FACTORS ASSOCIATED WITH UNDERNUTRITION AMONG CHILDREN WITH SICKLE CELL DISEASE ATTENDING THE SICKLE CELL CLINIC IN MULAGO NATIONAL REFERRAL HOSPITAL, UGANDA. A CROSS SECTIONAL STUDY.

Background:  Sickle cell disease (SCD) is among the neglected non-communicable diseases, which significantly contributes to early childhood mortality. In Uganda, over 20,000 children are estimated to be sicklers. Undernutrition is common among children with SCD and contributes to increased morbidity and mortality. There is a paucity of data on the prevalence of undernutrition and associated factors in Uganda. Objective:  To assess the extent of undernutrition and related factors among children aged 5-12 years with SCD attending the sickle cell clinic at Mulago National Referral Hospital (MNRH), Uganda.   Methods:  A hospital-based cross-sectional study was conducted. A total of 270 children with SCD attending the sickle cell clinic at MNRH were recruited consecutively between May and June 2017. The nutritional status of the children was assessed by BMI-for-age (wasting) and height-for-age (stunting) z-scores calculated using STATA in accordance with WHO reference. Binary logistic regression was conducted using odds ratios with 95% CI to measure the strength of association among the predictors. Results:  About 11.4% were wasted and 13.7% were stunted. Wasting was significantly associated with older age (10-12 years) (AOR=4.27, CI=2.20-8.29) and living in a female-headed household (AOR=0.39, CI=0.16-0.92). Stunting was significantly associated with older age (10-12 years) (AOR=2.90, CI=1.39-6.06).  Conclusion:  Wasting and stunting were prevalent among children with SCD attending MNRH. The factors associated with undernutrition were older age and living in a female-headed household.  Recommendations:  Interventions like skills-based nutrition education integrating older children and enhancement of women’s control of household resources by improving the social economic status of caretakers through business training and providing vocational skills can improve undernutrition in children with SCD

Efficacy of quinine, artemether-lumefantrine and dihydroartemisinin-piperaquine as rescue treatment for uncomplicated malaria in Ugandan children.

BACKGROUND: The treatment of falciparum malaria poses unique challenges in settings where malaria transmission intensity is high because recurrent infections are common. These could be new infections, recrudescences, or a combination of the two. Though several African countries continue to use quinine as the second line treatment for patients with recurrent infections, there is little information on its efficacy when used for rescue therapy. Moreover, such practice goes against the World Health Organisation (WHO) recommendation to use combination therapy for uncomplicated malaria. METHODS: We conducted a nested, randomized, open label, three-arm clinical trial of rescue therapy in children 6-59 months old with recurrent malaria infection during 28 days post treatment with artemisinin combination treatment (ACT). Patients were randomly assigned to receive either quinine, artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPQ), and actively followed up for 28 days. FINDINGS: Among 220 patients enrolled, 217 (98·6%) were assigned an efficacy outcome and 218 (99·1%) were assessed for safety. The risk of recurrent infection was significantly higher in patients treated with quinine (70%, 74/110, HR = 3·9; 95% CI: 2·4-6·7, p<0·0001) and AL (60%, 21/35, HR = 3·3; 95% CI: 1·8-6·3, p<0·0002), compared to DHAPQ (25%, 18/72). Recrudescence tended to be lower in the DHAPQ (1%, 1/72) than in the quinine (7%, 8/110) or AL (6%, 2/35) group, though it was not statistically significant. No serious adverse events were reported. CONCLUSION: Recurrent infections observed after the administration of an ACT can be successfully treated with an alternative ACT rather than with quinine. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99046537

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

Background The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. Methods This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. Results Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns. Conclusions This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin

Sponsorship in non-commercial clinical trials: definitions, challenges and the role of Good Clinical Practices guidelines.

BACKGROUND: Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations. DISCUSSION: Our limited analysis suggests that the sponsors definition from the 1995 WHO Good Clinical Practices code has been integrated as such into many legislations, guidelines and regulations, and that it is not adequate to cover today's reality of funding arrangements in global health, where the legal responsibility and the funding source are de facto split. In agreement with other groups, we suggest that the international Good Clinical Practices codes should be updated to reflect the reality of non-commercial clinical research. In particular, they should explicitly include the distinction between commercial and non-commercial sponsors, and provide guidance to non-commercial sponsors for negotiating with external funding agencies and other research counterparts. Non-commercial sponsors of clinical trials should surely invest in the development of adequate legal, administrative and management skills. By acknowledging their role and specificities, and by providing them with adapted guidance, the international Good Clinical Practices codes would provide valuable guidance and support to non-commercial clinical research, whose relevance for global health is increasingly evident

Factors associated with malaria parasitemia, anemia and serological responses in a spectrum of epidemiological settings in Uganda.

BACKGROUND: Understanding the current epidemiology of malaria and the relationship between intervention coverage, transmission intensity, and burden of disease is important to guide control activities. We aimed to determine the prevalence of anemia, parasitemia, and serological responses to P. falciparum antigens, and factors associated with these indicators, in three different epidemiological settings in Uganda. METHODS AND FINDINGS: In 2012, cross-sectional surveys were conducted in 200 randomly selected households from each of three sites: Walukuba, Jinja district (peri-urban); Kihihi, Kanungu district (rural); and Nagongera, Tororo district (rural) with corresponding estimates of annual entomologic inoculation rates (aEIR) of 3.8, 26.6, and 125.0, respectively. Of 2737 participants, laboratory testing was done in 2227 (81.4%), including measurement of hemoglobin, parasitemia using microscopy, and serological responses to P. falciparum apical membrane antigen 1 (AMA-1) and merozoite surface protein 1, 19 kilodalton fragment (MSP-119). Analysis of laboratory results was restricted to 1949 (87.5%) participants aged ≤ 40 years. Prevalence of anemia (hemoglobin < 11.0 g/dL) was significantly higher in Walukuba (18.9%) and Nagongera (17.4%) than in Kihihi (13.1%), and was strongly associated with decreasing age for those ≤ 5 years at all sites. Parasite prevalence was significantly higher in Nagongera (48.3%) than in Walukuba (12.2%) and Kihihi (12.8%), and significantly increased with age to 11 years, and then significantly decreased at all sites. Seropositivity to AMA-1 was 53.3% in Walukuba, 63.0% in Kihihi, and 83.7% in Nagongera and was associated with increasing age at all sites. AMA-1 seroconversion rates strongly correlated with transmission intensity, while serological responses to MSP-119 did not. CONCLUSION: Anemia was predominant in young children and parasitemia peaked by 11 years across 3 sites with varied transmission intensity. Serological responses to AMA-1 appeared to best reflect transmission intensity, and may be a more accurate indicator for malaria surveillance than anemia or parasitemia

Survival time and its predictors among preterms in the neonatal period post-discharge in Busoga region-Uganda June – July 2017

Introduction: Globally, out of 15 million babies born preterm each year, one million die. In Uganda, preterm deaths contribute 30% of the neonatal mortality rate. There is a paucity of information on the most critical time to conduct high impact interventions among neonate born preterm especially post-discharge from hospital. We determined the survival time to mortality and its predictors among preterm infants in the neonatal period post-discharge from hospital. Methods: We conducted a prospective cohort study in which 128 preterm infants were recruited from six hospitals including Jinja Regional Referral, St. Francis Buluba, Kamuli mission, Iganga, Kamuli and Bugiri district hospitals were prematurity was confirmed using gestation age and birth weight. Initially, background characteristics of the participants were assessed and then followed prospectively until 28 days. Kaplan-Meier survival analysis was used to estimate survival probabilities while time to preterm mortality was described using the 5thpercentile. Cox proportional hazards regression was used to determine predictors of survival. Results: Overall, 8% (10/128) of the preterm infants died; the 5th percentile survival time was 17 days. There was a 6-fold increase in hazard to mortality among preterm infants who had Kangaroo Mother Care (KMC) compared to those who did not (adjusted HR: 6.4, 95%CI: 1.7 – 24.5), a 5-fold increase in the hazard to preterm mortality among preterm infants born to HIV positive mothers compared to their counterparts who had HIV negative mothers (adjusted HR: 4.9, 95%CI: 1.1 – 22.2); and a 4-fold increase in the hazard to preterm mortality among preterm infants who were not exclusively breastfed compared to those who were exclusively breastfed (adjusted HR: 4.4, 95%CI: 1.1 – 18.3). Conclusion: Among babies who died, death occurred in the first 17 days while factors negatively associated with preterm survival included; not practicing Kangaroo Mother Care, not being breastfed exclusively and being born to an HIV positive mother. We recommend follow-up care for preterm infants following hospital discharge, implementation of prevention of mother to child transmission of HIV and exclusive breastfeeding of preterm babies

Community facilitators and barriers to a successful implementation of mass drug administration and indoor residual spraying for malaria prevention in Uganda: a qualitative study

Abstract Background There is growing interest to add mass drug administration (MDA) to the already existing malaria prevention strategies, such as indoor residual spraying (IRS). However, successful MDA and IRS requires high population-wide coverage, emphasizing the importance of community acceptance. This study’s objectives were to identify community-level facilitators and barriers during the implementation of both MDA and IRS in communities with high malaria transmission intensity. Methods This was a qualitative study conducted in two sub-counties in Katakwi district. Kapujan sub-county residents received two rounds of IRS and MDA while Toroma sub-county residents received two rounds of IRS only. Key informant interviews and focus group discussions were conducted with key influential district and sub-county personnel and community members. Data were analysed using thematic analysis. Transcripts and interview notes from the in-depth interviews were analysed using a coding scheme developed from pre-defined topics together with themes emerging from the data. The Nvivo software program was used to aggregate the data by codes and to present study findings. Results Overall, 14 key informants were interviewed: 4 from Katakwi district and 5 each from Kapujan and Toroma sub-counties. Five focus group discussions were conducted: 4 with community members (men and women), 2 in each sub-county and one with medical staff of Toroma health centre IV. Important themes for consideration raised by the respondents include community sensitization, conducting implementation during the low activity dry season, involvement of government and local leadership, use of the competent locally composed team, community knowledge of malaria effects and consequences, combining interventions and evidence of malaria reduction from interventions. Potential barriers such as spreading of misinformation regarding interventions, the strong unpleasant smell from Actellic and inadequate duration of engagement with the community should be taken into consideration. Conclusion This study documents important community engagement strategies that need to be considered when implementing malaria MDA in combination with IRS, for malaria prevention in such settings. This information is useful for malaria programmes, especially during the design and implementation of such community level interventions

Avidity of anti-malarial antibodies inversely related to transmission intensity at three sites in Uganda.

BACKGROUND: People living in malaria endemic areas acquire protection from severe malaria quickly, but protection from clinical disease and control of parasitaemia is acquired only after many years of repeated infections. Antibodies play a central role in protection from clinical disease; however, protective antibodies are slow to develop. This study sought to investigate the influence of Plasmodium falciparum exposure on the acquisition of high-avidity antibodies to P. falciparum antigens, which may be associated with protection. METHODS: Cross-sectional surveys were performed in children and adults at three sites in Uganda with varied P. falciparum transmission intensity (entomological inoculation rates; 3.8, 26.6, and 125 infectious bites per person per year). Sandwich ELISA was used to measure antibody responses to two P. falciparum merozoite surface antigens: merozoite surface protein 1-19 (MSP1-19) and apical membrane antigen 1 (AMA1). In individuals with detectable antibody levels, guanidine hydrochloride (GuHCl) was added to measure the relative avidity of antibody responses by ELISA. RESULTS: Within a site, there were no significant differences in median antibody levels between the three age groups. Between sites, median antibody levels were generally higher in the higher transmission sites, with differences more apparent for AMA-1 and in ≥5 year group. Similarly, median avidity index (proportion of high avidity antibodies) showed no significant increase with increasing age but was significantly lower at sites of higher transmission amongst participants ≥5 years of age. Using 5 M GuHCl, the median avidity indices in the ≥5 year group at the highest and lowest transmission sites were 19.9 and 26.8, respectively (p = 0.0002) for MSP1-19 and 12.2 and 17.2 (p = 0.0007) for AMA1. CONCLUSION: Avidity to two different P. falciparum antigens was lower in areas of high transmission intensity compared to areas with lower transmission. Appreciation of the mechanisms behind these findings as well as their clinical consequences will require additional investigation, ideally utilizing longitudinal data and investigation of a broader array of responses

Comparison of routine health management information system versus enhanced inpatient malaria surveillance for estimating the burden of malaria among children admitted to four hospitals in Uganda.

The primary source of malaria surveillance data in Uganda is the Health Management Information System (HMIS), which does not require laboratory confirmation of reported malaria cases. To improve data quality, an enhanced inpatient malaria surveillance system (EIMSS) was implemented with emphasis on malaria testing of all children admitted in select hospitals. Data were compared between the HMIS and the EIMSS at four hospitals over a period of 12 months. After the implementation of the EIMSS, over 96% of admitted children under 5 years of age underwent laboratory testing for malaria. The HMIS significantly overreported the proportion of children under 5 years of age admitted with malaria (average absolute difference = 19%, range = 8-27% across the four hospitals) compared with the EIMSS. To improve the quality of the HMIS data for malaria surveillance, the National Malaria Control Program should, in addition to increasing malaria testing rates, focus on linking laboratory test results to reported malaria cases