Epidemiological description of a protracted cholera outbreak in Tonj East and Tonj North counties, former Warrap State, South Sudan, May-Oct 2017.

BACKGROUND: On 18th May 2017, State Ministry of Health of former Warrap State received a report from Tonj East County of an outbreak of acute watery diarrhoea and vomiting in Makuac payam. We conducted this investigation to confirm the causative organism and describe the epidemiology of the outbreak in order to support evidence-based control measures. METHODS: We defined a suspected case as a resident of Tonj East or Tonj North County with sudden onset of acute watery diarrhoea and vomiting between May 1 and October 15, 2017. A probable case was defined as a suspected case with a positive rapid test for Vibrio cholerae; a confirmed case was a probable case with a positive stool culture for V. cholerae. We conducted systematic case finding by visiting health facilities and villages in the affected payams. We reviewed patient records from 1 May 2017 to 15 October 2017, to identify suspected cholera case-patients. We conducted a descriptive epidemiologic study, examining the distribution of the cases. We computed the attack rates by age, sex, and payam of residence. Case fatality rate was calculated as the ratio of the total number of suspected cholera death to the total number of cholera case-patients. We conducted an oral cholera vaccination campaign after the peak of the outbreak to control and prevent the spread to other payams. RESULTS: We identified 1451 suspected cholera cases between May and October 2017. Of these, 81% (21/26) had a positive rapid diagnostic test for V. cholerae; out of the 16 rectal swabs transported to the National Public Laboratory, 88% (14/16) were confirmed to be V. cholerae O1 serotype Inaba. The epidemic curve shows continuous common source outbreak with several peaks. The mean age of the case-patients was 24 years (Range: 0.2-75y). The clinical presentations of the case-patients were consistent with cholera. Males had an attack rate of 9.9/10000. The highest attack rate was in ≥30y (14 per 10,000). Among the six payams affected, Makuac had the highest attack rate of 3/100. The case fatality rate (CFR) was 3.0% (44/1451). Paliang and Wunlit had an oral cholera vaccination coverage of ≥100%, while 4 payams had a vaccination coverage of < 90%. CONCLUSION: This was a continuous common source cholera outbreak caused by V. cholerae 01 sero type Inaba. We recommended strengthening of the surveillance system to improve early detection and effective response.

A cholera outbreak caused by drinking contaminated river water, Bulambuli District, Eastern Uganda, March 2016.

BACKGROUND: A cholera outbreak started on 29 February in Bwikhonge Sub-county, Bulambuli District in Eastern Uganda. Local public health authorities implemented initial control measures. However, in late March, cases sharply increased in Bwikhonge Sub-county. We investigated the outbreak to determine its scope and mode of transmission, and to inform control measures. METHODS: We defined a suspected case as sudden onset of watery diarrhea from 1 March 2016 onwards in a resident of Bulambuli District. A confirmed case was a suspected case with positive stool culture for V. cholerae. We conducted descriptive epidemiologic analysis of the cases to inform the hypothesis on mode of transmission. To test the hypothesis, we conducted a case-control study involving 100 suspected case-patients and 100 asymptomatic controls, individually-matched by residence village and age. We collected seven water samples for laboratory testing. RESULTS: We identified 108 suspected cases (attack rate: 1.3%, 108/8404), including 7 confirmed cases. The case-control study revealed that 78% (78/100) of case-patients compared with 51% (51/100) of control-persons usually collected drinking water from the nearby Cheptui River (ORMH = 7.8, 95% CI = 2.7-22); conversely, 35% (35/100) of case-patients compared with 54% (54/100) of control-persons usually collected drinking water from borehole pumps (ORMH = 0.31, 95% CI = 0.13-0.65). The index case in Bwikhonge Sub-county had onset on 29 February but the outbreak had been on-going in the neighbouring sub-counties in the previous 3 months. V. cholera was isolated in 2 of the 7 river water samples collected from different locations. CONCLUSIONS: We concluded that this cholera outbreak was caused by drinking contaminated water from Cheptui River. We recommended boiling and/or treating drinking water, improved sanitation, distribution of chlorine tablets to the affected villages, and as a long-term solution, construction of more borehole pumps. After implementing preventive measures, the number of cases declined and completely stopped after 6th April.

Individual and Household Risk Factors for Symptomatic Cholera Infection: A Systematic Review and Meta-analysis.

Background: Cholera has caused 7 global pandemics, including the current one which has been ongoing since 1961. A systematic review of risk factors for symptomatic cholera infection has not been previously published. Methods: In accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we performed a systematic review and meta-analysis of individual and household risk factors for symptomatic cholera infection. Results: We identified 110 studies eligible for inclusion in qualitative synthesis. Factors associated with symptomatic cholera that were eligible for meta-analysis included education less than secondary level (summary odds ratio [SOR], 2.64; 95% confidence interval [CI], 1.41-4.92; I2 = 8%), unimproved water source (SOR, 3.48; 95% CI, 2.18-5.54; I2 = 77%), open container water storage (SOR, 2.03; 95% CI, 1.09-3.76; I2 = 62%), consumption of food outside the home (SOR, 2.76; 95% CI, 1.62-4.69; I2 = 64%), household contact with cholera (SOR, 2.91; 95% CI, 1.62-5.25; I2 = 89%), water treatment (SOR, 0.37; 95% CI, .21-.63; I2 = 74%), and handwashing (SOR, 0.29; 95% CI, .20-.43; I2 = 37%). Other notable associations with symptomatic infection included income/wealth, blood group, gastric acidity, infant breastfeeding status, and human immunodeficiency virus infection. Conclusions: We identified potential risk factors for symptomatic cholera infection including environmental characteristics, socioeconomic factors, and intrinsic patient factors. Ultimately, a combination of interventional approaches targeting various groups with risk-adapted intensities may prove to be the optimal strategy for cholera control.

Cell Propagation of Cholera Toxin CTA ADP-Ribosylating Factor by Exosome Mediated Transfer.

In this study, we report how the cholera toxin (CT) A subunit (CTA), the enzyme moiety responsible for signaling alteration in host cells, enters the exosomal pathway, secretes extracellularly, transmits itself to a cell population. The first evidence for long-term transmission of CT's toxic effect via extracellular vesicles was obtained in Chinese hamster ovary (CHO) cells. To follow the CT intracellular route towards exosome secretion, we used a novel strategy for generating metabolically-labeled fluorescent exosomes that can be counted by flow cytometry assay (FACS) and characterized. Our results clearly show the association of CT with exosomes, together with the heat shock protein 90 (HSP90) and Protein Disulfide Isomerase (PDI) molecules, proteins required for translocation of CTA across the ER membrane into the cytoplasm. Confocal microscopy showed direct internalization of CT containing fluorescent exo into CHO cells coupled with morphological changes in the recipient cells that are characteristic of CT action. Moreover, Me665 cells treated with CT-containing exosomes showed an increase in Adenosine 3',5'-Cyclic Monophosphate (cAMP) level, reaching levels comparable to those seen in cells exposed directly to CT. Our results prompt the idea that CT can exploit an exosome-mediated cell communication pathway to extend its pathophysiological action beyond an initial host cell, into a multitude of cells. This finding could have implications for cholera disease pathogenesis and epidemiology.

A prolonged, community-wide cholera outbreak associated with drinking water contaminated by sewage in Kasese District, western Uganda.

BACKGROUND: In May 2015, a cholera outbreak that had lasted 3 months and infected over 100 people was reported in Kasese District, Uganda, where multiple cholera outbreaks had occurred previously. We conducted an investigation to identify the mode of transmission to guide control measures. METHODS: We defined a suspected case as onset of acute watery diarrhoea from 1 February 2015 onwards in a Kasese resident. A confirmed case was a suspected case with Vibrio cholerae O1 El Tor, serotype Inaba cultured from a stool sample. We reviewed medical records to find cases. We conducted a case-control study to compare exposures among confirmed case-persons and asymptomatic controls, matched by village and age-group. We conducted environmental assessments. We tested water samples from the most affected area for total coliforms using the Most Probable Number (MPN) method. RESULTS: We identified 183 suspected cases including 61 confirmed cases of Vibrio cholerae 01; serotype Inaba, with onset between February and July 2015. 2 case-persons died of cholera. The outbreak occurred in 80 villages and affected all age groups; the highest attack rate occurred in the 5-14 year age group (4.1/10,000). The outbreak started in Bwera Sub-County bordering the Democratic Republic of Congo and spread eastward through sustained community transmission. The first case-persons were involved in cross-border trading. The case-control study, which involved 49 confirmed cases and 201 controls, showed that 94% (46/49) of case-persons compared with 79% (160/201) of control-persons drank water without boiling or treatment (ORM-H=4.8, 95% CI: 1.3-18). Water collected from the two main sources, i.e., public pipes (consumed by 39% of case-persons and 38% of control-persons) or streams (consumed by 29% of case-persons and 24% control-persons) had high coliform counts, a marker of faecal contamination. Environmental assessment revealed evidence of open defecation along the streams. No food items were significantly associated with illness. CONCLUSIONS: This prolonged, community-wide cholera outbreak was associated with drinking water contaminated by faecal matter and cross-border trading. We recommended rigorous disposal of patients' faeces, chlorination of piped water, and boiling or treatment of drinking water. The outbreak stopped 6 weeks after these recommendations were implemented.

Bile salt-induced intermolecular disulfide bond formation activates Vibrio cholerae virulence.

To be successful pathogens, bacteria must often restrict the expression of virulence genes to host environments. This requires a physical or chemical marker of the host environment as well as a cognate bacterial system for sensing the presence of a host to appropriately time the activation of virulence. However, there have been remarkably few such signal-sensor pairs identified, and the molecular mechanisms for host-sensing are virtually unknown. By directly applying a reporter strain of Vibrio cholerae, the causative agent of cholera, to a thin layer chromatography (TLC) plate containing mouse intestinal extracts, we found two host signals that activate virulence gene transcription. One of these was revealed to be the bile salt taurocholate. We then show that a set of bile salts cause dimerization of the transmembrane transcription factor TcpP by inducing intermolecular disulfide bonds between cysteine (C)-207 residues in its periplasmic domain. Various genetic and biochemical analyses led us to propose a model in which the other cysteine in the periplasmic domain, C218, forms an inhibitory intramolecular disulfide bond with C207 that must be isomerized to form the active C207-C207 intermolecular bond. We then found bile salt-dependent effects of these cysteine mutations on survival in vivo, correlating to our in vitro model. Our results are a demonstration of a mechanism for direct activation of the V. cholerae virulence cascade by a host signal molecule. They further provide a paradigm for recognition of the host environment in pathogenic bacteria through periplasmic cysteine oxidation.

Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel.

US cholera surveillance offers insight into global and domestic trends. Between 2001 and 2011, 111 cases were reported to the Centers for Disease Control and Prevention. Cholera was associated with international travel in 90 (81%) patients and was domestically acquired in 20 (18%) patients; for one patient, information was not available. From January 2001 to October 2010, the 42 (47%) travel-associated cases were associated with travel to Asia. In October 2010, a cholera epidemic started in Haiti, soon spreading to the Dominican Republic (Hispaniola). From then to December 2011, 40 (83%) of the 48 travel-associated cases were associated with travel to Hispaniola. Of 20 patients who acquired cholera domestically, 17 (85%) reported seafood consumption; 10 (59%) ate seafood from the US Gulf Coast. In summary, an increase in travel-associated US cholera cases was associated with epidemic cholera in Hispaniola in 2010-2011. Travel to Asia and consumption of Gulf Coast seafood remained important sources of US cholera cases.

Assessing the risk factors of cholera epidemic in the Buea Health District of Cameroon.

BACKGROUND: Cholera is an acute diarrheal disease caused by the bacterium, Vibrio cholerae. A cholera epidemic occurred in Cameroon in 2010. After a cholera-free period at the end of 2010, new cases started appearing in early 2011. The disease affected 23,152 people and killed 843, with the South West Region registering 336 cases and 13 deaths. Hence, we assessed the risk factors of cholera epidemic in the Buea Health District to provide evidence-based cholera guidelines. METHODS: We conducted an unmatched case-control study. Cases were identified from health facility records and controls were neighbours of the cases in the same community. We interviewed 135 participants on socio-economic, household hygiene, food and water exposures practices using a semi-structured questionnaire. Data was analyzed using STATA. Fisher exact test and logistic regression were computed. P < 0.05 was considered to be statistically significant. RESULTS: The 135 participants included 34 (25.2 %) cholera cases and 101 (74.8 %) controls. More females [78 (57.8 %)] participated in the study. Ages ranged from 1 year 3 months to 72 years; with a mean of 29.86 (±14.51) years. The cholera attack rate was 0.03 % with no fatality. Most participants [129 (99.2 %)] had heard of cholera. Poor hygienic practices [77 (59.2 %)] and contaminated water sources [54 (41.5 %)] were the main reported transmission routes of cholera. Good hygienic practices [108 (83.1 %)] were the main preventive methods of cholera in both cases [23 (76.6 %)] and controls [85 (85.0 %)]. Logistic regression analysis showed age below 21 years (OR = 1.72, 95 % CI: 0.73-4.06, p = 0.251), eating outside the home (OR = 1.06, CI: 0.46-2.43, p = 1.00) and poor food preservation method (OR = 9.20, CI: 3.67-23.08, p < 0.0001) were independent risk factors of cholera. Also, irregular water supply (OR = 0.66, 95 % CI: 0.30-1.43, p = 0.320), poor kitchen facility (OR = 0.60, CI: 0.16-2.23, p = 0.560), lack of home toilet (OR = 0.69, CI: 0.25-1.86, p = 0.490), and education below tertiary (OR = 0.87, 95 % CI: 0.36-2.11, p = 0.818) were independent protective factors for the occurrence of cholera. CONCLUSION: There was a good knowledge of cholera among participants. Poor food preservation method was a significant independent risk factor of cholera. Improvement in hygiene and sanitation conditions and water infrastructural development is crucial to combating the epidemic.

Modern cholera in the Americas: an opportunistic societal infection.

In the Americas, the only two cholera epidemics of the past century have occurred in the past 25 years. Lessons from the 1991 Peruvian cholera epidemic can help to focus and refine the response to the current Haitian epidemic. After three years of acute epidemic response, we have an opportunity to refocus on the chronic conditions that make societies vulnerable to cholera. More importantly, even as international attention wanes in the aftermath of the earthquake and acute epidemic, we are faced with a need for continued and coordinated investment in improving Haiti's structural defenses against cholera, in particular access to improved water and sanitation.

Assessment of the relationship between bacteriological quality of dug-wells, hygiene behaviour and well characteristics in two cholera endemic localities in Douala, Cameroon.

BACKGROUND: Access to potable water is grossly inadequate in Douala-Cameroon. The situation is worse in slum areas, compelling inhabitants to obtain water from sources of doubtful quality. This has contributed to frequent outbreaks of water-borne diseases particularly cholera, which results in severe morbidity and mortality. Shallow wells are a major source of water in these areas. We analyzed the influence of some factors on the bacteriological quality of well water in Bepanda and New Bell, cholera endemic localities in Douala to generate data that would serve as basis for strengthening of water and health policies. METHODS: Questionnaires were administered to inhabitants of study sites to appraise their hygiene and sanitation practices, and level of awareness of waterborne diseases. The bacteriological quality of water was determined by investigating bacterial indicators of water quality. Relationship between well characteristics and bacteriological quality of water was determined using χ² test. The Kendall tau_b nonparametric correlation was used to measure the strength of association between well characteristics and bacteriological parameters. Statistics were discussed at 95% confidence level. Antibiotic susceptibility of isolates was investigated by the Kirby-Bauer and broth dilution techniques. Multidrug resistant species were tested for extended ß-lactamase production potential. RESULTS: Inhabitants demonstrated adequate knowledge of waterborne diseases but employed inappropriate method (table salt) for well disinfection. Well construction and location violated guidelines. Indicator bacterial counts greatly exceeded the WHO guidelines. Variation in bacteriologic parameters between sites was not significant (P > 0.05) since well characteristics and hygiene and sanitary practices were similar. Differences in bacteriologic quality with respect to state of well, and presence of molded casing and lid, and height of casing were not significant (P > 0.05). Well distance from sanitary structure negatively correlated with bacteriological characteristics indicating it could be a major contributory factor to poor water quality. Bacteria isolated were predominantly enteric organisms. Ciprofloxacin was the most active agent. Extended ß-lactamase producers were detected among Salmonella species, Citrobacter fruendii and E. coli. CONCLUSION: Poor well location, construction, and hygiene and sanitary practices were among the factors affecting water quality. There is an urgent need for education of inhabitants on effective water disinfection strategies and for regular monitoring of wells.

Food as a Driver of a Cholera Epidemic in Jijiga, Ethiopia-June 2017.

We conducted a case-control study to identify risk and protective factors during a cholera outbreak in Jijiga, Ethiopia, in June 2017. A case-patient was defined as anyone > 5 years old with at least three loose stools in 24 hours who was admitted to a cholera treatment center in Jijiga on or after June 16, 2017. Two controls were matched to each case by type of residency (rural or urban) and age group. We enrolled 55 case-patients and 102 controls from June 16 to June 23, 2017. Identified risk factors for cholera were male sex, eating cold food, and eating food outside the home. Eating hot food was protective, as was reported handwashing after defecation; no other reported water, sanitation, and hygiene factors were associated with cholera risk. Recommendations included continuing messaging about safe food handling practices at home, the dangers of consuming meals prepared away from home, and the importance of hand hygiene practices.

A rapidly-progressing outbreak of cholera in a shelter-home for mentally-retarded females, amta-II block, Howrah, West Bengal, India.

On 13 May 2010, a cluster of diarrhoeal disease cases was reported among the inmates of a shelter-home for mentally-retarded females in Parbaksi village of Howrah district in West Bengal, India. The outbreak was investigated to identify the aetiological agent and source of infection and to propose recommendations. A suspected case of cholera was defined as an acute onset of >3 loose watery stools in a female resident of the shelter-home since 1 May 2010. The demographic and clinical details were collected from the suspected case-patients, and the outbreak was described by time, place, and person. A retrospective cohort study was conducted to identify the risk factors associated with the illness. Of the 101 inmates, 91 (90%) developed diarrhoea, and three patients died (case fatality-3%). Four of the five stool specimens were positive for Vibrio cholerae O1 Ogawa. Drinking of water from the pond-connected tubewell (adjusted odds ratio=25.7, 95% confidence interval 2.7-236.4) was associated with the illness. Relocation of the pond-connected tubewell away from the groundwater tubewell, colour-coding of the tubewells meant for drinking purposes, and regular disinfection of the tubewells were recommended.

Outbreak of cholera in Tilathi VDC Saptari Nepal.

BACKGROUND: On 2011, Cluster of cholera cases was reported in the Tilathi VDC of Saptari, Nepal. OBJECTIVE: The outbreak was investigated to identify the etiological agent and possible source of infection and guiding the prevention and control measures. METHODS: Demographic and clinical details were collected from the suspected case-patients, and the outbreak was described by time, place, and person. Focus group discussion and Key informant interview were conducted to assess the practice of sanitation, source of drinking water and probable cause of diarrheal disease. Five stool samples and 10 water samples of tube well and ponds were collected and microbiological study was done in BPKIHS Dharan. RESULTS: A total of 111 persons suffered with diarrhea and 02 died of it (attack rate 3.05%, case fatality rate 1.8%). All age groups were affected with disease (median age 26 yrs) and males were affected more than females. Descriptive epidemiology suggested the clustering of cases were around the pond where they clean utensils, take bath and wash clothes. The Vibrio cholerae 01 El Tor, Ogawa serotype was isolated in 03 out of 05 suspected stool samples and in all three of the pond water samples. They reported that most of the houses do not have the toilet and people do not wash their hands regularly with soap and water after defecation. CONCLUSION: Vibrio cholerae was the causative agent behind the outbreak and probable source of infection was the problematic pond water which they used for different purpose. Immediate chlorination of the pond was recommended to halt further spread of the epidemics.

Contribution of microbial genomics to cholera epidemiology.

In 2022, the burden of cholera-an acute watery diarrheal disease caused by Vibrio cholerae serogroup O1 (or more rarely O139) bacteria, which produce cholera toxin-remains high in many African and Asian countries. In the last few years, microbial genomics has made it possible to define the bacterial populations responsible for cholera more precisely. It has been shown that the current, seventh pandemic is due to a single lineage with a reservoir in the countries of the Bay of Bengal (India and Bangladesh). There have been several transmissions of the causal agent of cholera from this region to Africa, Asia and Latin America, suggesting a human-to-human transmission of the disease. Microbial genetics can help to fight this scourge by providing insight into cholera epidemiology and through its use in disease monitoring, thereby contributing to the achievement of the World Health Organization's goal of reducing cholera deaths by 90% by 2030.

En 2022, de nombreux pays d'Afrique et d'Asie restent des foyers épidémiques de choléra, maladie diarrhéique causée par la bactérie Vibrio cholerae de sérogroupe O1 (ou plus rarement O139) produisant la toxine cholérique. La génomique microbienne a permis ces dernières années de mieux définir les populations bactériennes responsables du choléra. Il a ainsi été montré qu'il n'existait qu'une seule lignée génétique de Vibrio cholerae O1 responsable de la septième pandémie dont le réservoir se situe dans la région du golfe du Bengale (Inde et Bangladesh). Plusieurs évènements de transmission de l'agent du choléra vers l'Afrique, l'Europe ou l'Amérique latine ont été identifiés et suggèrent une transmission interhumaine de la maladie. Les données issues des travaux de génomique microbienne ainsi que son utilisation pour la surveillance globale du choléra vont permettre de mieux lutter contre ce fléau et participer à l'objectif de l'Organisation mondiale de la Santé de réduire de 90 % les décès dus à cette maladie en 2030.

Inadequate Hand Washing, Lack of Clean Drinking Water and Latrines as Major Determinants of Cholera Outbreak in Somali Region, Ethiopia in 2019.

Introduction: Cholera remains a serious public health problem characterized by a large disease burden, frequent outbreaks, persistent endemicity, and high mortality, particularly in tropical and subtropical low-income countries including Ethiopia. The recent cholera outbreak in the Somali region began on 4 September to 1 November 2019. Cholera may spread rapidly through a population so that an early detection and reporting of the cases is mandatory. This study aimed to identify determinants of cholera infection among >5 years of age population in Somali region, Ethiopia. Methods: A community-based unmatched case-control study was conducted among 228 (76 cases and 152 controls, 1:2 ratio) systematically selected population. Data were collected using a structured questionnaire administered by an interviewer and a record review. Descriptive statistics and multivariable logistic regression analysis was used to identify the determinants of the risk factors of cholera infection with a 95% confidence interval and statistical significance was declared a tap-value < 0.05. Results: A total of 228 participants (33.3% cases and 66.7% controls) were enrolled in this study. The majority of the cases were in the range of 20-49 years of age (69.7%). The odds of acquiring cholera infection increased significantly by drinking unsafe pipe water (AOR 4.3, 95% CI 1.65-11.2), not having a household level toilet/latrine (AOR 3.25, 95% CI 1.57-6.76), hand washing only sometimes after the toilet (AOR 3.04, 95% CI 1.58-5.86) and not using water purification methods (AOR 2.3, 95% CI 1.13-4.54). Conclusion: Major risk factors for cholera infection were related to drinking water and latrine hygiene. Improvement in awareness creation about cholera prevention and control methods, including water treatment, hygiene and sanitation were crucial in combating this cholera outbreak. Primary public health actions are ensuring clean drinking water, delivery of water purification tablets, soap and hand sanitizers and provision of health care and outbreak response. Long term goals in cholera affected areas include comprehensive water and sanitation strategies. Overall, the strategic role of a multi-sectoral approach in the design and implementation of public health interventions aimed at preventing and controlling cholera are essential to avert cholera outbreaks. Preparedness should be highlighted in cholera prone areas like Somali region especially after drought periods.

Multinational cholera outbreak after wedding in the Dominican Republic.

We conducted a case­control study of a cholera outbreak after a wedding in the Dominican Republic, January 22, 2011. Ill persons were more likely to report having consumed shrimp on ice (odds ratio 8.50) and ice cubes in beverages (odds ratio 3.62). Travelers to cholera affected areas should avoid consuming uncooked seafood and untreated water.

Geographic profiling as a novel spatial tool for targeting infectious disease control.

BACKGROUND: Geographic profiling is a statistical tool originally developed in criminology to prioritise large lists of suspects in cases of serial crime. Here, we use two data sets--one historical and one modern--to show how it can be used to locate the sources of infectious disease. RESULTS: First, we re-analyse data from a classic epidemiological study, the 1854 London cholera outbreak. Using 321 disease sites as input, we evaluate the locations of 13 neighbourhood water pumps. The Broad Street pump--the outbreak's source--ranks first, situated in the top 0.2% of the geoprofile. We extend our study with an analysis of reported malaria cases in Cairo, Egypt, using 139 disease case locations to rank 59 mosquitogenic local water sources, seven of which tested positive for the vector Anopheles sergentii. Geographic profiling ranks six of these seven sites in positions 1-6, all in the top 2% of the geoprofile. In both analyses the method outperformed other measures of spatial central tendency. CONCLUSIONS: We suggest that geographic profiling could form a useful component of integrated control strategies relating to a wide variety of infectious diseases, since evidence-based targeting of interventions is more efficient, environmentally friendly and cost-effective than untargeted intervention.

A De in the life of cholera.

The 50-year commemoration of S.N. De's seminal 1959 publication in Nature provides an opportunity to reflect on scientific discovery, recognition, and public health. De's paper marked the first major conceptual advance in cholera research since 1884, when Robert Koch definitively identified Der Kommabazillus as the aetiological agent of cholera. Unfortunately, Koch reported that systemic toxinosis and multi-organ failure led to severe dehydrating diarrhoea, thereby mistaking cause for effect. As a consequence, while work on other microbial pathogens advanced into the development of vaccines and therapeutics, cholera research languished as scientists injected animals parenterally in decades of futile effort to develop an animal model of diarrhoea. This fundamental misconception in cholera pathogenesis was swept away when S.N. De used ligated loops of rabbit ileum to demonstrate lumenal fluid accumulation in the presence of Vibrio cholerae culture filtrates. After some delay, De's observation of a diarrhoeagenic exotoxin became the founding principle of modern cholera research, vaccination, and treatment; and a burst of discovery saw V. cholerae transformed into the enteric pathogen best understood at the molecular level. The scientific basis for orally administering vaccines to induce mucosal immunity was established, and the success of oral rehydration, what has been described as one of the 20 th century's most important medical advances, was explained. Nobel laureate Joshua Lederberg wrote of De's iconoclastic creativity, experimental skill, and observational mastery, and many other leaders in the field concurred. De was nominated for the Nobel Prize in Physiology or Medicine more than once. But despite the passage of half a century from De's work, cholera remains a frustrating problem: we are clearly missing something. In reviewing the scientific and programmatic impact of S.N. De on cholera, it is clear that a defining victory against the disease is achievable, but only if basic scientific discoveries are relentlessly driven towards progress in public health.

Mucosal penetration primes Vibrio cholerae for host colonization by repressing quorum sensing.

To successfully infect a host and cause the diarrheal disease cholera, Vibrio cholerae must penetrate the intestinal mucosal layer and express virulence genes. Previous studies have demonstrated that the transcriptional regulator HapR, which is part of the quorum sensing network in V. cholerae, represses the expression of virulence genes. Here, we show that hapR expression is also modulated by the regulatory network that governs flagellar assembly. Specifically, FliA, which is the alternative sigma-factor (sigma(28)) that activates late-class flagellin genes in V. cholerae, represses hapR expression. In addition, we show that mucin penetration by V. cholerae is sufficient to break flagella and so cause the secretion of FlgM, the anti-sigma factor that inhibits FliA activity. During initial colonization of host intestinal tissue, hapR expression is repressed because of low cell density. However, full repression of hapR expression does not occur in fliA mutants, which results in attenuated colonization. Our results suggest that V. cholerae uses flagellar machinery to sense particular intestinal signals before colonization and enhance the expression of virulence genes by modulating the output of quorum sensing signaling.