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Background: Paediatric injuries are among the leading causes of morbidity and mortality globally, especially in low- and middle-income countries. We aimed to characterize paediatric injuries as predictors of disposition from Mbarara Regional Referral Hospital Emergency Department (ED) Southwestern Uganda. Methods: This was a prospective cohort study done from 12th December 2022 to 31st March 2023. We described the characteristics of injuries sustained by children and evaluated the predictors of 24-hour disposition from the ED using logistic regression. Results: Of the 160 children followed up, 64.4% were male with a median age of 7 years, brought in with road traffic accidents (RTAs) (40.6%) and falls (35.6%) as the commonest mechanism of injury. Over half of the patients were triaged as yellow (urgent); polytrauma and head injuries were the top injury patterns. The majority (45.6%) of the children were admitted to the inpatient surgical ward. Only 1.9% and 5.0% ended up in intensive care unit (ICU) and died (to mortuary), respectively. The median time to disposition was 8 h and 14% stayed in the ED beyond 24-hours. Patients who needed more intensive initial treatment, including additional medications or interventions, were significantly more likely to be admitted to the ward (AOR= 5.3, 95%CI: 2.0-13.0, p

Abstract Background Several diagnostic environments in Uganda lack real-time, robust and high-throughput technologies for comprehensive typing of microbes, which is a setback to infectious disease surveillance. This study combined various wet laboratory diagnostics to understand the epidemiology of pathogenic staphylococci isolated from animals in Uganda and the implications for global health security priorities. Methods A retrospective study was conducted employing records and pathogenic staphylococci (from animals) archived at the Central Diagnostic Laboratory (CDL), Makerere University, Uganda, between January 2012 and December 2019. The bacteria were speciated by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and tested for virulence factors [beta lactamases, lecithinase, deoxyribonuclease (DNase), haemolysins] and resistance to ten antimicrobials of clinical and veterinary relevance. Tetracycline and methicillin resistance genes were also tested. Results The prevalent diseases were mastitis in cattle and skin infections in dogs. Of the 111 staphylococci tested by MALDI-TOF MS, 79 (71.2%) were Staphylococcus aureus, 27 (24.3%) were Staphylococcus pseudintermedius and 5 (4.5%) were Staphylococcus schleiferi. All these strains expressed haemolysins. The prevalence of strains with lecithinase, penicillinase, cephalosporinase and DNase was 35.9% (14/39), 89.7% (35/39), 0.0% (0/39) and 87.2% (34/39), respectively. Staphylococci were primarily resistant to early penicillins (over 80%), tetracycline (57.7%), and chloramphenicol (46.2%). Minimal resistance was noted with cloxacillin (0.0%), ciprofloxacin (9.6%), and cefoxitin (3.8%). The prevalence of multidrug resistance (MDR) was 78.8% for general staphylococci, 82.2% for S. aureus, 73.1% for S. pseudintermedius, and 60.0% for S. schleiferi. Multidrug resistant staphylococci were significantly more prevalent in the cattle isolates than in the dog isolates (P

Background: The “chain of survival” was first systematically addressed in 1991, and its sequence still forms the cornerstone of current resuscitation guidelines. The term “chain of survival” is widely used around the world in literature, education, and awareness campaigns, but growing heterogeneity in the components of the chain has led to confusion. It is unclear which of these emerging chains is most suitable, or if adaptations are needed in particular contexts to depict key actions of resuscitation in the 21st century. This scoping review provides an overview of the variety of chains of survival described. Objectives: To identify published facets of the chain of survival, to assess views and strategies about adapting the chain, and to identify reports on how the chain of survival affects teaching, implementation, or patient outcomes. Methods, eligibility criteria, and sources of evidence: A scoping review as part of the continuous evidence evaluation process of the International Liaison Committee on Resuscitation (ILCOR) was conducted. MEDLINE(R) ALL (Ovid), Embase (Ovid), APA PsycINFO (Ovid), CINAHL (Ebscohost), ERIC (Ebscohost), Web of Science (Clarivate), Scopus (Elsevier), and Cochrane Library (Wiley Online) were searched. All publications in all languages describing chains of survival were eligible, without time restrictions. Due to the heterogeneity and publication types of the relevant studies, we did not pursue a systematic review or meta-analysis. Results: A primary search yielded 1713 studies and after screening we included 43 publications. Modified versions of the chain of survival for specific contexts were found (e.g., in-hospital cardiac arrest or paediatric resuscitation). There were also numerous versions with minor adaptations of the existing chain. Three publications suggested an impact of the use of the chain of survival on patient outcomes. No educational or implementation outcomes were reported. Conclusion: There is a vast heterogeneity of chain of survival concepts published. Future research is warranted, especially into the concept’s importance concerning educational, implementation, and clinical outcomes.

Abstract Background There is a steadily increasing trend in obesity globally and in Sub-Saharan Africa that disproportionately affects women in most places. This is not different in Uganda, where the Uganda Demographic and Health Survey indicated an increase in obesity among women of reproductive age as measured by the body mass index (BMI). However, studies on the predictors of obesity in women are still limited. Particularly, studies using specific indicators of body fat are scant. This study explored the socio-demographic predictors of obesity as indicated by total body fat percentage among women in the age range of 18 to 69 years old living in Mukono Central Division in Central Uganda. Methods A cross sectional study design using quantitative methods was employed. A total of 384 women between 18 and 69 years old from Mukono Central Division in Central Uganda were randomly recruited. A structured questionnaire was used to collect socio-demographic data including age, level of education, marital status, childbearing status, household expenditure, household size and employment status. Total body fat percentage, the indicator for obesity was measured using the body composition meter from TANITA. The data was analyzed using multinomial logistic regression analysis using SPSS version 20. Results 155 women, nearly two fifths (40.4% CI 95% 38.4–42.4) were classified as obese. Age, marital status, childbearing status, and employment status were the factors that were associated with obesity among these women. Employment status was the only variable that remained significantly associated with obesity among the women after adjusting for other factors. Unemployed women were nearly two times more likely to be obese than the employed women (AOR 1.9; 95% CI 1.1–3.1). The prevalence of obesity among the unemployed and employed women was 48.2% and 34.4% respectively. Conclusions Obesity in women was predicted by employment status. An in-depth study on factors that predispose unemployed women to obesity, will be instrumental in guiding interventions to curb the emerging obesity epidemic in Uganda. In the same vein, strategies to reduce levels of unemployment among women living in urban Uganda are essential for protecting public health from the dimension of reducing obesity levels.

Introduction: Emergency medicine (EM) is a new specialty in Uganda. There is no current formal EM undergraduate curriculum. The Mbarara University of Science and Technology Emergency Medicine Interest Group (MUST-EMIG) was established to bridge this gap. This survey was done to assess the contributions of MUST-EMIG. Objectives of the study were to: discover students' reasons for joining the MUST-EMIG; assess whether interest in learning emergency medicine was affected by participation in MUST-EMIG; evaluate plans to pursue emergency medicine as a specialty before and after joining MUST-EMIG; determine whether MUST-EMIG affected students’ perception of emergency medicine's importance in Uganda's health care system; and elicit feedback from students on their experience as members of MUST-EMIG. Methods: The MUST-EMIG executive developed a membership survey which was reviewed by MUST-EMIG's faculty advisor for suitability. Members of MUST-EMIG were voluntarily asked to participate in the online survey. Results of the survey were summarized using descriptive statistics and thematic analysis. Results: 49 responses (46.7% response rate) were collected and analyzed. Participants included 29 (59.2%) male and 20 (40.8%) female medical students. The majority of participants were fourth year students 22 (44.9%). 44 (89.8%) students joined MUST-EMIG to learn how to handle medical emergencies, and expressed a desire of at least 6/10 to learn more about emergency medicine after utilizing opportunities provided by MUST-EMIG. Overall, students had a good experience with MUST-EMIG. They reported that our interest group had provided them networking, unique learning, and leadership opportunities. Having an EMIG significantly affects students’ desire to pursue a career in emergency medicine and their perception of the relevance of emergency medicine. Discussion: An EMIG helps develop interest of medical students in emergency medicine. Students passionate about emergency medicine need to be supported to help them preserve and further develop this passion.

Background: Hypoxia is a common presentation in the Emergency Department (ED) worldwide. It affects 9-12% of hospitalized adults in Sub-Saharan Africa. Timely diagnosis of the multiple causes such as pneumonia, heart failure among others is challenging. Chest X-Ray (CXR), one of the most utilized imaging modalities has many limitations, and the gold standard (Computed Tomography scan) is inaccessible. Point of care ultrasound (PoCUS) is more available and increasingly being used, however little is known of its performance in resource limited EDs. The study aimed to assess the diagnostic performance of PoCUS compared with CXR in identifying the causes of hypoxia in the medical ED. Methods: 49 adults presenting with hypoxia (SP02 ≤ 88%) in the medical ED were evaluated. Ultrasound of the lungs and heart (PoCUS) was done, then CXR obtained. Lung ultrasound (LUS) was compared with CXR (first reference standard). Chest X-Ray and PoCUS were each compared to the physician diagnosis (second reference standard) to determine agreement using an acceptable disagreement cut-off of 15%. Results: 31% more abnormalities were identified by LUS than CXR. Lung ultrasound findings agreed with CXR in 86% of the participants with moderate reliability (ĸ=0.75). There was no significant difference between the actual findings of the two tests (X2= 2, p 0.1). Using the second reference, 82% of the CXRs were similar with weak reliability (ĸ=0.5) compared to 98% of PoCUS findings with strong reliability (ĸ=0.9). Compared to PoCUS, CXRs significantly differed from the physician diagnosis (X2= 0.85, p 0.38 vs X2= 8.5, p 0.004 respectively). Conclusion: Overall, PoCUS was not inferior to CXR when compared to final physician diagnosis in identifying causes of hypoxia, and LUS and CXR had comparable performance. Significantly more abnormalities were identified on PoCUS and it demonstrated better agreement and strong reliability with the physician diagnosis than CXR. We recommend PoCUS use in patients with hypoxia attending resource limited in- and pre-hospital settings.

Abstract Background For children below 6 years with suspected severe malaria attending a health care provider unable to provide parenteral malaria treatment, pre-referral rectal artesunate (RAS) is recommended by the World Health Organization to prevent death and disability. A number of African countries are in the process of rolling out quality-assured RAS for pre-referral treatment of severe malaria at community-level. The success of RAS depends, among other factors, on the acceptability of RAS in the communities where it is being rolled-out. Yet to date, there is limited literature on RAS acceptability. This study aimed to determine the acceptability of RAS by health care providers and child caregivers in communities where quality assured RAS was rolled out. This study was nested within the comprehensive multi-country observational research project Community Access to Rectal Artesunate for Malaria (CARAMAL), implemented in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Data from three different sources were analysed to understand RAS acceptability: interviews with health workers during three health care provider surveys (N = 341 community health workers and 467 primary health facility workers), with caregivers of children

Abstract Background To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. Methods An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children

Introduction: Although the global suicide deaths due to intentional pesticide poisoning disproportionately occur in low income countries (LIC) and lower to middle income Countries (LMIC), there is a scarcity of reports on emergency centre (EC) mortality and its predictors in these settings. Our goal was to determine the case fatality rate of Acute Pesticide Poisoning (APP) presenting to Mbarara Regional Referral Hospital (MRRH) EC and find out whether initial triage category predicted mortality in these patients. Methods: This was a prospective observational longitudinal study. Patients presenting with APP were enrolled using data collection forms. Data collected included initial triage category, vital signs, demographics, initial assessment, and management. They were followed up for 1 week. Results: Out of 66 patients admitted with suspected pesticide poisoning, 61 had complete follow up during the study period. However, only 58 patients had the pesticide ingested confirmed. These were predominantly males 48 (73%) and farmers 28(42%) with a median age of 23 years (IQR 18-31). Majority of patients 58 (88%) were suicide attempts and had ingested mostly organophosphates 23 (35%), amitraz 11(17%), zinc phosphide 7(10%), and aluminium phosphide 4(6%). The median time from ingestion to presentation was 4hours (IQR 2.5-8). More than half 41(62%) of the patients were in the red triage category (ESI-1). The overall case fatality rate of APP was 18%. Majority of patients who died were in the red triage category but the initial triage category was not significantly associated with mortality (p=0.381). Male gender (p=0.018), time of admission (p= 0.037), and triage vitals including hypothermia (p=0.020), hypoxia (p= 0.004), hypotension (p= 0.031), and tachypnea (p= 0.031) were significantly associated with mortality. Discussion: Although initial triage category was a poor predictor, triage vital signs, gender, and time of admission were significantly associated with mortality in patients with APP.

Paediatric injuries are among the leading causes of morbidity and mortality globally, especially in low- and middle-income countries. We aimed to characterize paediatric injuries as predictors of disposition from Mbarara Regional Referral Hospital Emergency Department (ED) Southwestern Uganda. This was a prospective cohort study done from 12th December 2022 to 31st March 2023. We described the characteristics of injuries sustained by children and evaluated the predictors of 24-hour disposition from the ED using logistic regression. Of the 160 children followed up, 64.4% were male with a median age of 7 years, brought in with road traffic accidents (RTAs) (40.6%) and falls (35.6%) as the commonest mechanism of injury. Over half of the patients were triaged as yellow (urgent); polytrauma and head injuries were the top injury patterns. The majority (45.6%) of the children were admitted to the inpatient surgical ward. Only 1.9% and 5.0% ended up in intensive care unit (ICU) and died (to mortuary), respectively. The median time to disposition was 8 h and 14% stayed in the ED beyond 24-hours. Patients who needed more intensive initial treatment, including additional medications or interventions, were significantly more likely to be admitted to the ward (AOR= 5.3, 95%CI: 2.0-13.0, p <0.01). Paediatric injuries were caused mainly by RTAs and presenting with polytrauma and head injuries. Most patients were disposed of to the inpatient surgical ward within 24 h with severe KTS and initial management being strongest predictors of admission. These findings can be used to tailor quick risk stratification and decision-making tools and improve ED disposition of paediatric injuries in Low- and Middle- income countries. [ABSTRACT FROM AUTHOR]

BackgroundFor a full treatment course of severe malaria, community-administered pre-referral rectal artesunate (RAS) should be completed by post-referral treatment consisting of an injectable antimalarial and oral artemisinin-based combination therapy (ACT). This study aimed to assess compliance with this treatment recommendation in children under 5 years.Methods and findingsThis observational study accompanied the implementation of RAS in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Antimalarial treatment was assessed during admission in included referral health facilities (RHFs) in children under 5 with a diagnosis of severe malaria. Children were either referred from a community-based provider or directly attending the RHF. RHF data of 7,983 children was analysed for appropriateness of antimalarials; a subsample of 3,449 children was assessed additionally for dosage and method of ACT provision (treatment compliance). A parenteral antimalarial and an ACT were administered to 2.7% (28/1,051) of admitted children in Nigeria, 44.5% (1,211/2,724) in Uganda, and 50.3% (2,117/4,208) in DRC. Children receiving RAS from a community-based provider were more likely to be administered post-referral medication according to the guidelines in DRC (adjusted odds ratio (aOR) = 2.13, 95% CI 1.55 to 2.92, P < 0.001), but less likely in Uganda (aOR = 0.37, 95% CI 0.14 to 0.96, P = 0.04) adjusting for patient, provider, caregiver, and other contextual factors. While in DRC, inpatient ACT administration was common, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349). Study limitations include the unfeasibility to independently confirm the diagnosis of severe malaria due to the observational nature of the study.ConclusionsDirectly observed treatment was often incomplete, bearing a high risk for partial parasite clearance and disease recrudescence. Parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favour the selection of resistant parasites. In connection with the finding that pre-referral RAS had no beneficial effect on child survival in the 3 study countries, concerns about an effective continuum of care for children with severe malaria seem justified. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality.Trial registrationClinicalTrials.gov (NCT03568344).

Community health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria. An observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers. Of 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention.

• Our work presents an initiative for promoting emergency medicine among medical students in Africa. • It provides evidence of the impact of having an EM specialty interest group for medical students. • Our findings demonstrate the role of medical students in the development of EM. Emergency medicine (EM) is a new specialty in Uganda. There is no current formal EM undergraduate curriculum. The Mbarara University of Science and Technology Emergency Medicine Interest Group (MUST-EMIG) was established to bridge this gap. This survey was done to assess the contributions of MUST-EMIG. Objectives of the study were to: discover students' reasons for joining the MUST-EMIG; assess whether interest in learning emergency medicine was affected by participation in MUST-EMIG; evaluate plans to pursue emergency medicine as a specialty before and after joining MUST-EMIG; determine whether MUST-EMIG affected students' perception of emergency medicine's importance in Uganda's health care system; and elicit feedback from students on their experience as members of MUST-EMIG. The MUST-EMIG executive developed a membership survey which was reviewed by MUST-EMIG's faculty advisor for suitability. Members of MUST-EMIG were voluntarily asked to participate in the online survey. Results of the survey were summarized using descriptive statistics and thematic analysis. 49 responses (46.7% response rate) were collected and analyzed. Participants included 29 (59.2%) male and 20 (40.8%) female medical students. The majority of participants were fourth year students 22 (44.9%). 44 (89.8%) students joined MUST-EMIG to learn how to handle medical emergencies, and expressed a desire of at least 6/10 to learn more about emergency medicine after utilizing opportunities provided by MUST-EMIG. Overall, students had a good experience with MUST-EMIG. They reported that our interest group had provided them networking, unique learning, and leadership opportunities. Having an EMIG significantly affects students' desire to pursue a career in emergency medicine and their perception of the relevance of emergency medicine. An EMIG helps develop interest of medical students in emergency medicine. Students passionate about emergency medicine need to be supported to help them preserve and further develop this passion. [ABSTRACT FROM AUTHOR]

Hypoxia is a common presentation in the Emergency Department (ED) worldwide. It affects 9-12% of hospitalized adults in Sub-Saharan Africa. Timely diagnosis of the multiple causes such as pneumonia, heart failure among others is challenging. Chest X-Ray (CXR), one of the most utilized imaging modalities has many limitations, and the gold standard (Computed Tomography scan) is inaccessible. Point of care ultrasound (PoCUS) is more available and increasingly being used, however little is known of its performance in resource limited EDs. The study aimed to assess the diagnostic performance of PoCUS compared with CXR in identifying the causes of hypoxia in the medical ED. 49 adults presenting with hypoxia (SP02 ≤ 88%) in the medical ED were evaluated. Ultrasound of the lungs and heart (PoCUS) was done, then CXR obtained. Lung ultrasound (LUS) was compared with CXR (first reference standard). Chest X-Ray and PoCUS were each compared to the physician diagnosis (second reference standard) to determine agreement using an acceptable disagreement cut-off of 15%. 31% more abnormalities were identified by LUS than CXR. Lung ultrasound findings agreed with CXR in 86% of the participants with moderate reliability (ĸ=0.75). There was no significant difference between the actual findings of the two tests (X2= 2, p 0.1). Using the second reference, 82% of the CXRs were similar with weak reliability (ĸ=0.5) compared to 98% of PoCUS findings with strong reliability (ĸ=0.9). Compared to PoCUS, CXRs significantly differed from the physician diagnosis (X2= 0.85, p 0.38 vs X2= 8.5, p 0.004 respectively). Overall, PoCUS was not inferior to CXR when compared to final physician diagnosis in identifying causes of hypoxia, and LUS and CXR had comparable performance. Significantly more abnormalities were identified on PoCUS and it demonstrated better agreement and strong reliability with the physician diagnosis than CXR. We recommend PoCUS use in patients with hypoxia attending resource limited in- and pre-hospital settings. [ABSTRACT FROM AUTHOR]

• Acute pesticide poisoning disproportionately affects LMICs. • The scarcity of poison information centres in Africa leads to under-reporting of the problem. • Most African countries, like Uganda, are resource limited and would benefit from a quick and easy mode of prognostication. Although the global suicide deaths due to intentional pesticide poisoning disproportionately occur in low income countries (LIC) and lower to middle income Countries (LMIC), there is a scarcity of reports on emergency centre (EC) mortality and its predictors in these settings. Our goal was to determine the case fatality rate of Acute Pesticide Poisoning (APP) presenting to Mbarara Regional Referral Hospital (MRRH) EC and find out whether initial triage category predicted mortality in these patients. This was a prospective observational longitudinal study. Patients presenting with APP were enrolled using data collection forms. Data collected included initial triage category, vital signs, demographics, initial assessment, and management. They were followed up for 1 week. Out of 66 patients admitted with suspected pesticide poisoning, 61 had complete follow up during the study period. However, only 58 patients had the pesticide ingested confirmed. These were predominantly males 48 (73%) and farmers 28(42%) with a median age of 23 years (IQR 18-31). Majority of patients 58 (88%) were suicide attempts and had ingested mostly organophosphates 23 (35%), amitraz 11(17%), zinc phosphide 7(10%), and aluminium phosphide 4(6%). The median time from ingestion to presentation was 4hours (IQR 2.5-8). More than half 41(62%) of the patients were in the red triage category (ESI-1). The overall case fatality rate of APP was 18%. Majority of patients who died were in the red triage category but the initial triage category was not significantly associated with mortality (p=0.381). Male gender (p=0.018), time of admission (p= 0.037), and triage vitals including hypothermia (p=0.020), hypoxia (p= 0.004), hypotension (p= 0.031), and tachypnea (p= 0.031) were significantly associated with mortality. Although initial triage category was a poor predictor, triage vital signs, gender, and time of admission were significantly associated with mortality in patients with APP. [ABSTRACT FROM AUTHOR]

Artemisinin-based combination therapies (ACTs) were introduced as the standard of care for uncomplicated malaria in Africa almost two decades ago. Recent studies in East Africa have reported a gradual increase in kelch13 ( k13 ) mutant parasites associated with reduced artesunate efficacy. As part of the Community Access to Rectal Artesunate for Malaria project, we collected blood samples from 697 children with signs of severe malaria in northern Uganda between 2018 and 2020, before and after the introduction of rectal artesunate (RAS) in 2019. K13 polymorphisms were assessed, and parasite editing and phenotyping were performed to assess the impact of mutations on parasite resistance. Whole-genome sequencing was performed, and haplotype networks were constructed to determine the geographic origin of k13 mutations. Of the 697 children, 540 were positive for Plasmodium falciparum malaria by PCR and were treated with either RAS or injectable artesunate monotherapy followed in most cases by ACT. The most common k13 mutation was C469Y (6.7%), which was detected more frequently in samples collected after RAS introduction. Genome editing confirmed reduced in vitro susceptibility to artemisinin in C469Y-harboring parasites compared to wild-type controls ( P < 0.001). The haplotypic network showed that flanking regions of the C469Y mutation shared the same African genetic background, suggesting a single and indigenous origin of the mutation. Our data provide evidence of selection for the artemisinin-resistant C469Y mutation. The realistic threat of multiresistant parasites emerging in Africa should encourage careful monitoring of the efficacy of artemisinin derivatives and strict adherence to ACT treatment regimens., Competing Interests: The authors declare no conflict of interest.

Community health workers (CHW) usually refer children with suspected severe malaria to the nearest public health facility or a designated public referral health facility (RHF). Caregivers do not always follow this recommendation. This study aimed at identifying post-referral treatment-seeking pathways that lead to appropriate antimalarial treatment for children less than five years with suspected severe malaria. An observational study in Uganda enrolled children below five years presenting to CHWs with signs of severe malaria. Children were followed up 28 days after enrolment to assess their condition and treatment-seeking history, including referral advice and provision of antimalarial treatment from visited providers. Of 2211 children included in the analysis, 96% visited a second provider after attending a CHW. The majority of CHWs recommended caregivers to take their child to a designated RHF (65%); however, only 59% followed this recommendation. Many children were brought to a private clinic (33%), even though CHWs rarely recommended this type of provider (3%). Children who were brought to a private clinic were more likely to receive an injection than children brought to a RHF (78% vs 51%, p<0.001) and more likely to receive the second or third-line injectable antimalarial (artemether: 22% vs. 2%, p<0.001, quinine: 12% vs. 3%, p<0.001). Children who only went to non-RHF providers were less likely to receive an artemisinin-based combination therapy (ACT) than children who attended a RHF (odds ratio [OR] = 0.64, 95% CI 0.51-0.79, p<0.001). Children who did not go to any provider after seeing a CHW were the least likely to receive an ACT (OR = 0.21, 95% CI 0.14-0.34, p<0.001). Health policies should recognise local treatment-seeking practices and ensure adequate quality of care at the various public and private sector providers where caregivers of children with suspected severe malaria actually seek care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Brunner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: For a full treatment course of severe malaria, community-administered pre-referral rectal artesunate (RAS) should be completed by post-referral treatment consisting of an injectable antimalarial and oral artemisinin-based combination therapy (ACT). This study aimed to assess compliance with this treatment recommendation in children under 5 years., Methods and Findings: This observational study accompanied the implementation of RAS in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Antimalarial treatment was assessed during admission in included referral health facilities (RHFs) in children under 5 with a diagnosis of severe malaria. Children were either referred from a community-based provider or directly attending the RHF. RHF data of 7,983 children was analysed for appropriateness of antimalarials; a subsample of 3,449 children was assessed additionally for dosage and method of ACT provision (treatment compliance). A parenteral antimalarial and an ACT were administered to 2.7% (28/1,051) of admitted children in Nigeria, 44.5% (1,211/2,724) in Uganda, and 50.3% (2,117/4,208) in DRC. Children receiving RAS from a community-based provider were more likely to be administered post-referral medication according to the guidelines in DRC (adjusted odds ratio (aOR) = 2.13, 95% CI 1.55 to 2.92, P < 0.001), but less likely in Uganda (aOR = 0.37, 95% CI 0.14 to 0.96, P = 0.04) adjusting for patient, provider, caregiver, and other contextual factors. While in DRC, inpatient ACT administration was common, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349). Study limitations include the unfeasibility to independently confirm the diagnosis of severe malaria due to the observational nature of the study., Conclusions: Directly observed treatment was often incomplete, bearing a high risk for partial parasite clearance and disease recrudescence. Parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favour the selection of resistant parasites. In connection with the finding that pre-referral RAS had no beneficial effect on child survival in the 3 study countries, concerns about an effective continuum of care for children with severe malaria seem justified. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality., Trial Registration: ClinicalTrials.gov (NCT03568344)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Signorell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention., Competing Interests: Authors EO, BA, KA, CO, and OY are employees of Akena Associates. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the authors have any competing interests in the topic presented in this manuscript., (Copyright: © 2022 Lengeler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited., Methods: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways., Results: Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79)., Conclusions: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral., Trial Registrstion Number: NCT03568344; ClinicalTrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)