The BabySaver: Design of a New Device for Neonatal Resuscitation at Birth with Intact Placental Circulation.

The initial bedside care of premature babies with an intact cord has been shown to reduce mortality; there is evidence that resuscitation of term babies with an intact cord may also improve outcomes. This process has been facilitated by the development of bedside resuscitation surfaces. These new devices are unaffordable, however, in most of sub-Saharan Africa, where 42% of the world's 2.4 million annual newborn deaths occur. This paper describes the rationale and design of BabySaver, an innovative low-cost mobile resuscitation unit, which was developed iteratively over five years in a collaboration between the Sanyu Africa Research Institute (SAfRI) in Uganda and the University of Liverpool in the UK. The final BabySaver design comprises two compartments; a tray to provide a firm resuscitation surface, and a base to store resuscitation equipment. The design was formed while considering contextual factors, using the views of individual women from the community served by the local hospitals, medical staff, and skilled birth attendants in both Uganda and the UK.

Unsafe "crossover-use" of chloramphenicol in Uganda: importance of a One Health approach in antimicrobial resistance policy and regulatory action.

Since the introduction of antibiotics into mainstream health care, resistance to these drugs has become a widespread issue that continues to increase worldwide. Policy decisions to mitigate the development of antimicrobial resistance are hampered by the current lack of surveillance data on antibiotic product availability and use in low-income countries. This study collected data on the antibiotics stocked in human (42) and veterinary (21) drug shops in five sub-counties in Luwero district of Uganda. Focus group discussions with drug shop vendors were also employed to explore antibiotic use practices in the community. Focus group participants reported that farmers used human-intended antibiotics for their livestock, and community members obtain animal-intended antibiotics for their own personal human use. Specifically, chloramphenicol products licensed for human use were being administered to Ugandan poultry. Human consumption of chloramphenicol residues through local animal products represents a serious public health concern. By limiting the health sector scope of antimicrobial resistance research to either human or animal antibiotic use, results can falsely inform policy and intervention strategies. Therefore, a One Health approach is required to understand the wider impact of community antibiotic use and improve overall effectiveness of intervention policy and regulatory action.

Management of Childhood Infections in Poorly Planned Urban Settlements in Kampala and Wakiso Districts of Uganda.

The main objective of this study was to assess the management of childhood infections in high-density poorly planned urban areas of Kampala and Wakiso districts in Uganda, to develop a strategy to deliver integrated community case management (iCCM) of childhood illness services. A total of 72 private healthcare facilities were surveyed (36 drug shops, eight pharmacies, 27 private clinics, and one herbal clinic); supplemented by focus group discussions with village health teams (VHTs), drug shops, and private clinic providers. The majority of drug shops (96.4%, 27/28), pharmacies (100%, 8/8), and (68%, private clinics 17/27) were registered; however, supervision was poor. The majority of patients (> 77%) who visited private health facilities were children aged < 5 years. Furthermore, over 80% (29/64) of the children with uncomplicated malaria were reported to have been given artemether-lumefantrine, and 42% with difficulty breathing were given an antibiotic. Although > 72% providers said they referred children with severe illnesses, taking up referral was complicated by poverty, long distances, and the perception that there were inadequate drugs at referral facilities. Less than 38% of all the facilities had malaria treatment guidelines; < 15% had iCCM guidelines; 6% of the drug shops had iCCM guidelines; and < 13% of the facilities had pneumonia and diarrhea treatment guidelines. Village health teams existed in the study areas, although they had little knowledge on causes and prevention of pneumonia. In conclusion, this study found that quality of care was poor and introduction of iCCM delivered through VHTs, drug shops, and private clinics may, with proper training and support, be a feasible intervention to improve care.

Predicting the Impact of COVID-19 and the Potential Impact of the Public Health Response on Disease Burden in Uganda.

The COVID-19 pandemic and public health "lockdown" responses in sub-Saharan Africa, including Uganda, are now widely reported. Although the impact of COVID-19 on African populations has been relatively light, it is feared that redirecting focus and prioritization of health systems to fight COVID-19 may have an impact on access to non-COVID-19 diseases. We applied age-based COVID-19 mortality data from China to the population structures of Uganda and non-African countries with previously established outbreaks, comparing theoretical mortality and disability-adjusted life years (DALYs) lost. We then predicted the impact of possible scenarios of the COVID-19 public health response on morbidity and mortality for HIV/AIDS, malaria, and maternal health in Uganda. Based on population age structure alone, Uganda is predicted to have a relatively low COVID-19 burden compared with an equivalent transmission in comparison countries, with 12% of the mortality and 19% of the lost DALYs predicted for an equivalent transmission in Italy. By contrast, scenarios of the impact of the public health response on malaria and HIV/AIDS predict additional disease burdens outweighing that predicted from extensive SARS-CoV-2 transmission. Emerging disease data from Uganda suggest that such deterioration may already be occurring. The results predict a relatively low COVID-19 impact on Uganda associated with its young population, with a high risk of negative impact on non-COVID-19 disease burden from a prolonged lockdown response. This may reverse hard-won gains in addressing fundamental vulnerabilities in women and children's health, and underlines the importance of tailoring COVID-19 responses according to population structure and local disease vulnerabilities.

Treatment of Sick Children Seeking Care in the Private Health Sector in Uganda: A Cluster Randomized Trial.

The main objective of this study was to assess whether training of private health providers and community sensitization on the importance of effective prompt care seeking and the need for referral could improve treatment of sick children in the private health sector in Uganda. Private providers were trained to diagnose and treat sick children according to the integrated community case management (iCCM) guidelines. In the control arm, routine services were offered. The outcomes were seeking care within 24 hours of onset of symptoms and appropriate case management for malaria, pneumonia, and diarrhea among children aged < 5 years. A total of 10,809 sick children (5,955 in the intervention arm and 4,854 in the control arm) presented for diagnosis and treatment. The percentage seeking care within 24 hours of onset of symptoms was 45.4% (95% CI 36.0-48.8) in the intervention arm versus 43.9% (95% CI 38.1-49.8) in the control arm (P = 0.04). Adherence to malaria rapid diagnostic test (mRDT) results was high, with 1,459 (94.3%) in the intervention arm versus 1,402 (83.0%) in the control arm (P = 0.04). Appropriate treatment of mRDT-positive children with artemisinin-based combination therapy was seen in 93.1% (95% CI 88.5-97.7) in the intervention arm versus 85.1% (95% CI 78.6-91.7) in the control arm (P = 0.03). Adherence to iCCM guidelines was very high: 89.1% of children with diarrhea in the intervention arm and 80.4% in the control arm were given oral rehydration salts and zinc (P = 0.01). Of the children with a respiratory rate > 40 breaths/minute, 1,596 (85.1%) in the intervention arm versus 104 (54.5%) in the control arm were given amoxicillin (P = 0.01). In conclusion, the intervention improved treatment of malaria, pneumonia, and diarrhea because of provider adherence to treatment guidelines. The policy implications of these findings are to initiate a dialogue at district and national levels on how to scale up the intervention in the private sector. NCT02450630 registered with ClinicalTrials.gov: May 9, 2015.

Patients with positive malaria tests not given artemisinin-based combination therapies: a research synthesis describing under-prescription of antimalarial medicines in Africa.

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 < 5-year-olds not prescribed ACT ranged up to 41.8% across sites. The odds of not being prescribed an ACT were 2-32 times higher for patients in settings with lower-transmission intensity (using test positivity as a proxy) compared to areas of higher transmission. mRDT-positive children in low-transmission settings were especially likely not to be prescribed ACT, with proportions untreated up to 70%. Of the 7426 mRDT-positive patients not prescribed an ACT, 4121 (55.5%) were prescribed other, non-recommended non-ACT antimalarial medications, and the remainder (44.5%) were prescribed no antimalarial. 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 < 5 years and those in low-transmission settings, were most likely to not be prescribed antimalarials, and young children in low-transmission settings were least likely to be treated for malaria. This major public health risk must be addressed in training and practice. TRIAL REGISTRATION: Reported in individual primary studies.

Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA.

Many pathogens evolve extensive genetic variation in virulence proteins as a strategy to evade host immunity. This poses a significant challenge for the host to develop broadly neutralizing antibodies. In Plasmodium falciparum, we show that a mechanism to circumvent this challenge is to elicit antibodies to cryptic epitopes that are not under immune pressure. We previously discovered that antibodies to the Plasmodium vivax invasion protein, PvDBP, cross-react with P. falciparum VAR2CSA, a distantly related virulence factor that mediates placental malaria. Here, we describe the molecular mechanism underlying this cross-species immunity. We identified an epitope in subdomain 1 (SD1) within the Duffy binding-like (DBL) domain of PvDBP that gives rise to cross-reactive antibodies to VAR2CSA and show that human antibodies affinity purified against a synthetic SD1 peptide block parasite adhesion to chondroitin sulfate A (CSA) in vitro The epitope in SD1 is subdominant and highly conserved in PvDBP, and in turn, SD1 antibodies target cryptic epitopes in P. falciparum VAR2CSA. The epitopes in VAR2CSA recognized by vivax-derived SD1 antibodies (of human and mouse origin) are distinct from those recognized by VAR2CSA immune serum. We mapped two peptides in the DBL5ε domain of VAR2CSA that are recognized by SD1 antibodies. Both peptides map to regions outside the immunodominant sites, and antibodies to these peptides are not elicited following immunization with VAR2CSA or natural infection with P. falciparum in pregnancy, consistent with the cryptic nature of these target epitopes.IMPORTANCE In this work, we describe a molecular mechanism of heterologous immunity between two distant species of Plasmodium Our results suggest a mechanism that subverts the classic parasite strategy of presenting highly polymorphic epitopes in surface antigens to evade immunity to that parasite. This alternative immune pathway can be exploited to protect pregnant women from falciparum placental malaria by designing vaccines to cryptic epitopes that elicit broadly inhibitory antibodies against variant parasite strains.

Using Reference Quantitative Polymerase Chain Reaction to Assess the Clinical Performance of the Paracheck-Pf® Rapid Diagnostic Test in a Field Setting in Uganda.

Malaria rapid diagnostic tests (RDTs) are widely used in clinical and surveillance settings. However, the performance of most RDTs has not been characterized at parasite densities below detection by microscopy. We present findings from Uganda, where RDT results from 491 participants with suspected malaria were correlated with quantitative polymerase chain reaction (qPCR)-defined parasitemia. Compared with qPCR, the sensitivity and specificity of the RDT for Plasmodium falciparum mono-infections were 76% (95% confidence interval [CI]: 68-83%) and 95% (95% CI: 92-97%), respectively. The sensitivity of the RDT at parasite densities between 0.2 and 200 parasites/µL was surprisingly high (87%, 95% CI: 74-94%). The high sensitivity of the RDT is likely because of histidine-rich protein 2 from submicroscopic infections, gametocytes, or sequestered parasites. These findings underscore the importance of evaluating different RDTs in field studies against qPCR reference testing to better define the sensitivity and specificity, particularly at low parasite densities.

Prevalence of protective tetanus antibodies and immunological response following tetanus toxoid vaccination among men seeking medical circumcision services in Uganda.

INTRODUCTION: Tetanus infection associated with men who had male circumcision has been reported in East Africa, suggesting a need for tetanus toxoid-containing vaccines (TTCV). OBJECTIVE: To determine the prevalence of tetanus toxoid antibodies following vaccination among men seeking circumcision. METHODS: We enrolled 620 consenting men who completed a questionnaire and received TTCV at enrollment (day 0) prior to circumcision on day 28. Blood samples were obtained at day 0 from all enrollees and on days 14, 28 and 42 from a random sample of 237 participants. Tetanus toxoid (TT) IgG antibody levels were assayed using EUROIMMUN. Analyses included prevalence of TT antibodies at enrollment and used a mixed effects model to determine the immunological response. RESULTS: Mean age was 21.4 years, 65.2% had knowledge of tetanus, 56.6% knew how tetanus was contracted, 22.8% reported ever receipt of TTCV, and 16.8% had current/recently healed wounds. Insufficient tetanus immunity was 57.1% at enrollment, 7.2% at day 14, 3.8% at day 28, and 0% at day 42. Antibody concentration was 0.44IU/ml (CI 0.35-0.53) on day 0, 3.86IU/ml (CI 3.60-4.11) on day 14, 4.05IU/ml (CI 3.81-4.29) on day 28, and 4.48IU/ml (CI 4.28-4.68) on day 42. TT antibodies increased by 0.24IU/ml (CI 0.23, 0.26) between days 0 and 14 and by 0.023IU/ml (CI 0.015, 0.031) between days 14 and 42 days. Immunological response was poorer in HIV-infected clients and men aged 35+ years. CONCLUSION: Insufficient immunity was common prior to TTCV, and a protective immunological response was achieved by day 14. Circumcision may safely be provided 14 days after vaccination in HIV-uninfected men aged less than 35 years.