Appropriate targeting of artemisinin-based combination therapy by community health workers using malaria rapid diagnostic tests: findings from randomized trials in two contrasting areas of high and low malaria transmission in south-western Uganda.

OBJECTIVE: To compare the impact of malaria rapid diagnostic tests (mRDTs), used by community health workers (CHWs), on the proportion of children <5 years of age receiving appropriately targeted treatment with artemisinin-based combination therapy (ACT), vs. presumptive treatment. METHODS: Cluster-randomized trials were conducted in two contrasting areas of moderate-to-high and low malaria transmission in rural Uganda. Each trial examined the effectiveness of mRDTs in the management of malaria and targeting of ACTs by CHWs comparing two diagnostic approaches: (i) presumptive clinical diagnosis of malaria [control arm] and (ii) confirmatory diagnosis with mRDTs followed by ACT treatment for positive patients [intervention arm], with village as the unit of randomisation. Treatment decisions by CHWs were validated by microscopy on a reference blood slide collected at the time of consultation, to compare the proportion of children <5 years receiving appropriately targeted ACT treatment, defined as patients with microscopically-confirmed presence of parasites in a peripheral blood smear receiving artemether-lumefantrine or rectal artesunate, and patients with no malaria parasites not given ACT. RESULTS: In the moderate-to-high transmission area, ACT treatment was appropriately targeted in 79.3% (520/656) of children seen by CHWs using mRDTs to diagnose malaria, vs. 30.8% (215/699) of children seen by CHWs using presumptive diagnosis (P < 0.001). In the low transmission area, 90.1% (363/403) children seen by CHWs using mRDTs received appropriately targeted ACT treatment vs. 7.8% (64/817) seen by CHWs using presumptive diagnosis (P < 0.001). Low mRDT sensitivity in children with low-density parasitaemia (<200 parasites/µl) was identified as a potential concern. CONCLUSION: When equipped with mRDTs, ACT treatments delivered by CHWs are more accurately targeted to children with malaria parasites. mRDT use could play an important role in reducing overdiagnosis of malaria and improving fever case management within iCCM, in both moderate-to-high and low transmission areas. Nonetheless, missed treatments due to the low sensitivity of current mRDTs in patients with low parasite density are a concern. For community-based treatment in areas of low transmission and/or non-immune populations, presumptive treatment of all fevers as malaria may be advisable, until more sensitive diagnostic assays, suitable for routine use by CHWs in remote settings, become available.

Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis.

BACKGROUND: Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. METHODS: For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2,015,019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. FINDINGS: Pooled overall RRs for preterm were 6·82 (95% CI 3·56-13·07) for neonatal mortality and 2·50 (1·48-4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34-2·50) for neonatal mortality and 1·90 (1·32-2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11-26·12). INTERPRETATION: Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4--the reduction of child mortality. FUNDING: Bill & Melinda Gates Foundation.

Neonatal mortality risk associated with preterm birth in East Africa, adjusted by weight for gestational age: individual participant level meta-analysis.

BACKGROUND: Low birth weight and prematurity are amongst the strongest predictors of neonatal death. However, the extent to which they act independently is poorly understood. Our objective was to estimate the neonatal mortality risk associated with preterm birth when stratified by weight for gestational age in the high mortality setting of East Africa. METHODS AND FINDINGS: Members and collaborators of the Malaria and the MARCH Centers, at the London School of Hygiene & Tropical Medicine, were contacted and protocols reviewed for East African studies that measured (1) birth weight, (2) gestational age at birth using antenatal ultrasound or neonatal assessment, and (3) neonatal mortality. Ten datasets were identified and four met the inclusion criteria. The four datasets (from Uganda, Kenya, and two from Tanzania) contained 5,727 births recorded between 1999-2010. 4,843 births had complete outcome data and were included in an individual participant level meta-analysis. 99% of 445 low birth weight (< 2,500 g) babies were either preterm (< 37 weeks gestation) or small for gestational age (below tenth percentile of weight for gestational age). 52% of 87 neonatal deaths occurred in preterm or small for gestational age babies. Babies born < 34 weeks gestation had the highest odds of death compared to term babies (odds ratio [OR] 58.7 [95% CI 28.4-121.4]), with little difference when stratified by weight for gestational age. Babies born 34-36 weeks gestation with appropriate weight for gestational age had just three times the likelihood of neonatal death compared to babies born term, (OR 3.2 [95% CI 1.0-10.7]), but the likelihood for babies born 34-36 weeks who were also small for gestational age was 20 times higher (OR 19.8 [95% CI 8.3-47.4]). Only 1% of babies were born moderately premature and small for gestational age, but this group suffered 8% of deaths. Individual level data on newborns are scarce in East Africa; potential biases arising due to the non-systematic selection of the individual studies, or due to the methods applied for estimating gestational age, are discussed. CONCLUSIONS: Moderately preterm babies who are also small for gestational age experience a considerably increased likelihood of neonatal death in East Africa.

Characteristics of persons who complied with and failed to comply with annual ivermectin treatment.

OBJECTIVE: To assess individual compliance with annual ivermectin treatment in onchocerciasis-endemic villages. METHODS: Multi-site study in eight APOC-sponsored projects in Cameroon, Nigeria and Uganda to identify the socio-demographic correlates of compliance with ivermectin treatment. A structured questionnaire was administered on 2305 persons aged 10 years and above. Two categories of respondents were purposively selected to obtain both high and low compliers: people who took ivermectin 6-8 times and 0-2 times previously. Simple descriptive statistics were employed in characterizing the respondents into high and low compliers, while some socio-demographic and key perceptual factors were employed in regression models constructed to explain levels of compliance among the respondents. RESULTS: Some demographic and perceptual factors associated with compliance were identified. Compliance was more common among men (54.4%) (P < 0.001). Adults (54.6%) had greater rates of high compliance (P < 0.001. The mean age of high compliers (41.5 years) was significantly older (35.8 years) (t = 8.46, P < 0.001). Perception of onchocerciasis and effectiveness of ivermectin influenced compliance. 81.4% of respondents saw benefits in annual ivermectin treatment, high compliance among those who saw benefits was 59.3% compared to 13.3% of those who did not (P < 0.001). CONCLUSION: Efforts to increase compliance with ivermectin treatment should focus on providing health education to youth and women. Health education should also highlight the benefits of taking ivermectin.

Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS) pilot study.

BACKGROUND: Artemisinin-based combination therapy (ACT), the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS) pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. METHODS: Four intervention districts were purposefully selected to receive branded subsidized medicines - "ACT with a leaf", while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention's impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. RESULTS: At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, "ACT with a leaf" accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2%) at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%). The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4) at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p<0.0001) at evaluation. Children less than five years of age had "ACT with a leaf" purchased for them more often than those aged above five years. There was no evidence of price gouging. CONCLUSIONS: These data demonstrate that a supply-side subsidy and an intensive communications campaign significantly increased the uptake and use of ACT in the private sector in Uganda.

The feasibility of introducing rapid diagnostic tests for malaria in drug shops in Uganda.

BACKGROUND: National malaria control programmes and international agencies are keen to scale-up the use of effective rapid diagnostic tests (RDTs) for malaria. The high proportion of the Ugandan population seeking care at drug shops makes these outlets attractive as providers of malaria RDTs. However, there is no precedent for blood testing at drug shops and little is known about how such tests might be perceived and used. Understanding use of drug shops by communities in Uganda is essential to inform the design of interventions to introduce RDTs. METHODS: We conducted a qualitative study, with 10 community focus group discussions, and 18 in-depth interviews with drug shop attendants, health workers and district health officials. The formative study was carried out in Mukono district, central Uganda an area of high malaria endemicity from May-July 2009. RESULTS: Drug shops were perceived by the community as important in treating malaria and there was awareness among most drug sellers and the community that not all febrile illnesses were malaria. The idea of introducing RDTs for malaria diagnosis in drug shops was attractive to most respondents. It was anticipated that RDTs would improve access to effective treatment of malaria, offset high costs associated with poor treatment, and avoid irrational drug use. However, communities did express fear that drug shops would overprice RDTs, raising the overall treatment cost for malaria. Other fears included poor adherence to the RDT result, reuse of RDTs leading to infections and fear that RDTs would be used to test for human immune deficiency virus (HIV). All drug shops visited had no record on patient data and referral of cases to health units was noted to be poor. CONCLUSION: These results not only provide useful lessons for implementing the intervention study but have wide implications for scaling up malaria treatment in drug shops.

After a decade of annual dose mass ivermectin treatment in Cameroon and Uganda, onchocerciasis transmission continues.

OBJECTIVE: To evaluate the effectiveness of 10 years' annual single dose ivermectin treatment on onchocerciasis transmission in hyperendemic areas of Cameroon and Uganda. METHODS: Baseline nodule and microfilaria ('skin snip') prevalence data were available from 10 hyperendemic sentinel communities in Cameroon (from 1996) and hyperendemic 20 sentinel communities in Uganda (from 1993). We returned to these villages in 2005, 10 months after the last annual ivermectin distribution, to repeat the cross-sectional surveys. Each sentinel community reported a mean interval treatment coverage of eligible persons of >88% (range 37-100%). Data were analyzed for more than 6200 person examinations. In Cameroon, 719 people >or=10 years were examined at the baseline survey in 1996 and 838 at the follow-up survey in 2005. In Uganda, 1590 people >or=10 years were examined at the baseline survey in 1993 and 2122 people at the follow-up survey in 2005. We also examined children under 10 in Cameroon (1996, n = 185; 2005, n = 448) and Uganda (1993, n = 177; 2005, n = 130). In Uganda, the vitality of worms was judged using standard histological criteria in 80 nodules excised in 2005. RESULTS: The prevalence of microfilaria carriers among older children and adults (>or=10 years) in Cameroon sentinel communities dropped from 70.1% to 7.04% (P < 0.0001) over the 10-year treatment period; that of nodule carriers from 58% to 9.55% (P < 0.0001). Similarly, in Uganda, the prevalence of microfilaria carriers fell from 71.9% to 7.49% (P < 0.0001) over the 13-year treatment period, and that of nodule carriers from 53.21% to 9.66% (P < 0.0001). The number of microfilaria carriers among children <10 years in Cameroon decreased from 29.73% to 3.8% (P < 0.0001), and in Uganda from 33.89% to 3.1% (P < 0.0001). In 2005, worms excised from nodules in Uganda, 81.4% of males remained alive, and 64% of females, with 24% of them inseminated. CONCLUSION: A decade or more of annual single dose ivermectin treatment in hyperendemic areas has reduced onchocerciasis to 'hypoendemicity', but onchocerciasis transmission persists. For now, annual treatment with ivermectin should be continued in formerly mesoendemic and hyperendemic zones.

Malaria and hookworm infections in relation to haemoglobin and serum ferritin levels in pregnancy in Masindi district, western Uganda.

This study examined the predictors of haemoglobin (Hb) concentration and serum ferritin (SF) levels in pregnant women in an area of stable malaria transmission and high prevalence of intestinal helminth infections. In total, 834 women attending antenatal care for the first time were examined. Blood slides for malaria parasites were prepared for 802, of which 154 were primigravidae (PG) and 648 were multigravidae (MG). Malaria parasitaemia rate was 42.6% (66) in PG and 33.3% (216) in MG (P=0.04). The geometric mean parasite density was 1695.8 (95% CI 1005.0-2386.5) in PG and 922.7 (95% CI 626.7-1382.6) in MG (P=0.02). Anaemia (Hb<100g/l) was found in 18.0% (94) of aparasitaemic women compared to 28.5% (80) among parasitaemic women (P<0.001). The prevalence of anaemia was 15.1% (42) in women without hookworm infection compared to 23.3% (129) among infected women (P=0.006). Malaria parasitaemia, hookworm infection, C-reactive protein, gravidity and gestational age were associated with Hb status. Malaria parasitaemia, Ascaris lumbricodes and Trichuris trichiura infections and age were associated with SF. Malaria, hookworm infections and iron deficiency were associated with anaemia in the study population.

Neglected tropical diseases in Uganda: the prospect and challenge of integrated control.

So-called 'neglected tropical diseases' (NTDs) are becoming less neglected, with increasing political and financial commitments to their control. These recent developments were preceded by substantial advocacy for integrated control of different NTDs, on the premise that integration is both feasible and cost-effective. Although the approach is intuitively attractive, there are few countrywide experiences to confirm or refute this assertion. Using the example of Uganda, this article reviews the geographical and epidemiological bases for integration and assesses the potential opportunities for, and operational challenges of, integrating existing control activities for several of these diseases under an umbrella vertical programme.

Diagnosis and treatment of malaria in peripheral health facilities in Uganda: findings from an area of low transmission in south-western Uganda.

BACKGROUND: Early recognition of symptoms and signs perceived as malaria are important for effective case management, as few laboratories are available at peripheral health facilities. The validity and reliability of clinical signs and symptoms used by health workers to diagnose malaria were assessed in an area of low transmission in south-western Uganda. METHODS: The study had two components: 1) passive case detection where all patients attending the out patient clinic with a febrile illness were included and 2) a longitudinal active malaria case detection survey was conducted in selected villages. A malaria case was defined as any slide-confirmed parasitaemia in a person with an axillary temperature > or = 37.5 degrees C or a history of fever within the last 24 hrs and no signs suggestive of other diseases. RESULTS: Cases of malaria were significantly more likely to report joint pains, headache, vomiting and abdominal pains. However, due to the low prevalence of malaria, the predictive values of these individual signs alone, or in combination, were poor. Only 24.8% of 1627 patients had malaria according to case definition and > 75% of patients were unnecessarily treated for malaria and few slide negative cases received alternative treatment. CONCLUSION: In low-transmission areas, more attention needs to be paid to differential diagnosis of febrile illnesses In view of suggested changes in anti-malarial drug policy, introducing costly artemisinin combination therapy accurate, rapid diagnostic tools are necessary to target treatment to people in need.

Malaria treatment-seeking behaviour and drug prescription practices in an area of low transmission in Uganda: implications for prevention and control.

Knowledge of malaria and treatment-seeking behaviour was investigated in an area of low transmission in Uganda to help health services to plan for appropriate interventions to control malaria. Although knowledge of malaria symptoms, preventive methods and malaria risks was widespread, few were actually using insecticide-treated nets. Many patients (25%) had received treatment prior to visiting a health facility, with drug shops and general stores being the main sources of treatment. Some shops dispensed quinine, a second-line drug recommended for complicated malaria. Prescription practices of health staff often did not comply with guidelines. Only 30% of patients received treatment at a health facility within 24h of onset of symptoms. Findings indicate a need for community-level information campaigns on prompt treatment and introduction of home-based management of fever. Measures are needed to protect second-line drugs from misuse. Failure to comply with drug policy in both the private and public sectors is of concern in an era of rapidly evolving drug policy changes and highlights the need for reorientation and training of health staff and drug vendors to improve malaria diagnostic and treatment skills.

Cost-effectiveness analysis of malaria rapid diagnostic tests for appropriate treatment of malaria at the community level in Uganda.

In Sub-Saharan Africa, malaria remains a major cause of morbidity and mortality among children under 5, due to lack of access to prompt and appropriate diagnosis and treatment. Many countries have scaled-up community health workers (CHWs) as a strategy towards improving access. The present study was a cost-effectiveness analysis of the introduction of malaria rapid diagnostic tests (mRDTs) performed by CHWs in two areas of moderate-to-high and low malaria transmission in rural Uganda. CHWs were trained to perform mRDTs and treat children with artemisinin-based combination therapy (ACT) in the intervention arm while CHWs offered treatment based on presumptive diagnosis in the control arm. Data on the proportion of children with fever 'appropriately treated for malaria with ACT' were captured from a randomised trial. Health sector costs included: training of CHWs, community sensitisation, supervision, allowances for CHWs and provision of mRDTs and ACTs. The opportunity costs of time utilised by CHWs were estimated based on self-reporting. Household costs of subsequent treatment-seeking at public health centres and private health providers were captured in a sample of households. mRDTs performed by CHWs was associated with large improvements in appropriate treatment of malaria in both transmission settings. This resulted in low incremental costs for the health sector at US$3.0 per appropriately treated child in the moderate-to-high transmission area. Higher incremental costs at US$13.3 were found in the low transmission area due to lower utilisation of CHW services and higher programme costs. Incremental costs from a societal perspective were marginally higher. The use of mRDTs by CHWs improved the targeting of ACTs to children with malaria and was likely to be considered a cost-effective intervention compared to a presumptive diagnosis in the moderate-to-high transmission area. In contrast to this, in the low transmission area with low attendance, RDT use by CHWs was not a low cost intervention.

Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets.

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard.Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated.Setting CHERG birth cohorts from 14 population based sites in low and middle income countries.Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%.Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700).Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries.

Examining Intervention Design: Lessons from the Development of Eight Related Malaria Health Care Intervention Studies.

Abstract-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.

Epidemiology of helminth infections and their relationship to clinical malaria in southwest Uganda.

It has recently been suggested that helminth infections may adversely influence susceptibility to other infections, including malaria. To investigate this hypothesis in a sub-Saharan African setting, surveys of helminth infections were conducted in 2003 among individuals who had been under weekly active case detection for clinical malaria during the preceding 18 months in four villages in Kabale District, southwest Uganda. Overall, 47.3% of individuals had at least one intestinal nematode species infection: hookworm, Ascaris lumbricoides and Trichuris trichiura were detected in 32.1, 17.4 and 8.1% of individuals, respectively. We found evidence of significant household clustering of A. lumbricoides, T. trichiura and hookworm, and clustering of heavy infection of each species. The association between helminth infection and clinical malaria was investigated in two villages and no evidence for an association was observed between the presence of infection or heavy infection and risk of malaria.

Comparison of US Birth Weight References and the International Fetal and Newborn Growth Consortium for the 21st Century Standard.

IMPORTANCE: This study introduces how the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) international birth weight standards alter our previous understanding and interpretations of fetal growth restriction as represented by small for gestational age (SGA) status. OBJECTIVES: To compare the birth weight distributions of the INTERGROWTH-21st international standard to commonly used US references and examine the differences in the prevalence and neonatal mortality risk of SGA status (below the 10th percentile of a population reference). DESIGN, SETTING, AND PARTICIPANTS: We analyzed data from 16 prospective cohorts of newborns on gestational age, birth weight, and systematic mortality follow-up through 28 days from 10 low- and middle-income countries. The studies included were conducted between 1983 and 2008. The analysis was conducted in 2014. Infants were categorized as SGA using the 1991 US birth weight reference, the 1999-2000 US birth weight reference, and the new INTERGROWTH-21st standard. For each study, we compared the SGA prevalence and the risk ratio between SGA status and neonatal mortality, calculated using Poisson regression with robust error variance. MAIN OUTCOMES AND MEASURES: We examine neonatal mortality (death within the first 28 days after birth) as the main outcome measure. RESULTS: The pooled SGA prevalence was 23.7% (95% CI, 16.5%-31.0%) using the INTERGROWTH-21st standard compared with 36.0% (95% CI, 27.0%-45.0%) with the US 2000 reference. The relative decrease in prevalence was larger among infants born at 33 to less than 37 weeks' gestation compared with term infants. The pooled neonatal mortality risk did not differ significantly; the adjusted risk ratios were 2.13 (95% CI, 1.78-2.54; P < .001) for the INTERGROWTH-21st standard and 2.12 (95% CI, 1.81-2.48; P < .001) for the US 2000 reference. CONCLUSIONS AND RELEVANCE: To our knowledge, INTERGROWTH-21st is the first international newborn standard for size for gestational age for healthy fetal growth. We observed a greater-than-one-quarter reduction in SGA prevalence and no significant change in the associated neonatal mortality risk, resulting in a decrease in the percentage of neonatal death attributable to SGA. Our study sheds light on how previously published studies on SGA status may be reinterpreted with the introduction of this new birth weight standard.

Transmission of Onchocerca volvulus by Simulium neavei in Mount Elgon focus of Eastern Uganda has been interrupted.

The study determined that Simulium neavei-transmitted onchocerciasis in Mount Elgon onchocerciasis focus had been interrupted. Annual mass treatment with ivermectin changed to two times per year along with vector elimination in 2007. Then, baseline microfilaria (mf) prevalence data of 1994 in five sentinel communities were compared with follow-up data in 2005 and 2011. Blood spots from 3,051 children obtained in 2009 were analyzed for Onchocerca volvulus immunoglobulin G4 antibodies. Fresh water crab host captures and blackflies collected indicated their infestation with larval stages of S. neavei and presence or absence of the vector, respectively. Mf rates dropped from 62.2% to 0.5%, and 1 (0.03%) of 3,051 children was positive for O. volvulus antibodies. Crab infestation dropped from 41.9% in 2007 to 0%, and S. neavei biting reduced to zero. Both remained zero for the next 3 years, confirming interruption of onchocerciasis transmission, and interventions were halted.

Bioefficacy of long-lasting insecticidal nets against pyrethroid-resistant populations of Anopheles gambiae s.s. from different malaria transmission zones in Uganda.

BACKGROUND: There are major concerns over sustaining the efficacy of current malaria vector control interventions given the rapid spread of resistance, particularly to pyrethroids. This study assessed the bioefficacy of five WHO-recommended long-lasting insecticidal nets (LLINs) against pyrethroid-resistant Anopheles gambiae field populations from Uganda. METHODS: Adult An. gambiae from Lira, Tororo, Wakiso and Kanungu districts were exposed to permethrin (0.75%) or deltamethrin (0.05%) in standard WHO susceptibility tests. Cone bioassays were used to measure the bioefficacy of four mono-treated LLINs (Olyset®, Interceptor®, Netprotect® and PermaNet® 2.0) and one combination LLIN (PermaNet® 3.0) against the four mosquito populations. Wireball assays were similarly conducted to determine knockdown rates. Species composition and kdr mutation frequency were determined for a sample of mosquitoes from each population. Chemical assays confirmed that test nets fell within target dose ranges. RESULTS: Anopheles gambiae s.s. predominated at all four sites (86-99% of Anopheles spp.) with moderate kdr L1014S allelic frequency (0.34-0.37). Confirmed or possible resistance to both permethrin and deltamethrin was identified for all four test populations. Reduced susceptibility to standard LLINs was observed for all four populations, with mortality rates as low as 45.8% even though the nets were unused. The combination LLIN PermaNet®3.0 showed the highest overall bioefficacy against all four An. gambiae s.l. populations (98.5-100% mortality). Wireball assays provided a more sensitive indicator of comparative bioefficacy, and PermaNet 3.0 was again associated with the highest bioefficacy against all four populations (76.5-91.7% mortality after 30 mins). CONCLUSIONS: The bioefficacy of mono-treated LLINs against pyrethroid-resistant field populations of An. gambiae varied by LLIN type and mosquito population, indicating that certain LLINs may be more suitable than others at particular sites. In contrast, the combination LLIN PermaNet 3.0 performed optimally against the four An. gambiae populations tested. The observed reduced susceptibility of malaria vectors to mono-treated LLINs is of particular concern, especially considering all nets were unused. With ongoing scale-up of insecticidal tools in the advent of increasing resistance, it is essential that those interventions with proven enhanced efficacy are given preference particularly in areas with high resistance.

An Epidemiologic Investigation of Potential Risk Factors for Nodding Syndrome in Kitgum District, Uganda.

INTRODUCTION: Nodding Syndrome (NS), an unexplained illness characterized by spells of head bobbing, has been reported in Sudan and Tanzania, perhaps as early as 1962. Hypothesized causes include sorghum consumption, measles, and onchocerciasis infection. In 2009, a couple thousand cases were reportedly in Northern Uganda. METHODS: In December 2009, we identified cases in Kitgum District. The case definition included persons who were previously developmentally normal who had nodding. Cases, further defined as 5- to 15-years-old with an additional neurological deficit, were matched to village controls to assess risk factors and test biological specimens. Logistic regression models were used to evaluate associations. RESULTS: Surveillance identified 224 cases; most (95%) were 5-15-years-old (range = 2-27). Cases were reported in Uganda since 1997. The overall prevalence was 12 cases per 1,000 (range by parish = 0·6-46). The case-control investigation (n = 49 case/village control pairs) showed no association between NS and previously reported measles; sorghum was consumed by most subjects. Positive onchocerciasis serology [age-adjusted odds ratio (AOR1) = 14·4 (2·7, 78·3)], exposure to munitions [AOR1 = 13·9 (1·4, 135·3)], and consumption of crushed roots [AOR1 = 5·4 (1·3, 22·1)] were more likely in cases. Vitamin B6 deficiency was present in the majority of cases (84%) and controls (75%). CONCLUSION: NS appears to be increasing in Uganda since 2000 with 2009 parish prevalence as high as 46 cases per 1,000 5- to 15-year old children. Our results found no supporting evidence for many proposed NS risk factors, revealed association with onchocerciasis, which for the first time was examined with serologic testing, and raised nutritional deficiencies and toxic exposures as possible etiologies.

Clinical, neurological, and electrophysiological features of nodding syndrome in Kitgum, Uganda: an observational case series.

BACKGROUND: Nodding syndrome is an unexplained illness characterised by head-bobbing spells. The clinical and epidemiological features are incompletely described, and the explanation for the nodding and the underlying cause of nodding syndrome are unknown. We aimed to describe the clinical and neurological diagnostic features of this illness. METHODS: In December, 2009, we did a multifaceted investigation to assess epidemiological and clinical illness features in 13 parishes in Kitgum District, Uganda. We defined a case as a previously healthy child aged 5-15 years with reported nodding and at least one other neurological deficit. Children from a systematic sample of a case-control investigation were enrolled in a clinical case series which included history, physical assessment, and neurological examinations; a subset had electroencephalography (EEG), electromyography, brain MRI, CSF analysis, or a combination of these analyses. We reassessed the available children 8 months later. FINDINGS: We enrolled 23 children (median age 12 years, range 7-15 years) in the case-series investigation, all of whom reported at least daily head nodding. 14 children had reported seizures. Seven (30%) children had gross cognitive impairment, and children with nodding did worse on cognitive tasks than did age-matched controls, with significantly lower scores on tests of short-term recall and attention, semantic fluency and fund of knowledge, and motor praxis. We obtained CSF samples from 16 children, all of which had normal glucose and protein concentrations. EEG of 12 children with nodding syndrome showed disorganised, slow background (n=10), and interictal generalised 2·5-3·0 Hz spike and slow waves (n=10). Two children had nodding episodes during EEG, which showed generalised electrodecrement and paraspinal electromyography dropout consistent with atonic seizures. MRI in four of five children showed generalised cerebral and cerebellar atrophy. Reassessment of 12 children found that six worsened in their clinical condition between the first evaluation and the follow-up evaluation interval, as indicated by more frequent head nodding or seizure episodes, and none had cessation or decrease in frequency of these episodes. INTERPRETATION: Nodding syndrome is an epidemic epilepsy associated with encephalopathy, with head nodding caused by atonic seizures. The natural history, cause, and management of the disorder remain to be determined. FUNDING: Division of Global Disease Detection and Emergency Response, US Centers for Disease Control and Prevention.