin-piperaquine (artekin) in Cambodian children and adults with uncomplicated falciparum malaria

The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children.

Diabetes education and knowledge in patients with type 2 diabetes from the community: The Fremantle Diabetes Study

BACKGROUND Diabetic patients obtain knowledge of the condition from a variety of sources. These include education programs and encounters with health-care staff such as during instruction on self-monitoring of blood glucose (SMBG). OBJECTIVE To assess whether diabetes knowledge is related to prior attendance at diabetes education programs, visits to dieticians or the current use of SMBG in a community-based cohort of subjects with type 2 diabetes. PATIENTS 1264 type 2 patients from the Fremantle Diabetes Study (FDS) cohort. METHODS Subjects answered 15 standard multiple-choice questions about diabetes and its management. Recall of past diabetes education, dietician consultations, and use of SMBG were recorded. Analysis of variance was used to determine whether these activities or other social and demographic factors predicted diabetes knowledge. RESULTS Attendance at education programs, visits to dieticians, and SMBG were independently associated with greater diabetes knowledge. Subjects who were older, whose schooling was limited, who were not fluent in English and/or who were from Southern European or indigenous Australian ethnic groups had significantly lower knowledge scores. Patients who were older, not fluent in English or from an indigenous Australian background were significantly less likely to have received diabetes education, dietetic advice or to be performing SMBG. CONCLUSIONS Diabetes education programs, diabetes-related visits to dieticians and SMBG are associated with, and may be important sources of, improved diabetes knowledge in patients with type 2 diabetes. Our data provide evidence that barriers to access or utilization of contemporary diabetes education confront older patients, minority groups and those with language difficulties. These groups are likely to benefit from specialized programs.

Autoantibodies to glutamic acid decarboxylase in diabetic patients from a multi-ethnic Australian community: the Fremantle Diabetes Study.

SUMMARY

Selective high-performance liquid chromatographic determination of artesunate and α- and β-dihydroartemisinin in patients with falciparum malaria

Abstract A novel solid-phase extraction and a robust high-performance liquid chromatographic (HPLC) separation procedure for artesunate and α- and β-dihydroartemisinin, using post-column alkali decomposition and UV detection, is described. Extraction was performed with Bond-Elut Phenyl solid-phase extraction cartridges and analysis by HPLC was carried out using a Waters Symmetry C8 5-μm 150 × 3.9 mm I.D. column. The mobile phase was 50% acetonitrile in 0.1 M acetate buffer (pH 4.8) delivered at a flow-rate of 0.7 ml/min. The column eluate was mixed with 1.2 M potassium hydroxide in 90% methanol delivered at 0.3 ml/min, in a 1-ml reaction coil at 69°C, to form UV-absorbing chromophores which were detected at 290 mm. The recovery of all analytes was greater than 80%. There was no significant difference in the peak-area ratio of α- and β-dihydroartemisinin in plasma. Preliminary pharmacokinetic data from six adult Vietnamese patients who received 120 mg of artesunate by intravenous injection for the treatment of acute falciparum malaria are presented. Despite limited data, the mean half-life of artesunate was approximately 3.5 min while that for dihydroartemisinin was 34 min. These data confirm the relatively rapid clearance of both artesunate and its principal active metabolite, dihydroartemisinin.

A prospective study of depression and mortality in patients with type 2 diabetes : the Fremantle Diabetes study

Aims/hypothesisDepression is associated with excess mortality in patients with type 2 diabetes. We investigated the impact, and possible causal mechanisms, of depression on all-cause and cardiac mortality in patients with type 2 diabetes.MethodsWe recruited 1,273 patients with type 2 diabetes from a postcode-defined community (average age 64.1±11.2 years, 48.7% males, median duration of diabetes 4 years [range 1.0–9.0]) and followed them for 7.8±2.4 years. Depression was assessed using data obtained using a quality-of-life questionnaire, and cause and date of death were obtained from the state registry.ResultsDepression was present in 31.5% of subjects at recruitment. Depressed subjects had a longer duration of diabetes, more cardiovascular risk factors, CHD, cerebrovascular disease and diabetic microvascular complications at baseline, and higher all-cause and cardiac mortality rates during follow-up. In Cox proportional hazards models and after adjustment for demographic and diabetes-related variables and cardiovascular risk factors, depression was significantly associated with excess all-cause and cardiac mortality. When diabetic microvascular and macrovascular complications were added to the Cox models, depression was not significantly associated with excess all-cause or cardiac mortality.Conclusions/interpretationDepression in patients with type 2 diabetes is associated with a greater prevalence of complications but is not an independent predictor of all-cause or cardiac mortality. Depression may contribute to the progression of important prognostic variables in diabetes, particularly macrovascular and microvascular disease.