Solar-powered oxygen delivery: proof of concept.

SETTING: A resource-limited paediatric hospital in Uganda. OBJECTIVE: Pneumonia is a leading cause of child mortality worldwide. Access to life-saving oxygen therapy is limited in many areas. We designed and implemented a solar-powered oxygen delivery system for the treatment of paediatric pneumonia. DESIGN: Proof-of-concept pilot study. A solar-powered oxygen delivery system was designed and piloted in a cohort of children with hypoxaemic illness. RESULTS: The system consisted of 25 × 80 W photovoltaic solar panels (daily output 7.5 kWh [range 3.8-9.7kWh]), 8 × 220 Ah batteries and a 300 W oxygen concentrator (output up to 5 l/min oxygen at 88% [±2%] purity). A series of 28 patients with hypoxaemia were treated with solar-powered oxygen. Immediate improvement in peripheral blood oxygen saturation was documented (median change +12% [range 5-15%], P < 0.0001). Tachypnoea, tachycardia and composite illness severity score improved over the first 24 h of hospitalisation (P < 0.01 for all comparisons). The case fatality rate was 6/28 (21%). The median recovery times to sit, eat, wean oxygen and hospital discharge were respectively 7.5 h, 9.8 h, 44 h and 4 days. CONCLUSION: Solar energy can be used to concentrate oxygen from ambient air and oxygenate children with respiratory distress and hypoxaemia in a resource-limited setting.

Illness in Canadian travellers and migrants from Brazil: CanTravNet surveillance data, 2013-2016.

BACKGROUND: In light of the 2016 summer Olympic games it is anticipated that Canadian practitioners will require information about common illnesses that may affect travellers returning from Brazil. OBJECTIVE: To identify the demographic and travel correlates of illness among recent Canadian travellers and migrants from Brazil attending a network of travel health clinics across Canada. METHODS: Data was analyzed on returned Canadian travellers and migrants presenting to a CanTravNet site for care of an illness between June 2013 and June 2016. RESULTS: During the study period, 7,707 ill travellers and migrants presented to a CanTravNet site and 89 (0.01%) acquired their illness in Brazil. Tourists were most well represented (n=45, 50.6%), followed by those travelling to "visit friends and relatives" (n=14, 15.7%). The median age was 37 years (range <1-78 years), 49 travellers were men (55.1%) and 40 were women (44.9%). Of the 40 women, 26 (65%) were of childbearing age. Nine percent (n=8) of travellers were diagnosed with arboviruses including dengue (n=6), chikungunya (n=1) and Zika virus (n=1), while another 14.6% (n=13) presented for care of non-specific viral syndrome (n=7), non-specific febrile illness (n=1), peripheral neuropathy (n=1) and non-specific rash (n=4), which are four syndromes that may be indicative of Zika virus infection. Ill returned travellers to Brazil were more likely to present for care of arboviral or Zika-like illness than other ill returned travellers to South America (23.6 per 100 travellers versus 10.5 per 100 travellers, respectively [p=0.0024]). INTERPRETATION: An epidemiologic approach to illness among returned Canadian travellers to Brazil can inform Canadian practitioners encountering both prospective and returned travellers to the Olympic games. Analysis showed that vector-borne illnesses such as dengue are common and even in this small group of travellers, both chikungunya and Zika virus were represented. It is extremely important to educate travellers about mosquito-avoidance measures in advance of travel to Brazil.

Travel-acquired infections in Canada: CanTravNet 2011-2012.

BACKGROUND: Important gaps remain in our knowledge of the infectious diseases people acquire while travelling and the impact of pathogens imported by Canadian travellers. OBJECTIVE: To provide a surveillance update of illness in a cohort of returned Canadian travellers and new immigrants. METHODS: Data on returning Canadian travellers and new immigrants presenting to a CanTravNet site between September 2011 and September 2012 were extracted and analyzed by destination, presenting symptoms, common and emerging infectious diseases and disease severity. RESULTS: During the study period, 2283 travellers and immigrants presented to a CanTravNet site, 88% (N=2004) of whom were assigned a travel-related diagnosis. Top three destinations for non-immigrant travellers were India (N=132), Mexico (N=103) and Cuba (N=89). Fifty-one cases of malaria were imported by ill returned travellers during the study period, 60% (N=30) of which were Plasmodium falciparum infections. Individuals travelling to visit friends and relatives accounted for 83% of enteric fever cases (15/18) and 41% of malaria cases (21/51). The requirement for inpatient management was over-represented among those with malaria compared to those without malaria (25% versus 2.8%; p<0.0001) and those travelling to visit friends and relatives versus those travelling for other reasons (12.1% versus 2.4%; p<0.0001). Nine new cases of HIV were diagnosed among the cohort, as well as one case of acute hepatitis B. Emerging infections among travellers included hepatitis E virus (N=6), chikungunya fever (N=4) and cutaneous leishmaniasis (N=16). Common chief complaints included gastrointestinal (N=804), dermatologic (N=440) and fever (N=287). Common specific causes of chief complaint of fever in the cohort were malaria (N=47/51 total cases), dengue fever (14/18 total cases), enteric fever (14/17 total cases) and influenza and influenza-like illness (15/21 total cases). Animal bites were the tenth most common diagnosis among tourist travellers. INTERPRETATION: Our analysis of surveillance data on ill returned Canadian travellers provides a recent update to the spectrum of imported illness among travelling Canadians. Preventable travel-acquired illnesses and injuries in the cohort include malaria, enteric fever, HIV, hepatitis B, hepatitis A, influenza and animal bites. Strategies to improve uptake of preventive interventions such as malaria chemoprophylaxis, immunizations and arthropod/animal avoidance may be warranted.

Genetic diversity in human erythrocyte pyruvate kinase.

Previously, we have shown that pyruvate kinase, liver and red cell isoform (PKLR) deficiency protects mice in vivo against blood-stage malaria, and observed that reduced PKLR function protects human erythrocytes against Plasmodium falciparum replication ex vivo. Here, we have sequenced the human PKLR gene in 387 individuals from malaria-endemic and other regions in order to assess genetic variability in different geographical regions and ethnic groups. Rich genetic diversity was detected in PKLR, including 59 single-nucleotide polymorphisms and several loss-of-function variants (frequency 1.5%). Haplotype distribution and allele frequency varied considerably with geography. Neutrality testing suggested positive selection of the genein the sub-Saharan African and Pakistan populations. It is possible that such positive selection involves the malarial parasite.

Alanine aminotransferase is associated with atherothrombotic risk factors in a British South Asian population.

BACKGROUND: Alanine aminotransferase (ALT) predicts the development of Type 2 diabetes mellitus and cardiovascular disease in Caucasian subjects. OBJECTIVES: This study aimed to determine the incidence of an elevated ALT and its relationship to metabolic and atherothrombotic risk factors in a healthy British South Asian population. PATIENTS/METHODS: One hundred and forty-three participants from the West Yorkshire community were recruited randomly from general practice registers and were grouped according to whether their ALT was above or within the normal range (cut-off 35 IU L(-1)) and examined for differences in metabolic and atherothrombotic risk factors. All participants were originally from South Asia, with their grandparents being born in India, Pakistan, or Bangladesh. RESULTS: The incidence of a raised ALT was 24%. Those with a raised ALT had a more adverse metabolic profile, with significantly higher body mass index, waist/hip ratio, fasting insulin, glucose, homeostasis model assessment homeostasis model assessment insulin resistance (HOMA-IR), and triglycerides, and lower high-density lipoprotein (HDL) cholesterol. Fifty per cent had the metabolic syndrome [International Diabetes Federation (IDF) criteria]. They also had a more adverse atherothrombotic profile, with higher tissue-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) antigen. In accordance, the group as a whole showed a positive correlation of ALT (age-adjusted) with waist/hip ratio, insulin, glucose, triglycerides, PAI-1 antigen, factor XIII B subunit, and FXII, and a negative correlation with HDL cholesterol. CONCLUSION: Raised ALT is common in apparently healthy British South Asians, and is significantly associated with an adverse metabolic and atherothrombotic risk profile.

Ethnic differences in cardiovascular risk factors in healthy Caucasian and South Asian individuals with the metabolic syndrome.

BACKGROUND: The metabolic syndrome is a cluster of atherothrombotic risk factors that are commonly associated with insulin resistance. OBJECTIVES: The aim of this study was to investigate ethnic differences in insulin resistance and non-traditional cardiovascular risk factors in relation to the International Diabetes Federation (IDF) definition of the metabolic syndrome. PATIENTS AND METHODS: A total of 245 healthy South Asians and 245 age- and sex-matched Caucasians were studied. C-reactive protein (CRP), complement C3, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) were measured and homeostasis model assessment-insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin levels. RESULTS: Fifty Caucasian (20%) and 95 (39%) South Asian subjects had the metabolic syndrome as defined by the IDF. In South Asian subjects, HOMA-IR, CRP, C3, PAI-1 and t-PA were significantly higher in subjects with the metabolic syndrome. In contrast, in Caucasian individuals there was no difference in HOMA-IR or C3 levels and only CRP, PAI-1 and t-PA were higher in subjects with the metabolic syndrome. In a logistic regression model, plasma levels of CRP and PAI-1 were independent predictors of the metabolic syndrome in Caucasians, whereas plasma levels of C3 and t-PA as well as HOMA-IR were independent predictors of the metabolic syndrome in South Asian subjects. CONCLUSIONS: In the cohort of individuals studied, the IDF definition of the metabolic syndrome was associated with insulin resistance in the South Asian but not the Caucasian population. This work also showed ethnic differences in non-traditional cardiovascular risk factors in the presence of the metabolic syndrome.

Associations between insulin resistance and thrombotic risk factors in high-risk South Asian subjects.

AIMS: There is recognized association of thrombotic factors to insulin resistance in White Europeans. South Asians are more insulin resistant compared with white Europeans and express increased metabolic features of insulin resistance. The aim of the study was to determine whether there was any relationship between insulin resistance and thrombotic risk factors in healthy South Asian subjects. METHODS: Healthy South Asians (n = 185) clinically free from ischaemic heart disease, ischaemic stroke or peripheral vascular disease were randomly recruited. Partial correlations of homeostasis model assessment (HOMA) (surrogate of insulin resistance) were analysed with two fibrinolytic and five coagulation factors. RESULTS: Age and gender-adjusted HOMA was significantly correlated to plasminogen activator inhibitor-1 (0.51, P = 0.0001), tissue plasminogen activator antigen (r = 0.40, P = 0.0001), fibrinogen (r = 0.28, P = 0.0001), von Willebrand factor (r = 0.17, P = 0.03), factor XIIa (r = 0.22, P = 0.006) factor VII antigen (r = 0.19, P = 0.02) and factor XIII B subunit (r = 0.30, P = 0.001). CONCLUSIONS: Insulin resistance significantly clusters with fibrinolytic and coagulation factors in South Asians, which may contribute to high prevalence of vascular disease in this population.

Effects of starvation and desiccation on energy metabolism in desert and mesic Drosophila.

Energy availability can limit the ability of organisms to survive under stressful conditions. In Drosophila, laboratory experiments have revealed that energy storage patterns differ between populations selected for desiccation and starvation. This suggests that flies may use different sources of energy when exposed to these stresses, but the actual substrates used have not been examined. We measured lipid, carbohydrate, and protein content in 16 Drosophila species from arid and mesic habitats. In five species, we measured the rate at which each substrate was metabolized under starvation or desiccation stress. Rates of lipid and protein metabolism were similar during starvation and desiccation, but carbohydrate metabolism was several-fold higher during desiccation. Thus, total energy consumption was lower in starved flies than desiccated ones. Cactophilic Drosophila did not have greater initial amounts of reserves than mesic species, but may have lower metabolic rates that contribute to stress resistance.

Efficacy of a 14-day primaquine regimen in preventing relapses in patients with Plasmodium vivax malaria in Mumbai, India.

We studied the antirelapse efficacy of a supervised 14-d 15 mg/d regimen of primaquine therapy (n = 131) compared with no antirelapse therapy (n = 142) in 273 patients with confirmed Plasmodium vivax malaria in Mumbai, India, between July 1998 and April 2000. There were 6/131 (4.6%) recurrences in patients given primaquine compared with 13/142 (9.2%) in those not given antirelapse therapy. In the 14-d primaquine group, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) genotyping analysis of pre- and post-treatment blood samples was done for the 6 patients who had a recurrence of parasitaemia and the results gave a true relapse rate of 2.29% (3/131), 2 samples were classified as reinfections and 1 sample did not amplify. Our results indicate probable resistance to the 14-d regimen of primaquine for the first time in India and illustrate the need to (i) monitor patients given this regimen and (ii) carry out comparative studies between primaquine and new drugs such as tafenoquine and bulaquine for preventing relapses.

Genetically encoded fluorescent reporters of protein tyrosine kinase activities in living cells.

The complexity and specificity of many forms of signal transduction are widely believed to require spatial compartmentation of protein kinase and phosphatase activities, yet existing methods for measuring kinase activities in cells lack generality or spatial or temporal resolution. We present three genetically encoded fluorescent reporters for the tyrosine kinases Src, Abl, and epidermal growth factor (EGF) receptor. The reporters consist of fusions of cyan fluorescent protein (CFP), a phosphotyrosine binding domain, a consensus substrate for the relevant kinase, and yellow fluorescent protein (YFP). Stimulation of kinase activities in living cells with addition of growth factors causes 20-35% changes in the ratios of yellow to cyan emissions because of phosphorylation-induced changes in fluorescence resonance energy transfer (FRET). Platelet-derived growth factor (PDGF) stimulated Abl activity most strongly in actin-rich membrane ruffles, supporting the importance of this tyrosine kinase in the regulation of cell morphology. These results establish a general strategy for nondestructively imaging dynamic protein tyrosine kinase activities with high spatial and temporal resolution in single living cells.

Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model.

Plasmodia infect the liver for about 7 days before subsequently infecting the blood. Present prophylaxis against Plasmodium falciparum malaria employs agents that primarily kill blood stages and must be continued for 28 days after the last exposure. Atovaquone-proguanil (Malarone) is a new antimalarial agent that is licensed in 35 countries as treatment against blood-stage infection, but its components (atovaquone and proguanil) have separately been shown to be active also against liver stages. To determine whether atovaquone-proguanil is sufficiently active against liver stages to be discontinued 7 days after exposure, we challenged 16 volunteers with P. falciparum via infected mosquitoes. Twelve volunteers received atovaquone-proguanil (1 tablet daily) on the day prior to challenge, on the day of challenge, and for the next 6 days; 4 volunteers received matching placebo. All placebo volunteers demonstrated parasitaemia and malarial symptoms beginning on days 11-12 after challenge. No atovaquone-proguanil volunteer acquired malaria. Atovaquone-proguanil is the first licensed antimalarial agent that kills P. falciparum in the liver and that may be discontinued 7 days after the last exposure.

Insulin resistance and elevated levels of tissue plasminogen activator in first-degree relatives of South Asian patients with ischemic cerebrovascular disease.

BACKGROUND AND PURPOSE: South Asians in the United Kingdom suffer from an increased mortality from cerebrovascular disease compared with whites. Evidence suggests that the relatives of white stroke patients are at increased risk of vascular disease. The aim of this study was to investigate atherothrombotic risk factors in the first-degree relatives of South Asian patients suffering from ischemic cerebrovascular disease and to compare them with South Asian subjects free from clinically detectable cerebrovascular disease. METHODS: We compared 143 relatives of South Asians with ischemic stroke (South Asian relatives group) with 146 South Asian control subjects from West Yorkshire, UK. RESULTS: The ages and ethnic and sex distributions of South Asian relatives and South Asian controls were similar. There were no significant differences in body mass index, waist-hip ratio, number of current smokers, and past medical history of hypertension, diabetes mellitus, or myocardial infarction between the 2 groups. Fasting blood glucose, glycosylated hemoglobin (HbA(1c)), total cholesterol, triglycerides, and HDL cholesterol were similar in the 2 groups. Fasting insulin (South Asian relatives, 12.0; South Asian controls, 8.5 mU/L; P<0.0001) (independent of tissue plasminogen activator) and insulin resistance (derived by Homeostasis Model Assessment) (South Asian relatives, 2.7; South Asian controls, 1.9; P=0.001) were significantly raised in stroke relatives. Stroke relatives showed elevated levels of tissue plasminogen activator (South Asian relatives, 11.6; South Asian controls, 8.4 ng/mL; P<0.0001), which was independent of plasma insulin. There were no differences in plasminogen activator inhibitor antigen or activity between the groups. CONCLUSIONS: South Asians stroke relatives exhibit hyperinsulinemia, increased insulin resistance, and increased tissue plasminogen activator levels. These observations might account for increased susceptibility to atherothrombotic disease in this ethnic group.

Plasmodium vivax: ookinete destruction and oocyst development arrest are responsible for Anopheles albimanus resistance to circumsporozoite phenotype VK247 parasites.

Anopheles albimanus and An. pseudopunctipennis differ in their susceptibilities to Plasmodium vivax circumsporozoite phenotypes. An. pseudopunctipennis is susceptible to phenotype VK247 but almost refractory to VK210. In contrast, An. albimanus is almost refractory to VK247 but susceptible to VK210. To investigate the site in the mosquito and the parasite stage at which resistance mechanisms affect VK247 development in An. albimanus, parasite development was followed in a series of experiments in which both mosquitoes species were simultaneously infected with blood from patients. Parasite phenotype was determined in mature oocysts and salivary gland sporozoites by use of immunofluorescence and Western blot assays and/or gene identification. Ookinete maturation and their densities within the bloodmeal bolus were similar in both mosquito species. Ookinete densities on the internal midgut surface of An. albimanus were 4.7 times higher than those in An. pseudopunctipennis; however, the densities of developing oocysts on the external midgut surface were 6.12 times higher in the latter species. Electron microscopy observation of ookinetes in An. albimanus midgut epithelium indicated severe parasite damage. These results indicate that P. vivax VK247 parasites are destroyed at different parasite stages during migration in An. albimanus midguts. A portion, accumulated on the internal midgut surface, is probably destroyed by the mosquito's digestive enzymes and another portion is most likely destroyed by mosquito defense molecules within the midgut epithelium. A third group, reaching the external midgut surface, initiates oocyst development, but over 90% of them interrupt their development and die. The identification of mechanisms that participate in parasite destruction could provide new elements to construct transgenic mosquitoes resistant to malaria parasites.

Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study.

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Malaria rapid diagnostic devices: performance characteristics of the ParaSight F device determined in a multisite field study.

Microscopic detection of parasites has been the reference standard for malaria diagnosis for decades. However, difficulty in maintaining required technical skills and infrastructure has spurred the development of several nonmicroscopic malaria rapid diagnostic devices based on the detection of malaria parasite antigen in whole blood. The ParaSight F test is one such device. It detects the presence of Plasmodium falciparum-specific histidine-rich protein 2 by using an antigen-capture immunochromatographic strip format. The present study was conducted at outpatient malaria clinics in Iquitos, Peru, and Maesod, Thailand. Duplicate, blinded, expert microscopy was employed as the reference standard for evaluating device performance. Of 2,988 eligible patients, microscopy showed that 547 (18%) had P. falciparum, 658 (22%) had P. vivax, 2 (0.07%) had P. malariae, and 1,750 (59%) were negative for Plasmodium. Mixed infections (P. falciparum and P. vivax) were identified in 31 patients (1%). The overall sensitivity of ParaSight F for P. falciparum was 95%. When stratified by magnitude of parasitemia (no. of asexual parasites per microliter of whole blood), sensitivities were 83% (>0 to 500 parasites/microl), 87% (501 to 1,000/microl), 98% (1,001 to 5,000/microl), and 98% (>5,000/microl). Device specificity was 86%.

Malaria chemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future.

All current regimens of malaria chemoprophylaxis have serious drawbacks as a result of either suboptimal efficacy, difficulty with medication compliance, or adverse events. Two 8-aminoquinolines may be approaching registration, with primaquine having completed its prophylactic field testing and tafenoquine having begun advanced field testing at the end of 2000. Primaquine has long been used for management of relapses of malaria, but in the past decade, it has been reexamined for use in malaria prevention in order to stop infection in the liver. In field trials performed in Indonesia and Colombia, the efficacy of primaquine for malaria prevention was approximately 90%, compared with that of placebo. Because of its short half-life, primaquine requires daily administration. For adults, the prevention regimen is 30 mg base daily (0.5 mg base/kg/day), and it can probably be discontinued soon after departure from an area where malaria is endemic. To kill parasites that already exist in the liver, terminal prophylaxis is given after exposure to relapses of malaria infection; for adults, such prophylaxis usually consists of 15 mg base (0.3 mg base/kg/day) given daily for 2 weeks. Primaquine-induced gastrointestinal disturbances can be minimized if the drug is taken with food. Neither primaquine nor tafenoquine should be given to persons with glucose-6-phosphate dehydrogenase deficiency, to avoid the development of potentially severe drug-induced hemolysis. Tafenoquine is an analogue of primaquine that is more potent than the parent drug. Field trials in Kenya, Ghana, Gabon, and Southeast Asia have demonstrated an efficacy rate of approximately 90% for tafenoquine. Its long half-life allows for infrequent dosing (currently tested at 200 mg base/week), and its effect on parasites at the liver stage may allow for drug discontinuation at the time of departure from the area of endemicity.