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ObjectivesGastrointestinal (GI) infections are common. Most infections are self-limiting, with some people developing long-term sequelae following their GI infection. Currently, the surveillance of GI infections such as Campylobacter and Salmonella is primarily based on laboratory data held by Public Health England (PHE). Information on symptoms severity, treatment of infection and subsequent complications is not captured by this data source. Electronic Health Records (EHR) provide a platform to assemble cohorts for long-term follow-up at relatively low costs. Record linkage of existing EHR provides a powerful resource to estimate the burden of complications following gastrointestinal Infections (GI) and the associated risk factors such as treatment of the primary GI infection. A range of ethical and data governance approvals processes, motivated to protect patients and patient data, are required to allow use of routine and linked data for research. The aim of this project is to establish a bespoke linkage of PHE laboratory data on Campylobacter, non-typhoidal Salmonella (NTS) and verocytotoxin producing Escherichia coli (VTEC) to the Clinical Practice Research Datalink (CPRD, primary care records), hospital records and other secondary datasets in order to estimate the burden of complications following GI infections. ApproachLinkage of laboratory data, primary care data, hospital records, deaths and deprivation index were proposed following an initial data completeness check of laboratory data on Campylobacter spp., NTS and VTEC over a ten year (2004-2014) period. Linkage plans were discussed with all relevant organisations. Finalised study protocols were completed and application for approval for linkage was submitted to the Independent Scientific Advisory Committee (ISAC) and the NHS Research Ethics Committee. An additional application was sent to the Confidential Advisory Group (CAG) to comply with section 251 of the UK NHS Act 2006 on accessing patient identifiable information. ResultsISAC approval for CPRD linkage is dependent on CAG approval. Completion of data linkage will allow the measurement of complications following GI infections to be estimated more accurately than is possible using routine, unlinked population-level data. It allows the implementation of designs such as the case-crossover design for the investigation of patient-level risk factors such as use of antibiotics and their association with complications. ConclusionsBespoke record linkage to CPRD can allow the measurement of risk of long-term sequelae following acute infections. Considerable time should be built into research timelines to allow completion of all ethical, governance and data access procedures.

Genomic surveillance can effectively detect such outbreaks, providing increased intelligence to support infection control., Single-strain outbreaks of Streptococcus pyogenes infections are common and often go undetected. In 2013, two clusters of invasive group A Streptococcus (iGAS) infection were identified in independent but closely located care homes in Oxfordshire, United Kingdom. Investigation included visits to each home, chart review, staff survey, microbiologic sampling, and genome sequencing. S. pyogenes emm type 1.0, the most common circulating type nationally, was identified from all cases yielding GAS isolates. A tailored whole-genome reference population comprising epidemiologically relevant contemporaneous isolates and published isolates was assembled. Data were analyzed independently using whole-genome multilocus sequencing and single-nucleotide polymorphism analyses. Six isolates from staff and residents of the homes formed a single cluster that was separated from the reference population by both analytical approaches. No further cases occurred after mass chemoprophylaxis and enhanced infection control. Our findings demonstrate the ability of 2 independent analytical approaches to enable robust conclusions from nonstandardized whole-genome analysis to support public health practice.

Background Gastroenteritis is a common, transient disorder usually caused by infection and characterised by the acute onset of diarrhoea. Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify common bacterial, viral and parasitic pathogens using molecular testing. By providing test results more rapidly than conventional testing methods, GPP tests might positively influence the treatment and management of patients presenting in hospital or in the community. Objective To systematically review the evidence for GPP tests [xTAG® (Luminex, Toronto, ON, Canada), FilmArray (BioFire Diagnostics, Salt Lake City, UT, USA) and Faecal Pathogens B (AusDiagnostics, Beaconsfield, NSW, Australia)] and to develop a de novo economic model to compare the cost-effectiveness of GPP tests with conventional testing in England and Wales. Data sources Multiple electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Database were searched from inception to January 2016 (with supplementary searches of other online resources). Review methods Eligible studies included patients with acute diarrhoea; comparing GPP tests with standard microbiology techniques; and patient, management, test accuracy or cost-effectiveness outcomes. Quality assessment of eligible studies used tailored Quality Assessment of Diagnostic Accuracy Studies-2, Consolidated Health Economic Evaluation Reporting Standards and Philips checklists. The meta-analysis included positive and negative agreement estimated for each pathogen. A de novo decision tree model compared patients managed with GPP testing or comparable coverage with patients managed using conventional tests, within the Public Health England pathway. Economic models included hospital and community management of patients with suspected gastroenteritis. The model estimated costs (in 2014/15 prices) and quality-adjusted life-year losses from a NHS and Personal Social Services perspective. Results Twenty-three studies informed the review of clinical evidence (17 xTAG, four FilmArray, two xTAG and FilmArray, 0 Faecal Pathogens B). No study provided an adequate reference standard with which to compare the test accuracy of GPP with conventional tests. A meta-analysis (of 10 studies) found considerable heterogeneity; however, GPP testing produces a greater number of pathogen-positive findings than conventional testing. It is unclear whether or not these additional ‘positives’ are clinically important. The review identified no robust evidence to inform consequent clinical management of patients. There is considerable uncertainty about the cost-effectiveness of GPP panels used to test for suspected infectious gastroenteritis in hospital and community settings. Uncertainties in the model include length of stay, assumptions about false-positive findings and the costs of tests. Although there is potential for cost-effectiveness in both settings, key modelling assumptions need to be verified and model findings remain tentative. Limitations No test–treat trials were retrieved. The economic model reflects one pattern of care, which will vary across the NHS. Conclusions The systematic review and cost-effectiveness model identify uncertainties about the adoption of GPP tests within the NHS. GPP testing will generally correctly identify pathogens identified by conventional testing; however, these tests also generate considerable additional positive results of uncertain clinical importance. Future work An independent reference standard may not exist to evaluate alternative approaches to testing. A test–treat trial might ascertain whether or not additional GPP ‘positives’ are clinically important or result in overdiagnoses, whether or not earlier diagnosis leads to earlier discharge in patients and what the health consequences of earlier intervention are. Future work might also consider the public health impact of different testing treatments, as test results form the basis for public health surveillance. Study registration This study is registered as PROSPERO CRD2016033320. Funding The National Institute for Health Research Health Technology Assessment programme.

Background Timely and accurate identification of people with latent tuberculosis infection (LTBI) is important for controlling Mycobacterium tuberculosis (TB). There is no gold standard for diagnosis of LTBI. Screening tests such as interferon gamma release assays (IGRAs) and tuberculin skin test (TST) provide indirect and imperfect information. This systematic review compared two types of IGRAs QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT.TB with TST for identification of LTBI by predicting progression to a diagnosis of active TB in three subgroups: children, immunocompromised people, and those recently arrived from countries with high TB burden. Methods Cohort studies were eligible for inclusion. We searched MEDLINE, EMBASE, the Cochrane Library and other databases from December 2009 to June 2015. One reviewer screened studies, extracted data, and assessed risk of bias with cross checking by a second reviewer. Strength of association between test results and incidence of TB was summarised using cumulative incidence ratios (CIRs with 95% CIs). Summary effect measures: the ratio of CIRs (R-CIR) with 95% CIs. R-CIRs, were pooled using a random-effects model. Heterogeneity was assessed using Chi-squared and I2 statistics. Results Seventeen studies, mostly of moderate or high risk of bias (five in children, 10 in immunocompromised people, and two in those recently arrived) were included. In children, while in two studies, there was no significant difference between QFT-GIT and TST (≥5 mm) (pooled R-CIR = 1.11, 95% CI: 0.71, 1.74), two other studies showed QFT-GIT to outperform TST (≥10 mm) in identifying LTBI. In immunocompromised people, IGRA (T-SPOT.TB) was not significant different from TST (≥10 mm) for identifying LTBI, (pooled R-CIR = 1.01, 95% CI: 0.65, 1.58). The forest plot of two studies in recently arrived people from countries with high TB burden demonstrated inconsistent findings (high heterogeneity; I2 = 92%). Conclusions Prospective studies comparing IGRA testing against TST on the progression from LTBI to TB were sparse, and these results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity. Population-based studies with adequate sample size and follow-up are required to adequately compare the performance of IGRA with TST in people at high risk of TB. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2301-4) contains supplementary material, which is available to authorized users.

Summary Background The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. Methods In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. Findings Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8–10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1–16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19–64 years (relative risk [RR] 0·85, 95% CrI 0·75–0·95) and 65 years and older (0·87, 0·84–0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. Interpretation Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. Funding Policy Research Programme of the Department of Health, England.

Campylobacter jejuni is a major cause of bacterial gastroenteritis worldwide, primarily associated with the consumption of contaminated poultry. C. jejuni lineages vary in host range and prevalence in human infection, suggesting differences in survival throughout the poultry processing chain. From 7,343 MLST-characterised isolates, we sequenced 600 C. jejuni and C. coli isolates from various stages of poultry processing and clinical cases. A genome-wide association study (GWAS) in C. jejuni ST-21 and ST-45 complexes identified genetic elements over-represented in clinical isolates that increased in frequency throughout the poultry processing chain. Disease-associated SNPs were distinct in these complexes, sometimes organised in haplotype blocks. The function of genes containing associated elements was investigated, demonstrating roles for cj1377c in formate metabolism, nuoK in aerobic survival and oxidative respiration, and cj1368-70 in nucleotide salvage. This work demonstrates the utility of GWAS for investigating transmission in natural zoonotic pathogen populations and provides evidence that major C. jejuni lineages have distinct genotypes associated with survival, within the host specific niche, from farm to fork.

Human campylobacteriosis, caused by Campylobacter jejuni and C. coli, remains a leading cause of bacterial gastroenteritis in many countries, but the epidemiology of campylobacteriosis outbreaks remains poorly defined, largely due to limitations in the resolution and comparability of isolate characterization methods. Whole-genome sequencing (WGS) data enable the improvement of sequence-based typing approaches, such as multilocus sequence typing (MLST), by substantially increasing the number of loci examined. A core genome MLST (cgMLST) scheme defines a comprehensive set of those loci present in most members of a bacterial group, balancing very high resolution with comparability across the diversity of the group. Here we propose a set of 1,343 loci as a human campylobacteriosis cgMLST scheme (v1.0), the allelic profiles of which can be assigned to core genome sequence types. The 1,343 loci chosen were a subset of the 1,643 loci identified in the reannotation of the genome sequence of C. jejuni isolate NCTC 11168, chosen as being present in >95% of draft genomes of 2,472 representative United Kingdom campylobacteriosis isolates, comprising 2,207 (89.3%) C. jejuni isolates and 265 (10.7%) C. coli isolates. Validation of the cgMLST scheme was undertaken with 1,478 further high-quality draft genomes, containing 150 or fewer contiguous sequences, from disease isolate collections: 99.5% of these isolates contained ≥95% of the 1,343 cgMLST loci. In addition to the rapid and effective high-resolution analysis of large numbers of diverse isolates, the cgMLST scheme enabled the efficient identification of very closely related isolates from a well-defined single-source campylobacteriosis outbreak.

Objective Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify bacterial, viral and parasitic pathogens from the stool samples of patients with suspected infectious gastroenteritis presenting in hospital or the community. We undertook a systematic review to compare the accuracy of GPP tests with standard microbiology techniques. Review methods Searches in Medline, Embase, Web of Science and the Cochrane library were undertaken from inception to January 2016. Eligible studies compared GPP tests with standard microbiology techniques in patients with suspected gastroenteritis. Quality assessment of included studies used tailored QUADAS-2. In the absence of a reference standard we analysed test performance taking GPP tests and standard microbiology techniques in turn as the benchmark test, using random effects meta-analysis of proportions. Results No study provided an adequate reference standard with which to compare the test accuracy of GPP and conventional tests. Ten studies informed a meta-analysis of positive and negative agreement. Positive agreement across all pathogens was 0.93 (95% CI 0.90 to 0.96) when conventional methods were the benchmark and 0.68 (95% CI: 0.58 to 0.77) when GPP provided the benchmark. Negative agreement was high in both instances due to the high proportion of negative cases. GPP testing produced a greater number of pathogen-positive findings than conventional testing. It is unclear whether these additional ‘positives’ are clinically important. Conclusions GPP testing has the potential to simplify testing and accelerate reporting when compared to conventional microbiology methods. However the impact of GPP testing upon the management, treatment and outcome of patients is poorly understood and further studies are needed to evaluate the health economic impact of GPP testing compared with standard methods. The review protocol is registered with PROSPERO as CRD42016033320.

• The extent and characteristics of influenza outbreaks in three primary schools have been described.

The aim of this study was to determine the effects of ultrasound on the dissolution properties of milk protein concentrate (MPC) powders. A high intensity ultrasound (20 kHz; power 70.2 W) was used to dissolve MPC powder and the dissolution rate was compared to conventional methods of dispersion (e.g., stirring). Rehydration of MPC by stirring at 50 °C complied with the 2-step dissolution model whereby the disappearance of larger particles coincided with the formation of smaller ones over time. MPC dispersal by sonication dramatically accelerated this process, achieving >90% levels of powder solubilisation. Temperature rise (>70 °C) during sonication causes protein denaturation and aggregation, but this can be alleviated using thermal dissipation. Overall, the use of a combination rehydration process for MPC powders involving (i) conventional dissolution (stirring) for 10 min at 50 °C followed by (ii) ultrasonication (

Lactoferrin and β-casein represent a large proportion of the proteins in human milk and, as a result, are important ingredients for the manufacture of infant formula. At pH 7, lactoferrin has a net positive charge, compared to the negatively charged β-casein. The effects of CaCl 2 and heat treatment on the stability of oil-in-water emulsions stabilised by lactoferrin and/or β-casein were investigated. The ζ-potential values of emulsions stabilised with β-casein or a 1:1 mixture of β-casein/lactoferrin significantly ( P 2 , while CaCl 2 had no significant ( P > 0.05) effect on the ζ-potential of lactoferrin-stabilised emulsions. Particle size of β-casein-stabilised emulsions increased significantly ( P 2 , due to flocculation, while emulsions stabilised with lactoferrin and β-casein/lactoferrin remained unaffected by CaCl 2 addition. Oscillatory rheology measurements showed that β-casein-stabilised emulsions formed a gel when CaCl 2 was added, due to calcium-bridging, compared to lactoferrin-stabilised emulsions, where a weaker gel was formed in the presence of CaCl 2 . While, 30 mM CaCl 2 did not increase the elastic modulus ( G ′) of β-casein/lactoferrin-stabilised emulsions. Lactoferrin protected β-casein from calcium-induced flocculation by: (1) binding calcium ions via sialic acid groups on lactoferrin molecules and reducing the number of free ions available to form calcium linkages between β-casein molecules; (2) electrostatically interacting with negatively charged phosphate groups on β-casein molecules, blocking calcium–phosphate interactions and (3) providing additional stability through increased steric repulsion between β-casein/lactoferrin conjugates, due to the large molecular size of lactoferrin.

The impact of immunisation is best understood through a historical lens, since so many of the diseases which placed a burden on our population have been eliminated or controlled through immunisation. The United Kingdom (UK) National Health Service (NHS), which celebrated its 70thbirthday in 2018, is responsible for delivering the highly successful universal national immunisation programme. However, the first vaccines used in the UK were not part of a centrally coordinated programme until the 1960s. Resources that summarise the first 200 years of immunisation in the UK are not readily accessible. Here we provide a two part chronological insight into the history of the UK immunisation programme from primary sources. In Part I, we highlight the importance of wartime conditions, unprecedented vaccine development, and the polio outbreaks in the in driving developments in immunisation and discuss subsequent changes in the use of the original vaccines of the immunisation programme, namely, diphtheria, tetanus, pertussis, and polio. In Part 2, we discuss the formation of the Joint Committee on Vaccination and Immunisation and its role, working with public health agencies and advising the UK Governments on vaccine policy, to bring a comprehensive programme to defend the health of the population against serious infectious diseases, highlighting the importance of programme organisation and leadership.

Campylobacter­ spp.–related gastroenteritis in diners at a catering college restaurant was associated with consumption of duck liver pâte. Population genetic analysis indicated that isolates from duck samples were typical of isolates from farmed poultry. Campylobacter spp. contamination of duck liver may present a hazard similar to the increasingly recognized contamination of chicken liver.

Bovine β-casein was purified from phosphocasein by rennet coagulation and cold solubilisation from the resultant curd. β-Casein was then dephosphorylated using potato acid phosphatase. Urea-polyacrylamide gel electrophoresis (PAGE) of partially dephosphorylated β-casein showed a number of bands, depending on the final level of phosphorylation. Dephosphorylating β-casein increased its pH of minimum solubility from ∼pH 5 to 5.5 and reduced its net negative charge from −30.8 to −27.0 mV. During the acidification of β-casein solutions, partially dephosphorylated β-casein failed to form a gel, unlike the phosphorylated (i.e., control) β-casein. Use of partially dephosphorylated β-casein to stabilise oil-in-water emulsions resulted in larger fat globules compared to control β-casein, but such globules were less susceptible to aggregation in the presence of 15 or 30 mM CaCl 2 . Overall, the dephosphorylation of β-casein resulted in a protein similar to human β-casein in terms of physicochemical functionality, with increased stability against calcium-induced aggregation.

Background Cryptosporidium is a major cause of gastroenteritis (cryptosporidiosis). Case and outbreak report rates vary geographically, which may in part reflect public health practice. Methods To examine the public health management of cryptosporidiosis, an online questionnaire was administered to the 28 Health Protection Teams (HPTs) in England and Wales in 2014. Practices for investigation and management of cases and outbreaks were compared. Results Practice varied among the 24 (86%) respondents in terms of who undertook actions (HPT or Local Authority) to investigate and manage cryptosporidiosis. HPTs without exceedance monitoring detected fewer outbreaks (1/5, 20%) than those with it (13/19, 68%) (P = 0.12), and those that always administered a risk-factor questionnaire detected more outbreaks (12/19, 63%) than those who did this only sometimes (2/5, 40%) (P = 0.62). Significantly more HPTs with a system to detect common exposures reported at least one outbreak (14/19, 74%) compared to HPTs with no system (0/5) (P = 0.01). Conclusions Applying exceedance monitoring, using a standardized questionnaire taking into account the incubation period for Cryptosporidium, and having a structured system to detect common exposures increased outbreak detection. Information about all cases should be shared between local public health authorities, and current guidance used for the prevention of spread.

Genetic attribution of bacterial genotypes has become a major tool in the investigation of the epidemiology of campylobacteriosis and has implicated retail chicken meat as the major source of human infection in several countries. To investigate the robustness of this approach to the provenance of the reference data sets used, a collection of 742 Campylobacter jejuni and 261 Campylobacter coli isolates obtained from United Kingdom-sourced chicken meat was established and typed by multilocus sequence typing. Comparative analyses of the data with those from other isolates sourced from a variety of host animals and countries were undertaken by genetic attribution, genealogical, and population genetic approaches. The genotypes from the United Kingdom data set were highly diverse, yet structured into sequence types, clonal complexes, and genealogical groups very similar to those seen in chicken isolates from the Netherlands, the United States, and Senegal, but more distinct from isolates obtained from ruminant, swine, and wild bird sources. Assignment analyses consistently grouped isolates from different host animal sources regardless of geographical source; these associations were more robust than geographic associations across isolates from three continents. We conclude that, notwithstanding the high diversity of these pathogens, there is a strong signal of association of multilocus genotypes with particular hosts, which is greater than the geographic signal. These findings are consistent with local and international transmission of host-associated lineages among food animal species and provide a foundation for further improvements in genetic attribution.

Wild European Starlings (Sturnus vulgaris) shed Campylobacter at high rates, suggesting that they may be a source of human and farm animal infection. A survey of Campylobacter shedding of 957 wild starlings was undertaken by culture of faecal specimens and genetic analysis of the campylobacters isolated: shedding rates were 30.6% for Campylobacter jejuni, 0.6% for C. coli and 6.3% for C. lari. Genotyping by multilocus sequence typing (MLST) and antigen sequence typing established that these bacteria were distinct from poultry or human disease isolates with the ST-177 and ST-682 clonal complexes possibly representing starling-adapted genotypes. There was seasonal variation in both shedding rate and genotypic diversity, both exhibiting a maximum during the late spring/early summer. Host age also affected Campylobacter shedding, which was higher in younger birds, and turnover was rapid with no evidence of cross-immunity among Campylobacter species or genotypes. In nestlings, C. jejuni shedding was evident from 9 days of age but siblings were not readily co-infected. The dynamics of Campylobacter infection of starlings differed from that observed in commercial poultry and consequently there was no evidence that wild starlings represent a major source of Campylobacter infections of food animals or humans.

Background: Patients born outside the UK have contributed to a 20% rise in the UK's tuberculosis incidence since 2000, but their effect on domestic transmission is not known. Here we use whole-genome sequencing to investigate the epidemiology of tuberculosis transmission in an unselected population over 6 years. Methods: We identified all residents with Oxfordshire postcodes with a Mycobacterium tuberculosis culture or a clinical diagnosis of tuberculosis between Jan 1, 2007, and Dec 31, 2012, using local databases and checking against the national Enhanced Tuberculosis Surveillance database. We used Illumina technology to sequence all available M tuberculosis cultures from identified cases. Sequences were clustered by genetic relatedness and compared retrospectively with contact investigations. The first patient diagnosed in each cluster was defined as the index case, with links to subsequent cases assigned first by use of any epidemiological linkage, then by genetic distance, and then by timing of diagnosis. Findings: Although we identified 384 patients with a diagnosis of tuberculosis, country of birth was known for 380 and we sequenced isolates from 247 of 269 cases with culture-confirmed disease. 39 cases were genomically linked within 13 clusters, implying 26 local transmission events. Only 11 of 26 possible transmissions had been previously identified through contact tracing. Of seven genomically confirmed household clusters, five contained additional genomic links to epidemiologically unidentified non-household members. 255 (67%) patients were born in a country with high tuberculosis incidence, conferring a local incidence of 109 cases per 100000 population per year in Oxfordshire, compared with 3·5 cases per 100000 per year for those born in low-incidence countries. However, patients born in the low-incidence countries, predominantly UK, were more likely to have pulmonary disease (adjusted odds ratio 1·8 [95% CI 1·2-2·9]; p=0·009), social risk factors (4·4 [2·0-9·4]; p

Hybridization between distantly related organisms can facilitate rapid adaptation to novel environments, but is potentially constrained by epistatic fitness interactions among cell components. The zoonotic pathogens Campylobacter coli and C. jejuni differ from each other by around 15% at the nucleotide level, corresponding to an average of nearly 40 amino acids per protein-coding gene. Using whole genome sequencing, we show that a single C. coli lineage, which has successfully colonized an agricultural niche, has been progressively accumulating C. jejuni DNA. Members of this lineage belong to two groups, the ST-828 and ST-1150 clonal complexes. The ST-1150 complex is less frequently isolated and has undergone a substantially greater amount of introgression leading to replacement of up to 23% of the C. coli core genome as well as import of novel DNA. By contrast, the more commonly isolated ST-828 complex bacteria have 10-11% introgressed DNA, and C. jejuni and nonagricultural C. coli lineages each have

Zoonotic pathogens often infect several animal species, and gene flow among populations infecting different host species may affect the biological traits of the pathogen including host specificity, transmissibility and virulence. The bacterium Campylobacter jejuni is a widespread zoonotic multihost pathogen, which frequently causes gastroenteritis in humans. Poultry products are important transmission vehicles to humans, but the bacterium is common in other domestic and wild animals, particularly birds, which are a potential infection source. Population genetic studies of C. jejuni have mainly investigated isolates from humans and domestic animals, so to assess C. jejuni population structure more broadly and investigate host adaptation, 928 wild bird isolates from Europe and Australia were genotyped by multilocus sequencing and compared to the genotypes recovered from 1366 domestic animal and human isolates. Campylobacter jejuni populations from different wild bird species were distinct from each other and from those from domestic animals and humans, and the host species of wild bird was the major determinant of C. jejuni genotype, while geographic origin was of little importance. By comparison, C. jejuni differentiation was restricted between more phylogenetically diverse farm animals, indicating that domesticated animals may represent a novel niche for C. jejuni and thereby driving the evolution of those bacteria as they exploit this niche. Human disease is dominated by isolates from this novel domesticated animal niche. © 2013 Blackwell Publishing Ltd.

BACKGROUND: Cross-sectional relationships between moderate and vigorous physical activity and the metabolic syndrome (MS) were examined in the Whitehall II study of civil servants (age 45-68 years). We assessed cardiovascular fitness and body mass index (BMI) as possible mediators of the observed association. METHODS: Measures of 2-hour glucose, systolic blood pressure, fasting triglycerides, waist-hip ratio, and high density lipoprotein (HDL) cholesterol were obtained in 5153 white European participants. Participants in the most adverse sex-specific quintile for three or more of these risk factors were classified as having MS. Self-reported leisure-time physical activity was categorized into separate moderate and vigorous activity classes. BMI and resting heart rate (HR) were used to estimate body fatness and cardiovascular fitness respectively. RESULTS: The odds ratios (95% CI) for having the metabolic syndrome in the top categories of vigorous and moderate activity were 0.52 (95% CI: 0.40, 0.67) and 0.78 (95% CI: 0.63, 0.96) respectively, adjusted for age, sex, smoking, alcohol intake, socioeconomic status, and other activity. Adjustment for BMI and resting HR substantially attenuated both of the above associations. CONCLUSIONS: Moderate and vigorous physical leisure-time activity are each associated with reduced risk of being classified with MS independently of age, smoking, and high alcohol intake. Both vigorous and moderate activities may be beneficial to the MS cluster of risk factors among middle-aged populations. Reduced BMI and increased cardiovascular fitness may be important mediators of this association for both intensities of activity.

BACKGROUND: Outbreaks of measles in Gypsy-Traveller communities are well recognized. Their contribution to the overall burden of disease is less clear. METHODS: Measles case-management information was collated retrospectively for the Thames Valley population comprising 2.2 million people over the 4-year period from 2006 to 09. Suspected cases notified by general practitioners and hospital clinicians were sent a saliva testing kit. Cases were defined as those whose measles IgM was positive. Risk factor information was collected and collated including vaccination and membership of the Gypsy-Traveller communities. RESULTS: Of 142 cases of laboratory confirmed measles, 63% were in Gypsy-Traveller communities. These included 10 family clusters and outbreaks confined to the Gypsy-Traveller communities and one with a wider spread. The pattern was consistent across the 4 years studied. Among the Gypsy-Traveller communities 27 of 55 cases eligible for measles, mumps and rubella (MMR) vaccination had received one MMR vaccination. Overall seven cases were admitted to hospital with either pneumonia or dehydration. CONCLUSION: These findings showed a more than 100-fold higher incidence in the Gypsy-Traveller communities than the rest of the population. The high burden of disease in the Gypsy-Traveller communities highlights the importance of targeting immunization resources towards these communities.

Horizontal genetic exchange strongly influences the evolution of many bacteria, substantially contributing to difficulties in defining their position in taxonomic groups. In particular, how clusters of related bacterial genotypes – currently classified as microbiological species – evolve and are maintained remains controversial. The nature and magnitude of gene exchange between two closely related (approx. 15 % nucleotide divergence) microbiologically defined species,Campylobacter jejuniandCampylobacter coli, was investigated by the examination of mosaic alleles, those with some ancestry from each population. A total of 1738 alleles from 2953 seven-locus housekeeping gene sequence types (STs) were probabilistically assigned to each species group with the model-based clustering algorithmstructure. Alleles with less than 75 % assignment probability to one of the populations were confirmed as mosaics using thestructurelinkage model. For each of these, the putative source of the recombinant region was determined and the allele was mapped onto aclonalframegenealogy derived from concatenated ST sequences. This enabled the direction and frequency of introgression between the two populations to be established, with 8.3 % ofC. coliclade 1 alleles having acquiredC. jejunisequence, compared to 0.5 % for the reciprocal process. Once generated, mosaic genes spread withinC. coliclade 1 by a combination of clonal expansion and lateral gene transfer, with some evidence of erosion of the mosaics by reacquisition ofC. colisequence. These observations confirm previous analyses of the exchange of complete housekeeping alleles and extend this work by describing the processes of horizontal gene transfer and subsequent spread within recipient species.

BACKGROUND: Immunization advice services can support health professionals by providing rapid access to accurate and reliable current information and advice. The Vaccine Advice for Clinicians Service (VACCSline) is a service for health professionals working within the Thames Valley Area of the UK. METHODS: We reviewed all 4299 enquiries received by VACCSline over 3 years. Queries were summarized by vaccine type and topic of enquiry. Associations with profession and workplace of the enquirer were tested using Fisher's exact tests. RESULTS: Incomplete immunization status and non-UK schedules were the most common topics of enquiry. Practice nurses were the main service users followed by doctors. Enquiries varied by professional role. Alterations to the immunization programme led to temporary changes to enquiry content and some more persistent adjustments in the balance of enquiries were identified, such as an increase in enquiries relating to vaccination in pregnancy. CONCLUSIONS: The content of enquiries to VACCSline is broad, confirming the need for immunizers to have a wide knowledge base and access to specialist advice to assist with complex scenarios. Systematic data capture provided intelligence to guide training and materials to support immunizers. A wider networked application of this approach could improve support for immunizers.

BACKGROUND: Group C meningococcal conjugate-vaccine effectiveness in the United Kingdom declines from ~90% in the first year to 0% between 1 and 4 years after immunization in infants immunized at 2, 3, and 4 months of age and to 61% in toddlers given a single dose. Confidence intervals are wide, and the extent of protection is uncertain. METHODS: Serum samples were obtained from children 3-5 years of age who were participants in a preschool booster-vaccine trial. Serum bactericidal activity was measured with human complement. Group C anticapsular antibody concentrations were measured by a radioantigen binding assay. Passive protection was analyzed in an infant rat bacteremia model. RESULTS: Serum samples from UK children who had been immunized 2-3 years earlier as infants or toddlers had higher levels of radioantigen binding, bactericidal activity, and passive protection than did historical control serum samples from unimmunized children (P or =1 : 4 (considered to be protective) than those immunized as toddlers (61% vs. 24%; P

This open, randomised controlled trial studied the immunogenicity and reactogenicity of two combined low-dose diphtheria, tetanus and acellular pertussis vaccines (Td5aP-IPV, REPEVAX™, Aventis Pasteur MSD; and Td5aP, COVAXIS™, Aventis Pasteur MSD + OPV, GlaxoSmithKline) in comparison with a standard dose diptheria pre-school booster vaccine (DT2aP-IPV, TETRAVAC™, Aventis Pasteur MSD) in a population of 3.5-6 year-old children administered concomitantly with measles, mumps and rubella vaccine (M-M-R™II, Aventis Pasteur MSD). A linked sub-study aimed to evaluate the immunogenicity and reactogenicity of Td5aP-IPV in a population of younger children, aged 3-3.5 years. This study demonstrated non-inferiority of seroprotection rates for diphtheria and tetanus for the study vaccines and comparable immunogenicity for pertussis and polio components of the vaccines. Reactogenicity was similar for all three vaccines. The study vaccines containing low-dose diphtheria antigen (Td5aP-IPV and Td5aP + OPV) are immunogenic and have acceptable reactogenicity for use as a pre-school booster vaccine administered concomitantly with MMR.

Two apparently linked fatal cases of pneumococcal meningitis were investigated. Pneumolysin PCR performed on blood and cerebrospinal fluid was positive in a culture-negative case. A second case yielded Streptococcus pneumoniae from blood culture. Multilocus sequence typing performed on DNA extracted from case 1 (specimens) and case 2 (isolate) revealed identical sequence types (ST53) substantiating the link between them.

Background Sepsis is a life-threatening condition and major contributor to public health and economic burden in the industrialised world. The difficulties in accurate diagnosis lead to great variability in estimates of sepsis incidence. There has been even greater uncertainty regarding the incidence of and risk factors for community-onset sepsis (COS). We systematically reviewed the recent evidence on the incidence and risk factors of COS in high income countries (North America, Australasia, and North/Western Europe). Methods Cohort and case-control studies were eligible for inclusion. Medline and Embase databases were searched from 2002 onwards. References of relevant publications were hand-searched. Two reviewers screened titles/abstracts and full-texts independently. One reviewer extracted data and appraised studies which were cross-checked by independent reviewers. Disagreements were resolved via consensus. Odds ratios (ORs) and 95 percent confidence intervals (95 % CIs) were ascertained by type of sepsis (non-severe, severe, and septic shock). Results Ten cohort and 4 case-control studies were included. There was a wide variation in the incidence (# cases per 100,000 per year) of non-severe sepsis (range: 64–514), severe sepsis (range: 40–455), and septic shock (range: 9–31). Heterogeneity precluded statistical pooling. Two cohort and 4 case-control studies reported risk factors for sepsis. In one case-control and one cohort study, older age and diabetes were associated with increased risk of sepsis. The same case-control study showed an excess risk for sepsis in participants with clinical conditions (e.g., immunosuppression, lung disease, and peripheral artery disease). In one cohort study, higher risk of sepsis was associated with being a nursing home resident (OR = 2.60, 95 % CI: 1.20, 5.60) and in the other cohort study with being physically inactive (OR = 1.33, 95 % CI: 1.13, 1.56) and smoking tobacco (OR = 1.85, 95 % CI: 1.54, 2.22). The evidence on sex, ethnicity, statin use, and body mass index as risk factors was inconclusive. Conclusions The lack of a valid standard approach for defining sepsis makes it difficult to determine the true incidence of COS. Differences in case ascertainment contribute to the variation in incidence of COS. The evidence on COS is limited in terms of the number and quality of studies. This review highlights the urgent need for an accurate and standard method for identifying sepsis. Future studies need to improve the methodological shortcomings of previous research in terms of case definition, identification, and surveillance practice. Systematic review registration PROSPERO CRD42015023484 Electronic supplementary material The online version of this article (doi:10.1186/s13643-016-0243-3) contains supplementary material, which is available to authorized users.

Infant follow-on foods may be defined as weaning and/or complementary foods and may start to be introduced 4–6 months postpartum . Complementary feeding is necessary to provide infants older than 4–6 months with sufficient micro- and macronutrients needed for healthy growth and development. The introduction of complementary food is carried out in conjunction with the use of mothers' breast milk and/or infant follow-on formulae and is done gradually to minimize the risk of developing allergies or intolerances to certain food types. The variety and suitability of foods for infants and young children are described in this article.

The objective of this study was to examine the effects of lowering protein content of a model infant formula on its processing characteristics and physical stability. Formulations containing five different protein:fat ratios (0.21–0.43) were investigated. Increasing protein:fat ratio increased viscosity and decreased fat globule size. Fat globule size increased significantly upon evaporation ( P P τ ) did not differ significantly between treatments. Increasing protein:fat ratio resulted in decreased creaming rates and improved emulsion stability. In conclusion, decreasing the protein:fat ratio of the formulae, particularly to 0.21, reduced the physical stability of the emulsions.

SUMMARYA pandemic influenza A(H1N1) 2009 outbreak in a summer school affected 117/276 (42%) students. Residential social contact was associated with risk of infection, and there was no evidence for transmission associated with the classroom setting. Although the summer school had new admissions each week, which provided susceptible students the outbreak was controlled using routine infection control measures (isolation of cases, basic hygiene measures and avoidance of particularly high-risk social events) and prompt treatment of cases. This was in the absence of chemoprophylaxis or vaccination and without altering the basic educational activities of the school. Modelling of the outbreak allowed estimation of the impact of interventions on transmission. These models and follow-up surveillance supported the effectiveness of routine infection control measures to stop the spread of influenza even in this high-risk setting for transmission.

Bacterial populations can display high levels of genetic structuring but the forces that influence this are incompletely understood. Here, by combining modelling approaches with multilocus sequence data for the zoonotic pathogen Campylobacter, we investigated how ecological factors such as niche (host) separation relate to population structure. We analysed seven housekeeping genes from published C. jejuni and C. coli isolate collections from a range of food and wild animal sources as well as abiotic environments. By reconstructing genetic structure and the patterns of ancestry, we quantified C. jejuni host association, inferred ancestral populations, investigated genetic admixture in different hosts and determined the host origin of recombinant C. jejuni alleles found in hybrid C. coli lineages. Phylogenetically distinct C. jejuni lineages were associated with phylogenetically distinct wild birds. However, in the farm environment, phylogenetically distant host animals shared several C. jejuni lineages that could not be segregated according to host origin using these analyses. Furthermore, of the introgressed C. jejuni alleles found in C. coli lineages, 73% were attributed to genotypes associated with food animals. Our results are consistent with an evolutionary scenario where distinct Campylobacter lineages are associated with different host species but the ecological factors that maintain this are different in domestic animals such that phylogenetically distant animals can harbour closely related strains.

Identifying the Campylobacter genotypes that colonize farmed and wild ducks will help to assess the proportion of human disease that is potentially attributable to the consumption of duck meat and environmental exposure to duck faeces. Comparison of temporally and geographically matched farmed and wild ducks showed that they had different Campylobacter populations in terms of: (i) prevalence, (ii) Campylobacter species and (iii) diversity of genotypes. Furthermore, 92.4% of Campylobacter isolates from farmed ducks were sequence types (STs) commonly associated with human disease, in contrast to just one isolate from the wild ducks. Only one ST, ST-45, was shared between the two sources, accounting for 0.9% of wild duck isolates and 5% of farmed duck isolates. These results indicate that domestic ‘niche’ as well as host type may affect the distribution of Campylobacter, and that husbandry practises associated with intensive agriculture may be involved in generating a reservoir of human disease associated lineages.

We present the investigation of an outbreak of gastroenteritis at a UK restaurant incorporating both epidemiological and microbiological analysis.Structured postal questionnaires were sent to 30 diners who ate at the restaurant during the outbreak period (5-7 February 2010). Stool specimens collected from staff and diners were submitted for bacterial culture and norovirus testing, and 15 Pacific oysters (Crassostrea gigas) from the batch served during the outbreak period were tested for norovirus.A strong association was observed between illness and oyster consumption (odds ratio undefined, confidence interval: 11.7 to infinity, P = 0.00001). Multiple different sequences of norovirus RNA were present in both stool and oyster specimens, typical of a shellfish origin. Several contemporaneous norovirus outbreaks throughout the UK were linked to oysters, particularly, though not exclusively, those sourced from Carlingford Lough in Ireland (as in this study), which were subsequently withdrawn from distribution.Despite the risk to human health, there is significant uncertainty surrounding the quantitative correlation between oyster norovirus levels and consumer illness. Continued research should help further our understanding of this crucial correlation and identify ways in which viral depuration of oysters can be enhanced.

We describe an outbreak of pertussis with transmission between health care workers (HCWs) in a hospital oncology department and a patient identified as a possible source. Three of the four HCWs testing positive for pertusssis had received primary immunization as children, consistent with waning immunity into adulthood. The fourth health care worker was unimmunized. No evidence of onward nosocomial acquisition within the patient group was found; however, transmission within the household of one health care worker was identified. Countries differ in their approach to protecting health care staff and patients from occupational and nosocomial pertussis infection with immunization recommended for some HCWs in some countries. Surveillance for pertussis in the UK and response to suspected or confirmed cases requires further development.

Objectives: Infants infected with HIV-1 perinatally despite single-dose nevirapine progress rapidly. Data on treatment outcome in sub-Saharan African infants exposed to single-dose nevirapine are urgently required. This feasibility study addresses efficacy of infant antiretroviral therapy in this setting. Methods: HIV-infected infants in Durban, South Africa, received randomized immediate or deferred (when CD4 cell count reached

Background. A resurgence of Haemophilus influenzae type b (Hib) disease occurred in the United Kingdom between 1999 and 2003 and was partially attributed to lower immunogenicity of combination vaccines. The reservoir for Hib that led to transmission in this period is unknown. Methods. We estimated the point prevalence of Hib carriage in school-aged children and adults, using oropharyngeal swabbing and selective media. We characterized the Hib isolates by multilocus sequence typing (MLST) and measured Hib antibody concentrations in adults by enzyme-linked immunosorbent assay. Results. Point prevalence for Hib carriage in 855 children aged 6 –16 years was 4.2% (95% confidence interval [CI], 2.5%–5.9%). Five clonal groups of Hib were identified by MLST, 86% from the lineage of sequence type 6. No Hib was isolated in 385 adults (upper limit of 95% CI, 0.95%). The geometric mean concentration of serum antibody to polyribosylribitol phosphate was 0.47 g/mL (95% CI, 0.37– 0.59 g/mL) in adults. Conclusions. Hib carriage is common in school-aged children, who are a significant reservoir for ongoing transmission of Hib to susceptible individuals in the United Kingdom. Surveillance of transmission and immunity across all ages of the population is essential to monitor the evolution of Hib epidemiology. Haemophilus influenzae type b (Hib) conjugate vaccines have been widely used around the world since the late 1980s to protect against invasive Hib disease in early childhood. Conjugation of the Hib surface polysaccha

C. jejuni genomes have a host signature that enables attribution of isolates to animal sources., Establishing sources of human infection supports effective disease control measures. Host association with Campylobacter jejuni was analyzed by using multilocus sequence typing data for 713 isolates from chickens and bovids (cattle and sheep). Commonly used summary measures of genotypes (sequence type and clonal complex) showed poor accuracy, but a method using the full allelic profile showed 80% accuracy in distinguishing isolates from these 2 host groups. We explored the biologic basis of more accurate results with allelic profiles. Strains isolated from specific hosts have imported a substantial number of alleles while circulating in those host species. These results imply that 1) although Campylobacter moves frequently between hosts, most transmission is within species, and 2) lineages can acquire a host signature and potentially adapt to the host through recombination. Assignment using this signature enables improved prediction of source for pathogens that undergo frequent genetic recombination.

Healthcare consumers, researchers, patients and policy makers increasingly use systematic reviews (SRs) to aid their decision-making process. However, the conduct of SRs can be a time-consuming and resource-intensive task. Often, clinical practice guideline developers or other decision-makers need to make informed decisions in a timely fashion (e.g. outbreaks of infection, hospital-based health technology assessments). Possible approaches to address the issue of timeliness in the production of SRs are to (a) implement process parallelisation, (b) adapt and apply innovative technologies, and/or (c) modify SR processes (e.g. study eligibility criteria, search sources, data extraction or quality assessment). Highly parallelised systematic reviewing requires substantial resources to support a team of experienced information specialists, reviewers and methodologists working alongside with clinical content experts to minimise the time for completing individual review steps while maximising the parallel progression of multiple steps. Effective coordination and management within the team and across external stakeholders are essential elements of this process. Emerging innovative technologies have a great potential for reducing workload and improving efficiency of SR production. The most promising areas of application would be to allow automation of specific SR tasks, in particular if these tasks are time consuming and resource intensive (e.g. language translation, study selection, data extraction). Modification of SR processes involves restricting, truncating and/or bypassing one or more SR steps, which may risk introducing bias to the review findings. Although the growing experiences in producing various types of rapid reviews (RR) and the accumulation of empirical studies exploring potential bias associated with specific SR tasks have contributed to the methodological development for expediting SR production, there is still a dearth of research examining the actual impact of methodological modifications and comparing the findings between RRs and SRs. This evidence would help to inform as to which SR tasks can be accelerated or truncated and to what degree, while maintaining the validity of review findings. Timely delivered SRs can be of value in informing healthcare decisions and recommendations, especially when there is practical urgency and there is no other relevant synthesised evidence.

Background:\ud Sepsis is a life-threatening condition and major contributor of public health and economic burden in the industrialised world. The heterogeneity, absence of more specific definition, and difficulties in accurate diagnosis lead to great variability in the estimates of sepsis incidence. There has been uncertainty regarding the incidence and risk factors attributable to community-onset as opposed to hospital-acquired sepsis. Community-onset sepsis has distinct host characteristics, risk factors, pathogens, and prognosis. A systematic assessment of recent evidence is warranted in light of secular changes in epidemiology, pathogens, and the uncertainties around the incidence and risk factors of community-onset sepsis. This protocol describes a systematic review which aims to synthesise the recent empirical evidence on the incidence and risk factors of community-onset sepsis, severe sepsis, and septic shock in high-income countries.\ud \ud Methods/design:\ud English-language publications of cohort and case-control studies reporting incidence and risk factors of community-onset sepsis will be eligible for inclusion. MEDLINE and Embase databases will be searched from 2002 and onwards. References of relevant publications will be hand-searched. Two reviewers will independently screen titles/abstracts and full texts as well as extract data and appraise the risk of bias of included studies. The data extractions and risk of bias assessments will be cross-checked. Any disagreements will be resolved via consensus. The data on incidence and risk factors of sepsis will be organised and synthesised in text, tables, and forest plots. The evidence will be pooled given sufficient data and degree of similarity across study populations, exposures, and outcomes. The heterogeneity will be assessed through visual inspection of forest plots, Chi-square-based p value, and I (2) statistic. The sources of heterogeneity will be explored via subgroup analysis.\ud \ud Discussion:\ud Timeliness and accuracy of diagnosis of sepsis are both crucial aspects for improving the patient's outcome. The findings of this review will be discussed with a view to better inform future recommendations on improving public-facing campaigns, timely presentation, and diagnosis of sepsis in the community. The review will also discuss gaps in evidence and highlight future research and policy-making avenues for improving public health planning.\ud \ud Systematic review registration:\ud PROSPERO CRD42015023484.

Highlights •Two hospitals implemented booster vaccination programmes in response to suspected staff exposure to pertussis. •Perceived vulnerability of patients was the single most important reason for healthcare workers accepting vaccination. •Pertussis vaccine uptake was high among those who had not received influenza vaccination the previous year. •Self-reported adverse effect profile following vaccination was reassuring. •Fourteen percent of staff reported a recent illness compatible with pertussis but had not notified occupational health.

Cattle are the second most common source of human campylobacteriosis. However, routes to account for this scale of transmission have not been identified. In contrast to chicken, red meat is not heavily contaminated at point of sale. Although effective pasteurization prevents milk-borne infection, apparently sporadic infections may include undetected outbreaks from raw or perhaps incompletely pasteurized milk.A rise in Campylobacter gastroenteritis in an isolated population was investigated using whole-genome sequencing (WGS), an epidemiological study, and environmental investigations.A single strain was identified in 20 cases, clearly distinguishable from other local strains and a reference population by WGS. A case-case analysis showed association of infection with the outbreak strain and milk from a single dairy (odds ratio, 8; Fisher exact test P value = .023). Despite temperature records indicating effective pasteurization, mechanical faults likely to lead to incomplete pasteurization of part of the milk were identified by further testing and examination of internal components of dairy equipment.Here, milk distribution concentrated on a small area, including school-aged children with low background incidence of campylobacteriosis, facilitated outbreak identification. Low-level contamination of widely distributed milk would not produce as detectable an outbreak signal. Such hidden outbreaks may contribute to the substantial burden of apparently sporadic Campylobacter from cattle where transmission routes are not certain. The effective discrimination of outbreak isolates from a reference population using WGS shows that integrating these data and approaches into surveillance could support the detection as well as investigation of such outbreaks.

PURPOSE:\ud Despite substantial morbidity and mortality of influenza and pneumococcal infections in cancer patients treated with chemotherapy, vaccination against both illnesses is infrequent. We evaluated the impact of implementation of clinical guidelines on vaccination of chemotherapy patients treated in our institute.\ud \ud METHODS:\ud We performed a prospective audit before (2012) and after (2013-2014) the introduction of immunisation guidelines for chemotherapy patients in a UK tertiary cancer centre.\ud \ud RESULTS:\ud Guideline implementation was associated with a significant increase in the rate of pneumococcal vaccination compared to the 2012 baseline (47 vs. 25 %, P = 0.0018), though this was not sustained the following year (34 %, P = 0.13, vs. baseline). Influenza vaccine coverage was high (∼70 %) throughout. There was a marked disparity between patients aged ≤65 and those >65 years in the rate of pneumococcal vaccination in both 2013 and 2014 (38 vs. 68 % and 17 vs. 53 %, respectively, both P < 0.001), and, to a lesser extent, in the rate of influenza vaccination in the same period (64 vs. 82 %, P < 0.1, and 63 vs. 85 %, P = 0.009, respectively).\ud \ud CONCLUSIONS:\ud The implementation of clinical vaccine guidelines was associated with a significant increase in pneumococcal vaccination, though continued effort appears required to deliver persistent improvement. Initiatives to increase vaccination uptake in patients aged ≤65 are merited.

Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

Neisseria lactamica, a harmless human commensal found predominantly in the upper respiratory tracts of infants, is closely related toNeisseria meningitidis, a pathogen of global significance. Colonization withN. lactamicamay be responsible for the increase in immunity to meningococcal disease that occurs during childhood, when rates of meningococcal carriage are low. This observation has led to the suggestion thatN. lactamicawhole cells or components are potential constituents of novel meningococcal vaccines. However, the dynamics of carriage and population diversity ofN. lactamicain children are poorly understood, presenting difficulties for the choice of representative isolates for use in vaccine development. This problem was addressed by the multilocus sequence typing ofN. lactamicaisolates from two longitudinal studies of bacterial carriage in infants. The studies comprised 100 and 216 subjects, withN. lactamicacarriage monitored from age 4 weeks until age 96 weeks and from age 2 weeks until age 24 weeks, respectively. The maximum observed carriage rate was 44% at 56 weeks of age, with isolates obtained on multiple visits for the majority (54 of 75, 72%) of carriers. TheN. lactamicaisolates were genetically diverse, with 69 distinct genotypes recovered from the 75 infants. Carriage was generally long-lived, with an average rate of loss of under 1% per week during the 28 weeks following acquisition. Only 11 of the 75 infants carried more than one genotypically unique isolate during the course of the study. Some participants shared identical isolates with siblings, but none shared identical isolates with their parents. These findings have implications for the design of vaccines based on this organism.

The distribution of serogroups and multilocus sequence types (STs) in collections of disease-associated and carried meningococci from the period 1991 to 2000 in three European countries (the Czech Republic, Greece, and Norway) was investigated. A total of 314 patient isolates and 353 isolates from asymptomatic carriers were characterized. The frequency distributions of serogroups and clone complexes differed among countries and between disease and carrier isolate collections. Highly significant differentiation was seen at each housekeeping locus. A marked positive association of serogroup C with disease was evidenced. The ST-11 complex was strongly positively associated with disease; associations for other clone complexes were weaker. The genetic diversity of the clone complexes differed. A single ST dominated the ST-11 clone complex, while the ST-41/44 complex exhibited greater levels of diversity. These data robustly demonstrated differences in the distribution of meningococcal genotypes in disease and carrier isolates and among countries. Further, they indicated that differences in genotype diversity and pathogenicity exist between meningococcal clone complexes.

The success of immunisation programmes depends on the quality with which they are administered. The Vaccine Advice for CliniCians Service (VACCSline) is an advice service to support immunisers and promote excellence in immunisation practice, through specialist guidance and local education, covering a catchment population of two million people. All enquiries are recorded onto a database and categorised. Vaccine error is selected when a vaccine has not been prepared or administered according to national recommendations or relevant expert guidance.All enquiries from 2009 to 2011, categorised on the VACCSline database as 'vaccine error' were analysed and subjected to a detailed free-text review.Of 4301 enquiries, 158 (3.7%) concerned vaccine errors. The greatest frequency of errors, 145 (92.9%) concerned immunisations delivered in primary care services; 92% of all errors occurred during either vaccine selection and preparation or history checking and scheduling. Administration of the wrong vaccine was the most frequent error recorded in 33.3% of reports. A shared first letter of the vaccine name was noted to occur in 13 error reports in which the incorrect vaccine was inadvertently administered. Consultations involving pairs of siblings were associated with various errors in seven enquiries. Failure to revaccinate after spillage (seven reports) showed a widespread knowledge gap in this area.Advice line enquiries provide intelligence to alert immunisers to the errors that are commonly reported and may serve to highlight processes that predispose to errors, thus informing immuniser training and updating.

This chapter summarizes the various modern genotypic methods available for subtyping the various Campylobacter species, the use of genetic methods for investigating outbreaks of disease, the application and interpretation of large-scale techniques in broader epidemiological studies, and a perspective of future developments in the field. Discussions of three methods (pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and amplified fragment length polymorphism (AFLP)) used to compare relatively large numbers of strains follow in a section aimed at summarizing our knowledge of Campylobacter molecular epidemiology in a broader perspective. Limitations of MLST include cost and the degree of resolution that is possible with the quantity of data provided by seven highly conserved gene fragments. The molecular epidemiology of Campylobacter coli is less well studied, but more recent work offers some insights into host association. Current results suggest that the attribution of C. jejuni and C. coli isolates from human cases to their source will be best undertaken by means of a phylogenetic approach that uses analysis based on allele frequencies, or that follows robust definition of host associated sublineages within the main clonal groups. Molecular epidemiological studies of Campylobacter species have matured considerably since the early applications of plasmid profiling and restriction enzyme analysis in homogeneous electric fields.

SUMMARYWater supply-associated cryptosporidiosis outbreaks have decreased in England since the application of risk reduction measures to public water supplies. We hypothesized that smaller outbreaks were occurring which could be better detected by enhanced surveillance. Rolling analysis of detailed questionnaire data was applied prospectively in a population of 2·2 million in the south of England in 2009 and 2010. Detection of spatiotemporal clusters using SaTScan was later undertaken retrospectively. Together these approaches identified eight outbreaks, compared to an expectation of less than one based on national surveillance data. These outbreaks were small and associated with swimming pool use or, less commonly, direct (e.g. petting-farm) contact with animals. These findings suggest that frequent small-scale transmission in swimming pools is an important contributor to disease burden. Identification of swimming pool-level risk factors may inform preventative measures. These findings and the approaches described may be applicable to many other populations and to some other diseases.