Publications by authors named "Martin Mengel"

30 Publications

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Epidemiology of cholera.

Vaccine 2020 02 5;38 Suppl 1:A31-A40. Epub 2019 Aug 5.

iccdr,b, GPO Box 128, Dhaka 1000, Bangladesh; UCLA Fielding School of Public Health, 650 Charles E Young Drive South, Los Angeles, CA 90095-1772, USA.

Cholera is an ancient disease that remains a public health problem in many impoverished locations around the world. Seven pandemics of cholera have been recorded since the first pandemic in 1817, the last of which is on going. Overcrowding, poverty, insufficient water and sanitation facilities increase the risk for cholera outbreaks. The epidemiology of cholera in the areas in Asia, Africa and the Americas where the disease occurs continues to evolve.
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http://dx.doi.org/10.1016/j.vaccine.2019.07.078DOI Listing
February 2020

Cholera prevention and control in Asian countries.

BMC Proc 2018 7;12(Suppl 13):62. Epub 2018 Dec 7.

26World Health Organization, New Delhi, India.

Cholera remains a major public health problem in many countries. Poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries. In March 2017, a group of experts from 10 Asian cholera-prone countries that belong to the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA), together with representatives from the World Health Organization, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs (Save the Children) and UNICEF, met in Hanoi (Vietnam) to share progress in terms of prevention and control interventions on water, sanitation and hygiene (WASH), surveillance and oral cholera vaccine use. This paper reports on the country situation, gaps identified in terms of cholera prevention and control and strategic interventions to bridge these gaps.
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http://dx.doi.org/10.1186/s12919-018-0158-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284268PMC
December 2018

Oral cholera vaccination in hard-to-reach communities, Lake Chilwa, Malawi.

Bull World Health Organ 2018 Dec 27;96(12):817-825. Epub 2018 Sep 27.

Epicentre, 8 rue Saint-Sabin, 75011 Paris, France.

Objective: To evaluate vaccination coverage, identify reasons for non-vaccination and assess satisfaction with two innovative strategies for distributing second doses in an oral cholera vaccine campaign in 2016 in Lake Chilwa, Malawi, in response to a cholera outbreak.

Methods: We performed a two-stage cluster survey. The population interviewed was divided in three strata according to the second-dose vaccine distribution strategy: (i) a standard strategy in 1477 individuals (68 clusters of 5 households) on the lake shores; (ii) a simplified cold-chain strategy in 1153 individuals (59 clusters of 5 households) on islands in the lake; and (iii) an out-of-cold-chain strategy in 295 fishermen (46 clusters of 5 to 15 fishermen) in floating homes, called .

Finding: Vaccination coverage with at least one dose was 79.5% (1153/1451) on the lake shores, 99.3% (1098/1106) on the islands and 84.7% (200/236) on . Coverage with two doses was 53.0% (769/1451), 91.1% (1010/1106) and 78.8% (186/236), in the three strata, respectively. The most common reason for non-vaccination was absence from home during the campaign. Most interviewees liked the novel distribution strategies.

Conclusion: Vaccination coverage on the shores of Lake Chilwa was moderately high and the innovative distribution strategies tailored to people living on the lake provided adequate coverage, even among hard-to-reach communities. Community engagement and simplified delivery procedures were critical for success. Off-label, out-of-cold-chain administration of oral cholera vaccine should be considered as an effective strategy for achieving high coverage in hard-to-reach communities. Nevertheless, coverage and effectiveness must be monitored over the short and long term.
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http://dx.doi.org/10.2471/BLT.17.206417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249704PMC
December 2018

Oral cholera vaccine coverage during a preventive door-to-door mass vaccination campaign in Nampula, Mozambique.

PLoS One 2018 3;13(10):e0198592. Epub 2018 Oct 3.

Agence de Médecine Préventive, Paris, France.

Background: In addition to improving water, sanitation and hygiene (WASH) measures and optimal case management, the introduction of Oral cholera vaccine (OCV) is a complementary strategy for cholera prevention and control for vulnerable population groups. In October 2016, the Mozambique Ministry of Health implemented a mass vaccination campaign using a two-dose regimen of the Shanchol™ OCV in six high-risk neighborhoods of Nampula city, in Northern Mozambique. Overall 193,403 people were targeted by the campaign, which used a door-to-door strategy. During campaign follow-up, a population survey was conducted to assess: (1) OCV coverage; (2) frequency of adverse events following immunization; (3) vaccine acceptability and (4) reasons for non-vaccination.

Methodology/principal Findings: In the absence of a household listing and clear administrative neighborhood delimitations, we used geospatial technology to select households from satellite images and used the support of community leaders. One person per household was randomly selected for interview. In total, 636 individuals were enrolled in the survey. The overall vaccination coverage with at least one dose (including card and oral reporting) was 69.5% (95%CI: 51.2-88.2) and the two-dose coverage was 51.2% (95%CI: 37.9-64.3). The campaign was well accepted. Among the 185 non-vaccinated individuals, 83 (44.6%) did not take the vaccine because they were absent when the vaccination team visited their houses. Among the 451 vaccinated individuals, 47 (10%) reported minor and non-specific complaints, and 78 (17.3%) mentioned they did not receive any information before the campaign.

Conclusions/significance: In spite of overall coverage being slightly lower than expected, the use of a mobile door-to-door strategy remains a viable option even in densely-populated urban settings. Our results suggest that campaigns can be successfully implemented and well accepted in Mozambique in non-emergency contexts in order to prevent cholera outbreaks. These findings are encouraging and complement the previous Mozambican experience related to OCV.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198592PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169854PMC
March 2019

Mapping the burden of cholera in sub-Saharan Africa and implications for control: an analysis of data across geographical scales.

Lancet 2018 05 1;391(10133):1908-1915. Epub 2018 Mar 1.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Médecins sans Frontières, Geneva, Switzerland.

Background: Cholera remains a persistent health problem in sub-Saharan Africa and worldwide. Cholera can be controlled through appropriate water and sanitation, or by oral cholera vaccination, which provides transient (∼3 years) protection, although vaccine supplies remain scarce. We aimed to map cholera burden in sub-Saharan Africa and assess how geographical targeting could lead to more efficient interventions.

Methods: We combined information on cholera incidence in sub-Saharan Africa (excluding Djibouti and Eritrea) from 2010 to 2016 from datasets from WHO, Médecins Sans Frontières, ProMED, ReliefWeb, ministries of health, and the scientific literature. We divided the study region into 20 km × 20 km grid cells and modelled annual cholera incidence in each grid cell assuming a Poisson process adjusted for covariates and spatially correlated random effects. We combined these findings with data on population distribution to estimate the number of people living in areas of high cholera incidence (>1 case per 1000 people per year). We further estimated the reduction in cholera incidence that could be achieved by targeting cholera prevention and control interventions at areas of high cholera incidence.

Findings: We included 279 datasets covering 2283 locations in our analyses. In sub-Saharan Africa (excluding Djibouti and Eritrea), a mean of 141 918 cholera cases (95% credible interval [CrI] 141 538-146 505) were reported per year. 4·0% (95% CrI 1·7-16·8) of districts, home to 87·2 million people (95% CrI 60·3 million to 118·9 million), have high cholera incidence. By focusing on the highest incidence districts first, effective targeted interventions could eliminate 50% of the region's cholera by covering 35·3 million people (95% CrI 26·3 million to 62·0 million), which is less than 4% of the total population.

Interpretation: Although cholera occurs throughout sub-Saharan Africa, its highest incidence is concentrated in a small proportion of the continent. Prioritising high-risk areas could substantially increase the efficiency of cholera control programmes.

Funding: The Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S0140-6736(17)33050-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946088PMC
May 2018

Sensitivity, Specificity, and Public-Health Utility of Clinical Case Definitions Based on the Signs and Symptoms of Cholera in Africa.

Am J Trop Med Hyg 2018 04 22;98(4):1021-1030. Epub 2018 Feb 22.

Agence de Medecine Préventive, Paris, France.

During 2014, Africa reported more than half of the global suspected cholera cases. Based on the data collected from seven countries in the African Cholera Surveillance Network (Africhol), we assessed the sensitivity, specificity, and positive and negative predictive values of clinical cholera case definitions, including that recommended by the World Health Organization (WHO) using culture confirmation as the gold standard. The study was designed to assess results in real-world field situations in settings with recent cholera outbreaks or endemicity. From June 2011 to July 2015, a total of 5,084 persons with suspected cholera were tested for in seven different countries of which 35.7% had culture confirmation. For all countries combined, the WHO case definition had a sensitivity = 92.7%, specificity = 8.1%, positive predictive value = 36.1%, and negative predictive value = 66.6%. Adding dehydration, vomiting, or rice water stools to the case definition could increase the specificity without a substantial decrease in sensitivity. Future studies could further refine our findings primarily by using more sensitive methods for cholera confirmation.
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http://dx.doi.org/10.4269/ajtmh.16-0523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928804PMC
April 2018

Temporo-spatial dynamics and behavioural patterns of 2012 cholera epidemic in the African mega-city of Conakry, Guinea.

Infect Dis Poverty 2018 Feb 15;7(1):13. Epub 2018 Feb 15.

Division Prévention et Lutte contre la Maladie (DPLM), Ministère de la santé Publique et de l'Hygiène Publique Conakry, Conakry, Guinea.

Background: Cholera is endemic in Guinea, having suffered consecutive outbreaks from 2004 to 2008 followed by a lull until the 2012 epidemic. Here we describe the temporal-spatial and behavioural characteristics of cholera cases in Conakry during a three-year period, including the large-scale 2012 epidemic.

Methods: We used the national and African Cholera Surveillance Network (Africhol) surveillance data collected from every cholera treatment centre in Conakry city from August 2011 to December 2013. The prevalence of suspect and confirmed cholera cases, the case fatality ratio (CFR), and the factors associated with suspected cholera were described according to three periods: pre-epidemic (A), epidemic 2012 (B) and post epidemic (C). Weekly attack rates and temporal-spatial clustering were calculated at municipality level for period B. Cholera was confirmed by culture at the cholera national reference laboratory.

Results: A total of 4559 suspect cases were reported: 66, 4437, and 66 suspect cases in periods A, B and C, respectively. Among the 204 suspect cases with culture results available, 6%, 60%, and 70% were confirmed in periods A, B, and C, respectively. With 0.3%, the CFR was significantly lower in period B than in periods A (7.6%) and C (7.1%). The overall attack rate was 0.28% in period B, ranging from 0.17% to 0.31% across municipalities. Concomitantly, a cluster of cases was identified in two districts in the northern part of Conakry. At 14%, rice water stools were less frequent in period A than in period B and C (78% and 84%). Dehydration (31% vs 94% and 89%) and coma (0.4% vs 3.1% and 2.9%) were lower during period B than in periods A and C. The treatment of drinking water was less frequent in period A, while there were more reports of recent travel in period C.

Conclusions: The epidemic dynamic and the sociological description of suspect cases before, during, and after the large-scale epidemic revealed that the Vibrio cholerae was already present before the epidemic. However, it appeared that infected individuals reacted differently in terms of disease severity as well as their access to treated water and travel habits. Such an in-depth description of cholera epidemics should be systematically carried out in cholera endemic settings in order to prioritize higher risk areas, identify transmission factors, and optimize preventive interventions.
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http://dx.doi.org/10.1186/s40249-018-0393-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815196PMC
February 2018

A rapid qualitative assessment of oral cholera vaccine anticipated acceptability in a context of resistance towards cholera intervention in Nampula, Mozambique.

Vaccine 2018 10 27;36(44):6497-6505. Epub 2017 Nov 27.

Agence de Médecine Préventive, Bât. JB Say, 4e étage, aile A, 13 chemin du Levant, 01210 Ferney-Voltaire, France.

Introduction: While planning an immunization campaign in settings where public health interventions are subject to politically motivated resistance, designing context-based social mobilization strategies is critical to ensure community acceptability. In preparation for an Oral Cholera Vaccine campaign implemented in Nampula, Mozambique, in November 2016, we assessed potential barriers and levers for vaccine acceptability.

Methods: Questionnaires, in-depth interviews, and focus group discussions, as well as observations, were conducted before the campaign. The participants included central and district level government informants (national immunization program, logistics officers, public health directors, and others), community leaders and representatives, and community members.

Results: During previous well chlorination interventions, some government representatives and health agents were attacked, because they were believed to be responsible for spreading cholera instead of purifying the wells. Politically motivated resistance to cholera interventions resurfaced when an OCV campaign was considered. Respondents also reported vaccine hesitancy related to experiences of problems during school-based vaccine introduction, rumors related to vaccine safety, and negative experiences following routine childhood immunization. Despite major suspicions associated with the OCV campaign, respondents' perceived vulnerability to cholera and its perceived severity seem to override potential anticipated OCV vaccine hesitancy.

Discussion: Potential hesitancy towards the OCV campaign is grounded in global insecurity, social disequilibrium, and perceived institutional negligence, which reinforces a representation of estrangement from the central government, triggering suspicions on its intentions in implementing the OCV campaign. Recommendations include a strong involvement of community leaders, which is important for successful social mobilization; representatives of different political parties should be equally involved in social mobilization efforts, before and during campaigns; and public health officials should promote other planned interventions to mitigate the lack of trust associated with perceived institutional negligence. Successful past initiatives include public intake of purified water or newly introduced medication by social mobilizers, teachers or credible leaders.
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http://dx.doi.org/10.1016/j.vaccine.2017.10.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190029PMC
October 2018

Innovative vaccine delivery strategies in response to a cholera outbreak in the challenging context of Lake Chilwa. A rapid qualitative assessment.

Vaccine 2018 10 7;36(44):6491-6496. Epub 2017 Nov 7.

Agence de Médecine Préventive, Ferney-Voltaire, France.

A reactive campaign using two doses of Shanchol Oral Cholera Vaccine (OCV) was implemented in 2016 in the Lake Chilwa Region (Malawi) targeting fish dependent communities. Three strategies for the second vaccine dose delivery (including delivery by a community leader and self-administration) were used to facilitate vaccine access. This assessment collected vaccine perceptions and opinions about the OCV campaign of 313 study participants, including: fishermen, fish traders, farmers, community leaders, and one health and one NGO officer. Socio-demographic surveys were conducted, In Depth Interviews and Focus Group Discussions were conducted before and during the campaign. Some fishermen perceived the traditional delivery strategy as reliable but less practical. Delivery by traditional leaders was acceptable for some participants while others worried about traditional leaders not being trained to deliver vaccines or beneficiaries taking doses on their own. A slight majority of beneficiaries considered the self-administration strategy practical while some beneficiaries worried about storing vials outside of the cold chain or losing vials. During the campaign, a majority of participants preferred receiving oral vaccines instead of injections given ease of intake and lack of pain. OCV was perceived as efficacious and safe. However, a lack of information on how sero-protection may be delayed and the degree of sero-protection led to loss of trust in vaccine potency among some participants who witnessed cholera cases among vaccinated individuals. OCV campaign implementation requires accompanying communication on protective levels, less than 100% vaccine efficacy, delays in onset of sero-protection, and out of cold chain storage.
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http://dx.doi.org/10.1016/j.vaccine.2017.10.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189868PMC
October 2018

Genomic history of the seventh pandemic of cholera in Africa.

Science 2017 11;358(6364):785-789

Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

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 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.
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http://dx.doi.org/10.1126/science.aad5901DOI Listing
November 2017

Cost-of-illness of cholera to households and health facilities in rural Malawi.

PLoS One 2017 21;12(9):e0185041. Epub 2017 Sep 21.

Agence de Médecine Préventive, Ferney-Voltaire, France.

Cholera remains an important public health problem in many low- and middle-income countries. Vaccination has been recommended as a possible intervention for the prevention and control of cholera. Evidence, especially data on disease burden, cost-of-illness, delivery costs and cost-effectiveness to support a wider use of vaccine is still weak. This study aims at estimating the cost-of-illness of cholera to households and health facilities in Machinga and Zomba Districts, Malawi. A cross-sectional study using retrospectively collected cost data was undertaken in this investigation. One hundred patients were purposefully selected for the assessment of the household cost-of-illness and four cholera treatment centres and one health facility were selected for the assessment conducted in health facilities. Data collected for the assessment in households included direct and indirect costs borne by cholera patients and their families while only direct costs were considered for the assessment conducted in health facilities. Whenever possible, descriptive and regression analysis were used to assess difference in mean costs between groups of patients. The average costs to patients' households and health facilities for treating an episode of cholera amounted to US$65.6 and US$59.7 in 2016 for households and health facilities, respectively equivalent to international dollars (I$) 249.9 and 227.5 the same year. Costs incurred in treating a cholera episode were proportional to duration of hospital stay. Moreover, 52% of households used coping strategies to compensate for direct and indirect costs imposed by the disease. Both households and health facilities could avert significant treatment expenditures through a broader use of pre-emptive cholera vaccination. These findings have direct policy implications regarding priority investments for the prevention and control of cholera.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185041PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608291PMC
October 2017

The African cholera surveillance network (Africhol) consortium meeting, 10-11 June 2015, Lomé, Togo.

BMC Proc 2017 31;11(Suppl 1). Epub 2017 Jan 31.

Agence de Médecine Préventive, 21 bd Pasteur, 75015 Paris, France.

The fifth annual meeting of the African cholera surveillance network (Africhol) took place on 10-11 June 2015 in Lomé, Togo. Together with international partners, representatives from the 11 member countries -Cameroon, Côte d'Ivoire, Democratic Republic of Congo, Guinea, Kenya, Mozambique, Nigeria, Tanzania, Togo, Uganda, Zimbabwe- and an invited country (Malawi) shared their experience. The meeting featured three sessions: i) cholera surveillance, prevention and control in participating countries, ii) cholera surveillance methodology, such as cholera mapping, cost-effectiveness studies and the issue of overlapping epidemics from different diseases, iii) cholera laboratory diagnostics tools and capacity building. The meeting has greatly benefitted from the input of technical expertise from participating institutions and the observations emerging from the meeting should enable national teams to make recommendations to their respective governments on the most appropriate and effective measures to be taken for the prevention and control of cholera. Recommendations for future activities included collecting precise burden estimates in surveillance sites; modeling cholera burden for Africa; setting up cross-border collaborations; strengthening laboratory capacity for the confirmation of suspected cholera cases and for vaccine impact assessment in settings where oral cholera vaccine would be used; adapting cholera surveillance to concurrent issues (e.g., Ebola); and developing national cholera control plans including rationale vaccination strategies together with other preventive and control measures such as improvements in water, sanitation and hygiene (WASH).
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http://dx.doi.org/10.1186/s12919-016-0068-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301166PMC
January 2017

Oral cholera vaccine coverage in hard-to-reach fishermen communities after two mass Campaigns, Malawi, 2016.

Vaccine 2017 09 10;35(38):5194-5200. Epub 2017 Aug 10.

Ministry of Health, Community Health Sciences Unit, Lilongwe, Malawi. Electronic address:

Context: From December 2015 to August 2016, a large epidemic of cholera affected the fishermen of Lake Chilwa in Malawi. A first reactive Oral Cholera Vaccines (OCV) campaign was organized, in February, in a 2km radius of the lake followed by a preemptive one, conducted in November, in a 25km radius. We present the vaccine coverage reached in hard-to-reach population using simplified delivery strategies.

Method: We conducted two-stage random-sampling cross-sectional surveys among individuals living in a 2km and 25km radius of Lake Chilwa (islands and floating homes included). Individuals aged 12months and older from Machinga and Zomba districts were sampled: 43 clusters of 14 households were surveyed. Simplified strategies were used for those living in islands and floating homes: self- delivery and community-supervised delivery of the second dose. Vaccine coverage (VC) for at-least-two-doses was estimated taking into account sampling weights and design effects.

Results: A total of 1176 households were surveyed (2.7% of non-response). Among the 2833 individuals living in the 2km radius of Lake and the 2915 in the 25km radius: 457 (16.1%) and 239 (8.2%) lived in floating homes or on islands at some point in the year, respectively. For the overall population, VC was 75.6% and 54.2%, respectively. In the 2km radius, VC was 92.2% for those living on the lake at some point of the year: 271 (64.8%) used the simplified strategies. The main reasons for non-vaccination were absence during the campaign and vaccine shortage. Few adverse events occurring in the 24h following vaccination was reported.

Conclusions: We reached a high two-dose coverage of the most at-risk population using simplified delivery strategies. Because of the high fishermen mobility, regular catch-up campaigns or another strategy specifically targeting fishermen need to be assessed for more efficient vaccines use.
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http://dx.doi.org/10.1016/j.vaccine.2017.07.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594244PMC
September 2017

Epidemiology of cholera outbreaks and socio-economic characteristics of the communities in the fishing villages of Uganda: 2011-2015.

PLoS Negl Trop Dis 2017 03 13;11(3):e0005407. Epub 2017 Mar 13.

Agence de Médecine Préventive (AMP), Paris, France.

Background: The communities in fishing villages in the Great Lakes Region of Africa and particularly in Uganda experience recurrent cholera outbreaks that lead to considerable mortality and morbidity. We evaluated cholera epidemiology and population characteristics in the fishing villages of Uganda to better target prevention and control interventions of cholera and contribute to its elimination from those communities.

Methodology/principal Findings: We conducted a prospective study between 2011-15 in fishing villages in Uganda. We collected, reviewed and documented epidemiological and socioeconomic data for 10 cholera outbreaks that occurred in fishing communities located along the African Great Lakes and River Nile in Uganda. These outbreaks caused 1,827 suspected cholera cases and 43 deaths, with a Case-Fatality Ratio (CFR) of 2.4%. Though the communities in the fishing villages make up only 5-10% of the Ugandan population, they bear the biggest burden of cholera contributing 58% and 55% of all reported cases and deaths in Uganda during the study period. The CFR was significantly higher among males than females (3.2% vs. 1.3%, p = 0.02). The outbreaks were seasonal with most cases occurring during the months of April-May. Male children under age of 5 years, and 5-9 years had increased risk. Cholera was endemic in some villages with well-defined "hotspots". Practices predisposing communities to cholera outbreaks included: the use of contaminated lake water, poor sanitation and hygiene. Additional factors were: ignorance, illiteracy, and poverty.

Conclusions/significance: Cholera outbreaks were a major cause of morbidity and mortality among the fishing communities in Uganda. In addition to improvements in water, sanitation, and hygiene, oral cholera vaccines could play an important role in the prevention and control of these outbreaks, particularly when targeted to high-risk areas and populations. Promotion and facilitation of access to social services including education and reduction in poverty should contribute to cholera prevention, control and elimination in these communities.
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http://dx.doi.org/10.1371/journal.pntd.0005407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370135PMC
March 2017

Cholera Incidence and Mortality in Sub-Saharan African Sites during Multi-country Surveillance.

PLoS Negl Trop Dis 2016 05 17;10(5):e0004679. Epub 2016 May 17.

Agence de Medecine Preventive, Paris, France.

Background: Cholera burden in Africa remains unknown, often because of weak national surveillance systems. We analyzed data from the African Cholera Surveillance Network (www.africhol.org).

Methods/ Principal Findings: During June 2011-December 2013, we conducted enhanced surveillance in seven zones and four outbreak sites in Togo, the Democratic Republic of Congo (DRC), Guinea, Uganda, Mozambique and Cote d'Ivoire. All health facilities treating cholera cases were included. Cholera incidences were calculated using culture-confirmed cholera cases and culture-confirmed cholera cases corrected for lack of culture testing usually due to overwhelmed health systems and imperfect test sensitivity. Of 13,377 reported suspected cases, 34% occurred in Conakry, Guinea, 47% in Goma, DRC, and 19% in the remaining sites. From 0-40% of suspected cases were aged under five years and from 0.3-86% had rice water stools. Within surveillance zones, 0-37% of suspected cases had confirmed cholera compared to 27-38% during outbreaks. Annual confirmed incidence per 10,000 population was <0.5 in surveillance zones, except Goma where it was 4.6. Goma and Conakry had corrected incidences of 20.2 and 5.8 respectively, while the other zones a median of 0.3. During outbreaks, corrected incidence varied from 2.6 to 13.0. Case fatality ratios ranged from 0-10% (median, 1%) by country.

Conclusions/significance: Across different African epidemiological contexts, substantial variation occurred in cholera incidence, age distribution, clinical presentation, culture confirmation, and testing frequency. These results can help guide preventive activities, including vaccine use.
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http://dx.doi.org/10.1371/journal.pntd.0004679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871502PMC
May 2016

Comparative Characterization of Vibrio cholerae O1 from Five Sub-Saharan African Countries Using Various Phenotypic and Genotypic Techniques.

PLoS One 2015 25;10(11):e0142989. Epub 2015 Nov 25.

Centre for Enteric Diseases, National Institute for Communicable Diseases, Division in the National Health Laboratory Service (NHLS), Johannesburg, South Africa.

We used standardized methodologies to characterize Vibrio cholerae O1 isolates from Guinea, Democratic Republic of the Congo (DRC), Togo, Côte d'Ivoire and Mozambique. We investigated 257 human isolates collected in 2010 to 2013. DRC isolates serotyped O1 Inaba, while isolates from other countries serotyped O1 Ogawa. All isolates were biotype El Tor and positive for cholera toxin. All isolates showed multidrug resistance but lacked ciprofloxacin resistance. Antimicrobial susceptibility profiles of isolates varied between countries. In particular, the susceptibility profile of isolates from Mozambique (East-Africa) included resistance to ceftriaxone and was distinctly different to the susceptibility profiles of isolates from countries located in West- and Central-Africa. Molecular subtyping of isolates using pulsed-field gel electrophoresis (PFGE) analysis showed a complex relationship among isolates. Some PFGE patterns were unique to particular countries and clustered by country; while other PFGE patterns were shared by isolates from multiple countries, indicating that the same genetic lineage is present in multiple countries. Our data add to a better understanding of cholera epidemiology in Africa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142989PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659613PMC
June 2016

Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies.

BMC Pharmacol Toxicol 2015 Sep 22;16:25. Epub 2015 Sep 22.

Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

Background: The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand.

Methods/design: ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables.

Discussion: The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system.

Trial Registration: clinicaltrials.gov ID NCT02364986.
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http://dx.doi.org/10.1186/s40360-015-0025-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578256PMC
September 2015

Nosocomial Cholera Outbreak in a Mental Hospital: Challenges and Lessons Learnt from Butabika National Referral Mental Hospital, Uganda.

Am J Trop Med Hyg 2015 Sep 20;93(3):534-8. Epub 2015 Jul 20.

Control of Diarrheal Diseases Section, Ministry of Health, Kampala, Uganda; Epidemiological Surveillance Division, Ministry of Health, Kampala, Uganda; U.S. Centers for Disease Control and Prevention, Atlanta, Georgia; Central Public Health Laboratory, Kampala, Uganda; Agence de Médicine Préventive, Paris, France; Makerere University School of Public Health, Kampala, Uganda.

During the last four decades, Uganda has experienced repeated cholera outbreaks in communities; no cholera outbreaks have been reported in Ugandan health facilities. In October 2008, a unique cholera outbreak was confirmed in Butabika National Mental Referral Hospital (BNMRH), Uganda. This article describes actions taken to control the outbreak, challenges, and lessons learnt. We reviewed patient and hospital reports for clinical symptoms and signs, treatment and outcome, patient mental diagnosis, and challenges noted during management of patients and contacts. Out of 114 BNMRH patients on two affected wards, 18 cholera cases and five deaths were documented for an attack rate of 15.8% and a case fatality rate of 28%. Wards and surroundings were intensively disinfected and 96 contacts (psychiatric patients) in the affected wards received chemoprophylaxis with oral ciprofloxacin 500 mg twice daily until November 5, 2008. We documented a nosocomial cholera outbreak in BNMRH with a high case fatality of 28% compared with the national average of 2.4% for cholera outbreaks in communities. To avoid cholera outbreaks and potentially high mortality among patients in mental institutions, procedures for prompt diagnosis, treatment, disinfection, and prophylaxis are needed and preemptive use of oral cholera vaccines should be considered.
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http://dx.doi.org/10.4269/ajtmh.14-0730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559692PMC
September 2015

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy.

Gastroenterology 2015 Sep 16;149(3):660-8.e1. Epub 2015 May 16.

Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

Background & Aims: Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis.

Methods: We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures.

Results: A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups.

Conclusions: Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.
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http://dx.doi.org/10.1053/j.gastro.2015.05.011DOI Listing
September 2015

The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites): study protocol for a randomized controlled trial.

Trials 2015 Mar 8;16:83. Epub 2015 Mar 8.

Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.

Background: Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP.

Methods/design: The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥ 15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014.

Discussion: Preventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms.

Trial Registrations: German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.
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http://dx.doi.org/10.1186/s13063-015-0594-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359533PMC
March 2015

Deciphering the origin of the 2012 cholera epidemic in Guinea by integrating epidemiological and molecular analyses.

PLoS Negl Trop Dis 2014 Jun 5;8(6):e2898. Epub 2014 Jun 5.

Aix-Marseille Université, UMD 3, Marseille, France.

Cholera is typically considered endemic in West Africa, especially in the Republic of Guinea. However, a three-year lull period was observed from 2009 to 2011, before a new epidemic struck the country in 2012, which was officially responsible for 7,350 suspected cases and 133 deaths. To determine whether cholera re-emerged from the aquatic environment or was rather imported due to human migration, a comprehensive epidemiological and molecular survey was conducted. A spatiotemporal analysis of the national case databases established Kaback Island, located off the southern coast of Guinea, as the initial focus of the epidemic in early February. According to the field investigations, the index case was found to be a fisherman who had recently arrived from a coastal district of neighboring Sierra Leone, where a cholera outbreak had recently occurred. MLVA-based genotype mapping of 38 clinical Vibrio cholerae O1 El Tor isolates sampled throughout the epidemic demonstrated a progressive genetic diversification of the strains from a single genotype isolated on Kaback Island in February, which correlated with spatial epidemic spread. Whole-genome sequencing characterized this strain as an "atypical" El Tor variant. Furthermore, genome-wide SNP-based phylogeny analysis grouped the Guinean strain into a new clade of the third wave of the seventh pandemic, distinct from previously analyzed African strains and directly related to a Bangladeshi isolate. Overall, these results highly suggest that the Guinean 2012 epidemic was caused by a V. cholerae clone that was likely imported from Sierra Leone by an infected individual. These results indicate the importance of promoting the cross-border identification and surveillance of mobile and vulnerable populations, including fishermen, to prevent, detect and control future epidemics in the region. Comprehensive epidemiological investigations should be expanded to better understand cholera dynamics and improve disease control strategies throughout the African continent.
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http://dx.doi.org/10.1371/journal.pntd.0002898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046952PMC
June 2014

Use of Vibrio cholerae vaccine in an outbreak in Guinea.

N Engl J Med 2014 May;370(22):2111-20

From Epicentre (F.J.L., L.G., A.-L.P., R.F.G.), African Cholera Surveillance Network, Agence de Médicine Préventive (K.S., M.A.M.), and National Reference Center for Vibrios and Cholera, Enteric Bacterial Pathogens Research and Expertise Unit, Institut Pasteur (M.-L.Q.) - all in Paris; Médecins sans Frontières, Geneva (L.G., I.C., M.S., D.L.); Ministry of Health (K.S.), Direction Préfectorale de la Santé (B.T.) and Research and Documentation Service, Ministry of Health (A.A.D.), Médecins sans Frontières (M.H.), and World Health Organization (C.I.) - all in Conakry, Guinea; and the Department of Microbiology, University of Valladolid, Valladolid, Spain (J.M.E.).

Background: The use of vaccines to prevent and control cholera is currently under debate. Shanchol is one of the two oral cholera vaccines prequalified by the World Health Organization; however, its effectiveness under field conditions and the protection it confers in the first months after administration remain unknown. The main objective of this study was to estimate the short-term effectiveness of two doses of Shanchol used as a part of the integrated response to a cholera outbreak in Africa.

Methods: We conducted a matched case-control study in Guinea between May 20 and October 19, 2012. Suspected cholera cases were confirmed by means of a rapid test, and controls were selected among neighbors of the same age and sex as the case patients. The odds of vaccination were compared between case patients and controls in bivariate and adjusted conditional logistic-regression models. Vaccine effectiveness was calculated as (1-odds ratio)×100.

Results: Between June 8 and October 19, 2012, we enrolled 40 case patients and 160 controls in the study for the primary analysis. After adjustment for potentially confounding variables, vaccination with two complete doses was associated with significant protection against cholera (effectiveness, 86.6%; 95% confidence interval, 56.7 to 95.8; P=0.001).

Conclusions: In this study, Shanchol was effective when used in response to a cholera outbreak in Guinea. This study provides evidence supporting the addition of vaccination as part of the response to an outbreak. It also supports the ongoing efforts to establish a cholera vaccine stockpile for emergency use, which would enhance outbreak prevention and control strategies. (Funded by Médecins sans Frontières.).
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http://dx.doi.org/10.1056/NEJMoa1312680DOI Listing
May 2014

Cholera in Africa: new momentum in fighting an old problem.

Authors:
Martin A Mengel

Trans R Soc Trop Med Hyg 2014 Jul;108(7):391-2

Cholera remains a grave public health problem in Africa. It is endemic with seasonal variations around the central African Great Lakes. Along the coasts, it occurs mostly in rapidly expanding epidemics, with intercalated 3-5 year lull-periods. Case-fatality ratios remain high at 2–5% against the global declining trend. Insufficient safe water and sanitation coverage are the main causes of persistent cholera in Africa and this is unlikely to improve soon. However, an efficacious oral cholera vaccine is now available and new groups and initiatives like the African Cholera Surveillance Network (Africhol) allow countries to enhance their capacities for an integrated cross-border approach using all means necessary to tackle cholera in Africa.
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http://dx.doi.org/10.1093/trstmh/tru077DOI Listing
July 2014

Cholera outbreaks in Africa.

Curr Top Microbiol Immunol 2014 ;379:117-44

Agence de Médecine Préventive, 164 rue de Vaugirard, 75015, Paris, France,

During the current seventh cholera pandemic, Africa bore the major brunt of global disease burden. More than 40 years after its resurgence in Africa in 1970, cholera remains a grave public health problem, characterized by large disease burden, frequent outbreaks, persistent endemicity, and high CFRs, particularly in the region of the central African Great Lakes which might act as reservoirs for cholera. There, cases occur year round with a rise in incidence during the rainy season. Elsewhere in sub-Saharan Africa, cholera occurs mostly in outbreaks of varying size with a constant threat of widespread epidemics. Between 1970 and 2011, African countries reported 3,221,050 suspected cholera cases to the World Health Organization, representing 46 % of all cases reported globally. Excluding the Haitian epidemic, sub-Saharan Africa accounted for 86 % of reported cases and 99 % of deaths worldwide in 2011. The number of cholera cases is possibly much higher than what is reported to the WHO due to the variation in modalities, completeness, and case definition of national cholera data. One source on country specific incidence rates for Africa, adjusting for underreporting, estimates 1,341,080 cases and 160,930 deaths (52.6 % of 2,548,227 estimated cases and 79.6 % of 209,216 estimated deaths worldwide). Another estimates 1,411,453 cases and 53,632 deaths per year, respectively (50 % of 2,836,669 estimated cases and 58.6 % of 91,490 estimated deaths worldwide). Within Africa, half of all cases between 1970 and 2011 were notified from only seven countries: Angola, Democratic Republic of the Congo, Mozambique, Nigeria, Somalia, Tanzania, and South Africa. In contrast to a global trend of decreasing case fatality ratios (CFRs), CFRs have remained stable in Africa at approximately 2 %. Early propagation of cholera outbreaks depends largely on the extent of individual bacterial shedding, host and organism characteristics, the likelihood of people coming into contact with an infectious dose of Vibrio cholerae and on the virulence of the implicated strain. Cholera transmission can then be amplified by several factors including contamination of human water- or food sources; climate and extreme weather events; political and economic crises; high population density combined with poor quality informal housing and poor hygiene practices; spread beyond a local community through human travel and animals, e.g., water birds. At an individual level, cholera risk may increase with decreasing immunity and hypochlorhydria, such as that induced by Helicobacter pylori infection, which is endemic in much of Africa, and may increase individual susceptibility and cholera incidence. Since contaminated water is the main vehicle for the spread of cholera, the obvious long-term solution to eradicate the disease is the provision of safe water to all African populations. This requires considerable human and financial resources and time. In the short and medium term, vaccination may help to prevent and control the spread of cholera outbreaks. Regardless of the intervention, further understanding of cholera biology and epidemiology is essential to identify populations and areas at increased risk and thus ensure the most efficient use of scarce resources for the prevention and control of cholera.
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http://dx.doi.org/10.1007/82_2014_369DOI Listing
November 2014

Elimination of cholera in the democratic Republic of the Congo: the new national policy.

J Infect Dis 2013 Nov;208 Suppl 1:S86-91

Service de Microbiologie, Département de Biologie Médicale, Faculté de Médecine, Université de Kinshasa, Kinshasa, Republique Democratique du Congo.

We evaluated published and unpublished data on cholera cases and deaths reported from clinical care facilities in the 56 health districts of the Democratic Republic of Congo to the National Ministry of Health during 2000-2011. Cholera incidence was highest in the eastern provinces bordering lakes and epidemics primarily originated in this region. Along with a strong seasonal component, our data suggest a potential Vibrio cholerae reservoir in the Rift Valley lakes and the possible contribution of the lakes' fishing industry to the spread of cholera. The National Ministry of Health has committed to the elimination-rather than control-of cholera in DRC and has adopted a new national policy built on improved alert, response, case management, and prevention. To achieve this goal and implement all these measures it will require strong partners in the international community with a similar vision.
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http://dx.doi.org/10.1093/infdis/jit204DOI Listing
November 2013

Cholera surveillance in Uganda: an analysis of notifications for the years 2007-2011.

J Infect Dis 2013 Nov;208 Suppl 1:S78-85

Ministry of Health Uganda, Control of Diarrheal Diseases Unit.

Introduction: Cholera outbreaks have occurred periodically in Uganda since 1971. The country has experienced intervals of sporadic cases and localized outbreaks, occasionally resulting in prolonged widespread epidemics.

Methods: Cholera surveillance data reported to the Uganda Ministry of Health from 2007 through 2011 were reviewed to determine trends in annual incidence and case fatality rate. Demographic characteristics of cholera cases were analyzed from the national line list for 2011. Cases were analyzed by district and month of report to understand the geographic distribution and identify any seasonal patterns of disease occurrence.

Results: From 2007 through 2011, Uganda registered a total of 7615 cholera cases with 181 deaths (case fatality rate = 2.4%). The absolute number of cases and incidence per 100 000 varied from year to year with the highest incidence occurring in 2008 following heavy rainfall and flooding in eastern Uganda. For 2011, cholera cases occurred in 1.6 times more males than females. The geographical areas affected by the outbreaks shifted each year, with the exception of a few endemic districts. No clear seasonal trends in cholera occurrence were identified for this time period.

Conclusions: We observed an overall decline in cases reported during the 5 years under review. During this period, concerted efforts were made by the Ugandan government and development partners to educate communities on proper sanitation and hygiene and provide safe water and timely treatment. Mechanisms to ensure timely and complete cholera surveillance data are reported to the national level should continue to be strengthened.
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November 2013

Editorial committee introduction.

J Infect Dis 2013 Nov;208 Suppl 1:S1-3

Agence de Medecine Preventive, Paris, France.

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http://dx.doi.org/10.1093/infdis/jit403DOI Listing
November 2013

Influence of time after extraction on the development of gingival invagination: study protocol for a multicenter pilot randomized controlled clinical trial.

Trials 2013 Apr 24;14:108. Epub 2013 Apr 24.

Department of Orthodontics, University Hospital Bonn, Welschnonnenstraße 17, 53111 Bonn, Germany.

Background: Gingival invaginations are a common side effect of orthodontic therapy involving tooth extraction and subsequent space closure. Consequences of gingival invaginations are a jeopardized stability of the space closure and hampered oral hygiene. In a retrospective study, the factor time until initiation of orthodontic space closure after tooth extraction has been identified as a potential risk factor for the development of gingival invaginations. The aim of this pilot study is to proof this hypothesis and to enable a caseload calculation for further clinical trials. The referring question is: is it possible to reduce the number of developing gingival invaginations by initiation of orthodontic space closure after tooth extraction at an early point of time?

Design: The intended pilot study is designed as a multicenter randomized controlled clinical trial, comparing the impact of two different time intervals from tooth extraction to initiation of orthodontic space closure on the development of gingival invaginations.Forty participants, men and women in the age range of 11 to 30 years with orthodontically related indication for tooth extraction in the lower jaw, will be randomized 1:1 in one of two treatment groups. In group A the orthodontic tooth movement into the extraction area will be initiated in a time interval 2 to 4 weeks after tooth extraction. In group B the tooth movement will be initiated in a time interval >12 weeks after extraction. A possible effect of these treatment modalities on the development of gingival invaginations will be documented at the moment of space closure or 10 months +/- 14 days after initiation of space closure respectively, by clinical documentation of the primary (reduced number of gingival invagination) and the secondary endpoint (reduction of the severity of gingival invaginations).

Trial Registration: Universal Trial Number U1111-1132-6655; German Clinical Trials Register DRKS00004248.
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http://dx.doi.org/10.1186/1745-6215-14-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748838PMC
April 2013

VKORC1-dependent pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation.

Eur J Clin Pharmacol 2013 Mar 5;69(3):467-75. Epub 2012 Aug 5.

Institute of Experimental Hematology and Transfusion Medicine, University Clinics Bonn, Sigmund- Freud-Strasse 25, 53127 Bonn, Germany.

Objective: The pharmacokinetics of phylloquinone (vitamin K1) were evaluated in healthy human adult volunteers (15 male and 15 female) following oral and intravenous administration of a mixed micelles formulation (Konakion MM 2 mg) in an open label study design. The subjects were allocated to one of three genotype-specific groups (n = 10 in each group) in terms of VKORC1 promoter polymorphism c.-1639 G > A to explore the relationship between genotype and pharmacokinetic parameters.

Methods: Blood samples were collected for up to 24 h after administration. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. Pharmacokinetic evaluation was performed using non-compartmental analysis.

Results: Pharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in the main pharmacokinetic parameters between groups. Upon oral administration, VKORC1 AG carriers showed 41 % higher mean bioavailability (p = 0.01) compared with homozygous AA individuals. Furthermore, AG subjects exhibited 30 % (p = 0.042) and 36 % (p = 0.021) higher mean AUC compared with GG and AA respectively. Terminal half-life was 32 % and 27 % longer for AG carriers in comparison to GG (p = 0.004) and AA (p = 0.015) genotypes respectively.

Conclusion: Pharmacokinetic differences indicated significant inter-individual variance of vitamin K fate in the human body. The influence of the VKORC1 promoter polymorphism c.-1639 G > A on the pharmacokinetic properties of phylloquinone could be demonstrated in humans. To gain deeper insight in other potential genetic determinants of systemic vitamin K exposure, further correlation of the phenotype-genotype relationship of different players in vitamin K turnover has to be gained.
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http://dx.doi.org/10.1007/s00228-012-1362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572390PMC
March 2013