British Library Dataset Programme: Supporting Research in the Library of the 21st Century

J Max Wilkinson firstname.lastname@example.com
The British Library
96 Euston RoadNW1 2DBLondonUnited Kingdom

Tom Pollard email@example.com
The British Library
96 Euston RoadNW1 2DBLondonUnited Kingdom

Adam Farquhar email@example.com
The British Library
96 Euston RoadNW1 2DBLondonUnited Kingdom

British Library Dataset Programme: Supporting Research in the Library of the 21st Century
iSSN: 1435-5205. P94-104E2A5AFEBE14F9DBD8D47887EBFBA84E1data citationscholarly recorddatasetsDigital Object Identifiers (DOI)
Advances in computational science and its application are reshaping the social landscape and the practice of research.Researchers are increasingly exploiting technology for collaborative, experimental and observational research in all disciplines.Digital data and datasets are the fuel that drives these trends; increasingly datasets are being recognised as a national asset that requires preservation, attribution and access in much the same way as text-based communication.The British Library is in a unique position to enhance UK and international research by extending its presence from the physical collection to the digital dataset domain.To meet this challenge and be a responsible steward of the scholarly record, the Library has defined a programme of activity to support the datasets that underlie modern research and promote them as a national asset.We are designing a mixed model of activity where specific service-level projects with clear goals will provide support for collaborative work aimed at revealing and clarifying requirements related to datasets.For example, there is a clear community need for stable, scalable and agreed data citation mechanisms.In response the British Library became a founding member of Data-Cite, the International Data Citation Initiative which, as a member of the International DOI foundation, assigns Digital Object Identifiers (DOIs) to datasets.We are leveraging the services built for DataCite to actively partner with a number of UK data centres and data publishers to add value to their collections and facilitate the rejoining to the scholarly record by linking the published record with the datasets that underlie it.We are also implementing a similar strategy to promote dataset discovery services through the Library's catalogues and streamlining access to national external collections.The British Library datasets programme will guide activities across the Library and provide a focus for stakeholder communities to address the challenge of integrating J. Max Wilkinson et al.

Introduction Background

Advances in computational science and its application are reshaping the social landscape and the practice of research.Researchers are increasingly exploiting computational capacity and capability for collaborative, experimental and observational research in all disciplines.Digital datasets fuel these trends in cultural and scholarly endeavours and are increasingly being recognised as a national asset.For a number of reasons these data assets are not being exploited to the extent that traditional publications have been and there is a groundswell of community interest in bridging the widening gulf between publications and the datasets that underlie them.

In the UK, research councils and funding bodies have responded by mandating data management plans in requests for funding (Serco Consulting, 2008).Publishers have responded by accepting supplementary data alongside articles or requiring submission of data into recognised repositories.Specific disciplines, organisations and institutions have created data management centres for explicit data types irrespective of publication status. 1 Research libraries have been largely absent from the discussion and there is growing awareness of a widening fissure in the scholarly record -the gap between published research and the datasets that underlie it (Buneman et al., 2000, 2004; Gray et  al., 2002; Hey et al., 2003; Lord & Macdonald, 2003; Borgman, 2007; Lyon, 2007;  RIN, 2008; Serco Consulting, 2008).While there are well-established services for published research, there is only an incomplete patchwork of services for datasets.For example, there are no agreed ways to identify, search, cite, or catalogue datasets.The British Library is in a unique position to enhance UK research and strengthen its profile as a critical component of modern research by extending its presence from the physical collection to the digital dataset domain.

The Library is one of the largest research libraries in the world.It has a statutory responsibility to acquire, preserve and make accessible the UK national published archive.It holds over 150 million items ranging from historic manuscripts to modern electronic journals, digital music files and patents and is leading international collaborations to find solutions to ensure this rich and varied collection is sustained far into the future.Strategic priorities for the Library  (2008-2011) are to build its digital infrastructure, capture digital publications and support research with innovative and integrated processes.The Datasets Programme is one of several programmes of work that will help reach these strategic goals.

Motivation

Awareness of the impact of the digital age on research is growing.The British Library Chief Executive, Dame Lynne Brindley DBE, observed that the biggest challenge facing the British Library is presented by 'the data deluge and the increasing need to integrate datasets that underlie published research with the more traditional formats and preserve these digital formats into the long term' (IWR Horizons, 2008).This view is supported by three studies conducted by the Library in 2007 and 2008 looking specifically at options and approaches to dealing with datasets in Science Technology & Medicine, Arts & Humanities and Social Sciences (Key Perspectives, 2007; Education  for Change, 2008; Rothenberg & Hoorens, 2008).

In order to meet this challenge, be a responsible steward of the scientific record and improve its relevance to researchers, the British Library is undertaking a programme of activity to support the data that underlie modern research and promote them as a national, intellectual asset.

Scope

A dataset can be regarded as an organised collection of data.Our programme focuses on digital formats that exist as content within or external to the Library, including images, audio and numerical data.We consider datasets to be collections of data that are generated or consumed by users in the process of their research.The Library already contains many digital objects that can be considered datasets.Digitised maps, books and even the Library catalogues may be considered datasets based on specific requests or operational needs.In addition, mass digitisation programmes like the Library's newspaper digitisation projects generate large datasets. 2External to the Library data centres provide for the preservation and persistence of data generated by UK-funded research, government departments and national programmes, e.g., the UK Data Archive, the census and other national data collections.

As ever more data are generated, modern researchers are confronted with new challenges, such as how to persist their data and how to reference them as required.These challenges are all the more relevant as most UK research funding organisations are implementing data sharing in response to the agreed notion that the results of publicly funded research should return the maximum benefit possible to the research community and the wider public.As these data sharing policies and requirements are implemented, researchers find themselves with significant data management needs.Data sharing is not new in the research paradigm.Many researchers and discipline networks share data as part of their common practices.Despite this, primary research data are often referenced via network locations on a plethora obsolete or near-obsolete media.As we explored possible contributions that the British Library could make, two clear requirements came to the forefront: data require preservation and data require persistent identification.

Persistent identification is necessary for the stable referencing of data and the Datasets Programme sees a clear role here.Once datasets are cited in an agreed, stable and scalable way, they can be connected with associated research publications and may be shared and reused more easily.Clearly referenced and accessible datasets help to create an audit trail in the research process and provide a foundation for quantitative metrics for tracking the reuse and re-purposing of data.

We will work across disciplines and promote a joined-up infrastructure to help address the demands of the researcher to be able to locate and access data, regardless of physical location.This will involve establishing partnerships, principles, guidelines and agreements with external stakeholders parallel to establishing Library services that facilitate dataset citation, cataloguing and access.

The Library has made significant progress in establishing its presence in the domain.The Library is a founding member of the European Alliance for Permanent Access to the Records of Science, it chairs the World Wide Science Alliance, it is a signatory to the UK National Data Strategy for Economic and Social Data, and it is a member of the Steering Committee for the UK Research Data Service.In addition, it was a founding member of the UK Digital Preservation Coalition and the co-ordinator for the FP6 funded PLANETS digital preservation project and subsequent Open PLANETS Foundation.

Strategy and Objectives

Traditionally libraries were built around printed and visual media, which now have agreed standards of citation and bibliographic formats.In contrast quantitative empirical data have not kept pace with their printed counterpart and are often fragmented and unobtainable, existing in a range of locations on various media in a variety of formats.

To determine what roles libraries should have in the datasets domain the Datasets Programme has undertaken a number of strategic and exploratory activities and has established a strategy that outlines how the Library can build on work already achieved.The strategy 3 takes a cross-department and cross-discipline approach to coordinate dataset activity across the Library and across external stakeholders.

We have established a multi-discipline team that directly engages with key stakeholders to reveal and gather requirements based on user need and user behaviour.Efforts are being made to establish the Library as a key stakeholder and partner in the datasets domain and to build communication channels to place the Library as a hub to focus the wider community.Modern social technologies will be used alongside more traditional printed and directed tools of communication.

By investing in this programme the Library will further expand its skill base in the digital world and provide a solid foundation for providing high-value services to its users based on their requirements.

Core Activity and Areas of Focus

Core Programme

The British Library Datasets Programme undertakes both cross-department activity within the Library and external project-focused activity.All activities attempt to address a clear community need and often require stakeholder relationships to be established or developed.We aim to build on current infrastructure and achievements to deliver new and useful services to the library community.

DataCite

The British Library joins many other organisations that believe research data are an essential component of the scholarly record and that increasing access to these data has a number of well-recognized benefits.Just as scientific research is global, it seems appropriate to take a global approach to dealing with the challenges of increasing access to data.This principle underlies the formation of DataCite 4 , which aims to remove one of the barriers in the fragmented data landscape by providing efficient, effective and persistent data citation facilities.

We have agreed to work together to promote global access to research data.The long-term vision is to support researchers by providing methods for them to locate, identify and cite research datasets with confidence.In order to achieve this long-term vision, the members established a not-for-profit agency that enables organizations to register research datasets and assign persistent identifiers to them.The agency will take global leadership for promoting the use of persistent identifiers for datasets to satisfy needs of scientists.It will, through its members, establish and promote common methods, best practices and guidance.National members work independently with data centres and other data publishers in their own domains, respecting and being familiar with different research funding frameworks and practices.

DataCite builds on the approach developed by the German National Library of Science and Technology and promotes the use of Digital Object Identifiers (DOIs) for datasets.The DataCite model of governance is composed of national representation in a global presence, because researchers create, share, and access data globally.Most data centres and data publishers are embedded within their national funding structures and research frameworks.With the DataCite governance structure national representatives provide DataCite services to national-level parties and are familiar with the environment in which the data publishers operate.

Collaborative Projects

The Datasets Programme has joined with a number of key stakeholders to establish complementary programmes aimed at specific issues of data citation and management.In addition the Library has actively supported several projects that illustrate specific issues of data citation and management.

Data journals: This project is a partnership between the British Library, a national data centre and an established publisher to develop the mechanisms required to run an operational overlay data journal.We aim to provide incentives for scientific researchers to deposit their data in accredited data repositories, thereby improving the transparency and traceability of the data which underpins important scientific conclusions.

Data repositories:

In partnership with UK Higher Education Institutions, a number of publishers and an international consortium, we are undertaking preparative work for the establishment of a repository for bioscience research datasets linked to the peer-reviewed articles they underpin.This work targets disciplines that are not well served by the current data centre infrastructures and will present us with unique and valuable experience in dataset construct and variability.

Data attribution: This collaborative project will develop and test a citation framework for complex network models of disease and associated data.Citations of network models will be embedded in two leading publications and will be based on an international biomedical project that is collecting and analysing massive coherent datasets from a number of contributing partners.

Outreach

Identifying, engaging and maintaining a stakeholder community is essential to the Library's datasets strategy.The Programme has built an initial stakeholder map and will review and build on this map at regular intervals to keep it relevant.From this map a strong communication strategy has been formed that articulates clear key messages to each stakeholder community to ensure consistent and correct communication.Modern communication tools will be used alongside traditional techniques to reach stakeholders in convenient and useful ways.Collectively our outreach and communications activities will provide a focus for the datasets community to identify needs and solutions, and will help to promote the emerging services of the Library.

Areas of Focus

Science, Technology and Medicine

During 2007/08, the Science, Technology and Medicine (STM) team commissioned a study to help define the British Library's approach to scientific data. 5his work provided an initial list of over 400 bioscience open data resources, a set of recommendations for potential data services that the Library could develop and guidelines for the selection of 'datasets as content'.Dedicated STM staff have been working to develop these recommendations into tangible solutions for the Library and its users.

The team are developing and testing selection criteria for high-value reference datasets to include in the British Library 'collection', initially concentrating on biosciences and environmental sciences.In undertaking this work the team have developed working relationships with data centres, data curators and stakeholders to aid discovery of and access to datasets.

The STM team is piloting dataset discovery services through the Library's search engine facility in order to better connect users to datasets and data resources.This pilot will help the Library better understand researcher behaviour and requirements and provide a first look at resource discovery of datasets alongside other materials.

Complementary to this activity, draft selection criteria for datasets have been developed and are being trialled.The Library has well-established criteria, principles and mechanisms for selecting and acquiring published content in both the print and digital environment.These are being augmented for datasets, which introduce new challenges around quality, stability and sustainability of resources -especially when connecting to them, rather than holding them directly.

Arts and Humanities

A traditional area for the Library, the Arts and Humanities discipline offers unique challenges for the Datasets Programme.We are working with the Archaeological Data Service to enrich the current web presence with the ability to use and reliably cite their collections.Internal to the Library, the team is piloting citation services to collection items, specifically music files in the sound archive, so that users of the sound collections can reference with confidence particular collection items in their research.

Social Science Collections Research

In the social sciences, dataset activity has focused on support of and access to existing, often under utilised resources.This activity is generating guides to social science resources for Library users, streamlining access to established external data publishers and data centres and exploiting national events to showcase the relevance of the Library's facilities.

The social science team are creating resource guides to help researchers use different types of datasets and find commonly used datasets.Initially the guides will cover areas including: food studies, management and business studies, health and wellbeing, and socio-legal studies.In the future these will be expanded into further subject disciplines.

Prior to the London 2012 Olympic Games the team will launch a website for research around aspects of the Olympic Games.A separate portal for management and business studies is also being developed.Dataset resource guides and links to relevant datasets will be included in the websites at launch.Further activities, including an exhibition, are being planned to mark the 2011 UK census.

The UK Data Archive (UKDA) provides access to major governmental and ESRC-funded datasets and is a key resource for social science researchers.Currently British Library readers are unable to access UKDA if they are not members of UK Higher Education Institutions, so the social science team is working with the UKDA to widen the access to this service.If successful, many more readers would gain access to this rich resource of social science and humanities datasets.

In addition to these activities the social science team is working on a pilot project to expand the Library's searchable catalogue to include social sciences datasets.

Summary

Advances in information technology have provided a means to generate, manipulate and share ever increasing volumes of data.These data form an essential part of the scholarly record and there is great risk that this foundation of knowledge will be lost.

Datasets are essential to the British Library's mission to advance the world's knowledge and are becoming ever more critical to researchers and policy makers.Our activities will place the British Library at the forefront of institutions that are connecting researchers to data and will help the datasets community to identify and tackle the challenges presented by our changing digital landscape.

C L Borgman, Scholarship in the digital age: information, infrastructure, and the Internet. Cambridge, MassMIT Press2007

P Buneman, S Khanna, W C Tan, Foundations of Software Technology and Theoretical Computer Science. 2000Data Provenance: Some Basic Issues

Education for Change Ltd. P Buneman, S Khanna, K Tajima, W C Tan, Research into type, scope, location and availability of qualitative and quantitative datasets in the arts and humanities and social sciences. 2004. 2008. Feb29Archiving Scientific Data

J Gray, A S Szalay, A R Thakar, C Stoughton, Arxiv preprint cs.DL/0208012Online Scientific Data Curation, Publication, and Archiving. 2002

T Hey, A Trefethen, The Data Deluge: An e-Science Perspective. IWR Horizons2003. 2008Grid Computing: Making the Global Infrastructure a Reality

Research into Reference Datasets of High Scientific Value. Key Perspectives, Ltd , 2007. Nov. 2007

Data Curation for e-Science in the UK: an Audit to Establish Requirements for Future Curation and Provision, prepared for the JISC Committee for the Support of Research. P Lord, A Macdonald, e-Science Curation Report. 2003

L Lyon, Dealing with Data: Roles, Rights, Responsibilities and Relationships -Consultancy Report. 2007. June

Rin, Mind the Skills Gap: Information-handling Training for Researchers. Research Information Network2008

UK Data Service Feasibility Study -Interim Report, HEFCE. Notes 1 For example, the UK Data Archive for historical and social sciences, the EMBL European Bioinformatics Institute's nucleotide sequence database, and the Defra funded Master Chemical Mechanism database for tropospheric ozone formation. J Rothenberg, S Hoorens, Rand Europe. Serco Consulting. 2008. 2008Enabling Longterm Access to Science, Technology and Medical Data Collections

3 To be available shortly at.


Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women -a modified observational study

Alexandra E Burleigh
Susan M Benck
Sarah E Mcachran
Jess D Reed
Christian G Krueger
Walter J Hopkins
Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women -a modified observational study
R E S E A R C H Open Access
Background: Urinary tract infections (UTIs) are one of the most common bacterial infections, and over 50% of women will have a UTI during their lifetimes. Antibiotics are used for prophylaxis of recurrent UTIs but can lead to emergence of drug-resistant bacteria. Therefore, it is reasonable to investigate nutritional strategies for prevention of UTIs. Cranberry juices and supplements have been used for UTI prophylaxis, but with variable efficacy. Because dried cranberries may contain a different spectrum of polyphenolics than juice, consuming berries may or may not be more beneficial than juice in decreasing the incidence of UTIs in susceptible women. The primary objectives of this study were to determine if consumption of sweetened, dried cranberries (SDC) decreases recurrent UTIs and whether this intervention would alter the heterogeneity, virulence factor (VF) profiles, or numbers of intestinal E. coli.Methods: Twenty women with recurrent UTIs were enrolled in the trial and consumed one serving of SDC daily for two weeks. Clinical efficacy was determined by two criteria, a decrease in the six-month UTI rates pre-and postconsumption and increased time until the first UTI since beginning the study. Strain heterogeneity and virulence factor profiles of intestinal E. coli isolated from rectal swabs were determined by DNA fingerprinting and muliplex PCR, respectively. The numbers of intestinal E. coli eluted from rectal swabs pre-and post-consumption were also quantified.Results: Over one-half of the patients did not experience a UTI within six months of SDC consumption, and the mean UTI rate per six months decreased significantly. Kaplan-Meier analysis of infection incidence in women consuming SDC compared to patients in a previous control group showed a significant reduction in time until first UTI within six months. The heterogeneity, VF profiles, and prevalence of intestinal E. coli strains were not significantly different after cranberry consumption.Conclusions: Results of this study indicate a beneficial effect from consuming SDC to reduce the number of UTIs in susceptible women. Because there were no changes in the heterogeneity or VF profiles of E. coli, additional studies are needed to determine the mechanism of action of SDC for reduction of UTIs.

Background

Urinary tract infections (UTIs) are one of the most commonly acquired bacterial infections. Over 50% of women will have a UTI during their lifetimes, and approximately 25% of women will have at least one recurrence [1][2][3]. Recurrent UTIs (RUTI), defined as at least three episodes of UTI in the last 12 months or two episodes in the last six months, can occur in susceptible women and are a significant source of patient morbidity and health care costs [4].

The treatment of RUTIs can vary depending upon the physician and patient. The Infectious Disease Society of America 2010 recommends a five-day course of nitrofurantoin as a first line treatment of acute, uncomplicated cystitis; however, patients may be prescribed other antibiotics as well [5]. Antibiotic prophylaxis can also be initiated in patients with recurrent UTIs. One study showed that 6 to 12 months of antimicrobial prophylaxis was more effective than placebo in reducing the risk of RUTIs in pre-and postmenopausal women [4]. In some cases, patients may self-treat with post-coital antibiotics if RUTIs are related to intercourse [6]. Unfortunately, continuous and sporadic antibiotic use has the potential to select for highly adaptive, multi-drug resistant organisms and can reduce the numbers of beneficial, commensal bacteria in the intestinal flora. Also, long-term use of nitrofurantoin, a common prophylactic antibiotic, has been associated with health risks including pulmonary toxicity, acute and chronic hepatic disease, neuropathy, and anemia [7]. Further, there is no evidence-based recommendation of ideal prophylactic antibiotic, dosage, or duration of treatment for RUTI [8]. Therefore, it is reasonable to consider alternative, readily-available nutritional supplements as prophylactic agents for RUTIs in susceptible women.

Cranberry products have been studied for UTI prevention and treatment. The most common products tested include juices and pills or capsules containing cranberry extracts or powdered fruit, both of which have demonstrated conflicting evidence for prevention of RUTIs [9][10][11]. One proposed mechanism of action is that one of the primary compounds in cranberries, proanthocyanidins (PACs), inhibit P-fimbriated E. coli from adhering to uroepithelial cells [12]. P-fimbriae mediate adherence to uroepithelial cells via the P adhesin gene (papG), which contains three unique allelic variants, with the allele III variant being highly associated with acute cystitis [13].

While previous studies have evaluated cranberry juice and other cranberry products for UTI prophylaxis, none have investigated whether consumption of dried cranberries have the potential to decrease the incidence of RUTIs in susceptible women. Dried cranberries contain high concentrations of polyphenols that may be active in interfering with E. coli biologic or metabolic processes in the intestine or inhibiting bacterial adherence to vaginal or bladder epithelial cells. In addition, because E. coli is the predominant uropathogen isolated from acute and RUTIs in women and it is believed that the infecting bacteria originate from the intestinal flora, the intestinal tract may be an alternate site in which components of the dried cranberries can interact with E. coli to reduce infectivity [14,15].

The clinical study presented here investigated the efficacy of consuming sweetened, dried cranberries (SDC) to reduce UTI incidence in women with RUTIs. We observed a reduction in the number of UTIs in the six months following consumption of SDC daily for two weeks. There were no significant changes in the virulence profiles of intestinal E. coli during the study period.

Materials and methods

Twenty women with a history of recurrent UTI, defined as at least three UTIs in the past year (subjects with two UTI's in the past six months but not three in the past year were also enrolled) provided informed consent at the outpatient clinic of the University of Wisconsin Hospital and Clinics, and were enrolled in the trial approved by the University of Wisconsin Health Sciences Institutional Review Board. The number of subjects was based on achieving a statistical power of at least 80% for each of two parameters, infection-free status at the end of the study, and changes in the E. coli strain diversity measure. A six-month infection-free incidence of 60% in 20 UTI-susceptible women consuming SDC compared to a 20% incidence in untreated women would provide 80% power with p = 0.05 using a two-tailed t-test. Similarly, analysis of the diversity of E. coli strains isolated from 20 subjects pre-and post-consumption would have at least 80% power to detect a 0.66 standard deviation shift in the Kullback Liebler (KL) diversity measure [16] using a two-tailed t-test conducted at a significance level of 0.05. The mean age of participants was 37, with a range of 18 to 64, and the mean number of UTIs in the past six months was 2.4 with a range of two to five. Exclusion criteria included immune-compromising diseases, co-morbidities, chronic inflammatory bowel disease, diabetes, or cranberry allergy. Although target enrollment for the study was 20 subjects, data from 3 subjects were removed from the analysis due to one patient with exclusionary criteria realized after enrollment, one patient with sample contamination, and one patient with UTI contracted within one week of study enrollment.

A two-week antibiotic washout period of nonprophylactic antibiotics (i.e. full treatment course for acute UTI) was required before beginning the study.

Women who were taking daily prophylactic antibiotics, however, were allowed to participate in the study, provided they met the inclusion criteria. A total of three women who were taking prophylactic antibiotics were enrolled in this study. The women in the study consumed one serving (42 g) of SDC, provided by Ocean Spray Cranberries Inc., each day for two weeks. Rectal swabs were collected at the time of study entry to sample intestinal bacterial flora, and SDC consumption began the following day. Rectal swabs were again collected after two weeks of SDC consumption, and within one day of final SDC consumption.

Clinical efficacy was determined by 1.) Comparison of six-month UTI rates pre-and post-consumption, and 2.) Kaplan-Meier analysis of the time until a patient's first UTI since beginning the study compared to a previous control group with similar inclusion/exclusion criteria. The six-month UTI rate was based on patient selfreports and documentation of the total number of UTIs in the year prior to the study and six-months since beginning the study. Patients also reported the date of their first UTI since the start of the study.

The presence of E. coli, Enterococcus sp., Klebsiella sp., S. Saprophyticus, S. aureus, and Proteus sp. were quantified as colony forming units (CFU) per ml from rectal swab eluates on BBL™ CHROMagar Orientation media (24hr growth at 37°C). Lactobacillus was quantified as CFU/ml on deMan Rogosa Sharpe (MRS) Lactobacillus agar and grown anaerobically for 72hr at 37°C. In addition, rectal swab eluates were streaked separately onto eosin methylene blue agar to isolate E. coli, and the last five colonies at the end of the streak area, including any other morphologically distinct colonies, were stored for further analysis. This method provides ≥97% probability of capturing the predominant strain in the sample [17].

E. coli strain heterogeneity was determined by Diversilab™ DNA fingerprinting based on ERIC repetitive PCR [18]. Five E. coli strains were isolated from rectal swabs pre-and post-consumption, and the number of unique fingerprints was determined. The KL diversity measure was used to determine changes in intestinal E. coli heterogeneity pre-and post-SDC consumption [16].

All isolates were confirmed as E. coli by amplification of the glutamate decarboxylase (gad) gene in addition to the colorimetric reaction on BBL™ CHROMagar Orientation media [19]. Mulitplex PCR was used to determine phylotype (A, B1, B2, or D) and the presence of six pathogenicity islands (PAIs) and 15 VFs related to ironuptake, adhesion and toxicity [20][21][22]. The PAIs tested were from E. coli J96 (II J96 ), E. coli CFT073 (I CFT , and II CFT ) and E. coli 536 (I 536 , II 536 , and IV 536 ) [23]. The individual siderophore genes tested included fyuA, iroN E. coli , and iutA . The adhesion genes tested were sfa, papG allele II/III, sfaS, and iha. The toxins included hlyA, cnf1, pic, tsh, sat, and tosA, and other genes tested were K1 and iss.

Two separate statistical analyses were used to evaluate clinical efficacy. A two-tailed paired t-test and mean differences with standard errors (SE) was used to determine significant differences in the six-month UTI rates pre-and post-consumption. A log-rank test was used to compare the time until first UTI between the current study group and two placebo groups from previous clinical trials. The two placebo groups from the previous trials were pooled (p = 0.83).

Significant differences in the numbers (CFU/ml) of bacteria present pre-and post-consumption were determined using the Wilcoxon matched pairs signed rank test using log-transformed values to calculate geometric means with 95% confidence intervals (CI), and the presence of VFs was expressed as percentages.

Results

Clinical efficacy of SDC consumption in UTI-susceptible women

There was a significant reduction in the incidence of UTIs and time until first UTI recurrence in women consuming SDC, as determined by two separate statistical analyses. First, the six-month UTI rate was compared pre-and post-consumption. Nine of 17 (53%) patients reported no UTIs within six months since beginning the study, and the mean UTI rate per six months decreased significantly from 2.4 to 1.1 (Figure 1, p = 0.004, mean difference = 1.26 ± 0.38SE). Since three patients were taking daily antibiotic prophylaxis which may affect the results, the clinical efficacy was determined with and without these patients. When these women were excluded from analysis, the six-month UTI rate also significantly decreased (p = 0.010, mean difference = 1.18 ± 0.39SE).

Second, Kaplan-Meier analysis compared the incidence of UTIs in study patients to patients receiving a placebo in two previous UTI vaccine trials [24]. Women in the current and previous trials had equivalent UTI histories. This analysis showed a significant reduction (p = 0.023) in the acquisition of UTIs within six months for patients consuming SDC (Figure 2). Fifty-three percent of women consuming SDC were uninfected compared to 20 percent of women receiving placebo who were uninfected six-months since beginning the study. When the three women who were taking prophylactic antibiotics were removed from the Kaplan-Meier analysis, the results were more statistically significant since the majority of women taking prophylactic antibiotics still acquired infections (p = 0.018).

Characterization of intestinal bacterial flora pre-and post-SDC consumption

Based on the positive clinical implications of SDC consumption, further microbiological analysis determined whether the intestinal flora was altered by SDC consumption. There was a significant decrease (p = 0.040) in the geometric mean of CFU/ml of E. coli isolated from rectal swab eluates pre-and post-consumption ( Figure 3). There were no significant increases or decreases in Enterococcus sp.

Heterogeneity of intestinal E. coli strains

To determine changes in E. coli heterogeneity preand post-consumption within each patient, Diversilab™ DNA-fingerprint banding patterns for each rectal E. coli strain were compared using KL clustering, and strains that were ≥95% similar were considered identical and those <95% similar were considered unique. The overall diversity measure was calculated for each patient, and those with both pre-and post-consumption rectal E. coli present were analysed (n = 11). Based on the number of unique E. coli strains isolated, the KL diversity measure was calculated to determine any changes in heterogeneity after SDC consumption. Seven of eleven patients (64%) had no change in the diversity measure, 2/11 (18%) had increased heterogeneity (A16 and A18), and 2/11 (18%) had decreased heterogeneity post-consumption (A7, A11). The overall mean diversity measure was 0.0080, which indicates that there was no change in the heterogeneity of E. coli after consumption of SDC (Table 1). Also, it is important to note that 8/11 (72%) of the patients had at least one dominant E. coli strain that was present before and after SDC consumption.

The E. coli strains were further characterized by phylotype and the prevalence of 15 VFs and 6 PAIs for each unique strain. The VFs tested were those involved in toxin production, adhesion, and iron regulation. Of the phylotypes, VFs, and PAIs tested, only two of the phylotypes, one iron-regulation gene (iutA), and one PAI (I CFT ) changed by more than ten percent after SDC consumption. The least pathogenic phylotypes, A and B1, increased by 8% and decreased by 14%, respectively, and the more pathogenic phylotypes, B2 and D, decreased by 8% and increased by 11%, respectively. The proportion of E. coli strains with iutA increased from 6/21 (29%) to 9/21 (45%) after SDC consumption and the proportion of I CFT decreased from 10/21 (48%) to 7/21 (35%). All of the other VFs and PAIs tested did not change by more than ten percent.

Discussion

Here we report the results of a modified observational clinical trial of two-week SDC consumption for the prevention of UTIs in susceptible women. Using two different methods to determine efficacy, consumption Figure 1 Six-month UTI rates Pre-and Post-sweetened dried cranberry consumption. In 17 patients, the mean pre-and post-SDC consumption UTI rates were 2.4 and 1.1, respectively (p = 0.004). The pre-consumption UTI rate is based on one half of the total number of UTIs in the past year or the total UTIs in six months prior to entering the study. Post-consumption six-month UTI rate is based on the total number of UTIs reported six months since beginning the study. Figure 2 Increased time until first UTI following two-week consumption of sweetened dried cranberries. Seventeen patients consumed cranberries for the first two weeks of the study and were followed for a total of six months. Twenty-four control patients were given three doses of a placebo at one-month intervals in a previous vaccine trial. Kaplan-Meier analysis of patients remaining infectionfree following SDC consumption compared to a previous control had p = 0.023. of SDC was shown to be beneficial in reducing the occurrence of UTIs in susceptible women. The significant decrease in six-month UTI rates per individual patient and the comparison of UTI recurrences to a previous control group of women with equivalent UTI histories provide evidence of the potential prophylactic effect of SDC.

Based on the significant decrease in UTI incidence, potential mechanisms of SDC action were investigated. We examined whether the reduction in UTIs could be accounted for by significant changes in the numbers or prevalence of intestinal E. coli or other bacterial species following SDC. E. coli was the only bacteria that showed a significant decrease in overall numbers over the course of the study. It is possible that polyphenols from SDC blocked adherence of E. coli to the intestinal surface and thus decreased their overall numbers, rather than exerting a bactericidal effect. The lack of SDC toxicity is also supported by the observation of no significant changes in the numbers of the other intestinal bacteria surveyed. It is thus likely that SDC are not affecting the growth of commensal bacteria, which is contrary to what would occur if patients were taking prophylactic antibiotics. The lower numbers of intestinal E. coli, combined with the lack of interference with other types of bacteria, may provide a potential benefit since it produces no adverse effects and results in decreased likelihood of UTI.

Although there were no changes in the heterogeneity of intestinal E. coli strains after SDC consumption, we questioned whether there were differences in the intestinal E. coli phylotypes or virulence gene profiles after SDC consumption. The proportion of E. coli with A and D phylotypes was higher after SDC consumption than E. coli with B1 and B2 phylotypes. Phylotypes A and B1 are considered to be less uropathogenic than D and B2. Thus, the increased presence of the A phylotype and    Five E. coli strains were isolated from rectal swabs pre-and postconsumption, and the number of unique fingerprints was determined using Diversilab™ DNA-fingerprinting. Strains were compared using KL clustering, and strains that were ≥95% similar were considered identical and those <95% similar were considered unique. A type designated as 5/0 means that all 5 strains were ≥95% similar and there were no unique strains.

decreased presence of the B2 phylotype could be beneficial; however, this does not explain the increased and decreased presence of E. coli with D and B1 phylotypes, respectively. Although there were changes in the phylotypes of E. coli pre-and post-consumption, there was little change in the proportions of strains carrying VF genes associated with UTI. The prevalence of only the iutA and PAI I CFT VF genes in strains differed by more than ten percent after SDC consumption. Overall, the heterogeneity of E. coli and the presence of VFs did not change as a result of SDC consumption, which suggests that SDC do not directly influence the underlying makeup of E. coli in the intestinal flora.

Because the significant reduction in the number of UTIs following SDC consumption is most likely not related to reducing the prevalence or heterogeneity of intestinal uropathogenic E. coli or other potential uropathogens, alternative mechanisms whereby cranberry phytochemicals could directly influence bacterial phenotypes should be considered. One intriguing possibility is that some components of cranberries may be able to modulate expression of E. coli VF genes and reduce infectivity and pathogenicity. Support for this concept comes from several studies. Trans-cinnamaldehyde was shown to decrease E. coli attachment to uroepithelial cells and to reduce cellular invasion in vitro by downregulating expression of the fimH gene coding for the adhesin of type 1 pili [25]. Cinnamaldehyde and some of its derivatives were also shown to reduce the virulence of Vibrio species by decreasing the quorum sensing response [26]. It has also been reported that compounds in crushed cranberries or cranberry proanthocyanidins inhibited expression of the fliC flagella structural gene in the CFT073 UPEC strain, with subsequent loss of motility [27]. Resveratrol, which is present in cranberries, decreased the pathogenicity of Proteus mirabilis by inhibiting swarming as well as reduced hemolysin production and urothelial cell invasion [28]. It is possible that these, or other compounds found in cranberries could similarly decrease the virulence of intestinal E. coli by gene modulation that reduces motility as well as uroepithelial cell adherence and invasion, thereby reducing uropathogenic E. coli persistence and infectivity in the vagina and bladder.

Another potential mechanism to consider for the observed clinical benefits of SDC consumption is that cranberry phytochemicals may boost mucosal immunity to uropathogens in the gastrointestinal tract. A recent study has shown that cranberry proanthocyanidins can be used as an adjunct to increase intestinal sIgA levels in mice receiving enteral nutrition [29]. A clinical investigation found that consuming a cranberry beverage for ten weeks resulted in a five-fold increase in proliferation of T cells ex vivo, a 30% increase in NK cell proliferation, and a 20% reduction in IL-17 secretion, as well as a significant reduction in cold and flu symptoms compared to placebo [30]. Further studies on the immune enhancing effects of SDC in vivo could define which components of the intestinal immune system are targeted by cranberry phytochemicals.

Although SDC consumption did not prevent UTIs in every patient, none of the patients reported any adverse effects. Therefore, it may be suggested that SDC be used as a prophylactic supplement for patients with recurrent UTIs, since the potential benefits greatly outweigh the risks. A larger, randomized, placebo-controlled study is needed to confirm that daily consumption of SDC is beneficial in the reduction of recurrent UTIs.

One of the limitations of the efficacy assessment is the comparison of patients consuming SDC in this study to a control group from a previous study. We are confident, however, that this comparison between groups is applicable and informative even though it is not the most appropriate comparison for rigorous statistical analysis. Because the women in the current trial and the previous placebo-controlled study had equivalent UTI histories and similar demographics, we would expect women in both groups to acquire UTIs at the same rate over a six-month period without treatment interventions. Randomized, placebo-controlled studies are necessary to further determine the efficacy of SDC consumption.

Conclusions

The results of this study indicate a potential beneficial effect of consuming SDC in reducing the number of recurrent UTIs in susceptible women; however, the results shown here are only preliminary and further studies are necessary. Daily SDC consumption is an inexpensive and readily available supplement to a woman's diet and may provide potential prophylactic effects. Despite the observed clinical efficacy of SDC consumption, however, the underlying mechanism of SDC is still unclear. Twoweek consumption of SDC reduces the overall numbers of E. coli in the intestines but does not change the E. coli strain heterogeneity or the presence of other bacterial types. Future studies are needed to determine the underlying mechanism of SDC for reduction of UTIs in susceptible women.

(p = 0.315), Klebsiella sp. (p = 0.734), S. Saprophyticus (p = 0.875), Lactobacillus sp. (p = 0.600) or Unknown sp. (p = 0.508). S. aureus and Proteus sp. were not isolated from any rectal swab eluates pre-or postconsumption.

Figure 3
3Bacterial species present in rectal swab eluates pre-and post SDC consumption. Types of bacteria isolated from rectal swab eluates at study entry and two weeks after consuming sweetened, dried cranberries. Bacterial cell counts are presented as geometric means (CFU/ml) with 95% CI.

Table 1
1Diversity measures of rectal E. coli strains pre-and post-consumption of SDCDiversity
change 1

Pre
Post
Diversity
measure 3
Types 2 Diversity Types Diversity

http://www.nutritionj.com/content/12/1/139
When the DNA fingerprints of all five rectal E. coli isolates were the same, the diversity measure was zero. As the number of unique fingerprints increased, the diversity measure becomes an increasingly negative number.
Competing interestsThe authors declare they have no competing interests.Author contributions AB recruited patients for the study, obtained informed consent from subjects, conducted laboratory assays, analyzed data, and drafted the manuscript. SB was the clinic nurse for the study and interacted with study subjects. SM assisted with the development of the study design and recruited patients for the study from her clinical practice. JR and CK helped with the development of the study design and provided expertise on cranberry phytochemicals. WH was the principal investigator and provided oversight for the study. WH developed the study design and methods, and assisted with drafting the manuscript. All authors read and approved the final manuscript.
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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Burleigh, Nutrition Journal. 12139Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women -a modified observational study. Submit your manuscript at www.biomedcentral.com/submitCite this article as: Burleigh et al.: Consumption of sweetened, dried cranberries may reduce urinary tract infection incidence in susceptible women -a modified observational study. Nutrition Journal 2013 12:139. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit