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Suppressing infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will probably require the rapid identification and isolation of individuals infected with the virus on an ongoing basis. Reverse-transcription polymerase chain reaction (RT-PCR) tests are accurate but costly, which makes the regular testing of every individual expensive. These costs are a challenge for all countries around the world, but particularly for low-to-middle-income countries. Cost reductions can be achieved by pooling (or combining) subsamples and testing them in groups1-7. A balance must be struck between increasing the group size and retaining test sensitivity, as sample dilution increases the likelihood of false-negative test results for individuals with a low viral load in the sampled region at the time of the test8. Similarly, minimizing the number of tests to reduce costs must be balanced against minimizing the time that testing takes, to reduce the spread of the infection. Here we propose an algorithm for pooling subsamples based on the geometry of a hypercube that, at low prevalence, accurately identifies individuals infected with SARS-CoV-2 in a small number of tests and few rounds of testing. We discuss the optimal group size and explain why, given the highly infectious nature of the disease, largely parallel searches are preferred. We report proof-of-concept experiments in which a positive subsample was detected even when diluted 100-fold with negative subsamples (compared with 30-48-fold dilutions described in previous studies9-11). We quantify the loss of sensitivity due to dilution and discuss how it may be mitigated by the frequent re-testing of groups, for example. With the use of these methods, the cost of mass testing could be reduced by a large factor. At low prevalence, the costs decrease in rough proportion to the prevalence. Field trials of our approach are under way in Rwanda and South Africa. The use of group testing on a massive scale to monitor infection rates closely and continually in a population, along with the rapid and effective isolation of people with SARS-CoV-2 infections, provides a promising pathway towards the long-term control of coronavirus disease 2019 (COVID-19).
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Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/epidemiologia , COVID-19/virologia , Vigilância da População/métodos , SARS-CoV-2/isolamento & purificação , Algoritmos , COVID-19/diagnóstico , Humanos , Prevalência , Ruanda/epidemiologia , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Emerging artemisinin partial resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (k13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. k13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015, but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, an assessment was conducted to evaluate recent k13-561H prevalence changes, as well as other key mutations. Prevalence of hrp2/3 deletions was also assessed. METHODS: Samples collected in Rukara in 2021 were genotyped for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. RESULTS: Clinically validated k13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of k13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other anti-malarials were variable, with high levels of multidrug resistance 1 (mdr1) N86 (95.5%) associated with lumefantrine decreased susceptibility and dihydrofolate reductase (dhfr) 164L (24.7%) associated with a high level of antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (crt) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. CONCLUSIONS: Increasing prevalence of artemisinin partial resistance due to k13-561H and the rapid expansion of k13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative RDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin partial resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.
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Antimaláricos , Artemisininas , Resistência a Medicamentos , Malária Falciparum , Mutação , Plasmodium falciparum , Proteínas de Protozoários , Plasmodium falciparum/genética , Plasmodium falciparum/efeitos dos fármacos , Artemisininas/farmacologia , Antimaláricos/farmacologia , Proteínas de Protozoários/genética , Resistência a Medicamentos/genética , Ruanda , Malária Falciparum/parasitologia , Malária Falciparum/epidemiologia , Humanos , Antígenos de Protozoários/genética , Prevalência , Criança , Adulto Jovem , Adolescente , Adulto , Pré-EscolarRESUMO
BACKGROUND: From 2019 to 2021, Rwandan residents of the border with the Democratic Republic of the Congo were offered the Ad26.ZEBOV (adenovirus type 26 vector vaccine encoding Ebola virus glycoprotein) and MVA-BN-Filo (modified vaccinia virus Ankara vector vaccine, encoding glycoproteins from Ebola, Sudan, Marburg, and nucleoprotein from Tai Forest viruses) Ebola vaccine regimen. METHODS: Nonpregnant persons aged ≥2 years were eligible. Unsolicited adverse events (UAEs) were reported through phone calls or visits, and serious adverse events (SAEs) were recorded per International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. RESULTS: Following Ad26.ZEBOV, UAEs were reported by 0.68% of 216 113 vaccinees and were more common in younger children (aged 2-8 years, 1.2%) compared with older children (aged 9-17 years, 0.4%) and adults (aged ≥18 years, 0.7%). Fever and headache were the most reported symptoms. All 17 SAEs related to vaccine were in children aged 2-8 years (10 postvaccination febrile convulsions ± gastroenteritis and 7 fever and/or gastroenteritis). The incidence of febrile seizures was 8 of 26 062 (0.031%) prior to initiation of routine acetaminophen in December 2020 and 2 of 15 897 (0.013%) thereafter. Nonobstetric SAEs were similar in males and females. All 20 deaths were unrelated to vaccination. Young girls and adult women with UAEs were less likely to receive the second dose than those without UAEs. Seven unrelated SAEs occurred in 203 267 MVA-BN-Filo recipients. CONCLUSIONS: Postvaccination febrile convulsions in young children were rare but not previously described after Ad26.ZEBOV and were reduced with routine acetaminophen. The regimen was otherwise safe and well-tolerated.
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Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Convulsões Febris , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Acetaminofen , Anticorpos Antivirais , Vacinas contra Ebola/efeitos adversos , Glicoproteínas , Doença pelo Vírus Ebola/prevenção & controle , Convulsões Febris/induzido quimicamente , Vacinação/efeitos adversos , Vaccinia virusRESUMO
BACKGROUND: In low- and middle-income countries (LMIC) Staphylococcus aureus is regarded as one of the leading bacterial causes of neonatal sepsis, however there is limited knowledge on the species diversity and antimicrobial resistance caused by Gram-positive bacteria (GPB). METHODS: We characterised GPB isolates from neonatal blood cultures from LMICs in Africa (Ethiopia, Nigeria, Rwanda, and South Africa) and South-Asia (Bangladesh and Pakistan) between 2015-2017. We determined minimum inhibitory concentrations and performed whole genome sequencing (WGS) on Staphylococci isolates recovered and clinical data collected related to the onset of sepsis and the outcome of the neonate up to 60 days of age. RESULTS: From the isolates recovered from blood cultures, Staphylococci species were most frequently identified. Out of 100 S. aureus isolates sequenced, 18 different sequence types (ST) were found which unveiled two small epidemiological clusters caused by methicillin resistant S. aureus (MRSA) in Pakistan (ST8) and South Africa (ST5), both with high mortality (n = 6/17). One-third of S. aureus was MRSA, with methicillin resistance also detected in Staphylococcus epidermidis, Staphylococcus haemolyticus and Mammaliicoccus sciuri. Through additional WGS analysis we report a cluster of M. sciuri in Pakistan identified between July-November 2017. CONCLUSIONS: In total we identified 14 different GPB bacterial species, however Staphylococci was dominant. These findings highlight the need of a prospective genomic epidemiology study to comprehensively assess the true burden of GPB neonatal sepsis focusing specifically on mechanisms of resistance and virulence across species and in relation to neonatal outcome.
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Staphylococcus aureus Resistente à Meticilina , Sepse Neonatal , Hemocultura , Países em Desenvolvimento , Etiópia , Humanos , Recém-Nascido , Sepse Neonatal/epidemiologia , Estudos Prospectivos , Staphylococcus aureus/genéticaRESUMO
BACKGROUND: Recent gains in reducing the global burden of malaria are threatened by the emergence of Plasmodium falciparum resistance to artemisinins. The discovery that mutations in portions of a P. falciparum gene encoding kelch (K13)-propeller domains are the major determinant of resistance has provided opportunities for monitoring such resistance on a global scale. METHODS: We analyzed the K13-propeller sequence polymorphism in 14,037 samples collected in 59 countries in which malaria is endemic. Most of the samples (84.5%) were obtained from patients who were treated at sentinel sites used for nationwide surveillance of antimalarial resistance. We evaluated the emergence and dissemination of mutations by haplotyping neighboring loci. RESULTS: We identified 108 nonsynonymous K13 mutations, which showed marked geographic disparity in their frequency and distribution. In Asia, 36.5% of the K13 mutations were distributed within two areas--one in Cambodia, Vietnam, and Laos and the other in western Thailand, Myanmar, and China--with no overlap. In Africa, we observed a broad array of rare nonsynonymous mutations that were not associated with delayed parasite clearance. The gene-edited Dd2 transgenic line with the A578S mutation, which expresses the most frequently observed African allele, was found to be susceptible to artemisinin in vitro on a ring-stage survival assay. CONCLUSIONS: No evidence of artemisinin resistance was found outside Southeast Asia and China, where resistance-associated K13 mutations were confined. The common African A578S allele was not associated with clinical or in vitro resistance to artemisinin, and many African mutations appear to be neutral. (Funded by Institut Pasteur Paris and others.).
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Artemisininas/farmacologia , Resistência a Medicamentos/genética , Lactonas/farmacologia , Mutação , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas de Protozoários/genética , Algoritmos , Artemisininas/uso terapêutico , Sudeste Asiático , China , Doenças Endêmicas , Genótipo , Humanos , Lactonas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Análise de Sequência de DNARESUMO
OBJECTIVE: To determine prevalent MDR-TB genotypes and describe treatment outcome and bacteriology conversion in MDR-TB patients. METHODS: Review of laboratory records of 173 MDR-TB patients from all over Rwanda who initiated treatment under programmatic management of MDR-TB (PMDT) between 2014 and 2015. Fifty available archived isolates were genotyped by mycobacterial interspersed repetitive units - variable number of tandem repeats (MIRU-VNTR) genotyping. RESULT: Of the 170 patients whose outcome was known, 114 (66.3%) were cured and 36 (21%) completed the treatment, giving a successful outcome (cured and completed) of 150 (87.3%) patients. Of 20 MDR-TB patients with unfavourable treatment outcome, 18 died, one failed and one defaulted/stopped treatment. Of the 18 patients who died, 11 (61%) were HIV-coinfected. The treatment outcome was successful for 93.9% among HIV negative and 81.8% among HIV-coinfected patients (P = 0.02). Sputum smear conversion occurred in 3, 46, 57 and 78 patients before 2, 3, 4 and 6 months, respectively, with median time of sputum smear and culture conversion at 3 months. The 44 MDR-TB isolates with MIRU-VNTR result, showed high genetic diversity with low clustering rate (9.09%) and Uganda II being the most prevalent sub-family lineage detected in 68.2% of isolates. Beijing family was the least common genotype detected (2.3%, 1 isolate). CONCLUSION: The high success rates for MDR-TB treatment achieved in Rwanda were comparable to outcomes observed in resource-rich settings with HIV being an independent risk factor for poor treatment outcome. High genetic diversity and low clustering rate reported here suggest that reactivation of previous disease plays an important role in the transmission of MDR-TB in Rwanda.
OBJECTIF: Déterminer les génotypes prévalents de la TB-MDR et décrire les résultats du traitement et la conversion bactériologique chez les patients atteints de TB-MDR. MÉTHODES: Analyse des dossiers de laboratoire de 173 patients atteints de TB-MDR de l'ensemble du Rwanda qui ont débuté un traitement sous prise en charge programmatique de la TB-MDR (PMDT) entre 2014 et 2015. Cinquante isolats archivés disponibles ont été génotypés pour les unités répétitives intercalées de mycobactéries - nombre variable de tandems répétés (MIRU-VNTR). RÉSULTAT: Sur les 170 patients dont l'issue était connue, 114 (66,3%) étaient guéris et 36 (21%) avaient terminé le traitement, ce qui donne un résultat positif (guéri et complété) de 150 patients (87,3%). Sur 20 patients atteints de TB-MDR dont l'issue du traitement était défavorable, 18 sont décédés, un a eu un échec et le dernier a abandonné/arrêté le traitement. Sur les 18 patients décédés, 11 (61%) étaient coinfectés par le VIH. Le résultat du traitement a été positif pour 93,9% des personnes VIH négatives et 81,8% pour ceux coinfectées par le VIH (p = 0,02). La conversion des frottis d'expectoration est survenue chez 3, 46, 57 et 78 patients respectivement à 2, 3, 4 et 6 mois, avec une durée médiane entre le frottis d'expectoration et la conversion de culture de 3 mois. Les 44 isolats de TB-MDR avec un résultat MIRU-VNTR ont montré une diversité génétique élevée avec un faible taux de regroupement (9,09%) et la sous-famille de la lignée Ouganda II étant la plus prévalente détectée dans 68,2% des isolats. La famille Beijing était le génotype le moins fréquemment détecté (2,3%, 1 isolat). CONCLUSION: Les taux de succès élevés du traitement de la TB-MDR obtenus au Rwanda étaient comparables aux résultats observés dans les régions riches en ressources, le VIH étant un facteur de risque indépendant d'un mauvais résultat du traitement. La diversité génétique élevée et le faible taux de regroupement rapportés ici suggèrent que la réactivation d'une maladie antérieure joue un rôle important dans la transmission de la TB-MDR au Rwanda.
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Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Idoso , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/genética , Reação em Cadeia da Polimerase , Ruanda , Escarro , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/genética , Adulto JovemRESUMO
BACKGROUND AND AIMS: A common polymorphism in the tumor suppressor gene p53 at codon 72 has been suggested to play a role in the development of a number of cancers. This polymorphism has been studied in many populations worldwide, with conflicting results. The present study was planned to assess the association of p53 codon 72 polymorphism with breast cancer development in a Rwandese population. METHODS: In this study, the polymorphism was examined by allele-specific PCR analysis in 40 patients with breast cancer and 39 healthy controls. RESULTS: The heterozygous genotype Pro/Arg prevailed in both breast cancer patients and controls, and was present in 80% (32/40) and 92.3% (36/39) of cases, respectively. No statistically significant association was observed between p53 codon 72 polymorphism and breast cancer risk. Distribution of p53 genotypes was also studied according to familial history, tumor grade, and clinical stage, and results clearly showed no statistically significant difference. CONCLUSION: These results suggest that p53 codon 72 polymorphism could not be assessed as a risk factor marker for predisposition to breast cancer in Rwanda. However, further studies using larger sample sizes are needed to provide more conclusive results and to investigate other genetic mutations affecting the activity of p53.
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Neoplasias da Mama/genética , Genes p53/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Alelos , Códon/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Fatores de Risco , Ruanda , Adulto JovemRESUMO
Two decades ago, the genocide against the Tutsis in Rwanda led to the deaths of 1 million people, and the displacement of millions more. Injury and trauma were followed by the effects of a devastated health system and economy. In the years that followed, a new course set by a new government set into motion equity-oriented national policies focusing on social cohesion and people-centred development. Premature mortality rates have fallen precipitously in recent years, and life expectancy has doubled since the mid-1990s. Here we reflect on the lessons learned in rebuilding Rwanda's health sector during the past two decades, as the country now prepares itself to take on new challenges in health-care delivery.
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Atenção à Saúde/organização & administração , Criança , Mortalidade da Criança , Genocídio , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/terapia , Política de Saúde , Humanos , Ruanda/epidemiologia , Tuberculose Pulmonar/mortalidade , GuerraRESUMO
Background: Malaria remains a major cause of morbidity in sub-Saharan Africa. Undetected asymptomatic falciparum malaria results in a large transmission reservoir and there is evidence of increasing non-falciparum malaria as malaria is controlled in Africa, both resulting in challenges for malaria control programs. Methods: We performed quantitative real time PCR for 4 malaria species in 4,596 individuals from the 2014-2015 Rwanda Demographic Health Survey. Bivariate models were used to determine species-specific associations with risk factors. Results: Asymptomatic falciparum malaria, P. ovale spp., and P. malariae infection had broad spatial distribution across Rwanda. P. vivax infection was rare. Overall infection prevalence was 23.6% (95%CI [21.7%, 26.0%]), with falciparum and non-falciparum at 17.6% [15.9%, 19.0%] and 8.3% [7.0%, 10.0%], respectively. Parasitemias tended to be low and mixed species infections were common, especially where malaria transmission was the highest. Falciparum infection was associated with socio-econiomic status, rural residence and low altitude. Few risk factors were associated with non-falciparum malaria. Conclusions: Asymptomatic falciparum malaria and non-falciparum malaria are common and widely distributed across Rwanda. Continued molecular monitoring of Plasmodium spp. is needed to monitor these threats to malaria control in Africa.
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In Africa, the first Plasmodium falciparum Kelch13 (K13) artemisinin partial resistance mutation 561H was first detected and validated in Rwanda. Surveillance to better define the extent of the emergence in Rwanda and neighboring countries as other mutations arise in East Africa is critical. We employ a novel scheme of liquid blood drop preservation combined with pooled sequencing to provide a cost-effective rapid assessment of resistance mutation frequencies at multiple collection sites across Rwanda and neighboring countries. Malaria-positive samples (n=5,465) were collected from 39 health facilities in Rwanda, Uganda, Tanzania, and the Democratic Republic of the Congo (DRC) between May 2022 and March 2023 and sequenced in 199 pools. In Rwanda, K13 561H and 675V were detected in 90% and 65% of sites with an average frequency of 19.0% (0-54.5%) and 5.0% (0-35.5%), respectively. In Tanzania, 561H had high frequency in multiple sites while it was absent from the DRC although 675V was seen at low frequency. Conceringly candidate mutations were observed: 441L, 449A, and 469F co-occurred with validated mutations suggesting they are arising under the same pressures. Other resistance markers associated with artemether-lumefantrine are common: P. falciparum multidrug resistance protein 1 N86 at 98.0% and 184F at 47.0% (0-94.3%) and P. falciparum chloroquine resistance transporter 76T at 14.7% (0-58.6%). Additionally, sulfadoxine-pyrimethamine-associated mutations show high frequencies. Overall, K13 mutations are rapidly expanding in the region further endangering control efforts with the potential of engendering partner drug resistance.
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Hospital surfaces can harbour bacterial pathogens, which may disseminate and cause nosocomial infections, contributing towards mortality in low- and middle-income countries (LMICs). During the BARNARDS study, hospital surfaces from neonatal wards were sampled to assess the degree of environmental surface and patient care equipment colonisation by Gram-negative bacteria (GNB) carrying antibiotic resistance genes (ARGs). Here, we perform PCR screening for extended-spectrum ß-lactamases (blaCTX-M-15) and carbapenemases (blaNDM, blaOXA-48-like and blaKPC), MALDI-TOF MS identification of GNB carrying ARGs, and further analysis by whole genome sequencing of bacterial isolates. We determine presence of consistently dominant clones and their relatedness to strains causing neonatal sepsis. Higher prevalence of carbapenemases is observed in Pakistan, Bangladesh, and Ethiopia, compared to other countries, and are mostly found in surfaces near the sink drain. Klebsiella pneumoniae, Enterobacter hormaechei, Acinetobacter baumannii, Serratia marcescens and Leclercia adecarboxylata are dominant; ST15 K. pneumoniae is identified from the same ward on multiple occasions suggesting clonal persistence within the same environment, and is found to be identical to isolates causing neonatal sepsis in Pakistan over similar time periods. Our data suggests persistence of dominant clones across multiple time points, highlighting the need for assessment of Infection Prevention and Control guidelines.
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Países em Desenvolvimento , Sepse Neonatal , Recém-Nascido , Humanos , beta-Lactamases/genética , Proteínas de Bactérias/genética , Hospitais , Antibacterianos/farmacologia , Klebsiella pneumoniae/genética , Bactérias Gram-Negativas/genética , Testes de Sensibilidade MicrobianaRESUMO
Background: Artemisinin resistance mutations in Plasmodium falciparum kelch13 (Pfk13) have begun to emerge in Africa, with Pfk13-R561H being the first reported in Rwanda in 2014, but limited sampling left questions about its early distribution and origin. Methods: We genotyped P. falciparum positive dried blood spot (DBS) samples from a nationally representative 2014-2015 Rwanda Demographic Health Surveys (DHS) HIV study. DBS were subsampled from DHS sampling clusters with >15% P. falciparum prevalence, as determined by rapid testing or microscopy done during the DHS study (n clusters = 67, n samples = 1873). Results: We detected 476 parasitemias among 1873 residual blood spots from a 2014-2015 Rwanda Demographic Health Survey. We sequenced 351 samples: 341/351 were wild-type (97.03% weighted), and 4 samples (1.34% weighted) harbored R561H that were significantly spatially clustered. Other nonsynonymous mutations found were V555A (3), C532W (1), and G533A (1). Conclusions: Our study better defines the early distribution of R561H in Rwanda. Previous studies only observed the mutation in Masaka as of 2014, but our study indicates its presence in higher-transmission regions in the southeast of the country at that time.
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Background: Emerging artemisinin resistance and diagnostic resistance are a threat to malaria control in Africa. Plasmodium falciparum kelch13 (K13) propeller-domain mutations that confer artemisinin partial resistance have emerged in Africa. K13-561H was initially described at a frequency of 7.4% from Masaka in 2014-2015 but not present in nearby Rukara. By 2018, 19.6% of isolates in Masaka and 22% of isolates in Rukara contained the mutation. Longitudinal monitoring is essential to inform control efforts. In Rukara, we sought to assess recent K13-561H prevalence changes, as well as for other key mutations. Prevalence of hrp2/3 deletions was also assessed. Methods: We genotyped samples collected in Rukara in 2021 for key artemisinin and partner drug resistance mutations using molecular inversion probe assays and for hrp2/3 deletions using qPCR. Results: Clinically validated K13 artemisinin partial resistance mutations continue to increase in prevalence with the overall level of artemisinin resistance mutant infections reaching 32% in Rwanda. The increase appears to be due to the rapid emergence of K13-675V (6.4%, 6/94 infections), previously not observed, rather than continued expansion of 561H (23.5% 20/85). Mutations to partner drugs and other antimalarials were variable, with high levels of multidrug resistance 1 (MDR1) N86 (95.5%) associated with lumefantrine resistance and dihydrofolate reductase (DHFR) 164L (24.7%) associated with antifolate resistance, but low levels of amodiaquine resistance polymorphisms with chloroquine resistance transporter (CRT ) 76T: at 6.1% prevalence. No hrp2 or hrp3 gene deletions associated with diagnostic resistance were found. Conclusions: Increasing prevalence of artemisinin partial resistance due to K13-561H and the rapid expansion of K13-675V is concerning for the longevity of artemisinin effectiveness in the region. False negative mRDT results do not appear to be an issue with no hrp2 or hpr3 deletions detected. Continued molecular surveillance in this region and surrounding areas is needed to follow artemisinin resistance and provide early detection of partner drug resistance, which would likely compromise control and increase malaria morbidity and mortality in East Africa.
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INTRODUCTION: Precision medicine (PM) or personalized medicine is an innovative approach that aims to tailor disease prevention and treatment to consider the differences in people's genes, environments, and lifestyles. Although many efforts have been made to accelerate the universal adoption of PM, several challenges need to be addressed in order to advance PM in Africa. Therefore, our study aimed to establish baseline data on the knowledge and perceptions of the implementation of PM in the Rwandan healthcare setting. METHOD: A descriptive qualitative study was conducted in five hospitals offering diagnostics and oncology services to cancer patients in Rwanda. To understand the existing policies regarding PM implementation in the country, two additional institutions were surveyed: the Ministry of Health (MOH), which creates and sets policies for the overall vision of the health sector, and the Rwanda Biomedical Center (RBC), which coordinates the implementation of health sector policies in the country. The researchers conducted 32 key informant interviews and assessed the functionality of available PM equipment in the 5 selected health facilities. The data were thematically categorized and analyzed. RESULTS: The study revealed that PM is perceived as a complex and expensive program by most health managers and health providers. The most cited challenges to implementing PM included the following: the lack of policies and guidelines; the lack of supportive infrastructures and limited suppliers of required equipment and laboratory consumables; financial constraints; cultural, behavioral, and religious beliefs; and limited trained, motivated, and specialized healthcare providers. Regarding access to health services for cancer treatment, patients with health insurance pay 10% of their medical costs, which is still too expensive for Rwandans. CONCLUSION: The study participants highlighted the importance of PM to enhance healthcare delivery if the identified barriers are addressed. For instance, Rwandan health sector leadership might consider the creation of specialized oncology centers in all or some referral hospitals with all the necessary genomic equipment and trained staff to serve the needs of the country and implement a PM program.
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SUMMARY BACKGROUND: Multidrug-resistant (MDR) tuberculosis (TB) poses an important challenge in TB management and control. Rifampicin resistance (RR) is a solid surrogate marker of MDR-TB. We investigated the RR-TB clustering rates, bacterial population dynamics to infer transmission dynamics, and the impact of changes to patient management on these dynamics over 27 years in Rwanda. METHODS: We analysed whole genome sequences of a longitudinal collection of nationwide RR-TB isolates. The collection covered three important periods: before programmatic management of MDR-TB (PMDT; 1991-2005), the early PMDT phase (2006-2013), in which rifampicin drug-susceptibility testing (DST) was offered to retreatment patients only, and the consolidated phase (2014-2018), in which all bacteriologically confirmed TB patients had rifampicin DST done mostly via Xpert MTB/RIF assay. We constructed clusters based on a 5 SNP cut-off and resistance conferring SNPs. We used Bayesian modelling for dating and population size estimations, TransPhylo to estimate the number of secondary cases infected by each patient, and multivariable logistic regression to assess predictors of being infected by the dominant clone. RESULTS: Of 308 baseline RR-TB isolates considered for transmission analysis, the clustering analysis grouped 259 (84.1%) isolates into 13 clusters. Within these clusters, a single dominant clone was discovered containing 213 isolates (82.2% of clustered and 69.1% of all RR-TB), which we named the "Rwanda Rifampicin-Resistant clone" (R3clone). R3clone isolates belonged to Ugandan sub-lineage 4.6.1.2 and its rifampicin and isoniazid resistance were conferred by the Ser450Leu mutation in rpoB and Ser315Thr in katG genes, respectively. All R3clone isolates had Pro481Thr, a putative compensatory mutation in the rpoC gene that likely restored its fitness. The R3clone was estimated to first arise in 1987 and its population size increased exponentially through the 1990s', reaching maximum size (â¼84%) in early 2000 s', with a declining trend since 2014. Indeed, the highest proportion of R3clone (129/157; 82·2%, 95%CI: 75·3-87·8%) occurred between 2000 and 13, declining to 64·4% (95%CI: 55·1-73·0%) from 2014 onward. We showed that patients with R3clone detected after an unsuccessful category 2 treatment were more likely to generate secondary cases than patients with R3clone detected after an unsuccessful category 1 treatment regimen. CONCLUSIONS: RR-TB in Rwanda is largely transmitted. Xpert MTB/RIF assay as first diagnostic test avoids unnecessary rounds of rifampicin-based TB treatment, thus preventing ongoing transmission of the dominant R3clone. As PMDT was intensified and all TB patients accessed rifampicin-resistance testing, the nationwide R3clone burden declined. To our knowledge, our findings provide the first evidence supporting the impact of universal DST on the transmission of RR-TB.
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BACKGROUND: Neonatal sepsis is a primary cause of neonatal mortality and is an urgent global health concern, especially within low-income and middle-income countries (LMICs), where 99% of global neonatal mortality occurs. The aims of this study were to determine the incidence and associations with neonatal sepsis and all-cause mortality in facility-born neonates in LMICs. METHODS: The Burden of Antibiotic Resistance in Neonates from Developing Societies (BARNARDS) study recruited mothers and their neonates into a prospective observational cohort study across 12 clinical sites from Bangladesh, Ethiopia, India, Pakistan, Nigeria, Rwanda, and South Africa. Data for sepsis-associated factors in the four domains of health care, maternal, birth and neonatal, and living environment were collected for all mothers and neonates enrolled. Primary outcomes were clinically suspected sepsis, laboratory-confirmed sepsis, and all-cause mortality in neonates during the first 60 days of life. Incidence proportion of livebirths for clinically suspected sepsis and laboratory-confirmed sepsis and incidence rate per 1000 neonate-days for all-cause mortality were calculated. Modified Poisson regression was used to investigate factors associated with neonatal sepsis and parametric survival models for factors associated with all-cause mortality. FINDINGS: Between Nov 12, 2015 and Feb 1, 2018, 29â483 mothers and 30â557 neonates were enrolled. The incidence of clinically suspected sepsis was 166·0 (95% CI 97·69-234·24) per 1000 livebirths, laboratory-confirmed sepsis was 46·9 (19·04-74·79) per 1000 livebirths, and all-cause mortality was 0·83 (0·37-2·00) per 1000 neonate-days. Maternal hypertension, previous maternal hospitalisation within 12 months, average or higher monthly household income, ward size (>11 beds), ward type (neonatal), living in a rural environment, preterm birth, perinatal asphyxia, and multiple births were associated with an increased risk of clinically suspected sepsis, laboratory-confirmed sepsis, and all-cause mortality. The majority (881 [72·5%] of 1215) of laboratory-confirmed sepsis cases occurred within the first 3 days of life. INTERPRETATION: Findings from this study highlight the substantial proportion of neonates who develop neonatal sepsis, and the high mortality rates among neonates with sepsis in LMICs. More efficient and effective identification of neonatal sepsis is needed to target interventions to reduce its incidence and subsequent mortality in LMICs. FUNDING: Bill & Melinda Gates Foundation.
Assuntos
Sepse Neonatal , Nascimento Prematuro , Sepse , Países em Desenvolvimento , Feminino , Humanos , Mortalidade Infantil , Recém-Nascido , Sepse Neonatal/epidemiologia , Gravidez , Estudos Prospectivos , Sepse/epidemiologiaRESUMO
Tuberculosis (TB), including multidrug-resistant (MDR; i.e., resistant to at least rifampicin and isoniazid)/rifampicin-resistant (MDR/RR) TB, is the most important opportunistic infection among people living with HIV (PLHIV). In 2005, Rwanda launched the programmatic management of MDR/RR-TB. The shorter MDR/RR-TB treatment regimen (STR) has been implemented since 2014. We analyzed predictors of MDR/RR-TB mortality, including the effect of using the STR overall and among PLHIV. This retrospective study included data from patients diagnosed with RR-TB in Rwanda between July 2005 and December 2018. Multivariable logistic regression was used to assess predictors of mortality. Of 898 registered MDR/RR-TB patients, 861 (95.9%) were included in this analysis, of whom 360 (41.8%) were HIV coinfected. Overall, 86 (10%) patients died during MDR/RR-TB treatment. Mortality was higher among HIV-coinfected compared with HIV-negative TB patients (13.3% versus 7.6%). Among HIV-coinfected patients, patients aged ≥ 55 years (adjusted odds ratio = 5.89) and those with CD4 count ≤ 100 cells/mm3 (adjusted odds ratio = 3.77) had a higher likelihood of dying. Using either the standardized longer MDR/RR-TB treatment regimen or the STR was not correlated with mortality overall or among PLHIV. The STR was as effective as the long MDR/RR-TB regimen. In conclusion, older age and advanced HIV disease were strong predictors of MDR/RR-TB mortality. Therefore, special care for elderly and HIV-coinfected patients with ≤ 100 CD4 cells/mL might further reduce MDR/RR-TB mortality.
Assuntos
Antituberculosos/uso terapêutico , Farmacorresistência Bacteriana , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Rifampina/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Continued outbreaks of Ebola virus disease, including recent outbreaks in the Democratic Republic of the Congo (DRC), highlight the need for effective vaccine programs to combat future outbreaks. Given the population flow between DRC and Rwanda, the Rwanda Ministry of Health initiated a preventive vaccination campaign supported by a vaccination monitoring platform (VMP). The campaign aimed to vaccinate approximately 200,000 people from Rwanda's Rubavu and Rusizi districts with the two-dose vaccine regimen Ad26.ZEBOV, MVA-BN-Filo. The VMP encompassed: biometric identification (iris scanning), mobile messaging, and an interactive reporting dashboard. The VMP collected data used to register and identify participants at subsequent visits. Mobile message reminders supported compliance. To 13 November 2020, the campaign was half complete with Ad26.ZEBOV administered to 116,974 participants and MVA-BN-Filo to 76,464. MVA-BN-Filo should be given to participants approximately 8 weeks after the Ad26.ZEBOV with a compliance window of -14 and +28 days. Of the 83,850 participants who were eligible per this dosing window for the subsequent MVA-BN-Filo vaccine, 91.2% (76,453/83,850) received it and 82.9% (69,505/83,850) received it within the compliance window defined for this campaign. Utilization of the VMP was instrumental to the success of the campaign, using biometric technology, dashboard reporting of near real-time data analysis and mobile phone communication technology to support vaccine administration and monitoring. A comprehensive VMP is feasible in large-scale health-care campaigns, beneficial for public health surveillance, and can allow effective response to an infectious disease outbreak.
Assuntos
Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Programas de Imunização , Ruanda/epidemiologia , VacinaçãoRESUMO
BACKGROUND: Sepsis is a major contributor to neonatal mortality, particularly in low-income and middle-income countries (LMICs). WHO advocates ampicillin-gentamicin as first-line therapy for the management of neonatal sepsis. In the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs, common sepsis pathogens were characterised via whole genome sequencing (WGS) and antimicrobial resistance profiles. In this substudy of BARNARDS, we aimed to assess the use and efficacy of empirical antibiotic therapies commonly used in LMICs for neonatal sepsis. METHODS: In BARNARDS, consenting mother-neonates aged 0-60 days dyads were enrolled on delivery or neonatal presentation with suspected sepsis at 12 BARNARDS clinical sites in Bangladesh, Ethiopia, India, Pakistan, Nigeria, Rwanda, and South Africa. Stillborn babies were excluded from the study. Blood samples were collected from neonates presenting with clinical signs of sepsis, and WGS and minimum inhibitory concentrations for antibiotic treatment were determined for bacterial isolates from culture-confirmed sepsis. Neonatal outcome data were collected following enrolment until 60 days of life. Antibiotic usage and neonatal outcome data were assessed. Survival analyses were adjusted to take into account potential clinical confounding variables related to the birth and pathogen. Additionally, resistance profiles, pharmacokinetic-pharmacodynamic probability of target attainment, and frequency of resistance (ie, resistance defined by in-vitro growth of isolates when challenged by antibiotics) were assessed. Questionnaires on health structures and antibiotic costs evaluated accessibility and affordability. FINDINGS: Between Nov 12, 2015, and Feb 1, 2018, 36 285 neonates were enrolled into the main BARNARDS study, of whom 9874 had clinically diagnosed sepsis and 5749 had available antibiotic data. The four most commonly prescribed antibiotic combinations given to 4451 neonates (77·42%) of 5749 were ampicillin-gentamicin, ceftazidime-amikacin, piperacillin-tazobactam-amikacin, and amoxicillin clavulanate-amikacin. This dataset assessed 476 prescriptions for 442 neonates treated with one of these antibiotic combinations with WGS data (all BARNARDS countries were represented in this subset except India). Multiple pathogens were isolated, totalling 457 isolates. Reported mortality was lower for neonates treated with ceftazidime-amikacin than for neonates treated with ampicillin-gentamicin (hazard ratio [adjusted for clinical variables considered potential confounders to outcomes] 0·32, 95% CI 0·14-0·72; p=0·0060). Of 390 Gram-negative isolates, 379 (97·2%) were resistant to ampicillin and 274 (70·3%) were resistant to gentamicin. Susceptibility of Gram-negative isolates to at least one antibiotic in a treatment combination was noted in 111 (28·5%) to ampicillin-gentamicin; 286 (73·3%) to amoxicillin clavulanate-amikacin; 301 (77·2%) to ceftazidime-amikacin; and 312 (80·0%) to piperacillin-tazobactam-amikacin. A probability of target attainment of 80% or more was noted in 26 neonates (33·7% [SD 0·59]) of 78 with ampicillin-gentamicin; 15 (68·0% [3·84]) of 27 with amoxicillin clavulanate-amikacin; 93 (92·7% [0·24]) of 109 with ceftazidime-amikacin; and 70 (85·3% [0·47]) of 76 with piperacillin-tazobactam-amikacin. However, antibiotic and country effects could not be distinguished. Frequency of resistance was recorded most frequently with fosfomycin (in 78 isolates [68·4%] of 114), followed by colistin (55 isolates [57·3%] of 96), and gentamicin (62 isolates [53·0%] of 117). Sites in six of the seven countries (excluding South Africa) stated that the cost of antibiotics would influence treatment of neonatal sepsis. INTERPRETATION: Our data raise questions about the empirical use of combined ampicillin-gentamicin for neonatal sepsis in LMICs because of its high resistance and high rates of frequency of resistance and low probability of target attainment. Accessibility and affordability need to be considered when advocating antibiotic treatments with variance in economic health structures across LMICs. FUNDING: The Bill & Melinda Gates Foundation.