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Background There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given. Methods Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007–2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones. Results Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of Conclusions In eight studies of mRDT implementation in five African countries, substantial proportions of patients testing mRDT-positive were not prescribed an ACT antimalarial, and many were not prescribed an antimalarial at all. Patients most vulnerable to serious outcomes, children Trial registration Reported in individual primary studies.

Many people now have two or more diseases at once. It is time to rethink funding, research, publishing, training and treatment for this growing problem. Many people now have two or more diseases at once. It is time to rethink funding, research, publishing, training and treatment for this growing problem.

During the 2013-2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods.

Gastrointestinal (GI) symptoms are a frequent reason for primary care consultation, and common amongst patients with strongyloidiasis. We conducted a prospective cohort and nested case control study in East London to examine the predictive value of a raised eosinophil count or of GI symptoms, for Strongyloides infection in South Asian migrants. We included 503 patients in the final analyses and all underwent a standardised GI symptom questionnaire, eosinophil count and Strongyloides serology testing. Positive Strongyloides serology was found in 33.6% in the eosinophilia cohort against 12.5% in the phlebotomy controls, with adjusted odds ratio of 3.54 (95% CI 1.88&ndash, 6.67). In the GI symptoms cohort, 16.4% were seropositive but this was not significantly different compared with controls, nor were there associations between particular symptoms and Strongyloidiasis. Almost a third (35/115) of patients with a positive Strongyloides serology did not have eosinophilia at time of testing. Median eosinophil count declined post-treatment from 0.5 cells &times, 109/L (IQR 0.3&ndash, 0.7) to 0.3 (0.1&ndash, 0.5), p &lt, 0.001. We conclude Strongyloides infection is common in this setting, and the true symptom burden remains unclear. Availability of ivermectin in primary care would improve access to treatment. Further work should clarify cost-effectiveness of screening strategies for Strongyloides infection in UK migrant populations.

Eosinophilia in those returning or recently migrated from the tropics is a common presentation in symptomatic and asymptomatic patients. Helminths are the cause in a substantial proportion of these cases. Investigation should begin with consideration of the geographic area arrived from or visited and clinical manifestations, if any. Strongyloides stercoralis is a common cause worldwide, and other geohelminths also have widespread distribution, so stool microscopy and strongyloides serology is indicated from all areas. Evaluation for schistosomiasis and filariasis should also be considered depending on exposure. Any helminthic infection with a tissue-invasive phase can be associated with peripheral eosinophilia, and clinical clues can assist with identifying cases of toxocariasis, trichinosis, gnathostomiasis, fascioliasis, and angiostrongyliasis, among others. Protozoal parasitic causes include cystoisosporiasis, dientamoebiasis, and sarcocystosis. Non-parasitic causes of peripheral eosinophilia include HIV, HTLV-I, syphilis, tuberculosis, resolving scarlet fever, bartonellosis, allergic bronchopulmonary aspergillosis, and coccidioidomycosis. This chapter will outline a clinical approach to patients with peripheral eosinophilia.

Reward the creation of analyses for policymakers that are inclusive, rigorous, transparent and accessible, urge Christl A. Donnelly and colleagues. Reward the creation of analyses for policymakers that are inclusive, rigorous, transparent and accessible.

Summary Introduction Determining the cause of eosinophilia in patients returning from the tropics continues to present a diagnostic challenge. The history, symptoms and degree of eosinophilia are often poor predictors of eventual diagnosis, but helminths are an important cause. The current British Infection Association recommendations use travel history to guide investigation of eosinophilia. However the global burden of helminth disease and travel patterns have changed over the last 3 decades and guidelines based on previous epidemiology need to be reviewed in the light of current data. Methods Consecutive patients presenting with, or referred for, investigation of eosinophilia were identified prospectively. Case notes, laboratory results and electronic records were reviewed for demographic and clinical data. Patients with an eosinophil count ≥0.50 × 10 9 /L were included, and grouped based on lifetime history of travel to: West Africa, elsewhere in Africa, and the rest of the world. Results were compared to published data from 1997 to 2002 collected at the same centre. Results Of 410 patients who met the inclusion criteria, 407 had a documented travel history. Average yearly referrals for eosinophilia fell from 58 per year between 1997 and 2002, to 33 per year (2002–2015). The proportion of eosinophilia cases diagnosed with a parasitic cause fell from 64% to 50%, and yields for all parasitological investigations fell, the largest reduction in stool microscopy (20% yield to 9%) and day bloods for microfilariae (14% yield to 3%). Strongyloides stercoralis was the commonest diagnosis overall in our cohort, accounting for 50% of the total parasites diagnosed, and was present in 38% of patients from West Africa, 19% from rest of Africa, and 34% from rest of world; a relative increase compared to previous data. Schistosomiasis is slightly less common in those who had travelled to West Africa than the rest of Africa, and overall point prevalence has fallen from 33% (1997–2002) to 17% (2002–2015). Travellers were significantly less likely than patients who had immigrated to the UK to be diagnosed with any parasite (OR 0.54 95% CI 0.378–0.778 p = 0.0009). Discussion A parasitic cause will still be found in half of people returning from the tropics with an eosinophilia, but we observed a fall in the overall prevalence of parasitic diagnoses when compared with the earlier data. This may, in part, be explained by the impact of control programmes on the prevalence of parasites globally, especially filarial disease. S. stercoralis now represents the majority of parasites diagnosed in our cohort from all continents. We identified significantly higher rates of strongyloidiasis in immigrants than returning travellers. Despite the falling yields of stool microscopy and filarial serology the current guidelines based on travel history remain relevant with adequate yield.

Background We describe trends of malaria in London (2000–2014) in order to identify preventive opportunities and we estimated the cost of malaria admissions (2009/2010–2014/2015). Methods We identified all cases of malaria, resident in London, reported to the reference laboratory and obtained hospital admissions from Hospital Episode Statistics. Results The rate of malaria decreased (19.4[2001]-9.1[2014] per 100,000). Males were over-represented (62%). Cases in older age groups increased overtime. The rate was highest amongst people of Black African ethnicity followed by Indian, Pakistani, Bangladeshi ethnicities combined (103.3 and 5.5 per 100,000, respectively). The primary reason for travel was visiting friends and relatives (VFR) in their country of origin (69%), mostly sub-Saharan Africa (92%). The proportion of cases in VFRs increased (32%[2000]-50%[2014]) and those taking chemoprophylaxis decreased (36%[2000]-14%[2014]). The overall case fatality rate was 0.3%. We estimated the average healthcare cost of malaria admissions to be just over £1 million per year. Conclusion Our study highlighted that people of Black African ethnicity, travelling to sub-Saharan Africa to visit friends and relatives in their country of origin remain the most affected with also a decline in chemoprophylaxis use. Malaria awareness should focus on this group in order to have the biggest impact but may require new approaches.

This study describes the clinical features of a cohort of imported cases of strongyloidiasis and the performance of standard diagnostic techniques for this condition. A total of 413 cases were identified, of whom 86 had microscopically proven infection. In proven cases, 23% had normal eosinophil counts, 19% had negative Strongyloides-specific serology, and 9.3% had normal blood counts and were seronegative. Serological testing was less sensitive for returning travelers (46.2%) than for migrants (89.7%). Immunosuppression, including human T-cell lymphotropic virus 1, was significantly associated with proven infection after controlling for age, presence of symptoms, duration of infection, and eosinophilia (OR 5.60, 95% CI 1.54–20.4). Patients with proven infection had lower serology values than those diagnosed with strongyloidiasis on the basis of positive serology and eosinophilia alone (P = 0.016). Symptomatic patients were significantly younger, had a shorter presumed duration of infection, and lower serology values. These data suggest a correlation between immunologic control of strongyloidiasis and the amplitude of the humoral response.

Despite concerted efforts to eliminate malaria, it remains a major global cause of morbidity and mortality with over 200 million annual cases. Significant gains have been made, with the annual global malaria incidence and mortality halving over the past twenty years, using tools such as long-lasting insecticide-treated bed nets and artemisinin-based therapies. Malaria is also a significant cause of life-threatening imported infection in the UK. It is vital for front line clinical staff involved in the assessment of acutely ill patients to be aware of the need for early diagnostic testing, malaria epidemiology, markers of severe infection and developments in antimalarial treatments to optimise patient management. The difference between a good and poor outcome is early diagnosis and treatment. Many of the challenges faced in the quest for global eradication, such as availability of appropriate diagnostic tests, and drug and insecticide resistance could also have future implications for imported malaria.

Background Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections. Methods Antimalarial studies typically report the risk of recrudescence derived using the Kaplan–Meier (K–M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K–M method (1 minus K–M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K–M curves was assessed using the log-rank test, and the equality of CIFs using Gray’s k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray’s sub-distributional hazard model. Results Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K–M approach was 0.04% (interquartile range (IQR): 0.00–0.27%, Range: 0.00–3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson’s correlation coefficient (ρ): 0.38, 95% Confidence Interval (CI) 0.30–0.46] or new infection [ρ: 0.43; 95% CI 0.35–0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K–M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold. Conclusions The 1 minus K–M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings. Electronic supplementary material The online version of this article (10.1186/s12936-019-2837-4) contains supplementary material, which is available to authorized users.

Summary 1.Malaria is the tropical disease most commonly imported into the UK, with 1300–1800 cases reported each year, and 2–11 deaths. 2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. 3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. 4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. 5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints. 6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure. 7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered. 8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable. 9. Most patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h as patients can deteriorate suddenly, especially early in the course of treatment. In specialised units seeing large numbers of patients, outpatient treatment may be considered if specific protocols for patient selection and follow up are in place. 10. Uncomplicated P. falciparum malaria should be treated with an artemisinin combination therapy (Grade 1A). Artemether–lumefantrine (Riamet®) is the drug of choice (Grade 2C) and dihydroartemisinin-piperaquine (Eurartesim®) is an alternative. Quinine or atovaquone–proguanil (Malarone®) can be used if an ACT is not available. Quinine is highly effective but poorly-tolerated in prolonged treatment and should be used in combination with an additional drug, usually oral doxycycline. 11. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. Severe malaria is a rare complication of P. vivax or P. knowlesi infection and also requires parenteral therapy. 12. The treatment of choice for severe or complicated malaria in adults and children is intravenous artesunate (Grade 1A). Intravenous artesunate is unlicensed in the EU but is available in many centres. The alternative is intravenous quinine, which should be started immediately if artesunate is not available (Grade 1A). Patients treated with intravenous quinine require careful monitoring for hypoglycemia. 13. Patients with severe or complicated malaria should be managed in a high-dependency or intensive care environment. They may require haemodynamic support and management of: acute respiratory distress syndrome, disseminated intravascular coagulation, acute kidney injury, seizures, and severe intercurrent infections including Gram-negative bacteraemia/septicaemia. 14. Children with severe malaria should also be treated with empirical broad spectrum antibiotics until bacterial infection can be excluded (Grade 1B). 15. Haemolysis occurs in approximately 10–15% patients following intravenous artesunate treatment. Haemoglobin concentrations should be checked approximately 14 days following treatment in those treated with IV artemisinins (Grade 2C). 16. Falciparum malaria in pregnancy is more likely to be complicated: the placenta contains high levels of parasites, stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. 17. Uncomplicated falciparum malaria in the second and third trimester of pregnancy should be treated with artemether–lumefantrine (Grade 2B). Uncomplicated falciparum malaria in the first trimester of pregnancy should usually be treated with quinine and clindamycin but specialist advice should be sought. Severe malaria in any trimester of pregnancy should be treated as for any other patient with artesunate preferred over quinine (Grade 1C). 18. Children with uncomplicated malaria should be treated with an ACT (artemether–lumefantrine or dihydroartemisinin-piperaquine) as first line treatment (Grade 1A). Quinine with doxycycline or clindamycin, or atovaquone–proguanil at appropriate doses for weight can also be used. Doxycycline should not be given to children under 12 years. 19. Either an oral ACT or chloroquine can be used for the treatment of non-falciparum malaria. An oral ACT is preferred for a mixed infection, if there is uncertainty about the infecting species, or for P. vivax infection from areas where chloroquine resistance is common (Grade 1B). 20. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine (1A). Primaquine is more effective at preventing relapse if taken at the same time as chloroquine (Grade 1C). 21. Primaquine should be avoided or given with caution under expert supervision in patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. 22. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy and when breastfeeding (until the G6PD status of child is known); after initial treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery or cessation of breastfeeding when hypnozoite eradication can be considered. 23. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.

Background The West African Ebola crisis of 2013-15 is the largest outbreak since Ebola was first identified; Ebola has high case fatality. Sources of data Pubmed with terms 'Ebola' and 'EVD' from January 1976 to June 2015. Public domain material. Areas of agreement The emergence of Ebola virus, virology, clinical features and the major elements of the 2014 outbreak and the public health response. Ebola is only transmitted by direct contact with infected individuals (including dead bodies) and their body fluids. Methods of control in hospitals and burials, and protection of healthcare workers are well established if difficult to achieve. Areas of contention There remains uncertainty surrounding specific public health interventions and novel therapies (including vaccines). How best to reduce transmission in the community during major outbreaks remains unclear. Future directions The potential of vaccine and therapeutic candidates in the event of another outbreak on this scale. . Search strategy We searched all entries on the MedLine database/PubMed from 1976-2015 with the MeSH terms 'ebola', 'EVD', 'haemorrhagic fever'. We also reviewed publically available information via institutional websites from Governmental, NGOs and news organizations pertaining to the above search terms.

Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32 induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.

Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400–432,513). mRDTs were associated with significantly lower ACT prescription (range 8–69% versus 20–100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.

Background The World Health Organisation (WHO) recommends parasitological diagnosis of malaria before treatment, but use of malaria rapid diagnostic tests (mRDTs) by community health workers (CHWs) has not been fully tested within health services in south and central Asia. mRDTs could allow CHWs to diagnose malaria accurately, improving treatment of febrile illness. Methods A cluster randomised trial in community health services was undertaken in Afghanistan. The primary outcome was the proportion of suspected malaria cases correctly treated for polymerase chain reaction (PCR)-confirmed malaria and PCR negative cases receiving no antimalarial drugs measured at the level of the patient. CHWs from 22 clusters (clinics) received standard training on clinical diagnosis and treatment of malaria; 11 clusters randomised to the intervention arm received additional training and were provided with mRDTs. CHWs enrolled cases of suspected malaria, and the mRDT results and treatments were compared to blind-read PCR diagnosis. Results In total, 256 CHWs enrolled 2400 patients with 2154 (89.8%) evaluated. In the intervention arm, 75.3% (828/1099) were treated appropriately vs. 17.5% (185/1055) in the control arm (cluster adjusted risk ratio: 3.72, 95% confidence interval 2.40–5.77; p

BACKGROUND: Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions. METHODS: Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators. RESULTS: Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges. CONCLUSIONS: Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

Objectives\ud To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. \ud Design\ud Analysisof nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study).\ud Setting\ud Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda.\ud Participants\ud 522 480 children and adults with acute febrile illness.\ud Interventions\ud Rapid diagnostic tests for malaria.\ud Main outcome measures\ud Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings.\ud Results\ud Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole.Conclusions Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription.This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined. [Abstract copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.]

We examine the impact of removing user fees for healthcare in rural Ghana using data from a randomized experiment that includes rich information on objective measures of child health status. We find that free care increased use of formal healthcare shifting care seeking away from informal providers, with particularly strong effects for children who were anaemic at baseline. There was no health effect on the intervention population taken overall. However, consistent with the utilization findings, there were health improvements amongst those with anaemia initially. Further benefits included a large reduction in health spending, with the effect greater at higher levels of the medical spending distribution. Free care was found to have no influence on a range of malaria prevention behaviours or on the incidence of self-reported illness, suggesting that ex-ante moral hazard is unlikely to be a concern in this particular setting.

In the early 2000s, clinical research in the UK was at a low ebb; most universities prioritised basic biomedical research, training opportunities were limited and clinician-researchers were declining in number and felt disenfranchised. An Academy of Medical Sciences report[1][1] identified ‘a

Any area of medicine advances due to research in previous years, and paediatrics and child health is an excellent example of this. With research conducted now, child health in the future will continue to improve; without adequate research we are doomed to stagnate, and in some areas go backwards. Looking at the health of children both nationally and globally over the last four decades, the impact of research has been remarkable. Globally, we are seeing one of the fastest reductions in child mortality ever seen anywhere. Global neonatal and child mortality fell substantially in every age band over the last 35 years.1 This global improvement was driven by a combination of research and international development. In higher income countries the last decades have also seen a remarkable drop in mortality in neonates, children and adolescents; for example, a 58% drop in mortality in children aged 5–14 in Europe, and major improvements in all ages of children in the UK.2 3 Multiple types of research have contributed to this, from the most basic and translational science which helps to develop targets for new drugs and clinical techniques, through clinical and epidemiological studies and onto operational research which helps ensure the best science is taken up in practice. From improvements in survival in neonates to the massively improved prognosis for children born with cystic fibrosis4 and other genetic diseases multiple lines of science have led to incremental changes which when added together substantially improve outcome. Many children are alive now because of research undertaken in the last few years. There are also data from multiple directions demonstrating that patients enrolled in research studies are likely to do better.5 There are therefore clear current advantages to individual patients as well as to future children to more clinical research being undertaken. …

Summary Background The Malaria Reference Laboratory (MRL) provides a specialist advisory service for complex queries from healthcare professionals. This study was conducted to examine the types of queries that general practitioners and nurses ask around malaria prophylaxis, to identify issues which are not obvious from existing easily available sources. Methods We reviewed all the faxed requests received over a period of 6 months at the MRL. Results There were a total of 608 queries (104 concerning children) relating to 450 travellers. 98% of requests were from general practice (GP or practice nurse). The most common enquiries were about travellers to multiple destinations (95/529, 17.96%), prolonged duration of travel (70/529, 13.23%), the immunosuppressed (38/529, 7.18%), potential drug interactions (69/529, 13.04%), pregnancy and conception (36, 6.81%). 79/529 queries related to patients with multiple conditions requiring expert advice from the MRL. 27% of the enquiries could have been answered by consulting the UK malaria prophylaxis guidelines available on the MRL site. Conclusion Most queries where practitioners requested help were not easily answered with existing guidelines. Pregnancy and epilepsy are areas where guidance needs strengthening. Difficulties for practitioners were multifactorial, it would be difficult to address all scenarios in guidelines without making them unwieldy.

Rigorous evidence of "what works" to improve health care is in demand, but methods for the development of interventions have not been scrutinized in the same ways as methods for evaluation. This article presents and examines intervention development processes of eight malaria health care interventions in East and West Africa. A case study approach was used to draw out experiences and insights from multidisciplinary teams who undertook to design and evaluate these studies. Four steps appeared necessary for intervention design: (1) definition of scope, with reference to evaluation possibilities; (2) research to inform design, including evidence and theory reviews and empirical formative research; (3) intervention design, including consideration and selection of approaches and development of activities and materials; and (4) refining and finalizing the intervention, incorporating piloting and pretesting. Alongside these steps, projects produced theories, explicitly or implicitly, about (1) intended pathways of change and (2) how their intervention would be implemented.The work required to design interventions that meet and contribute to current standards of evidence should not be underestimated. Furthermore, the process should be recognized not only as technical but as the result of micro and macro social, political, and economic contexts, which should be acknowledged and documented in order to infer generalizability. Reporting of interventions should go beyond descriptions of final intervention components or techniques to encompass the development process. The role that evaluation possibilities play in intervention design should be brought to the fore in debates over health care improvement.

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.

BACKGROUND: Several public health interventions to improve management of patients with fever are largely focused on the public sector yet a high proportion of patients seek care outside the formal healthcare sector. Few studies have provided information on the determinants of utilization of the private sector as against formal public sector. Understanding the differences between those who attend public and private health institutions, and their pathway to care, has significant practical implications. The chemical shop is an important source of care for acute fever in Ghana. METHODS: Case-control methodology was used to identify factors associated with seeking care for fever in the Dangme West District, Ghana. People presenting to health centres, or hospital outpatients, with a history or current fever were compared to counterparts from the same community with fever visiting a chemical shop. RESULTS: Of 600 patients, 150 each, were recruited from the district hospital and two health centres, respectively, and 300 controls from 51 chemical shops. Overall, 103 (17.2 %) patients tested slide positive for malaria. Specifically, 13.7 % (41/300) of chemical shop patients, 30.7 % (46/150) health centre and 10.7 % (16/150) hospital patients were slide positive. While it was the first option for care for 92.7 % (278/300) chemical shop patients, 42.7 % (64/150) of health centre patients first sought care from a chemical shop. More health centre patients (61.3 %; 92/150) presented with fever after more than 3 days than chemical shop patients (27.7 %; 83/300) [AOR = 0.19; p

Falciparum malaria is the commonest life-threatening imported tropical infection. The most important critical care intervention is rapid high-dose antimalarial treatment with artesunate, or if that is not available quinine. The common complications of malaria are different in children and adults. Cerebral malaria may occur in both, for which there is no specific therapy. Renal failure and acute lung injury are much more common in adults, and may occur late in the course of the disease, even after parasites have cleared. In children acidosis, anaemia and Gram-negative sepsis are more common. Renal and respiratory support may be needed in adults. Malaria alone seldom causes shock and if patients are shocked, co-existing Gram-negative sepsis should be considered. In children there is evidence that bolus hydration increases mortality. Most patients make a full recovery even after prolonged periods of unconsciousness.

Evidence-based policy ensures that the best interventions are effectively implemented. Integrating rigorous, relevant science into policy is therefore essential. Barriers include the evidence not being there; lack of demand by policymakers; academics not producing rigorous, relevant papers within the timeframe of the policy cycle. This piece addresses the last problem. Academics underestimate the speed of the policy process, and publish excellent papers after a policy decision rather than good ones before it. To be useful in policy, papers must be at least as rigorous about reporting their methods as for other academic uses. Papers which are as simple as possible (but no simpler) are most likely to be taken up in policy. Most policy questions have many scientific questions, from different disciplines, within them. The accurate synthesis of existing information is the most important single offering by academics to the policy process. Since policymakers are making economic decisions, economic analysis is central, as are the qualitative social sciences. Models should, wherever possible, allow policymakers to vary assumptions. Objective, rigorous, original studies from multiple disciplines relevant to a policy question need to be synthesized before being incorporated into policy.

To assess the quality of medical treatment by disaggregating quality into components that distinguish between insufficient and unnecessary care.Randomly selected doctors were asked how they would treat a sick child. Their responses were disaggregated into how much of an evidence-based essential treatment plan was completed and the number of additional non-essential treatments that were given. Key variables included the expected cost, the health consequences of insufficient and unnecessary care and comparisons between public and private physicians. Responses to 160 clinical performance vignettes (CPVs) were analysed.Philippines.One hundred and forty-three public and private physicians in the Philippines, collected in November 2003-December 2004 and September 2006-June 2007.CPVs administered to physicians.Process quality measures (accounting for the possibility of both over-treatment and under-treatment).Based on CPVs, doctors gave both insufficient and unnecessary treatment to under-five children in 69% of cases. Doctors who provided the least sufficient care were also the most likely to give costly or harmful unnecessary care. Insufficient care typically had potentially worse health consequences for the patient than unnecessary care, though unnecessary care remains a concern because of overuse of antibiotics (47%) and unnecessary hospitalization (34%).Quality of care is complex, but over- and under-treatment coexist and, in our analysis physicians that were more likely to under-treat a sick child were also those more likely to over-treat.

Summary Background Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa. Methods The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840. Findings 75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2·4, 95% CI 1·3–4·2, p=0·003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug. Interpretation Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence. Funding Meningitis Research Foundation.

The possibility for one generation to eradicate a disease is very motivating. It is also very difficult. The many failed eradication attempts outnumber the one current success (smallpox), although two eradication campaigns for polio and Guinea worm are tantalisingly close to their goals. The early stages of a well-planned eradication campaign generally go well; it is the last stage where technical, biological, social and political problems occur. This paper considers the opportunities and pitfalls in planning for eradication of a disease.

A large number of tropical infections can cause neurological syndromes but the returning traveller is more likely to have a condition that is well known to a UK physician. Malaria is the most commonly imported life-threatening tropical infection and should be excluded urgently in all patients. It is also important not to miss herpes encephalitis, bacterial meningitis and systemic infection, especially typhoid, as early treatment will change prognosis. Infections caused by arboviruses, such as Japanese B encephalitis, are rare but rabies and human African trypanosomiasis can cause a classical encephalitic presentation. HIV must always be considered, and non-infectious causes including drugs may be more common in travellers. A detailed geographical history is crucial and a systematic, logical approach based on incubation periods and geographical epidemiology can help to minimize unnecessary investigation.

SUMMARYA capture–recapture study was undertaken to estimate the incidence and likely total burden of malaria cases in England. Cases diagnosed by the national Malaria Reference Laboratory (MRL) between July 2003 and December 2004 were matched with cases reported to Hospital Episode Statistics using demographic, geographical, parasitological, and temporal information. A total of 3861 cases were recorded in one or both datasets; the ‘unknown population’ was estimated as 746 cases (95% CI 677–822) giving a total of 4607 cases (95% CI 4446–4767) over 18 months. Eighty-four percent (95% CI 83–85) of cases were recorded in one or both datasets. Fifty-six percent (95% CI 54–58) of cases were captured by the MRL surveillance system; ascertainment for Plasmodium falciparum and London cases was higher at 66% and 62%, respectively. Improving case ascertainment will facilitate effective measures to reduce the burden of this preventable disease in the UK.

International travel is increasing. Most physicians and general practitioners will encounter returned travellers with fever and the majority of travel-related infection is associated with travel to the tropics. In those returning from the tropics malaria must always be excluded, and HIV considered, from all settings. Common causes of non-malarial fever include from Africa rickettsial diseases, amoebic liver abscess and Katayama syndrome; from South and South East Asia, enteric fever and arboviral infection; from the Middle East, brucellosis and from the Horn of Africa visceral leishmaniasis. Other rare but important diseases from particular geographical areas include leptospirosis, trypanosomiasis and viral haemorrhagic fever. North and South America, Europe and Australia also have infections which are geographically concentrated. Empirical treatment may have to be started based on epidemiological probability of infection whilst waiting for results to return. The evidence base for much of the management of tropical infections is limited. These recommendations provide a pragmatic approach to the initial diagnosis and management of fever in returned travellers, based on evidence where it is available and on consensus of expert opinion where it is not. With early diagnosis and treatment the majority of patients with a potentially fatal infection related to travel will make a rapid and full recovery.

Respiratory infections cause significant mortality in developing countries but are frequently undiagnosed. Reasons for this are unclear. We observed 1,081 outpatient consultations with patients less than five years of age in Tanzania. In 554 patients with cough or difficulty breathing, the absolute percentages examined were 5% for respiratory rate counted, 14% chest exposed, and 25% stethoscope used. Decisions to conduct particular examinations did appear to follow clinical logic, with odds ratios of 4.28 for counting respiratory rate (95% confidence interval [CI] = 1.75-10.47), 2.57 for exposing the chest (95% CI = 1.67-3.95), and 18.91 for using a stethoscope (95% CI = 9.52-37.57) in patients with cough or difficulty breathing. Non-clinical variables, including salary level, were also associated with examinations, and history taking was more common among clinicians originating outside the hospital area. Although respiratory examinations are relatively more common in those with cough or difficulty breathing, the absolute rates are low and related to non-clinical and clinical factors. Copyright © 2008 by The American Society of Tropical Medicine and Hygiene.

OBJECTIVE To investigate the impact of socio-economic and environmental factors on developing severe malaria in comparison with mild malaria in Yemen. METHOD Case-control study comparing 343 children aged 6 months to 10 years diagnosed with WHO-defined severe malaria (cases) at the main children's hospital in Taiz and 445 children with mild malaria (controls) diagnosed in the health centres, which serve the areas where the cases came from. RESULTS In univariate analysis, age 2 km was significantly associated with progression to severe disease. Environmental and vector control factors associated with protection from acquiring malaria (such as sleeping under bednets) were not associated with protection from moving from mild to severe disease. CONCLUSIONS Innovative ways to improve access to antimalarial treatment for those living more then 2 km away from health centres such as home management of malaria, especially for infants and young children, should be explored in malaria-endemic areas of Yemen.

Summary Background: The probability that a returned traveller with a history of fever has malaria is likely to vary by geographical area, but this has not been quantified in travellers. Aim: To collect data on prevalence of malaria in outpatients returning with a fever or history of fever from malaria-endemic countries, at the point of presentation for a malaria test. Design: Observational retrospective study. Consecutive patients presenting to an unselected ‘walk-in’ clinic for returned travellers. Results: Of 2867 patients meeting inclusion criteria, 337 (11.8%) had malaria, 89.5% originating in sub-Saharan Africa. Of travellers returning from sub-Saharan Africa excluding South Africa with fever/ history of fever, 291/1497 had malaria (19.4%, 95% CI 17–21%). A high proportion was visiting friends and relatives. In those from other areas the proportions were: 16/707 (2.3%, 95% CI 1.5–3.8) from Indian subcontinent/Southeast Asia; 2/143 (1.4%) from Southern America; 4/129 (3.1%) from South Africa; 1/44 (2.3%) from North Africa; and 8/41 (19.5%) from Oceania. Compared to other malaria-endemic regions, African travel gave an adjusted odds ratio of 7.8 (95% CI 5.4–11.2, P < 0.0001). Only 45.1% of malaria cases had a fever (37.58C) at the time of presentation. Only 3% of all diagnoses of malaria had no history of fever. In 28% of cases parasite count increased in the initial 24 h of antimalarial treatment. Conclusions: The likelihood that a patient with fever returning from Africa has malaria is high (around 1 in 5), and is significantly lower from other areas. Absence of fever at presentation does not exclude malaria.

OBJECTIVE In Africa antimalarials are often prescribed when malaria is unlikely, a problem that is becoming critical as more expensive antimalarials replace established drugs. However, little is known about what drives the overuse of antimalarials. We conducted this study to explore to what extent current prescribing behaviour in hospitals is driven by patient demand. METHODS Consultations were observed followed by exit interviews with patients or caretakers. Five district hospitals where microscopy was routinely available were selected in areas of low (n = 3) and high (n = 2) malaria transmission in north-eastern Tanzania. All outpatient consultations during the study period were observed (n = 669). Those sent for a malaria blood slide or treated with antimalarials presumptively were interviewed (n = 326). At the end of the study, clinicians were interviewed for their opinions on the use of antimalarials. Findings Patients were not observed to demand antimalarials from clinicians, but occasionally asked for a malaria slide. Patient satisfaction on exit was similar between those prescribed antimalarials and those not prescribed antimalarials, but more patients or carers expressed satisfaction when the patient had been tested than when not. Clinicians rarely reported perceiving patient demand for antimalarials and asserted that such demand for medication would not affect their prescribing behaviour. CONCLUSIONS Patient demand was not found to be driving the over-prescription of antimalarials found in the hospitals in our setting. To the contrary, the involvement of patients may provide an opportunity to improve prescribing practice if their expectations for testing and treatment in line with test results can be effectively communicated to clinicians.

Quinine and the artemisinin-derivative drugs artesunate and artemether are effective treatments for severe falciparum malaria. Trials comparing artemether with quinine have not demonstrated convincing evidence of a mortality advantage for artemether. The South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT), a multicenter, randomized, open-label trial in 1461 adults with severe malaria in Asia compared artesunate with quinine. Mortality was 15% in the artesunate group and 22% in the quinine group, a reduction of 34.7% (95% confidence interval: 18.5-47.6%) in the artesunate group, with almost all the benefit reported in those with high parasite counts. Artesunate should constitute first-line treatment for severe malaria in Asia. These results can probably be generalized to the treatment of severe malaria in adults from all areas, especially in those with hyperparasitemia. However, it is unclear whether these results can be generalized to children in Africa, who constitute the majority of those who die from severe malaria worldwide.

Although global efforts in the past decade have halved the number of deaths due to malaria, there are still an estimated 219 million cases of malaria a year, causing more than half a million deaths. In this forum article, we asked experts working in malaria research and control to discuss the ways in which malaria might eventually be eradicated. Their collective views highlight the challenges and opportunities, and explain how multi-factorial and integrated processes could eventually make malaria eradication a reality.