Developing a local antimicrobial resistance action plan: the Cornwall One Health Antimicrobial Resistance Group.

Objectives: The UK Five Year Antimicrobial Resistance (AMR) Strategy was published in September 2013 and recommended a One Health approach emphasizing the importance of collaboration to tackle AMR. We describe the inauguration of what we believe to be the first regional One Health group established in the UK. The purpose of the group was to ensure the implementation of a coordinated Cornwall-wide response to the UK AMR Strategy and we describe the outputs of the group to date. Methods: The Cornwall Antimicrobial Resistance Group was set up as a sub-group of the Health & Wellbeing Board's Health Protection Committee. Stakeholders reviewed the key objectives set out within the Five Year AMR strategy, identified local priorities and existing work streams within Cornwall, and completed a gap analysis. The annual work plan was developed from the gap analysis and provided a foundation for improved coordination of One Health antimicrobial stewardship (AMS) activity in Cornwall. Results: To date, outputs from the group can be arranged under the following themes: education and engagement with the public; education and engagement with healthcare workers and veterinarians; and a comprehensive AMS programme for all sectors. The group continues to grow in size with wider stakeholder engagement and increased variety of work streams. Conclusions: This unique group facilitates discussions across sectors, which has enabled the sharing of knowledge, ideas and resources, stimulated local AMS initiatives, and ensured a platform for the development of future AMR and AMS work.

An outbreak of norovirus infection linked to oyster consumption at a UK restaurant, February 2010.

BACKGROUND: We present the investigation of an outbreak of gastroenteritis at a UK restaurant incorporating both epidemiological and microbiological analysis. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Comparison of the management recommendations of the Kaiser Permanente neonatal early-onset sepsis risk calculator (SRC) with NICE guideline CG149 in infants ≥34 weeks' gestation who developed early-onset sepsis.

OBJECTIVE: To compare the management recommendations of the Kaiser Permanente neonatal early-onset sepsis risk calculator (SRC) with National Institute for Health and Care Excellence (NICE) guideline CG149 in infants ≥34 weeks' gestation who developed early-onset sepsis (EOS). DESIGN: Retrospective multicentre study. SETTING: Five maternity services in South West of England and Wales. PATIENTS: 70 infants with EOS (<72 hours) confirmed on blood or cerebrospinal fluid culture. METHODS: Retrospective virtual application of NICE and SRC through review of maternal and neonatal notes. MAIN OUTCOME MEASURE: The number of infants recommended antibiotics by 4 hours of birth. RESULTS: The incidence of EOS ≥34 weeks was 0.5/1000 live births. Within 4 hours of birth, antibiotics were recommended for 39 infants (55.7%) with NICE, compared with 27 (38.6%) with SRC. The 12 infants advised early treatment by NICE but not SRC remained well, only one showing transient mild symptoms after 4 hours. Another four babies received antibiotics by 4 hours outside NICE and SRC guidance. The remaining 27 infants (38.6%) received antibiotics when symptomatic after 4 hours. Only one infant who was unwell from birth, died. Eighty-one per cent of all EOS infants were treated for clinical reasons rather than for risk factors alone. CONCLUSION: While both tools were poor in identifying EOS within 4 hours, NICE was superior to SRC in identifying asymptomatic cases. Currently, four out of five EOS have symptoms at first identification, the majority of whom present within 24 hours of birth. Antibiotic stewardship programmes using SRC should include enhanced observation for infants currently treated within NICE guidance.

Birth season and environmental influences on blood leucocyte and lymphocyte subpopulations in rural Gambian infants.

BACKGROUND: In rural Gambia, birth season predicts infection-related adult mortality, providing evidence that seasonal factors in early life may programme immune development. This study tested whether lymphocyte subpopulations assessed by automated full blood count and flow cytometry in cord blood and at 8, 16 and 52 weeks in rural Gambian infants (N = 138) are affected by birth season (DRY = Jan-Jun, harvest season, few infections; WET = Jul-Dec, hungry season, many infections), birth size or micronutrient status. RESULTS: Geometric mean cord and postnatal counts were higher in births occurring in the WET season with both season of birth and season of sampling effects. Absolute CD3+, CD8+, and CD56+ counts, were higher in WET season births, but absolute CD4+ counts were unaffected and percentage CD4+ counts were therefore lower. CD19+ counts showed no association with birth season but were associated with concurrent plasma zinc status. There were no other associations between subpopulation counts and micronutrient or anthropometric status. CONCLUSION: These results demonstrate a seasonal influence on cell counts with a disproportionate effect on CD8+ and CD56+ relative to CD4+ cells. This seasonal difference was seen in cord blood (indicating an effect in utero) and subsequent samples, and is not explained by nutritional status. These findings are consistent with the hypothesis than an early environmental exposure can programme human immune development.

Parent-to-parent support interventions for parents of babies cared for in a neonatal unit-protocol of a systematic review of qualitative and quantitative evidence.

BACKGROUND: Parents of babies admitted to neonatal units experience an arduous emotional journey. Feelings of helplessness, fear, sadness, guilt, grief and anger are common. These feelings can lead to anxiety, depression and post-traumatic stress which may persist long after discharge from the unit. Support from a parent with first-hand experience able to empathise with problems and challenges may help. This systematic review will identify quantitative and qualitative evidence to address the role of parent-to-parent support interventions for families of babies cared for in neonatal units, and combine the findings in an integrated synthesis. METHODS: We are working in collaboration with a study-specific Parent Advisory Group (PAG) of parents who have relevant and varied lived experience of having a baby in neonatal care and those who have been involved in providing peer support. With the PAG, we will carry out a systematic review bringing together all existing research on parent-to-parent support for parents of babies cared for in neonatal units. This will be reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol has been produced in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol extension (PRISMA-P). We have co-produced a plain language protocol summary with the PAG which details the different stages of the project, and this is available via our website ( http://clahrc-peninsula.nihr.ac.uk/research/parent-to-parent-support ) for anyone interested in learning more about the detail of the project. DISCUSSION: All outputs will be available on the NIHR CLAHRC South West Peninsula (PenCLAHRC) website and promoted via PenCLAHRC networks as well as organisations that have been contacted throughout the project. PAG members will be involved in writing and reviewing the academic paper and final report and in co-producing dissemination products such as plain language summaries. The PAG will influence the main conclusions of the systematic review, aid interpretation and help to communicate results in the most appropriate ways. We will hold an impact conference with representatives from neonatal units, national neonatal networks, commissioners of services and parents to discuss what the findings mean for clinical practice and service provision. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018090569.

Aflatoxin exposure in utero causes growth faltering in Gambian infants.

BACKGROUND: Growth faltering in West African children has previously been associated with dietary exposure to aflatoxins, particularly upon weaning. However, in animal studies in utero exposure to low levels of aflatoxin also results in growth faltering. OBJECTIVE: This study investigated the effect of in utero aflatoxin exposure on infant growth in the first year of life in The Gambia. METHODS: Height and weight were measured for 138 infants at birth and at regular monthly intervals for one year. Aflatoxin-albumin (AF-alb) adduct level was measured in maternal blood during pregnancy, in cord blood and in infants at age 16 weeks. RESULTS: The geometric mean AF-alb levels were 40.4 pg/mg (range 4.8-260.8 pg/mg), 10.1 pg/mg (range 5.0-189.6 pg/mg) and 8.7 pg/mg (range 5.0-30.2 pg/mg) in maternal, cord and infant blood, respectively. AF-alb in maternal blood was a strong predictor of both weight (P = 0.012) and height (P = 0.044) gain, with lower gain in those with higher exposure. A reduction of maternal AF-alb from 110 pg/mg to 10 pg/mg would lead to a 0.8 kg increase in weight and 2 cm increase in height within the first year of life. CONCLUSIONS: This study shows a strong effect of maternal aflatoxin exposure during pregnancy on growth in the first year of life and thus extends earlier observations of an association between aflatoxin exposure during infancy and growth faltering. The findings imply value in targeting intervention strategies at early life exposures.

Schedules for Pneumococcal Vaccination of Preterm Infants: An RCT.

BACKGROUND AND OBJECTIVE: Premature infants have a higher risk of invasive pneumococcal disease and are more likely to have lower vaccine responses compared with term infants. Increasingly, immunization schedules are including a reduced, 2-dose, pneumococcal conjugate vaccine priming schedule. Our goal was to assess the immunogenicity of 3 commonly used 13-valent pneumococcal conjugate vaccine (PCV13) priming schedules in premature infants and their response to a 12-month booster dose. METHODS: Premature infants (<35 weeks' gestation) were randomized to receive PCV13 at 2 and 4 months (reduced schedule); 2, 3, and 4 months (accelerated schedule); or 2, 4, and 6 months (extended schedule). All infants received a 12-month PCV13 booster. Serotype-specific pneumococcal immunoglobulin G (IgG) for PCV13 serotypes was measured by using enzyme-linked immunosorbent assay 1 month after the primary and booster vaccinations. RESULTS: A total of 210 infants (median birth gestation, 29(+6) weeks; range, 23(+2)-34(+6) weeks) were included. After the primary vaccination, 75% (95% confidence interval [CI], 62-85), 88% (95% CI, 76-95), and 97% (95% CI, 87-99) of participants had protective antibody concentrations for at least one-half the PCV13 serotypes for the reduced, accelerated, and extended schedules, respectively. After the booster vaccination, participants receiving the extended schedule had significantly lower (P < .05) geometric mean concentrations compared with reduced (for 9 of 13 serotypes) and accelerated (for 4 of 13 serotypes) schedules, but nearly all participations, regardless of schedule or serotype, had seroprotective IgG concentrations. CONCLUSIONS: A reduced priming schedule of PCV13 resulted in higher post-booster IgG concentrations but lower post-primary concentrations. The optimum vaccine schedule for preterm infants will therefore depend on when they are most at risk for invasive pneumococcal disease.

Developmental changes in leptin as a measure of energy status in human infants in a natural ecologic setting.

BACKGROUND: Most human research on leptin has involved well-nourished subjects or clinical states such as anorexia nervosa or cancer cachexia. OBJECTIVE: We studied the development of leptin as a monitor of energy status in young African infants whose growth patterns probably reflect the evolutionary norm. DESIGN: We enrolled a prospective birth cohort of 138 rural Gambian mother-infant pairs. Plasma leptin was analyzed in maternal blood in late pregnancy, in cord blood, and at 8, 16, and 52 wk in the infants. Body mass index (BMI; in kg/m2) was used as a proxy for fatness. The mothers were lean (BMI: 21.6+/-2.5), and the infants grew poorly compared with Western standards (average weight-for-age z score of -1.9 at 52 wk). RESULTS: Maternal and cord blood leptin and birth weight were all positively correlated. Throughout infancy, leptin was highly correlated with BMI. A strong sex difference existed at birth (ie, leptin concentrations were significantly higher in females than in males), disappeared at 8 wk, and reappeared at 16 and 52 wk. Absolute leptin concentrations declined by almost 90% from birth to 52 wk, but leptin's ability to discriminate across a range of BMI values improved with age. In early infancy, leptin concentrations were uncorrelated with recent changes in BMI, but, by 52 wk, leptin was able to assess both the size of energy stores and the direction of recent changes. CONCLUSIONS: Leptin concentrations signal energy status from fetal life onward. As infancy progresses, leptin's power to discriminate both chronic and dynamic energy status increases, and this discrimination is achieved at much lower circulating peptide concentrations.

Improved thymic function in exclusively breastfed infants is associated with higher interleukin 7 concentrations in their mothers' breast milk.

BACKGROUND: In rural Gambians, the season of birth strongly predicts adult mortality. Those born during the harvest season have longer life spans than do those born during the hungry season, and the deaths associated with infectious diseases suggest permanent early-life influences on immunity. Thymic measurements showed significantly smaller thymuses in infants born during the hungry season than in those born during the harvest season. The differences were greatest at 8 wk of age, a time when all infants were exclusively breastfed, which suggests the involvement of breast milk factors. OBJECTIVE: This study tested whether thymic size differences reflect thymic output and ascertained whether thymic output is associated with breast milk interleukin 7 (IL-7) concentrations. DESIGN: We studied thymic size and output in a prospective cohort of 138 Gambian infants born in either the hungry or the harvest season by measuring signal-joint T cell receptor-rearrangement excision circles (sjTRECs) at birth and at 8 wk of age. IL-7 concentrations in breast milk were measured by using an enzyme-linked immunosorbent assay. RESULTS: By age 8 wk, those born in the hungry season had significantly lower sjTREC counts than did those born in the harvest season (0.97 and 2.12 sjTRECs/100 T cells, respectively; P = 0.006). At 1 wk postpartum, the breast milk of mothers of infants born in the hungry season had significantly lower IL-7 than did that of mothers of infants born in the harvest season (79 and 100 pg/mL, respectively; P = 0.02). The findings were similar at 8 wk postpartum. CONCLUSION: These data show a plausible pathway linking external seasonal insults to mothers with thymic development in their infants, which suggests possible implications for long-term programming of immunity.

Vaccine-preventable disease susceptibility in a British paediatric assessment unit.

Aims: To evaluate practice within a paediatric secondary-care centre before and after introduction of simple interventions to improve identification of under-immunised children and facilitate catch-up immunisations. Methods: The population-based child health database was used to check immunisation status for two cohorts of 200 consecutive admissions before and after routine printing of immunisation histories from the database and raising staff awareness. Vaccine-preventable disease (VPD) susceptibility burdens were calculated for each child. Case notes were assessed for accuracy and documentation of ward-based interventions. Results: Fourteen per cent of all children were under-immunised on admission and 27% of these were more than five years behind schedule. Under-immunised children's VPD susceptibility burdens ranged from 0-40,858 days and in 59% exceeded 1,000 days. Over one month the paediatric admission unit saw children with a combined VPD susceptibility burden of 1,323 child-years. Positive identification of under-immunised children increased by 40% (95% confidence interval: 12-62, p=0.002) following the introduction of routine database printouts. Conclusion: Children presenting to British secondary care units have large VPD susceptibility burdens. Positive identification of under-immunised children substantially improved after the introduction of routine database printouts, but catch-up immunisation rates did not increase.

Interventions to reduce acute paediatric hospital admissions: a systematic review.

OBJECTIVE: To compare the effectiveness of interventions aimed at reducing the rate of acute paediatric hospital admissions. DESIGN: Systematic review. DATA SOURCES: Medline, Embase, PsychINFO, The Cochrane Library, Science Citation Index Expanded from inception to September 2010; hand searches of the reference lists of included papers and other review papers identified in the search. REVIEW METHODS: Controlled trials were included. Articles were screened for inclusion independently by two reviewers. Data extraction and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. RESULTS: Seven papers were included. There is some evidence to suggest that short stay units may reduce admission rates. However, there is a general lack of detail in the reporting of interventions and the methods used in their evaluation which precludes detailed interpretation and extrapolation of the results. The authors found no evidence that the use of algorithms and guidelines to manage the admission decision was effective in reducing acute admission rates. Furthermore, the authors were unable to locate any eligible papers reporting the effects on admission rates of admission decision by paediatric consultant, telephone triage by paediatric consultant or the establishment of next day emergency paediatric clinics. CONCLUSION: There is little published evidence upon which to base an optimal strategy for reducing paediatric admission rates. The evidence that does exist is subject to substantial bias. There is a pressing need for high quality, well conducted research to enable informed service change.

Neonatal infections in England: the NeonIN surveillance network.

INTRODUCTION: Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time. DESIGN: Prospective multicentre surveillance using a web-based database. SETTING: 12 English neonatal units. PARTICIPANTS: Newborns admitted in 2006-2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days. OUTCOME MEASURE: Incidence, age at infection, pathogens and antibiotic resistance profiles. RESULTS: With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007-2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS). CONCLUSIONS: The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines.

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38 °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation.

Early immunological development and mortality from infectious disease in later life.

In rural Gambia the risk of mainly infection-related mortality is 10-fold higher for adults born in the nutritionally-debilitating 'hungry' season, suggesting that immune function may be compromised by events early in life. The current programme of research focuses on the biological mechanisms underlying this hypothesis, exploring early-life environmental influences on immune development and the long-term functional consequences these influences may have. Results obtained to date show that thymus development during infancy is critically sensitive to environmental exposures, with smaller thymuses observed in the hungry season. Measurement of the frequency of T-cell receptor excision circles indicate that thymus function is also sensitive to seasonal influences, with further studies implicating variations in breast-milk IL-7 as a possible mediator of these effects. Studies in adults have shown that size at birth is positively correlated with antibody responses to vaccination with polysaccharide antigens, thus providing evidence for long-term functional deficits. The present paper will review progress made to date within this field of research.

Effect of month of vaccine administration on antibody responses in The Gambia and Pakistan.

OBJECTIVE: To explore the relationship between calendar month of administration and antibody (Ab) response to vaccination in subjects from The Gambia and Pakistan, two countries with distinct patterns of seasonality. METHODS: Three cohorts were investigated: Responses to rabies and pneumococcal vaccine were assessed in 472 children (mean age 8 years, males 53%) from rural Gambia. Responses to tetanus, diphtheria and hepatitis B (HBsAg) were investigated in 138 infants also from The Gambia (birth to 52 weeks of age, males 54%). Responses to rabies and Vi typhoid vaccines were assessed in 257 adults from Lahore, Pakistan (mean age 29.4 years, males 57%). RESULTS: In Gambian children, significant associations were observed between month of vaccination and Ab response for the pneumococcal and rabies vaccines. As no consistent pattern by month was observed between the responses, it is assumed that different immunomodulatory stimuli or mechanisms were involved. In Pakistani adults, a significant pattern by month of vaccination was observed with both rabies and typhoid vaccine. No monthly influences were observed in the infant study to the tetanus, diphtheria or the HbsAg vaccines. CONCLUSIONS: Antibody responses to certain specific vaccines are influenced by month of administration. Further research is required to elucidate the precise mechanisms explaining these observations, but a co-stimulatory effect of seasonally variable environmental antigens is a likely cause. Future studies of Ab response to vaccination in countries with a seasonally dependent environment should consider month of vaccination when interpreting study findings.

Observational study of vaccine efficacy 14 years after trial of hepatitis B vaccination in Gambian children.

OBJECTIVE: To determine the duration of protection from hepatitis B vaccine given in infancy and early childhood. DESIGN: Cross sectional serological study of hepatitis B virus infection in children of various ages 14 years after the start of a trial of vaccination regimens. SETTING: Two villages in the Gambia. PARTICIPANTS: Children and adolescents given hepatitis B vaccine in infancy or early childhood: 232 were aged 1-5 years, 225 aged 5-9 years, 220 aged 10-14 years, and 175 aged 15-19 years. MAIN OUTCOME MEASURES: Vaccine efficacy against infection and against chronic infection in the different age groups. RESULTS: Vaccine efficacy against chronic carriage of hepatitis B virus was 94% (95% confidence interval 89% to 97%), which did not vary significantly between the age groups. Efficacy against infection was 80% (76% to 84%). This was significantly lower in the oldest age group (65%, 56 to 73). Of the uninfected participants in this age group, 36% had no detectable hepatitis B virus surface antibody. Time since vaccination and a low peak antibody response were the most powerful risk factors for breakthrough infection (P<0.001 in each case). Low peak antibody response was also a risk factor for chronic carriage (odds ratio 95, 19 to 466). CONCLUSIONS: Children vaccinated in infancy are at increased risk of hepatitis B virus infection in the late teens. The risk of chronic carriage after sexual exposure needs further assessment to determine if booster vaccines are necessary.