A large light-mass component of cosmic rays at 10(17)-10(17.5) electronvolts from radio observations.

Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 10(17)-10(18) electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal comes from accelerators capable of producing cosmic rays of these energies. Cosmic rays initiate air showers--cascades of secondary particles in the atmosphere-and their masses can be inferred from measurements of the atmospheric depth of the shower maximum (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground. Current measurements have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays is a rapidly developing technique for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 10(17)-10(17.5) electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 10(17.5) electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 10(17)-10(17.5) electronvolt range.

Evaluation of the therapeutic efficacy of praziquantel against schistosomes in seven countries with ongoing large-scale deworming programs.

The World Health Organization (WHO) recommends periodic assessment of the therapeutic efficacy of praziquantel (PZQ) to detect reduced efficacy that may arise from drug resistance in schistosomes. In this multi-country study (2014), we assessed the therapeutic efficacy of a single oral dose of PZQ (40 mg/kg) against Schistosoma mansoni (Brazil, Cameroon, Ethiopia, Mali, Madagascar and Tanzania), S. haematobium (Cameroon, Ethiopia, Mali, Tanzania and Zanzibar) and S. japonicum (the Philippines) infections in school-aged children, across a total of 12 different trials. Each trial was performed according to the standardized methodology for evaluating PZQ efficacy as described by the WHO. Overall, therapeutic efficacy, measured as the reduction in arithmetic mean of schistosome egg counts following drug administration (egg reduction rate; ERR), was high for all three schistosome species (S. mansoni: 93.4% (95%CI: 88.8-96.8); S. haematobium: 97.7% (95%CI: 96.5-98.7) and S. japonicum: 90.0% (95%CI: 68.4-99.3). At the trial level, therapeutic efficacy was satisfactory (point estimate ERR ≥90%) for all three Schistosoma species with the exception of S. mansoni in Cameroon where the ERR was 88.5% (95%CI: 79.0-95.1). Furthermore, we observed that in some trials individual drug response could vary significantly (wide 95%CI) and that few non-responsive individuals could significantly impact ERR point estimates. In conclusion, these results do not suggest any established reduced efficacy of the standard PZQ treatment to any of the three schistosome species within these countries. Nevertheless, the substantial degree of variation in individual responses to treatment in some countries underpins the need for future monitoring. The reported ERR values serve as reference values to compare with outcomes of future PZQ efficacy studies to ensure early detection of reduced efficacies that could occur as drug pressure continues increase. Finally, this study highlights that 95%CI should be considered in WHO guidelines to classify the therapeutic efficacy of PZQ.

Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs.

Treatment with praziquantel (PZQ) has become virtually the sole basis of schistosomiasis control in sub-Saharan Africa and elsewhere, and the drug is reviewed here in the context of the increasing rate that it is being used for this purpose. Attention is drawn to our relative lack of knowledge about the mechanisms of action of PZQ at the molecular level, the need for more work to be done on schistosome isolates that have been collected recently from endemic areas rather than those maintained in laboratory conditions for long periods, and our reliance for experimental work mainly on Schistosoma mansoni, little work having been done on S. haematobium. There is no evidence that resistance to PZQ has been induced in African schistosomes as a result of its large-scale use on that continent to date, but there is also no assurance that PZQ and/or schistosomes are in any way unique and that resistant organisms will not be selected as a result of widespread drug usage. The failure of PZQ to produce complete cures in populations given a routine treatment should therefore solicit considerable concern. With few alternatives to PZQ currently available and/or on the horizon, methods to monitor drug-susceptibility in African schistosomes need to be devised and used to help ensure that this drug remains effective for as long a time as possible.

The WHO dose pole for the administration of praziquantel is also accurate in non-African populations.

In 2001, WHO developed a pole for the administration of praziquantel without the use of weighing scales, with encouraging results in African populations. In the present study, the pole was tested on height/weight data from 9354 individuals from 11 non-African countries. In more than 98% of the individuals (95% CI 97.8-98.4) the pole estimated an acceptable dosage (30-60 mg/kg), a performance statistically similar to that observed in African populations. Reproducing the present pole in the form of a strip of paper and including it in each container of praziquantel would greatly facilitate the administration of the drug in large-scale interventions.

Day-to-day egg count fluctuation in Schistosoma mansoni infection and its operational implications.

In a study group of 183 people in a Schistosoma mansoni-endemic area in Burundi, stool examinations were performed with duplicate 25-mg Kato-Katz slides on seven occasions (days 1, 3, 5, 8, 10, 32, and 37). Point prevalences detected by single examinations of 25 mg and 50 mg of stool varied from 41.0% to 57.9% and from 55.7% to 63.9%, respectively. The cumulative prevalence for all seven measurements was 82.0%. The individual day-to-day variation in egg output was important. The majority of infections missed by the examination of single slides and specimens were light ones. The Kato-Katz method applied on a single stool specimen is more suitable for morbidity control, but less suitable for control of infection. When a precise quantitative diagnosis on the individual level is required, several measurements on different days are necessary. The data presented validate recently developed statistical models and charts predicting true prevalences.

Impact of repeated community-based selective chemotherapy on morbidity due to schistosomiasis mansoni.

The impact of repeated chemotherapy on morbidity due to schistosomiasis mansoni was evaluated in Gihungwe (initial prevalence 58%) and Buhandagaza/Kizina (33%), two village clusters in Burundi. Surveys were carried out with reference to the first treatment (month 0) at months -6, -3, 0, 3, 6, 9, 12, 24, and 36. Praziquantel (40 mg/kg) was given at months 0, 12, 24, and 36 to those showing eggs in the feces with a single 28-mg Kato slide. At each survey, duplicate Kato smears were examined, and all participants responded to a standardized medical history interview and underwent a clinical examination. In the three preintervention surveys, spleen and liver rates remained stable at the community and the individual level. The frequencies of diarrhea and abdominal pain varied to some extent, but they were consistently higher in the most heavily infected villages and age groups and remained relatively stable at the individual level. At the final survey, the prevalence of infection had decreased to 25%, and the frequency of diarrhea from 19-26% to 10% in both village clusters. This impact was strongest in the younger age groups. The frequency of abdominal pain was reduced only at the short term and in selected age groups. Organomegaly decreased only to a limited extent in those treated, and increased in those not treated, possibly due to the impact of malaria. The net result was that no measurable impact of the treatments on organomegaly at the community level could be demonstrated. In the light of these results, the relevance of community-based chemotherapy in moderate foci is questioned.

Repeated community-based chemotherapy for the control of Schistosoma mansoni: effect of screening and selective treatment on prevalences and intensities of infection.

The impact of repeated selective chemotherapy on prevalences and intensities of infection with Schistosoma mansoni was evaluated in Gihungwe Transversals 1 and 2 (initial prevalence 60%) and Buhandagaza/Kizina (initial prevalence 35%), two village clusters in Burundi. Surveys were carried out at months -6, -3, 0, 3, 6, 9, 12, 24, and 36, with reference to the first intervention; treatment with praziquantel (40 mg/kg) was given at months 0, 12, 24, and 36 to subjects showing parasite eggs on a single 28-mg Kato slide. A second slide was examined for monitoring purposes only. Over the pre-intervention period, the overall prevalences and intensities remained relatively stable, but important increases were observed in specific groups. The cure rate three months after the first treatment in those treated was 73% (Gihungwe) and 83% (Buhandagaza/Kizina), but the prevalence at the community level was reduced only by 50% and 46%, respectively. Fifty-six percent and 79%, respectively, of the remaining positive cases had not been treated, largely because they were (falsely) negative at the screening. Reinfection occurred mainly in Gihungwe and in younger age groups. One year after the second treatment, prevalences and intensities were further reduced in Gihungwe only; one year after the third treatment prevalences were not reduced further in either village group. The final prevalence of infection was approximately 25%, with infections with an intensity of over 100 eggs per gram of feces approximately 5%, in all four villages. Over 80% of the remaining cases had not been treated at the previous intervention; the sensitivity of the screening method appears to be a major determinant of the outcome of repeated selective treatment.

Intraspecimen fecal egg count variation in Schistosoma mansoni infection.

To determine the degree of intraspecimen fecal egg count variation in Schistosoma mansoni infection and its impact on commonly used parasitologic parameters obtained by single egg counts, 10 25-mg Kato-Katz slides were prepared from each of three stool specimens collected on different days in a study group of 20 infected people. Individual fecal egg counts in these series of examinations varied considerably and this had profound consequences for the reliability of both qualitative and quantitative diagnosis. In light infections, S. mansoni eggs in stools appeared to be homogeneously mixed. However, this distribution became heterogeneous as the intensity of infection increased, indicating clustering of eggs in stool. The cumulative egg counts in the 10 slides of the same 20 people examined in this study were compared with those in 14 slides prepared from seven stool samples collected on different days. This revealed significantly different mean egg counts for six people, even after such exhaustive series of examinations. Intraspecimen variation also biased considerably some operational parameters used to determine the infection status at the group level, particularly when these were determined by the examination of single 25-mg slides. The examination of duplicate or multiple slides improved the intraspecimen estimates of these parameters but did not overcome day-to-day variation. The examination of fewer samples taken on different days proved to be more adequate than examining more slides from one stool specimen for the determination of precise estimates of the real infection status.

Day-to-day fluctuation of schistosome circulating antigen levels in serum and urine of humans infected with Schistosoma mansoni in Burundi.

Day-to-day fluctuations of both circulating anodic antigen (CAA) and circulating cathodic antigen (CCA) in serum and urine were examined simultaneously in a group of Schistosoma mansoni-infected individuals from Burundi and compared with each other and with fecal egg count fluctuations. Significant correlations were found between fecal egg counts and circulating antigens (CAA and CCA) and between circulating antigen levels in serum and urine samples. The cumulative percentage of positive results after three samplings was highest for urine CCA detection, followed by fecal egg counts, serum CCA, serum CAA, and urine CAA detection, respectively. It was demonstrated that circulating antigen levels in both serum and urine showed less fluctuation than fecal egg counts, except for urine CAA levels. The serum CAA detection assay in particular, although less sensitive in this low endemic area in Burundi, gave very constant measurements over a period of one week. Our results indicate that detection of circulating antigens in a single serum or urine sample provides a quantitatively more stable diagnosis of S. mansoni infection than fecal egg counts based on a single stool examination.

Fluctuation of schistosome circulating antigen levels in urine of individuals with Schistosoma mansoni infection in Burundi.

We studied the fluctuations of schistosome circulating antigens in urine as compared with fecal egg counts in 60 Burundese individuals infected with Schistosoma mansoni. Levels of circulating anodic antigen (CAA) and circulating cathodic antigen (CCA) in the urine were determined by quantitative enzyme-linked immunosorbent assays. Fecal samples were simultaneously collected and examined with duplicate Kato-Katz slides. Significant correlations were consistently found between circulating antigen levels in urine and fecal egg counts. Although both antigen levels and egg output fluctuated, there was less fluctuation of CCA levels in urine than of fecal egg counts. All individuals had CCA in at least one urine sample and 82% were at least once positive for egg counts. Positive CCA levels were found in at least one urine sample in 75% of all individuals, but levels were low. Our results show that detection of CCA in urine is a sensitive, quantitative, and reliable method for noninvasive diagnosis and screening of S. mansoni infections, due to the relatively low fluctuations.

Sustainability of schistosomiasis case detection based on primary health care.

PIP: Since 1989 in Burundi, primary health care (PHC) services have integrated schistosomiasis control in Cibitoke, Bubanza, Bujumbura, Bururi, Kirundo, and Makamba provinces, all of which are low-lying areas. Schistosoma mansoni infection is endemic in these provinces. Civil unrest broke out in October 1993 in Burundi. This turmoil tested the sustainability of the integrated program. 15 months after the civil unrest, PHC services in most of these provinces have recovered their output of findings of schistosomiasis cases. Cibitoke province had recovered its output in case findings by the first quarter of 1994 and maintained this recovery through the next two quarters. A new wave of unrest in Cibitoke hampered its efforts in the last quarter of 1994, however. Bubanza and Bujumbura took longer to recover its case finding output but have been able to maintain a respectable level of output since then. Bubanza has not yet totally returned to its pre-unrest levels. Bururi and Makamba have been able to increase its output after the initial downturn in output caused by the unrest. These two provinces were least affected by the civil unrest. Given the fact that Kirundo borders Rwanda and its security has been precarious since the end of 1993, it has achieved satisfactory levels of case finding output. An electoral campaign during the second quarter of 1993 also affected the PHC/schistosomiasis program in Bubanza, Bururi, and Makamba. These findings show that once a schistosomiasis control program has become a routine part of basic health services, it can recover, even after intense civil turmoil. These same political conditions would necessitate discontinuation of a vertical program using mobile teams, likely for a long period.^ieng

Comparison of the direct faecal smear and two thick smear techniques for the diagnosis of intestinal parasitic infections.

Among 547 health centre patients in Burundi, the diagnostic performance of a glass coverslip modification of the Kato thick smear technique was compared with the combination of direct slide examination and the quick Kato-Katz method, currently recommended in basic health services, for the diagnosis of intestinal parasitic infections. The classical Kato-Katz method performed best for the diagnosis of common helminth infections, especially in combination with direct examination. For the diagnosis of protozoa, both trophozoites and cysts, the direct slide examination was superior to the glass coverslip technique. Despite its being a single and easy procedure, the glass coverslip technique could not be recommended as the method of choice for the diagnosis of intestinal parasites in basic health services.

Field test of the 'dose pole' for praziquantel in Zanzibar.

A graduated pole for height measurement, estimating the number of praziquantel tablets needed for treatment, was field-tested on 1289 children in Zanzibar. A bathroom-type scale performed better than the dose pole in delivering the optimal dose (40-60 mg/kg) and the 2 methods performed similarly in delivering a dose considered appropriate (30-60 mg/kg).

Prevalence of cysticercosis in epileptics and members of their families in Burundi.

In the province of Bururi in Burundi, 103 epileptics and 72 control subjects from the same households were examined for cysticercosis. Antigen was detected by enzyme-linked immunosorbent assay in 4.9% of epileptic persons and in 4.2% of controls. Antibody was detected by enzyme-linked electroimmunotransfer blot assay (EITB) in 11.7% of epileptics and in 2.8% of controls. Neither difference was statistically significant, nor was a history of taeniasis significantly more frequent in epileptics than in controls. However, cysticercosis was significantly more frequently diagnosed by EITB in people with a history of taeniasis than in those without such a history. The prevalence of taeniasis in schoolchildren ranged between 0 and 1.0%. Meat inspection detected cysticercosis in 2% and 39% of pigs in 2 localities, respectively.

Development and validation of a 'tablet pole' for the administration of praziquantel in sub-Saharan Africa.

A pole estimating, for each individual, the number of praziquantel tablets needed for treatment according to height was tested in 20 data sets (n = 25,688). In more than 98% of the cases the indicated dose was within the range that has proven efficacious and safe (30 and 60 mg/kg).

The global status of schistosomiasis and its control.

Schistosomiasis is being successfully controlled in many countries but remains a major public health problem, with an estimated 200 million people infected, mostly in Africa. Few countries in this region have undertaken successful and sustainable control programmes. The construction of water schemes to meet the power and agricultural requirements for development have lead to increasing transmission, especially of Schistosoma mansoni. Increasing population and movement have contributed to increased transmission and introduction of schistosomiasis to new areas. Most endemic countries are among the least developed whose health systems face difficulties to provide basic care at the primary health level. Constraints to control include, the lack of political commitment and infrastructure for public health interventions. Another constraint is that available anti-schistosomal drugs are expensive and the cost of individual treatment is a high proportion of the per capita drug budgets. There is need for increased support for schistosomiasis control in the most severely affected countries.

Control of Schistosoma mansoni and intestinal helminths: 8-year follow-up of an urban school programme in Bujumbura, Burundi.

Annual selective chemotherapy with praziquantel was implemented in primary schools in the endemic suburbs of Bujumbura from 1984 to 1992. During the first 6-year period, the overall prevalence among pupils decreased from 23.3% to 9.1%, a reduction of 61%. During the following 2-year period, in which only children from the 1st, 4th and 6th grade were examined in two of the four endemic suburbs (maintenance strategy), the prevalence decreased further to 6.4% or a 73% reduction from the beginning of the programme. The impact of annually repeated selective chemotherapy was more important on the intensity than on the prevalence of infection. It was also more pronounced in the senior grades of primary school. Its cumulative effect tended to decline over the years. The prevalence of infection in new entrants to the programme also decreased over the years, indicating a reduction of transmission. This change in transmission was different in each suburb and related to changes in the sanitary situation, the degree of urbanization and the accessibility to rural transmission sites. The results of helminth control, a secondary aspect of the school programme, were proportionately less pronounced than those obtained for schistosomiasis. The improvement in hygienic conditions has also contributed much to the outcome of this latter type of control. The cost, per person protected, of the programme was comparable with what has been reported by other, similar programmes. Application of a maintenance strategy to 57% of the target population has reduced the cost by 40%.

The global epidemiological situation of schistosomiasis and new approaches to control and research.

While the distribution of schistosomiasis has changed over the last 50 years and there have been successful control programmes, the number of people estimated to be infected or at risk of infection has not been reduced. Today, 85% of the number of infected people are estimated to be on the African continent where few control efforts are made. In terms of disease burden, there is therefore a growing discrepancy between sub-Saharan Africa and the rest of the world. WHO has now developed a dual strategy for the control of schistosomiasis: a strategy for morbidity control adapted to the public health context in high burden areas, and a strategy to consolidate control in areas where a low endemic level has been reached and elimination may be feasible. Related to this new vision, some research needs are pointed out.