Health seeking behavior after the 2013-16 Ebola epidemic: Lassa fever as a metric of persistent changes in Kenema District, Sierra Leone.

BACKGROUND: The West African Ebola epidemic of 2013-2016 killed nearly 4,000 Sierra Leoneans and devastated health infrastructure across West Africa. Changes in health seeking behavior (HSB) during the outbreak resulted in dramatic underreporting and substantial declines in hospital presentations to public health facilities, resulting in an estimated tens of thousands of additional maternal, infant, and adult deaths per year. Sierra Leone's Kenema District, a major Ebola hotspot, is also endemic for Lassa fever (LF), another often-fatal hemorrhagic disease. Here we assess the impact of the West African Ebola epidemic on health seeking behaviors with respect to presentations to the Kenema Government Hospital (KGH) Lassa Ward, which serves as the primary health care referral center for suspected Lassa fever cases in the Eastern Province of Sierra Leone. METHODOLOGY/PRINCIPAL FINDINGS: Presentation frequencies for suspected Lassa fever presenting to KGH or one of its referral centers from 2011-2019 were analyzed to consider the potential impact of the West African Ebola epidemic on presentation patterns. There was a significant decline in suspected LF cases presenting to KGH following the epidemic, and a lower percentage of subjects were admitted to the KGH Lassa Ward following the epidemic. To assess general HSB, a questionnaire was developed and administered to 200 residents from 8 villages in Kenema District. Among 194 completed interviews, 151 (78%) of respondents stated they felt hospitals were safer post-epidemic with no significant differences noted among subjects according to religious background, age, gender, or education. However, 37 (19%) subjects reported decreased attendance at hospitals since the epidemic, which suggests that trust in the healthcare system has not fully rebounded. Cost was identified as a major deterrent to seeking healthcare. CONCLUSIONS/SIGNIFICANCE: Analysis of patient demographic data suggests that fewer individuals sought care for Lassa fever and other febrile illnesses in Kenema District after the West African Ebola epidemic. Re-establishing trust in health care services will require efforts beyond rebuilding infrastructure and require concerted efforts to rebuild the trust of local residents who may be wary of seeking healthcare post epidemic.

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study.

BACKGROUND: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria. METHODS: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30. FINDINGS: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50). INTERPRETATION: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint. FUNDING: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.

Early onset of neurological features differentiates two outbreaks of Lassa fever in Ebonyi state, Nigeria during 2017-2018.

Lassa fever (LF) is an acute viral haemorrhagic illness with various non-specific clinical manifestations. Neurological symptoms are rare at the early stage of the disease, but may be seen in late stages, in severely ill patients.The aim of this study was to describe the epidemiological evolution, socio-demographic profiles, clinical characteristics, and outcomes of patients seen during two Lassa fever outbreaks in Ebonyi State, between December 2017 and December 2018. Routinely collected clinical data from all patients admitted to the Virology Centre of the hospital during the period were analysed retrospectively. Out of a total of 83 cases, 70(84.3%) were RT-PCR confirmed while 13 (15.7%) were probable cases. Sixty-nine (83.1%) patients were seen in outbreak 1 of whom 53.6% were urban residents, while 19%, 15%, and 10% were farmers, students and health workers respectively. There were 14 (16.8%) patients, seen in second outbreak with 92.9% rural residents. There were differences in clinical symptoms, signs and laboratory findings between the two outbreaks. The case fatality rates were 29.9% in outbreak 1 and 85.7% for outbreak 2. Neurological features and abnormal laboratory test results were associated with higher mortality rate, seen in outbreak 2. This study revealed significant differences between the two outbreaks. Of particular concern was the higher case fatality during the outbreak 2 which may be from a more virulent strain of the Lassa virus. This has important public health implications and further molecular studies are needed to better define its characteristics.

Infection pattern, case fatality rate and spread of Lassa virus in Nigeria.

BACKGROUND: Lassa fever (LF) is a zoonotic infectious disease of public concern in Nigeria. The infection dynamics of the disease is not well elucidated in Nigeria. This study was carried out to describe the pattern of infection, case fatality rate and spread of lassa virus (LASV) from 2017 to 2020. METHODS: Weekly epidemiological data on LF from December, 2016 to September, 2020 were obtained from Nigeria Centre for Disease Control. The number of confirmed cases and deaths were computed according to months and states. Descriptive statistics was performed and case fatality rate was calculated. Distribution and spread maps of LF over the four years period was performed on ArcMap 10.7. RESULTS: A total of 2787 confirmed cases and 516 deaths were reported in Nigeria from December, 2016 to September, 2020. Increase in number of cases and deaths were observed with 298, 528, 796 and 1165 confirmed cases and 79, 125, 158 and 158 deaths in 2017, 2018, 2019 and 2020 respectively. Over 60% of the cases were reported in two states, Edo and Ondo states. The LF cases spread from 19 states in 2017 to 32 states and Federal Capital Territory (FCT) in 2020. Ondo state (25.39%) had the highest of deaths rate from LF over the four years. Case fatality rate (CFR) of LF was highest in 2017 (26.5%) with CFR of 23.7, 19.6 and 13.4% in 2018, 2019 and 2020 respectively. The peak of infection was in the month of February for the four years. Infections increases at the onset of dry season in November and decline till April when the wet season sets-in. CONCLUSION: There is an annual increase in the number of LASV infection across the states in Nigeria. There is need to heighten control strategies through the use of integrated approach, ranging from vector control, health education and early diagnosis.

Factors associated with progression to death in patients with Lassa fever in Nigeria: an observational study.

BACKGROUND: Lassa fever is endemic in several west African countries. Case-fatality rates ranging from 21% to 69% have been reported. The pathophysiology of the disease in humans and determinants of mortality remain poorly understood. We aimed to determine host protein biomarkers capable of determining disease outcome. METHODS: In this observational study, we analysed left-over blood samples from patients who tested positive for Lassa fever at Irrua Specialist Teaching Hospital, Nigeria, between January, 2014, and April, 2017. We measured viral load, concentrations of clinical chemistry parameters, and levels of 62 circulating proteins involved in inflammation, immune response, and haemostasis. Patients with a known outcome (survival or death) and at least 200 µL of good-quality diagnostic sample were included in logistic regression modelling to assess the correlation of parameters with Lassa fever outcome. Individuals who gave consent could further be enrolled into a longitudinal analysis to assess the association of parameters with Lassa fever outcome over time. Participants were divided into two datasets for the statistical analysis: a primary dataset (samples taken between Jan 1, 2014, and April 1, 2016), and a secondary dataset (samples taken between April 1, 2016, and April 1, 2017). Biomarkers were ranked by area under the receiver operating characteristic curve (AUC) from highest (most predictive) to lowest (least predictive). FINDINGS: Of 554 patients who tested positive for Lassa fever during the study period, 201 (131 in the primary dataset and 70 in the secondary dataset) were included in the biomarker analysis, of whom 74 (49 in the primary dataset and 25 in the secondary dataset) had died and 127 (82 in the primary dataset and 45 in the secondary dataset) had survived. Cycle threshold values (indicating viral load) and levels of 18 host proteins at the time of admission to hospital were significantly correlated with fatal outcome. The best predictors of outcome in both datasets were plasminogen activator inhibitor-1 (PAI-1; AUC 0·878 in the primary dataset and 0·876 in the secondary dataset), soluble thrombomodulin (TM; 0·839 in the primary dataset and 0·875 in the secondary dataset), and soluble tumour necrosis factor receptor superfamily member 1A (TNF-R1; 0·807 in the primary dataset and 0·851 in the secondary dataset), all of which had higher prediction accuracy than viral load (0·774 in the primary dataset and 0·837 in the secondary dataset). Longitudinal analysis (150 patients, of whom 36 died) showed that of the biomarkers that were predictive at admission, PAI-1 levels consistently decreased to normal levels in survivors but not in those who died. INTERPRETATION: The identification of PAI-1 and soluble TM as markers of fatal Lassa fever at admission, and of PAI-1 as a marker of fatal Lassa fever over time, suggests that dysregulated coagulation and fibrinolysis and endothelial damage have roles in the pathophysiology of Lassa fever, providing a mechanistic explanation for the association of Lassa fever with oedema and bleeding. These novel markers might aid in clinical risk stratification and disease monitoring. FUNDING: German Research Foundation, Leibniz Association, and US National Institutes of Health.

Acute kidney injury and mortality in pediatric Lassa fever versus question of access to dialysis.

OBJECTIVES: To assess the prevalence of acute kidney injury (AKI), and its impact on outcome in hospitalized pediatric patients with Lassa fever (LF). METHODS: We reviewed the presenting clinical and laboratory features and outcomes of 40 successive hospitalized children with PCR-confirmed LF. The diagnosis and staging of AKI was based on KDIGO criteria. We compared groups of patients using t- or χ2 tests as necessary, and took p-values <0.05 as indicative of the presence of significant differences. RESULTS: Sixteen (40%) children had AKI. Case fatality rate (CFR) was 9/16 (56%) in children with and 1/24 (4%) in those without AKI (OR [95% CI] of CFR associated with AKI = 29.57 [3.17, 275.7]). Presentation with abnormal bleeding (p = 0.008), encephalopathy (p = 0.004), hematuria plus proteinuria (p = 0.013), and elevated serum transaminase levels (p <0.02) were significantly associated with an increased prevalence of AKI. CONCLUSION: AKI prevalence in hospitalized pediatric patients with Lassa fever is high, and correlated with illness severity/CFR. The high prevalence underscores the need for access to hemodialysis, and clinical presentation and/or presence of hematuria plus proteinuria could serve as a ready prompt for referral for such specialized care.

Severe Human Lassa Fever Is Characterized by Nonspecific T-Cell Activation and Lymphocyte Homing to Inflamed Tissues.

Lassa fever (LF) is a zoonotic viral hemorrhagic fever caused by Lassa virus (LASV), which is endemic to West African countries. Previous studies have suggested an important role for T-cell-mediated immunopathology in LF pathogenesis, but the mechanisms by which T cells influence disease severity and outcome are not well understood. Here, we present a multiparametric analysis of clinical immunology data collected during the 2017-2018 Lassa fever outbreak in Nigeria. During the acute phase of LF, we observed robust activation of the polyclonal T-cell repertoire, which included LASV-specific and antigenically unrelated T cells. However, severe and fatal LF cases were characterized by poor LASV-specific effector T-cell responses. Severe LF was also characterized by the presence of circulating T cells with homing capacity to inflamed tissues, including the gut mucosa. These findings in LF patients were recapitulated in a mouse model of LASV infection, in which mucosal exposure resulted in remarkably high lethality compared to skin exposure. Taken together, our findings indicate that poor LASV-specific T-cell responses and activation of nonspecific T cells with homing capacity to inflamed tissues are associated with severe LF.IMPORTANCE Lassa fever may cause severe disease in humans, in particular in areas of endemicity like Sierra Leone and Nigeria. Despite its public health importance, the pathophysiology of Lassa fever in humans is poorly understood. Here, we present clinical immunology data obtained in the field during the 2018 Lassa fever outbreak in Nigeria indicating that severe Lassa fever is associated with activation of T cells antigenically unrelated to Lassa virus and poor Lassa virus-specific effector T-cell responses. Mechanistically, we show that these bystander T cells express defined tissue homing signatures that suggest their recruitment to inflamed tissues and a putative role of these T cells in immunopathology. These findings open a window of opportunity to consider T-cell targeting as a potential postexposure therapeutic strategy against severe Lassa fever, a hypothesis that could be tested in relevant animal models, such as nonhuman primates.

Fifty years of imported Lassa fever: a systematic review of primary and secondary cases.

RATIONALE FOR SYSTEMATIC REVIEW: Lassa fever is the most common cause of imported haemorrhagic fevers cases in non-endemic countries. As a disease with a high case fatality rate that has regularly caused clusters of nosocomial transmission in endemic areas, prompt diagnosis is vital. We conducted a systematic review of imported cases of the last 50 years with the aim of defining the clinical and epidemiological characteristics that will enhance early diagnosis, prompt initiation of treatment and an appropriate public health response to Lassa fever cases. METHODS: We performed a retrospective, systematic review of 36 primary and two secondary cases of Lassa fever in non-endemic countries outside West Africa by searching the PubMed database. This yielded 56 relevant publications that were included in our analysis. RESULTS: The case fatality rate of 35.1% for imported cases was higher than that reported for endemic countries. The majority of patients showed clinical features consistent with Lassa fever and had a typical exposure. There was a considerable delay in diagnosis in imported cases with high associated numbers of contacts. Ribavirin was rarely used for post-exposure prophylaxis. Only two secondary transmissions occurred. Thirty-one percent of patients received Lassa fever-specific treatment and five required intensive care. CONCLUSIONS: Although importation of Lassa fever to non-endemic countries is a rare event, it has repeatedly happened over five decades. Suspicion of Lassa fever should be based on careful consideration of clinical features and exposure history in order to assist early diagnosis in returning travellers from West Africa.

Improving Cross-Border Preparedness and Response: Lessons Learned from 3 Lassa Fever Outbreaks Across Benin, Nigeria, and Togo, 2017-2019.

Long-standing cultural, economic, and political relationships among Benin, Nigeria, and Togo contribute to the complexity of their cross-border connectivity. The associated human movement increases the risk of international spread of communicable disease. The Benin and Togo ministries of health and the Nigeria Centre for Disease Control, in collaboration with the Abidjan Lagos Corridor Organization (a 5-country intergovernmental organization) and the US Centers for Disease Control and Prevention, sought to minimize the risk of cross-border outbreaks by defining and implementing procedures for binational and multinational public health collaboration. Through 2 multinational meetings, regular district-level binational meetings, and fieldwork to characterize population movement and connectivity patterns, the countries improved cross-border public health coordination. Across 3 sequential cross-border Lassa fever outbreaks identified in Benin or Togo between February 2017 and March 2019, the 3 countries improved their collection and sharing of patients' cross-border travel histories, shortened the time between case identification and cross-border information sharing, and streamlined multinational coordination during response efforts. Notably, they refined collaborative efforts using lessons learned from the January to March 2018 Benin outbreak, which had a 100% case fatality rate among the 5 laboratory-confirmed cases, 3 of whom migrated from Nigeria across porous borders when ill. Aligning countries' expectations for sharing public health information would assist in reducing the international spread of communicable diseases by facilitating coordinated preparedness and responses strategies. Additionally, these binational and multinational strategies could be made more effective by tailoring them to the unique cultural connections and population movement patterns in the region.

Lethal Infection of Lassa Virus Isolated from a Human Clinical Sample in Outbred Guinea Pigs without Adaptation.

Lassa virus (LASV), a member of the family Arenaviridae, is the causative agent of Lassa fever. Lassa virus is endemic in West African countries, such as Nigeria, Guinea, Liberia, and Sierra Leone, and causes outbreaks annually. Lassa fever onset begins with "flu-like" symptoms and may develop into lethal hemorrhagic disease in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few licensed vaccines or therapeutics against Lassa fever. The fact that animal models are limited and the fact that mostly laboratory-derived viruses are used for studies limit the successful development of countermeasures. In this study, we demonstrated that the LASV isolate LF2384-NS-DIA-1 (LF2384), which was directly isolated from a serum sample from a fatal human Lassa fever case in the 2012 Sierra Leone outbreak, causes uniformly lethal infection in outbred Hartley guinea pigs without virus-host adaptation. This is the first report of a clinically isolated strain of LASV causing lethal infection in outbred guinea pigs. This novel guinea pig model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.IMPORTANCE Lassa virus, the causative agent of Lassa fever, is a zoonotic pathogen causing annual outbreaks in West African countries. Human patients can develop lethal hemorrhagic fever in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few available countermeasures, such as antiviral drugs or vaccines. Moreover, the fact that animal models are not readily accessible and the fact that mostly laboratory viruses, which have been passaged many times after isolation, are used for studies further limits the successful development of countermeasures. In this study, we demonstrate that a human isolate of Lassa virus causes lethal infection uniformly in Hartley guinea pigs. This novel animal model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.

Ribavirin for the treatment of Lassa fever: A systematic review and meta-analysis.

OBJECTIVES: Lassa fever (LF) causes annual outbreaks in endemic regions with high mortality of symptomatic patients. Ribavirin is recommended as standard treatment for LF in national and international guidelines but the evidence base for this recommendation has been questioned recently. METHODS: We conducted a systematic review and included 6 studies providing efficacy data of ribavirin treatment for LF (PROSPERO protocol CRD42018103994). RESULTS: Besides retrospective case series, the evidence mostly relies on a single prospective clinical trial with critical risk of bias. In this trial, LF associated mortality is reduced for patients with elevated aspartate aminotransferase (AST) when treated with ribavirin (OR 0.41, 95% CI 0.23-0.73), while mortality is higher for patients without elevated AST (OR 2.37, 95% CI 1.07-5.25). CONCLUSIONS: Based on the available data, current treatment guidelines may therefore put patients with mild LF at increased risk of death. The role of ribavirin in the treatment of LF requires urgent reassessment.

Measures to control protracted large Lassa fever outbreak in Nigeria, 1 January to 28 April 2019.

Lassa fever cases have increased in Nigeria since 2016 with the highest number, 633 cases, reported in 2018. From 1 January to 28 April 2019, 554 laboratory-confirmed cases including 124 deaths were reported in 21 states in Nigeria. A public health emergency was declared on 22 January by the Nigeria Centre for Disease Control. We describe the various outbreak responses that have been implemented, including establishment of emergency thresholds and guidelines for case management.

A medical records and data capture and management system for Lassa fever in Sierra Leone: Approach, implementation, and challenges.

Situated in southeastern Sierra Leone, Kenema Government Hospital (KGH) maintains one of the world's only Lassa fever isolation wards and was a strategic Ebola virus disease (EVD) treatment facility during the 2014 EVD outbreak. Since 2006, the Viral Hemorrhagic Fever Consortium (VHFC) has carried out research activities at KGH, capturing clinical and laboratory data for suspected cases of Lassa fever. Here we describe the approach, progress, and challenges in designing and maintaining a data capture and management system (DCMS) at KGH to assist infectious disease researchers in building and sustaining DCMS in low-resource environments. Results on screening patterns and case-fatality rates are provided to illustrate the context and scope of the DCMS covered in this study. A medical records system and DCMS was designed and implemented between 2010 and 2016 linking historical and prospective Lassa fever data sources across KGH Lassa fever units and its peripheral health units. Data were captured using a case report form (CRF) system, enzyme-linked immunosorbent assay (ELISA) plate readers, polymerase chain reaction (PCR) machines, blood chemistry analyzers, and data auditing procedures. Between 2008 and 2016, blood samples for 4,229 suspected Lassa fever cases were screened at KGH, ranging from 219 samples in 2008 to a peak of 760 samples in 2011. Lassa fever case-fatality rates before and following the Ebola outbreak were 65.5% (148/226) and 89.5% (17/19), respectively, suggesting that fewer, but more seriously ill subjects with Lassa fever presented to KGH following the 2014 EVD outbreak (p = .040). DCMS challenges included weak specificity of the Lassa fever suspected case definition, limited capture of patient survival outcome data, internet costs, lapses in internet connectivity, low bandwidth, equipment and software maintenance, lack of computer teaching laboratories, and workload fluctuations due to variable screening activity. DCMS are the backbone of international research efforts and additional literature is needed on the topic for establishing benchmarks and driving goal-based approaches for its advancement in developing countries.

Current research for a vaccine against Lassa hemorrhagic fever virus.

Lassa virus (LASV) is a rodent-borne arenavirus endemic to several West African countries that causes Lassa fever (LF). LF is typically mild but it can cause severe disease characterized by hemorrhagic fever and multi-organ failure. A current outbreak of LASV in Nigeria has seen greater than 300 cases with a case fatality rate of 22%. Currently, there are limited treatment options and no vaccine candidates are approved to prevent LASV infection. The Coalition for Epidemic Preparedness Innovations has identified LASV as an emerging pathogen of high consequence and this has resulted in a push for several preclinical vaccine candidates to be advanced toward clinical trials. Here, we discuss several important aspects of LASV infection including immunobiology, immune evasion, and correlates of protection against LF, which have been identified through animal models and human infections. In addition, we discuss several vaccine candidates that have shown efficacy in animal models that could be advanced toward clinical trials. The increased fatality rate seen in the recent LASV outbreak in Nigeria highlights the importance of developing effective treatment and prevention strategies against LF. The spike in LASV cases seen in West Africa has the potential for increased mortality and human-to-human transmission, making the development and testing of effective vaccines for LASV critical.

Mortality Among Confirmed Lassa Fever Cases During the 2015-2016 Outbreak in Nigeria.

OBJECTIVES: To determine factors associated with mortality among confirmed Lassa fever cases. METHODS: We reviewed line lists and clinical records of laboratory-confirmed cases of Lassa fever during the 2016 outbreak in Nigeria to determine factors associated with mortality. We activated an incident command system to coordinate response. RESULTS: We documented 47 cases, 28 of whom died (case fatality rate [CFR] = 59.6%; mean age 31.4 years; SD = ±18.4 years). The youngest and the oldest were the most likely to die, with 100% mortality in those aged 5 years or younger and those aged 55 years or older. Patients who commenced ribavirin were more likely to survive (odds ratio [OR] = 0.1; 95% confidence interval [CI] = 0.03, 0.50). Fatality rates went from 100% (wave 1) through 69% (wave 2) to 31% (wave 3; χ2 for linear trend: P < .01). Patients admitted to a health care center before incident command system activation were more likely to die (OR = 4.4; 95% CI = 1.1, 17.6). The only pregnant patient in the study died postpartum. CONCLUSIONS: Effective, coordinated response reduces mortality from public health events. Attention to vulnerable groups during disasters is essential. Public Health Implications. Activating an incident command system improves the outcome of disasters in resource-constrained settings.