The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

Understanding monogenic Parkinson's disease at a global scale.

Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's (GP2) Monogenic Network took a different approach by targeting PD centers not yet represented in the medical literature. Here, we describe combining both efforts in a "merger project" resulting in a global monogenic PD cohort with build-up of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expression of monogenic PD. This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results.

Diffuseur artisanal de chlore pour desinfecter les puits lors de l'epidemie de cholera de Douala (2004)

La chloration des puits est recommandee en cas d'epidemie de cholera. Mais les techniques de chloration sont mal codifiees; leur efficacite n'a pas ete prouvee; et l'on ne sait pas a quel rythme doit se faire la chloration. L'objectif etait de tester un dispositif artisanal de chloration continue; mesurer les taux de chlore residuel libre obtenus; et en suivre l'evolution; pour prevoir le delai de renouvellement. Dans 2 quartiers de Douala; 18 puits (9/quartier) ont fait l'objet de la mesure quotidienne pendant deux semaines du volume d'eau; du pH et du chlore residuel; apres installation d'un diffuseur artisanal a base de sable et d'hypochlorite de calcium dans un sachet plastique perfore; renouvele apres annulation des taux de chlore. La concentration maximumde chlore residuel libre a ete atteinte apres 1 jour (31 chlorations sur 36) ou 2 jours (5 sur 36). Elle est demeuree superieure au niveau minimum de 0;2mg/l pendant au moins 48 heures dans 33 des 36 chlorations. A J4; la moitie des puits avaient une concentration de chlore inferieure a 0;2 mg/l. La concentration de chlore etait plus elevee dans les puits familiaux que dans les puits communautaires .Malgre des difficultes de faisabilite et d'acceptabilite; le diffuseur propose a permis d'assurer la diffusion de chlore a des taux efficaces et non toxiques pendant 3 jours. Des systemes de diffusion plus prolongee et moins couteux devraient pouvoir etre proposes; dans le cadre d'actions integrees de lutte contre une epidemie de chlolera

[Handmade devices for continuous delivery of hypochlorite for well disinfection during the cholera outbreak in Douala, Cameroon (2004)]. / Diffuseur artisanal de chlore pour désinfecter les puits lors de l'épidémie de choléra de Douala (2004).

Well disinfection is generally recommended as an emergency response measure during cholera outbreaks. However few studies have been carried out to document chlorination techniques, prove the efficacy of chlorination, or determine how often disinfection should be performed. The purpose of this study was to test a handmade device for continuous chlorination, to measure the initial concentration of free residual chlorine, and monitor chlorine concentration to determine when renewal is necessary. Eighteen wells in 2 neighbors of Douala, Cameroon, i.e., 9 wells/neighborhood, were tested. Testing included daily measurement of water volume, pH, and residual chlorine for a period of two weeks after installing the handmade device composed of river sand and hypochlorite in a pre-perforated plastic bag that was renewed after disappearance of free residual chlorine. The maximum concentration of residual chlorine was reached after 1 day in 31 out of 36 chlorinations or 2 days in 5 out of 36. On day 4 the chlorine level was less than 0.2 mg/l in half of the wells. The chlorine concentration was higher in family than community wells. Notwithstanding feasibility and acceptability issues, the device allowed chlorination at effective nontoxic levels for 3 days. These findings open the possibility of developing devices allowing longer diffusion at lower cost for use within the framework of integrated cholera epidemic control programs.

[Consumption of medications during the cholera epidemic in Douala, Cameroon (2004)]. / Consommation de médicaments lors de l'épidémie de choléra de Douala (2004).

To prepare for cholera outbreaks, stockpiles of supplies, rehydration salts/ solutions and appropriate antibiotics must be placed in strategic locations to ensure a prompt and effective response. However specific needs have not been evaluated up to now. The purpose of this report is to give an accurate account of medical supplies that were consumed during the cholera epidemic in Douala in 2004. Consumption of medication for the entire epidemic was measured by crosschecking data from the provincial pharmaceutical supply centre with the order forms, stock sheets and records of hospitals. Cost was calculated based on pricing data from the National Supply Center. For the 5 020 confirmed cases of cholera that were treated in the 14 hospitals in Douala from January to September 2004, consumption consisted of 499,746 doxycycline tablets, 235,881 amoxicilline tablets, 122,781 rehydration salt packets, and 60,217 units of Ringer Lactate (500 ml). The total cost of medications and consumables was 52,229,311 CFAF (approximately 80,000 Euro). Although updated recommendations are not available, comparison with the existing ones shows that the consumption levels observed were 5 times higher for both rehydration and antibiotherapy. The mean cost of treatment in Douala was 13 Euro per reported patient. This cost rose to 15 Euro if antibiotic prophylaxis was prescribed for all contacts. These findings can be useful in planning for future epidemics by allowing recommendations to be updated. We propose the follow supply levels for 50,000 inhabitants with an attack rate of 0.2%: 10,000 doxycycline tablets, 5000 amoxicilline tablets (500 mg), 2500 SRO packs (for 2500 liters) and 600 liters of Ringer Lactate.

[Factors contributing to endemic cholera in Douala, Cameroon]. / Déterminants du choléra a Douala.

Cholera has been endemic in Douala, Cameroon since 1971. A number of environmental factors favourize the survival of the Vibrio in Douala including location at the mouth of Wouri delta on the Atlantic Ocean, sandy clay soil, shallow dirty polluted foul-smelling groundwater, presence of vast expanses of swamp, streams/drainage ditches infested with algae, and high temperatures with low rainfall and drought during certain periods of the year. Most outbreaks have started in Bepanda, a slum area built on a garbage dump in a swampy zone fed by drainage ditches carrying the faecal pollution from neighbouring upstream districts. It is a densely overcrowded area of uncontrolled urbanization generated by the influx of poor city new-comers who live without adequate access to clean water or basic sanitary facilities. The most affected areas are those resulting from recent unregulated urban sprawl in polluted swamp zones or garbage dumps. Since access to the public water system is inadequate with only 65000 persons connected for 3 million inhabitants, dwellers in most areas must take water from the 70000 urban wells (estimated in 2004) that are often not more than 1.5 m deep. Sewage facilities are insufficient to provide complete evacuation of solid and liquid waste. The network of rivers, streams and man-made ditches waste are poorly maintained and often overflow during the rainy season. The contents of latrines are often discharged directly into the environment. Social factors such as the reformation of urban tribes and persistence of traditional attitudes toward waste disposal and water use have not only led to high-risk behaviour but also created barriers to sanitation and hygiene education. With an inadequate sanitation inspection system, a large but purely accessible public health system and a highly disorganized private health sector exists, effective preventive measures are difficult to implement. The combination of these factors probably account for the endemicity of cholera in Douala.

[Antibiotic susceptibility of Vibrio cholerae 01: evolution after prolonged curative and preventive use during the 2004 cholera epidemics in Douala (Cameroon)]. / Evolution de la sensibilité de Vibrio cholerae 01 après utilisation prolongée d'antibiotiques en traitement et en prophylaxie au cours de l'épidémie de choléra de Douala (Cameroun) 2004.

UNLABELLED: Antibiotics were extensively used, both for curative as for prophylactic purposes, to prevent an explosive spread of the 2004 cholera epidemic in Douala. It was thus necessary to control the antibiotic susceptibility of Vibrio cholerae. OBJECTIVE: The authors had for aim to describe the epidemic, the use of antibiotics, and to follow the susceptibility of V. cholerae. DESIGN: The 14 hospitals in the study all used the same diagnostic, treatment, and preventive protocols, as well as in community practice with home visits. All cases were clinically confirmed and reported. Samples were systematically taken at the beginning and at the end of the epidemic, and randomly during the epidemic. Each identified strain was tested by the disk method for antibiotic susceptibility. RESULTS: Between January and September 2004, 5013 patients and 177,353 people in contact with the patients were given a single dose of doxycycline or amoxicillin for 3 days. Sixty-nine deaths were recorded (lethality 1.37%). One hundred (and) eleven strains of V. cholerae were identified in 187 samples. All of them were resistant to sulfamides and colistin, but susceptible to cyclins, betalactams, and fluoroquinolones, without any modification during the 8 months of follow-up. CONCLUSION: Despite the risk of a massive and prolonged use of antibiotics, strictly prescribed and controlled, no resistance developed in the identified strain. Chemoprophylaxis must follow rigorous protocols and be continuously monitored.

Routine use of antimicrobial drugs during the 2004 cholera epidemic in Douala, Cameroon.

OBJECTIVES: To evaluate routine use of antimicrobial drugs for treatment and prevention of cholera with special regards to the evolution of the antimicrobial drug resistance patterns of V. cholerae strains. DESIGN: Retrospective population-based descriptive study. SUBJECTS: Four thousand nine hundred and forty one notified cholera cases, their 15,381 patients' guards and their 159,263 household members and close neighbours. RESULTS: A total of 4,941 patients received antibiotic therapy according to the treatment protocols. Prophylactic treatment was administered to 15,381 patients' guards in hospitals and to 159,263 household members and close neighbours during home visits. Over the entire outbreak, the antimicrobial susceptibility patterns of V. cholerae strains isolated remained stable. CONCLUSIONS: The routine use of antimicrobial therapy for cholera cases associated with simultaneous and large scale chemoprophylaxis of close contacts does not seem in our experience to compromise the stability of V. cholerae susceptibility profiles to drugs when applied within a comprehensive package of rigorously monitored community interventions. The role of therapy and chemoprophylaxis in limiting the extent of a cholera epidemic is however difficult to ascertain from our experience. Field trials need to be designed to elucidate this aspect.

[Mass antibiotic prophylaxis against cholera in the New Bell central prison in Douala during the 2004 epidemic]. / Antibioprophylaxie de masse contre le choléra dans la prison centrale de Douala (New Bell) au cours de l'épidémie de 2004.

In early January 2004, cases of severe watery diarrhea were reported in Douala, the economic capital of Cameroon (estimated population: 2.4 million inhabitants). Three stool samples examined at the Cameroon National Reference Laboratory grew Vibrio cholerae serogroup O1, later identified by the Pasteur Institute in Paris, France, as serotype Inaba. On 19 January, the provincial health authorities declared an outbreak of cholera. The epidemic lasted until that September. In all, 5,020 cholera cases were reported, and 69 deaths from cholera among hospital patients. The overall attack rate for Douala was 209 cases per 100,000 inhabitants, with a case-fatality ratio of 1.37%. New Bell Central Prison, the sole penitentiary facility for Douala, is situated in the center of the town, near the biggest market. It was originally built in 1930 for 700 prisoners but now houses an average of roughly 3,100 inmates. Living and sanitary conditions in the prison are deplorable. Half of the cells house more than 150 inmates with a surface area of less than 0.20 m2 per inmate. Approximately 400 people--visitors, new admissions, and discharged prisoners--enter and leave the prison. In February 2004, five suspected cases of cholera were reported in the prison's hospital ward. Immediate measures were taken to prevent an explosive spread of cholera within the prison: a) suspected cases were treated with rehydration therapy, antibiotics, and isolation; and b) preventive antibiotic treatment, consisting of a single 300-mg dose of doxycycline, was administered to all 3,036 prisoners and 164 prison staff members. No significant side effects were observed. Despite a reinforced surveillance system, no new cholera cases were reported except two suspected cases in June 2004 (four months later), and their diagnoses could not be confirmed. A cholera epidemic in an urban area mandates rigorous epidemiological surveillance system and provisions for safety stocks of therapeutic and prophylactic drugs in closed at-risk settings, such as prisons. Collective single-dose prophylaxis with an antibiotic the efficacy of which is confirmed by in vitro antibiotic susceptibility testing can provide immediate protection not available by other preventive measures (education, sanitation, immunization) against a cholera epidemic in a prison.