Spatiotemporal dynamics of cholera epidemics in Ethiopia: 2015-2021.

Since the onset of the seventh cholera pandemic, Ethiopia has been affected by recurrent epidemics. However, the epidemiology of cholera in this country remains poorly understood. This study aimed to describe cholera outbreak characteristics in Ethiopia from 2015 to 2021. During this period, Ethiopia experienced four epidemic waves. The first wave involved nationwide outbreaks during the second half of 2016 followed by outbreaks predominantly affecting Somali Region in 2017. The second wave primarily affected Tigray and Afar Regions. During the third wave, multiple smaller-scale outbreaks occurred during 2019. The fourth wave was limited to Bale Zone (Oromia Region) in 2021. Overall, a north to south shift was observed over the course of the study period. Major cholera transmission factors included limited access to safe water and sanitation facilities. Severe weather events (drought and flooding) appear to aggravate cholera diffusion. Cholera transmission between Ethiopia and nearby countries (Kenya and Somalia), likely plays a major role in regional cholera dynamics. Overall, this study provides the first understanding of recent spatiotemporal cholera dynamics in Ethiopia to inform cholera control and elimination strategies.

Comparison of analysis methods to classify cholera hotspots in Ethiopia from 2015 to 2021.

Cholera continues to represent a major public health concern in Ethiopia. The country has developed a Multi-sectoral National Cholera Elimination Plan in 2022, which targets prevention and control interventions in cholera hotspots. Multiple methods to classify cholera hotspots have been used in several countries. Since 2014, a classification method developed by United Nations Children's Fund has been applied to guide water, sanitation and hygiene interventions throughout Sub-Saharan Africa based on three outbreak parameters: frequency, duration and standardized attack rate. In 2019, the Global Task Force on Cholera Control (GTFCC) proposed a method based on two parameters: average annual cholera incidence and persistence. In 2023, an updated GTFCC method for multisectoral interventions considers three epidemiological indicators (cumulative incidence, cumulative mortality and persistence,) and a cholera-case confirmation indicator. The current study aimed to classify cholera hotspots in Ethiopia at the woreda level (equivalent to district level) applying the three methods and comparing the results to optimize the hotspot targeting strategy. From 2015 to 2021, cholera hotspots were located along major routes between Addis Ababa and woredas adjacent to the Kenya and Somalia borders, throughout Tigray Region, around Lake Tana, and in Afar Region. The multi-method comparison enables decision makers to prioritize interventions according to a sub-classification of the highest-priority areas.

Spatiotemporal dynamics of cholera hotspots in the Democratic Republic of the Congo from 1973 to 2022.

BACKGROUND: Since the early 1970s, cholera outbreaks have been a major public health burden in the Democratic Republic of Congo (DRC). Cholera cases have been reported in a quasi-continuous manner in certain lakeside areas in the Great Lakes Region. As these cholera-endemic health zones constitute a starting point for outbreaks and diffusion towards other at-risk areas, they play a major role in cholera dynamics in the country. Monitoring the spatiotemporal dynamics of cholera hotspots and adjusting interventions accordingly thus reduces the disease burden in an efficient and cost-effective manner. METHODS: A literature review was conducted to describe the spatiotemporal dynamics of cholera in the DRC at the province level from 1973 to 1999. We then identified and classified cholera hotspots at the provincial and health zone levels from 2003 to 2022 and described the spatiotemporal evolution of hotspots. We also applied and compared three different classification methods to ensure that cholera hotspots are identified and classified according to the DRC context. RESULTS: According to all three methods, high-priority hotspots were concentrated in the eastern Great Lakes Region. Overall, hotspots largely remained unchanged over the course of the study period, although slight improvements were observed in some eastern hotspots, while other non-endemic areas in the west experienced an increase in cholera outbreaks. The Global Task Force on Cholera Control (GTFCC) and the Department of Ecology and Infectious Disease Control (DEIDC) methods largely yielded similar results for the high-risk hotspots. However, the medium-priority hotspots identified by the GTFCC method were further sub-classified by the DEIDC method, thereby providing a more detailed ranking for priority targeting. CONCLUSIONS: Overall, the findings of this comprehensive study shed light on the dynamics of cholera hotspots in the DRC from 1973 to 2022. These results may serve as an evidence-based foundation for public health officials and policymakers to improve the implementation of the Multisectoral Cholera Elimination Plan, guiding targeted interventions and resource allocation to mitigate the impact of cholera in vulnerable communities.

Influence of force field choice on the conformational landscape of rat and human islet amyloid polypeptide.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein (IDP) whose abnormal aggregation into toxic soluble oligomers and insoluble amyloid fibrils is a pathological feature in type-2 diabetes. Rat IAPP (rIAPP) differs from hIAPP by only six amino acids yet has a reduced tendency to aggregate or form fibrils. The structures of the monomeric forms of IAPP are difficult to characterize due to their intrinsically disordered nature. Molecular dynamics simulations can provide a detailed characterization of the monomeric forms of rIAPP and hIAPP in near-physiological conditions. In this work, the conformational landscapes of rIAPP and hIAPP as a function of secondary structure content were predicted using well-tempered bias exchange metadynamics simulations. Several combinations of commonly used biomolecular force fields and water models were tested. The predicted conformational preferences of both rIAPP and hIAPP are typical of IDPs, exhibiting dominant random coil structures but showing a low propensity for transient α-helical conformations. Predicted nuclear magnetic resonance Cα chemical shifts reveal different preferences with each force field towards certain conformations, with AMBERff99SBnmr2/TIP4Pd showing the best agreement with the experiment. Comparisons of secondary structure content demonstrate residue-specific differences between hIAPP and rIAPP that may reflect their different aggregation propensities.

Cholera resurgence potentially induced by the consequences of climate in the El Niño phenomenon: an urgent call for strengthened cholera elimination in Africa.

A resurgence in cholera cases has been observed throughout Africa during the first half of 2023. Among the many factors that drive cholera transmission, the ongoing climate phenomenon El Niño is likely to continue until March to May 2024. To prevent further cholera spread, it is critical to strengthen cholera control efforts in Africa.

EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.

EMILIN1 (elastin-microfibril-interface-located-protein-1) is a structural component of the elastic fiber network and localizes to the interface between the fibrillin microfibril scaffold and the elastin core. How EMILIN1 contributes to connective tissue integrity is not fully understood. Here, we report bi-allelic EMILIN1 loss-of-function variants causative for an entity combining cutis laxa, arterial tortuosity, aneurysm formation, and bone fragility, resembling autosomal-recessive cutis laxa type 1B, due to EFEMP2 (FBLN4) deficiency. In both humans and mice, absence of EMILIN1 impairs EFEMP2 extracellular matrix deposition and LOX activity resulting in impaired elastogenesis, reduced collagen crosslinking, and aberrant growth factor signaling. Collagen fiber ultrastructure and histopathology in EMILIN1- or EFEMP2-deficient skin and aorta corroborate these findings and murine Emilin1-/- femora show abnormal trabecular bone formation and strength. Altogether, EMILIN1 connects elastic fiber network with collagen fibril formation, relevant for both bone and vascular tissue homeostasis.

Hereditary spastic paraparesis presenting as cerebral palsy due to ADD3 variant with mechanistic insight provided by a Drosophila γ-adducin model.

Cerebral palsy (CP) causes neurological disability in early childhood. Hypoxic-ischaemic injury plays a major role in its aetiology, nevertheless, genetic and epigenetic factors may contribute to the clinical presentation. Mutations in ADD3 (encoding γ-adducin) gene have been described in a monogenic form of spastic quadriplegic cerebral palsy (OMIM 601568). We studied a 16-year-old male with spastic diplegia. Several investigations including neurometabolic testing, brain and spine magnetic resonance imaging (MRI) and CGH-Array were normal. Further, clinical genetics assessment and whole exome sequencing (WES) gave the diagnosis. We generated an animal model using Drosophila to study the effects of γ-adducin loss and gain of function. WES revealed a biallelic variant in the ADD3 gene, NM_016824.5(ADD3): c.1100G > A, p.(Gly367Asp). Mutations in this gene have been described as an ultra-rare autosomal recessive, which is a known form of inherited cerebral palsy. Molecular modelling suggests that this mutation leads to a loss of structural integrity of γ-adducin and is therefore expected to result in a decreased level of functional protein. Pan-neuronal over-expression or knock-down of the Drosophila ortholog of ADD3 called hts caused a reduction of life span and impaired locomotion thereby phenocopying aspects of the human disease. Our animal experiments present a starting point to understand the biological processes underpinning the clinical phenotype and pathogenic mechanisms, to gain insights into potential future methods for treating or preventing ADD3 related spastic quadriplegic cerebral palsy.

Description of the targeted water supply and hygiene response strategy implemented during the cholera outbreak of 2017-2018 in Kinshasa, DRC.

BACKGROUND: Rapid control of cholera outbreaks is a significant challenge in overpopulated urban areas. During late-2017, Kinshasa, the capital of the Democratic Republic of the Congo, experienced a cholera outbreak that showed potential to spread throughout the city. A novel targeted water and hygiene response strategy was implemented to quickly stem the outbreak. METHODS: We describe the first implementation of the cluster grid response strategy carried out in the community during the cholera outbreak in Kinshasa, in which response activities targeted cholera case clusters using a grid approach. Interventions focused on emergency water supply, household water treatment and safe storage, home disinfection and hygiene promotion. We also performed a preliminary community trial study to assess the temporal pattern of the outbreak before and after response interventions were implemented. Cholera surveillance databases from the Ministry of Health were analyzed to assess the spatiotemporal dynamics of the outbreak using epidemic curves and maps. RESULTS: From January 2017 to November 2018, a total of 1712 suspected cholera cases were reported in Kinshasa. During this period, the most affected health zones included Binza Météo, Limeté, Kokolo, Kintambo and Kingabwa. Following implementation of the response strategy, the weekly cholera case numbers in Binza Météo, Kintambo and Limeté decreased by an average of 57% after 2 weeks and 86% after 4 weeks. The total weekly case numbers throughout Kinshasa Province dropped by 71% 4 weeks after the peak of the outbreak. CONCLUSION: During the 2017-2018 period, Kinshasa experienced a sharp increase in cholera case numbers. To contain the outbreak, water supply and hygiene response interventions targeted case households, nearby neighbors and public areas in case clusters using a grid approach. Following implementation of the response, the outbreak in Kinshasa was quickly brought under control. A similar approach may be adapted to quickly interrupt cholera transmission in other urban settings.

The case-area targeted rapid response strategy to control cholera in Haiti: a four-year implementation study.

BACKGROUND: In October 2010, Haiti was struck by a large-scale cholera epidemic. The Haitian government, UNICEF and other international partners launched an unprecedented nationwide alert-response strategy in July 2013. Coordinated NGOs recruited local rapid response mobile teams to conduct case-area targeted interventions (CATIs), including education sessions, household decontamination by chlorine spraying, and distribution of chlorine tablets. An innovative red-orange-green alert system was also established to monitor the epidemic at the communal scale on a weekly basis. Our study aimed to describe and evaluate the exhaustiveness, intensity and quality of the CATIs in response to cholera alerts in Haiti between July 2013 and June 2017. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the response to 7,856 weekly cholera alerts using routine surveillance data and severity criteria, which was based on the details of 31,306 notified CATIs. The odds of CATI response during the same week (exhaustiveness) and the number of complete CATIs in responded alerts (intensity and quality) were estimated using multivariate generalized linear mixed models and several covariates. CATIs were carried out significantly more often in response to red alerts (adjusted odds ratio (aOR) [95%-confidence interval, 95%-CI], 2.52 [2.22-2.87]) compared with orange alerts. Significantly more complete CATIs were carried out in response to red alerts compared with orange alerts (adjusted incidence ratio (aIR), 1.85 [1.73-1.99]). Over the course of the eight-semester study, we observed a significant improvement in the exhaustiveness (aOR, 1.43 [1.38-1.48] per semester) as well as the intensity and quality (aIR, 1.23 [1.2-1.25] per semester) of CATI responses, independently of funds available for the strategy. The odds of launching a CATI response significantly decreased with increased rainfall (aOR, 0.99 [0.97-1] per each accumulated cm). Response interventions were significantly heterogeneous between NGOs, communes and departments. CONCLUSIONS/SIGNIFICANCE: The implementation of a nationwide case-area targeted rapid response strategy to control cholera in Haiti was feasible albeit with certain obstacles. Such feedback from the field and ongoing impact studies will be very informative for actors and international donors involved in cholera control and elimination in Haiti and in other affected countries.

Hospital-acquired complications in intensive care unit patients with diabetes: A before-and-after study of a conventional versus liberal glucose control protocol.

BACKGROUND: Critically ill patients with diabetes mellitus (DM) are at increased risk of in-hospital complications and the optimal glycemic target for such patients remains unclear. A more liberal approach to glucose control has recently been suggested for patients with DM, but uncertainty remains regarding its impact on complications. METHODS: We aimed to test the hypothesis that complications would be more common with a liberal glycemic target in ICU patients with DM. Thus, we compared hospital-acquired complications in the first 400 critically ill patients with DM included in a sequential before-and-after trial of liberal (glucose target: 10-14 mmol/L) vs conventional (glucose target: 6-10 mmol/L) glucose control. RESULTS: Of the 400 patients studied, 165 (82.5%) patients in the liberal and 177 (88.5%) in the conventional-control group were coded for at least one hospital-acquired complication (P = 0.09). When comparing clinically relevant complications diagnosed between ICU admission and hospital discharge, we found no difference in the odds for infectious (adjusted odds ratio [aOR] for liberal-control: 1.15 [95% CI: 0.68-1.96], P = 0.60), cardiovascular (aOR 1.40 [95% CI: 0.63-3.12], P = 0.41) or neurological complications (aOR: 1.07 [95% CI: 0.61-1.86], P = 0.81), acute kidney injury (aOR 0.83 [95% CI: 0.43-1.58], P = 0.56) or hospital mortality (aOR: 1.09 [95% CI: 0.59-2.02], P = 0.77) between the liberal and the conventional-control group. CONCLUSION: In this prospective before-and-after study, liberal glucose control was not associated with an increased risk of hospital-acquired infectious, cardiovascular, renal or neurological complications in critically ill patients with diabetes.

Epidemiological and molecular forensics of cholera recurrence in Haiti.

Cholera has affected Haiti with damping waves of outbreaks since October 2010. However, mechanisms behind disease persistence during lull periods remain poorly understood. By mid 2014, cholera transmission seemed to only persist in the northern part of Haiti. Meanwhile, cholera appeared nearly extinct in the capital, Port-au-Prince, where it eventually exploded in September 2014. This study aimed to determine whether this outbreak was caused by local undetected cases or by re-importation of the disease from the north. Applying an integrated approach between November 2013 and November 2014, we assessed the temporal and spatial dynamics of cholera using routine surveillance data and performed population genetics analyses of 178 Vibrio cholerae O1 clinical isolates. The results suggest that the northern part of the country exhibited a persisting metapopulation pattern with roaming oligoclonal outbreaks that could not be effectively controlled. Conversely, undetected and unaddressed autochthonous low-grade transmission persisted in the Port-au-Prince area, which may have been the source of the acute outbreak in late-2014. Cholera genotyping is a simple but powerful tool to adapt control strategies based on epidemic specificities. In Haiti, these data have already yielded significant progress in cholera surveillance, which is a key component of the strategy to eventually eliminate cholera.

Characterisation of the Structure and Oligomerisation of Islet Amyloid Polypeptides (IAPP): A Review of Molecular Dynamics Simulation Studies.

Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer's disease. The soluble, oligomeric forms of hIAPP are the most toxic to ß-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions.

Dynamics of cholera epidemics from Benin to Mauritania.

BACKGROUND: The countries of West Africa are largely portrayed as cholera endemic, although the dynamics of outbreaks in this region of Africa remain largely unclear. METHODOLOGY/PRINCIPAL FINDINGS: To understand the dynamics of cholera in a major portion of West Africa, we analyzed cholera epidemics from 2009 to 2015 from Benin to Mauritania. We conducted a series of field visits as well as multilocus variable tandem repeat analysis and whole-genome sequencing analysis of V. cholerae isolates throughout the study region. During this period, Ghana accounted for 52% of the reported cases in the entire study region (coastal countries from Benin to Mauritania). From 2009 to 2015, we found that one major wave of cholera outbreaks spread from Accra in 2011 northwestward to Sierra Leone and Guinea in 2012. Molecular epidemiology analysis confirmed that the 2011 Ghanaian isolates were related to those that seeded the 2012 epidemics in Guinea and Sierra Leone. Interestingly, we found that many countries deemed "cholera endemic" actually suffered very few outbreaks, with multi-year lulls. CONCLUSIONS/SIGNIFICANCE: This study provides the first cohesive vision of the dynamics of cholera epidemics in a major portion of West Africa. This epidemiological overview shows that from 2009 to 2015, at least 54% of reported cases concerned populations living in the three urban areas of Accra, Freetown, and Conakry. These findings may serve as a guide to better target cholera prevention and control efforts in the identified cholera hotspots in West Africa.

Genomic history of the seventh pandemic of cholera in Africa.

The seventh cholera pandemic has heavily affected Africa, although the origin and continental spread of the disease remain undefined. We used genomic data from 1070 Vibrio cholerae O1 isolates, across 45 African countries and over a 49-year period, to show that past epidemics were attributable to a single expanded lineage. This lineage was introduced at least 11 times since 1970, into two main regions, West Africa and East/Southern Africa, causing epidemics that lasted up to 28 years. The last five introductions into Africa, all from Asia, involved multidrug-resistant sublineages that replaced antibiotic-susceptible sublineages after 2000. This phylogenetic framework describes the periodicity of lineage introduction and the stable routes of cholera spread, which should inform the rational design of control measures for cholera in Africa.

Perceived Physician-informed Weight Status Predicts Accurate Weight Self-Perception and Weight Self-Regulation in Low-income, African American Women.

BACKGROUND: Obese African American women under-appraise their body mass index (BMI) classification and report fewer weight loss attempts than women who accurately appraise their weight status. This cross-sectional study examined whether physician-informed weight status could predict weight self-perception and weight self-regulation strategies in obese women. METHODS: A convenience sample of 118 low-income women completed a survey assessing demographic characteristics, comorbidities, weight self-perception, and weight self-regulation strategies. BMI was calculated during nurse triage. Binary logistic regression models were performed to test hypotheses. RESULTS: The odds of obese accurate appraisers having been informed about their weight status were six times greater than those of under-appraisers. The odds of those using an "approach" self-regulation strategy having been physician-informed were four times greater compared with those using an "avoidance" strategy. DISCUSSION: Physicians are uniquely positioned to influence accurate weight self-perception and adaptive weight self-regulation strategies in underserved women, reducing their risk for obesity-related morbidity.

Genetic diversity of Plasmodium falciparum in human malaria cases in Mali.

BACKGROUND: In Mali, Plasmodium falciparum malaria is highly endemic and remains stable despite the implementation of various malaria control measures. Understanding P. falciparum population structure variations across the country could provide new insights to guide malaria control programmes. In this study, P. falciparum genetic diversity and population structure in regions of varying patterns of malaria transmission in Mali were analysed. METHODS: A total of 648 blood isolates adsorbed onto filter papers during population surveillance surveys (December 2012-March 2013, October 2013) in four distinct sites of Mali were screened for the presence of P. falciparum via quantitative PCR (qPCR). Multiple loci variable number of tandem repeats analysis (MLVA) using eight microsatellite markers was then performed on positive qPCR samples. Complete genotypes were then analysed for genetic diversity, genetic differentiation and linkage disequilibrium. RESULTS: Of 156 qPCR-positive samples, complete genotyping of 112 samples was achieved. The parasite populations displayed high genetic diversity (mean He = 0.77), which was consistent with a high level of malaria transmission in Mali. Genetic differentiation was low (FST < 0.02), even between sites located approximately 900 km apart, thereby illustrating marked gene flux amongst parasite populations. The lack of linkage disequilibrium further revealed an absence of local clonal expansion, which was corroborated by the genotype relationship results. In contrast to the stable genetic diversity level observed throughout the country, mean multiplicity of infection increased from north to south (from 1.4 to 2.06) and paralleled malaria transmission levels observed locally. CONCLUSIONS: In Mali, the high level of genetic diversity and the pronounced gene flux amongst P. falciparum populations may represent an obstacle to control malaria. Indeed, results suggest that parasite populations are polymorphic enough to adapt to their host and to counteract interventions, such as anti-malarial vaccination. Additionally, the panmictic parasite population structure imply that resistance traits may disseminate freely from one area to another, making control measures performed at a local level ineffective.

The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome.

The RASopathies, which include Noonan syndrome (NS) and Cardiofaciocutaneous syndrome (CFC), are autosomal dominant disorders with genetic heterogeneity associated with germline mutations of genes in the Ras/mitogen-activated protein kinase (MAPK; RAS-MAP kinase) pathway. The conditions overlap and are characterised by facial dysmorphism, short stature and congenital heart disease. NS and CFC, in particular, are known to be associated with lymphatic problems, but this has not been well characterised to date. We describe 11 patients with Noonan or CFC syndrome with significant, persistent and progressive lymphatic dysplasia. The lymphatic disorders in Noonan and CFC syndrome are rare, but have a characteristic pattern with bilateral lower limb lymphoedema, genital swelling with chylous reflux and frequent systemic involvement, including intestinal lymphangiectasia and chylothoraces, which may be progressive. Lymphoscintigraphy demonstrates reflux and/or rerouting of lymphatic drainage associated with incompetent veins on the venous duplex scans.

Relationship between Distinct African Cholera Epidemics Revealed via MLVA Haplotyping of 337 Vibrio cholerae Isolates.

BACKGROUND: Since cholera appeared in Africa during the 1970s, cases have been reported on the continent every year. In Sub-Saharan Africa, cholera outbreaks primarily cluster at certain hotspots including the African Great Lakes Region and West Africa. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we applied MLVA (Multi-Locus Variable Number Tandem Repeat Analysis) typing of 337 Vibrio cholerae isolates from recent cholera epidemics in the Democratic Republic of the Congo (DRC), Zambia, Guinea and Togo. We aimed to assess the relationship between outbreaks. Applying this method, we identified 89 unique MLVA haplotypes across our isolate collection. MLVA typing revealed the short-term divergence and microevolution of these Vibrio cholerae populations to provide insight into the dynamics of cholera outbreaks in each country. Our analyses also revealed strong geographical clustering. Isolates from the African Great Lakes Region (DRC and Zambia) formed a closely related group, while West African isolates (Togo and Guinea) constituted a separate cluster. At a country-level scale our analyses revealed several distinct MLVA groups, most notably DRC 2011/2012, DRC 2009, Zambia 2012 and Guinea 2012. We also found that certain MLVA types collected in the DRC persisted in the country for several years, occasionally giving rise to expansive epidemics. Finally, we found that the six environmental isolates in our panel were unrelated to the epidemic isolates. CONCLUSIONS/SIGNIFICANCE: To effectively combat the disease, it is critical to understand the mechanisms of cholera emergence and diffusion in a region-specific manner. Overall, these findings demonstrate the relationship between distinct epidemics in West Africa and the African Great Lakes Region. This study also highlights the importance of monitoring and analyzing Vibrio cholerae isolates.