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1.  Emergence and global spread of epidemic healthcare-associated Clostridium difficile 
Nature genetics  2012;45(1):109-113.
Epidemic Clostridium difficile (027/BI/NAP1) rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key moments in the evolutionary history leading to its emergence and subsequent patterns of global spread remain unknown. Here we define the global population structure of C. difficile 027/BI/NAP1 based on whole-genome sequencing and phylogenetic analysis. We demonstrate that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance mutation and a highly-related conjugative transposon. The two epidemic lineages displayed distinct patterns of global spread, and the FQR2 lineage spread more widely leading to healthcare outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid trans-continental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.
doi:10.1038/ng.2478
PMCID: PMC3605770  PMID: 23222960
2.  Analysing and recommending options for maintaining universal coverage with long-lasting insecticidal nets: the case of Tanzania in 2011 
Malaria Journal  2013;12:150.
Background
Tanzania achieved universal coverage with long-lasting insecticidal nets (LLINs) in October 2011, after three years of free mass net distribution campaigns and is now faced with the challenge of maintaining high coverage as nets wear out and the population grows. A process of exploring options for a continuous or “Keep-Up” distribution system was initiated in early 2011. This paper presents for the first time a comprehensive national process to review the major considerations, findings and recommendations for the implementation of a new strategy.
Methods
Stakeholder meetings and site visits were conducted in five locations in Tanzania to garner stakeholder input on the proposed distribution systems. Coverage levels for LLINs and their decline over time were modelled using NetCALC software, taking realistic net decay rates, current demographic profiles and other relevant parameters into consideration. Costs of the different distribution systems were estimated using local data.
Results
LLIN delivery was considered via mass campaigns, Antenatal Care-Expanded Programme on Immunization (ANC/EPI), community-based distribution, schools, the commercial sector and different combinations of the above. Most approaches appeared unlikely to maintain universal coverage when used alone. Mass campaigns, even when combined with a continuation of the Tanzania National Voucher Scheme (TNVS), would produce large temporal fluctuations in coverage levels; over 10 years this strategy would require 63.3 million LLINs and a total cost of $444 million USD. Community mechanisms, while able to deliver the required numbers of LLINs, would require a massive scale-up in monitoring, evaluation and supervision systems to ensure accurate application of identification criteria at the community level. School-based approaches combined with the existing TNVS would reach most Tanzanian households and deliver 65.4 million LLINs over 10 years at a total cost of $449 million USD and ensure continuous coverage. The cost of each strategy was largely driven by the number of LLINs delivered.
Conclusions
The most cost-efficient strategy to maintain universal coverage is one that best optimizes the numbers of LLINs needed over time. A school-based approach using vouchers targeting all students in Standards 1, 3, 5, 7 and Forms 1 and 2 in combination with the TNVS appears to meet best the criteria of effectiveness, equity and efficiency.
doi:10.1186/1475-2875-12-150
PMCID: PMC3694474  PMID: 23641705
Long-lasting insecticidal nets; Malaria; Schools; Continuous distribution; Universal coverage; Tanzania; Insecticide-treated nets; Mass campaign
3.  Design, implementation and evaluation of a national campaign to deliver 18 million free long-lasting insecticidal nets to uncovered sleeping spaces in Tanzania 
Malaria Journal  2013;12:85.
Background
Since 2004, the Tanzanian National Voucher Scheme has increased availability and accessibility of insecticide-treated nets (ITNs) to pregnant women and infants by subsidizing the cost of nets purchased. From 2008 to 2010, a mass distribution campaign delivered nine million long-lasting insecticidal nets (LLINs) free-of-charge to children under-five years of age in Tanzania mainland. In 2010 and 2011, a Universal Coverage Campaign (UCC) led by the Ministry of Health and Social Welfare (MoHSW) was implemented to cover all sleeping spaces not yet reached through previous initiatives.
Methods
The UCC was coordinated through a unit within the National Malaria Control Programme. Partners were contracted by the MoHSW to implement different activities in collaboration with local government authorities. Volunteers registered the number of uncovered sleeping spaces in every household in the country. On this basis, LLINs were ordered and delivered to village level, where they were issued over a three-day period in each zone (three regions). Household surveys were conducted in seven districts immediately after the campaign to assess net ownership and use.
Results
The UCC was chiefly financed by the Global Fund to Fight AIDS, Tuberculosis and Malaria with important contributions from the US President’s Malaria Initiative. A total of 18.2 million LLINs were delivered at an average cost of USD 5.30 per LLIN. Overall, 83% of the expenses were used for LLIN procurement and delivery and 17% for campaign associated activities. Preliminary results of the latest Tanzania HIV Malaria Indicator Survey (2011–12) show that household ownership of at least one ITN increased to 91.5%. ITN use, among children under-five years of age, improved to 72.7% after the campaign. ITN ownership and use data post-campaign indicated high equity across wealth quintiles.
Conclusion
Close collaboration among the MoHSW, donors, contracted partners, local government authorities and volunteers made it possible to carry out one of the largest LLIN distribution campaigns conducted in Africa to date. Through the strong increase of ITN use, the recent activities of the national ITN programme will likely result in further decline in child mortality rates in Tanzania, helping to achieve Millennium Development Goals 4 and 6.
doi:10.1186/1475-2875-12-85
PMCID: PMC3599368  PMID: 23496881
Malaria; Vector control; Insecticide-treated nets; Long-lasting insecticidal nets; Distribution campaign; Tanzania
4.  Dietary Habits of Female Urban Slum-dwellers in Mumbai 
Research Question
Intakes of micronutrient-rich foods are low among women of child-bearing age living in slums. We investigated relationships between consumption of these foods and socio-demographic variables.
Methodology
A 91-item Food Frequency Questionnaire was administered to women (n=1651) aged 16-40 yrs living in a Mumbai slum. We identified associations between categorical demographic variables and consumption frequency of these foods using chi-square tests. Associations with age and body mass index were investigated using one-way ANOVAs.
Results
A quarter of women ate fruit and green leafy vegetables < 3 times per week, Apart from in tea, median consumption of milk and milk products was < twice a week, 16% never consumed non-vegetarian foods. Median consumption of non-vegetarian foods was 4.5 times per week. Women employed in unskilled jobs and those whose husbands had skilled occupations ate green leafy vegetables more frequently. Participants educated to tertiary level consumed fruit and milk most frequently (p<0.05).
PMCID: PMC3568157  PMID: 23400755
diet; fruit; milk; green leafy vegetable; India; slum
5.  Automatic categorization of diverse experimental information in the bioscience literature 
BMC Bioinformatics  2012;13:16.
Background
Curation of information from bioscience literature into biological knowledge databases is a crucial way of capturing experimental information in a computable form. During the biocuration process, a critical first step is to identify from all published literature the papers that contain results for a specific data type the curator is interested in annotating. This step normally requires curators to manually examine many papers to ascertain which few contain information of interest and thus, is usually time consuming. We developed an automatic method for identifying papers containing these curation data types among a large pool of published scientific papers based on the machine learning method Support Vector Machine (SVM). This classification system is completely automatic and can be readily applied to diverse experimental data types. It has been in use in production for automatic categorization of 10 different experimental datatypes in the biocuration process at WormBase for the past two years and it is in the process of being adopted in the biocuration process at FlyBase and the Saccharomyces Genome Database (SGD). We anticipate that this method can be readily adopted by various databases in the biocuration community and thereby greatly reducing time spent on an otherwise laborious and demanding task. We also developed a simple, readily automated procedure to utilize training papers of similar data types from different bodies of literature such as C. elegans and D. melanogaster to identify papers with any of these data types for a single database. This approach has great significance because for some data types, especially those of low occurrence, a single corpus often does not have enough training papers to achieve satisfactory performance.
Results
We successfully tested the method on ten data types from WormBase, fifteen data types from FlyBase and three data types from Mouse Genomics Informatics (MGI). It is being used in the curation work flow at WormBase for automatic association of newly published papers with ten data types including RNAi, antibody, phenotype, gene regulation, mutant allele sequence, gene expression, gene product interaction, overexpression phenotype, gene interaction, and gene structure correction.
Conclusions
Our methods are applicable to a variety of data types with training set containing several hundreds to a few thousand documents. It is completely automatic and, thus can be readily incorporated to different workflow at different literature-based databases. We believe that the work presented here can contribute greatly to the tremendous task of automating the important yet labor-intensive biocuration effort.
doi:10.1186/1471-2105-13-16
PMCID: PMC3305665  PMID: 22280404
6.  Design, implementation and evaluation of a national campaign to distribute nine million free LLINs to children under five years of age in Tanzania 
Malaria Journal  2011;10:73.
Background
After a national voucher scheme in 2004 provided pregnant women and infants with highly subsidized insecticide-treated nets (ITNs), use among children under five years (U5s) in mainland Tanzania increased from 16% in 2004 to 26.2% in 2007. In 2008, the Ministry of Health and Social Welfare planned a catch-up campaign to rapidly and equitably deliver a free long-lasting insecticidal net (LLIN) to every child under five years in Tanzania.
Methods
The ITN Cell, a unit within the National Malaria Control Programme (NMCP), coordinated the campaign on behalf of the Ministry of Health and Social Welfare. Government contractors trained and facilitated local government officials to supervise village-level volunteers on a registration of all U5s and the distribution and issuing of LLINs. The registration results formed the basis for the LLIN order and delivery to village level. Caregivers brought their registration coupons to village issuing posts during a three-day period where they received LLINs for their U5s. Household surveys in five districts assessed ITN ownership and use immediately after the campaign.
Results
Nine donors contributed to the national campaign that purchased and distributed 9.0 million LLINs at an average cost of $7.07 per LLIN, including all campaign-associated activities. The campaign covered all eight zones of mainland Tanzania, the first region being covered separately during an integrated measles immunization/malaria LLIN distribution in August 2008, and was implemented one zone at a time from March 2009 until May 2010. ITN ownership at household level increased from Tanzania's 2008 national average of 45.7% to 63.4%, with significant regional variations. ITN use among U5s increased from 28.8% to 64.1%, a 2.2-fold increase, with increases ranging from 22.1-38.3% percentage points in different regions.
Conclusion
A national-level LLIN distribution strategy that fully engaged local government authorities helped avoid additional burden on the healthcare system. Distribution costs per net were comparable to other public health interventions. Particularly among rural residents, ITN ownership and use increased significantly for the intended beneficiaries. The upcoming universal LLIN distribution and further behaviour change communication will further improve ITN ownership and use in 2010-2011.
doi:10.1186/1475-2875-10-73
PMCID: PMC3078903  PMID: 21453519
7.  The Structure of Phosphorylase Kinase Holoenzyme at 9.9 Å Resolution and Location of the Catalytic Subunit and the Substrate Glycogen Phosphorylase 
Structure(London, England:1993)  2009;17(1):117-127.
Summary
Phosphorylase kinase (PhK) coordinates hormonal and neuronal signals to initiate the breakdown of glycogen. The enzyme catalyzes the phosphorylation of inactive glycogen phosphorylase b (GPb), resulting in the formation of active glycogen phosphorylase a. We present a 9.9 Å resolution structure of PhK heterotetramer (αβγδ)4 determined by cryo-electron microscopy single-particle reconstruction. The enzyme has a butterfly-like shape comprising two lobes with 222 symmetry. This three-dimensional structure has allowed us to dock the catalytic γ subunit to the PhK holoenzyme at a location that is toward the ends of the lobes. We have also determined the structure of PhK decorated with GPb at 18 Å resolution, which shows the location of the substrate near the kinase subunit. The PhK preparation contained a number of smaller particles whose structure at 9.8 Å resolution was consistent with a proteolysed activated form of PhK that had lost the α subunits and possibly the γ subunits.
doi:10.1016/j.str.2008.10.013
PMCID: PMC2639635  PMID: 19141288
PROTEINS; SIGNALING
8.  Yeast forms dominate fungal diversity in the deep oceans 
Fungi are the principal degraders of biomass in most terrestrial ecosystems. In contrast to surface environments, deep-sea environmental gene libraries have suggested that fungi are rare and non-diverse in high-pressure marine environments. Here, we report the diversity of fungi from 11 deep-sea samples from around the world representing depths from 1500 to 4000 m (146–388 atm) and two shallower water column samples (250 and 500 m). We sequenced 239 clones from 10 fungal-specific 18S rRNA gene libraries constructed from these samples, from which we detected only 18 fungal 18S-types in deep-sea samples. Our phylogenetic analyses show that a total of only 32 fungal 18S-types have so far been recovered from deep-sea habitats, and our results suggest that fungi, in general, are relatively rare in the deep-sea habitats we sampled. The fungal diversity detected suggests that deep-sea environments host an evolutionarily diverse array of fungi dominated by groups of distantly related yeasts, although four putative filamentous fungal 18S-types were detected. The majority of our new sequences branch close to known fungi found in surface environments. This pattern contradicts the proposal that deep-sea and hydrothermal vent habitats represent ancient ecosystems, and demonstrates a history of frequent dispersal between terrestrial and deep-sea habitats.
doi:10.1098/rspb.2007.1067
PMCID: PMC2293941  PMID: 17939990
life under huge barometric pressures; osmotrophy; environmental gene library; microbial diversity; SSU rDNA phylogeny
9.  Costs and consequences of large-scale vector control for malaria 
Malaria Journal  2008;7:258.
Background
Five large insecticide-treated net (ITN) programmes and two indoor residual spraying (IRS) programmes were compared using a standardized costing methodology.
Methods
Costs were measured locally or derived from existing studies and focused on the provider perspective, but included the direct costs of net purchases by users, and are reported in 2005 USD. Effectiveness was estimated by combining programme outputs with standard impact indicators.
Findings
Conventional ITNs: The cost per treated net-year of protection ranged from USD 1.21 in Eritrea to USD 6.05 in Senegal. The cost per child death averted ranged from USD 438 to USD 2,199 when targeting to children was successful.
Long-lasting insecticidal nets (LLIN) of five years duration: The cost per treated-net year of protection ranged from USD 1.38 in Eritrea to USD 1.90 in Togo. The cost per child death averted ranged from USD 502 to USD 692.
IRS: The costs per person-year of protection for all ages were USD 3.27 in KwaZulu Natal and USD 3.90 in Mozambique. If only children under five years of age were included in the denominator the cost per person-year of protection was higher: USD 23.96 and USD 21.63. As a result, the cost per child death averted was higher than for ITNs: USD 3,933–4,357.
Conclusion
Both ITNs and IRS are highly cost-effective vector control strategies. Integrated ITN free distribution campaigns appeared to be the most efficient way to rapidly increase ITN coverage. Other approaches were as or more cost-effective, and appeared better suited to "keep-up" coverage levels. ITNs are more cost-effective than IRS for highly endemic settings, especially if high ITN coverage can be achieved with some demographic targeting.
doi:10.1186/1475-2875-7-258
PMCID: PMC2625363  PMID: 19091114

Results 1-9 (9)