Invasive Pneumococcal Disease in UK Children <1 Year of Age in the Post–13-Valent Pneumococcal Conjugate Vaccine Era: What Are the Risks Now?

Background Invasive pneumococcal disease (IPD) has declined significantly since the introduction of pneumococcal conjugate vaccines (PCVs). It is not known whether certain infant populations remain at higher risk of IPD in countries with established 13-valent PCV (PCV13) programs. We aimed to describe the epidemiology, clinical characteristics, serotype distribution, and outcomes of IPD in infants, and to estimate the relative risk of PCV13-type, non-PCV13-type, and overall IPD in premature infants compared to term infants during a 4-year period after the PCV13 program was established. Methods This was a prospective, enhanced national surveillance of laboratory-confirmed IPD in England in infants aged <1 year diagnosed during 2013–2016. Results There were 517 cases of IPD (incidence: 19/100000 infants). Incidence was significantly higher in premature infants compared with those born at term (49/100000 vs 17/100000; incidence rate ratio [IRR], 2.87; P < .001), with infants born before 28 weeks’ gestation having the highest incidence (150/100000; IRR, 8.8; P < .001). Of the 454 IPD cases with serotyped isolates, most were caused by non-PCV13 serotypes (369 cases, 71.4%), with 85 cases (16.4%) due to PCV13 serotypes. There were 31 deaths (case fatality rate [CFR], 6.2% [95% confidence interval, 4.3%–8.6%]). Premature infants did not have a higher CFR than term infants (P = .62). Conclusions IPD incidence in infants remains lower than rates reported prior to PCV7 introduction in England. The risk of IPD remains significantly higher in premature infants compared to infants born at term, for both PCV13 and non-PCV13 serotypes. Any changes to the infant PCV13 immunization schedule may disproportionally affect premature infants

Population-genomic insights into emergence, crop-adaptation, and dissemination of Pseudomonas syringae pathogens

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Many bacterial pathogens are well characterized but, in some cases, relatively little is known about the populations from which they emerged. This limits understanding of the molecular mechanisms underlying disease. The crop pathogen Pseudomonas syringae sensu lato has been widely isolated from the environment, including wild plants and components of the water cycle, and causes disease in several economically important crops. Here, we compared genome sequences of 45 P. syringae crop pathogen outbreak strains with 69 closely related environmental isolates. Phylogenetic reconstruction revealed that crop pathogens emerged many times independently from environmental populations. Unexpectedly, differences in gene content between environmental populations and outbreak strains were minimal with most virulence genes present in both. However, a genome-wide association study identified a small number of genes, including the type III effector genes hopQ1 and hopD1, to be associated with crop pathogens, but not with environmental populations, suggesting that this small group of genes may play an important role in crop disease emergence. Intriguingly, genome-wide analysis of homologous recombination revealed that the locus Psyr 0346, predicted to encode a protein that confers antibiotic resistance, has been frequently exchanged among lineages and thus may contribute to pathogen fitness. Finally, we found that isolates from diseased crops and from components of the water cycle, collected during the same crop disease epidemic, form a single population. This provides the strongest evidence yet that precipitation and irrigation water are an overlooked inoculum source for disease epidemics caused by P. syringae.Caroline L. Monteil received support from INRA and the European Union, in the framework of the Marie-Curie FP7 COFUND People Programme, through the award of an AgreenSkills’ fellowship (under grant agreement n° 267196). Research in Boris A. Vinatzer’s laboratory and genome sequencing was funded by the National Science Foundation of the USA (grants IOS-1354215 and DEB-1241068). Funding for work in the Vinatzer laboratory was also provided in part by the Virginia Agricultural Experiment Station and the Hatch Program of the National Institute of Food and Agriculture, U.S. Department of Agriculture. Work carried out in the Sheppard laboratory was supported by the Medical Research Council (MRC) grant MR/L015080/1, and the Wellcome Trust grant 088786/C/09/Z. GM was supported by a NISCHR Health Research Fellowship (HF-14-13)

Characteristics and serotype distribution of childhood cases of invasive pneumococcal disease following pneumococcal conjugate vaccination in England and Wales, 2006-14

Background The 7-valent (PCV7) and 13-valent (PCV13) pneumococcal conjugate vaccines are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes. Vaccine failure (vaccine-type IPD after age-appropriate immunisation) is rare. Little is known about the risk, clinical characteristics or outcomes of PCV13 compared to PCV7 vaccine failure. Methods Public Health England conducts IPD surveillance and provides a national reference service for serotyping pneumococcal isolates in England and Wales. We compared the epidemiology, rates, risk factors, serotype distribution, clinical characteristics, and outcomes of IPD in children with PCV13 and PCV7 vaccine failure. Results A total of 163 episodes of PCV failure were confirmed in 161 children over eight years (04 September 2006 to 03 September 2014) in ten birth cohorts. After three vaccine doses, PCV7 and PCV13 failure rates were 0.19/100,000 (95% CI, 0.10-0.33; 57 cases) and 0.66/100,000 (95% CI, 0.44-0.99; 104 cases) vaccinated person-years, respectively. Children with PCV13 failure were more likely to be healthy (87/105 [82.9%] vs. 37/56 [66.1%]; P=0.02), present with bacteremic lower respiratory tract infection (61/105 [58.1%] vs. 11/56 [19.6%]; P<0.001) and develop empyema (41/61 [67.2%] vs. 1/11 [9.1%]; P<0.001) compared to PCV7 failures. Serotypes 3 (n=38, 36.2%) and 19A (n=30, 28.6%) were responsible for most PCV13 failures. Five children died (3.1%; 95% CI, 1.0-7.1%), including four with co-morbidities. Conclusions PCV failure is rare and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause bacteremic lower respiratory tract infection and empyema in healthy vaccinated children

Three monthly coral Sr/Ca records from the Chagos Archipelago covering the period of 1950-1995 A.D.: reproducibility and implications for quantitative reconstructions of sea surface temperature variations

In order to assess the fidelity of coral Sr/Ca for quantitative reconstructions of sea surface temperature variations, we have generated three monthly Sr/Ca time series from Porites corals from the lagoon of Peros Banhos (71°E, 5°S, Chagos Archipelago). We find that all three coral Sr/Ca time series are well correlated with instrumental records of sea surface temperature (SST) and air temperature. However, the intrinsic variance of the single-core Sr/Ca time series differs from core to core, limiting their use for quantitative estimates of past temperature variations. Averaging the single-core data improves the correlation with instrumental temperature (r > 0.7) and allows accurate estimates of interannual temperature variations (~0.35°C or better). All Sr/Ca time series indicate a shift towards warmer temperatures in the mid-1970s, which coincides with the most recent regime shift in the Pacific Ocean. However, the magnitude of the warming inferred from coral Sr/Ca differs from core to core and ranges from 0.26 to 0.75°C. The composite Sr/Ca record from Peros Banhos clearly captures the major climatic signals in the Indo-Pacific Ocean, i.e. the El Niño–southern oscillation and the Pacific decadal oscillation. Moreover, composite Sr/Ca is highly correlated with tropical mean temperatures (r = 0.7), suggesting that coral Sr/Ca time series from the tropical Indian Ocean will contribute to multi-proxy reconstructions of tropical mean temperatures

IL28B and IL10R -1087 polymorphisms are protective for chronic genotype 1 HCV infection and predictors of response to interferon-based therapy in an East-Central European cohort.

BACKGROUND: Previous studies have shown that single nucleotide polymorphisms (SNP) in IL28B and IL10R are associated with sustained virological response (SVR) in chronic hepatitis C patients treated with pegilated interferon plus ribavirin (P/R). The present study extends our earlier investigations on a large East-Central European cohort. The allele frequencies of IL28B and IL10R in genotype 1 HCV infection were compared with that of healthy controls for the purpose of examining the relationship between the polymorphisms and the SVR to P/R treatment. METHODS: A total of 748 chronic HCV1 infected patients (365 male, 383 female; 18-82 years) and 105 voluntary blood donors as controls were enrolled. Four hundred and twenty HCV patients were treated with P/R for 24-72 weeks, out of them 195 (46.4%) achieved SVR. The IL28 rs12979860 SNP was determined using Custom Taqman SNP Genotyping Assays. The IL10R -1087 (also known as IL10R -1082 (rs1800896) promoter region SNP was determined by RT-PCR and restriction fragment length polymorphism analysis. RESULTS: The IL28B CC genotype occurred with lower frequency in HCV patients than in controls (26.1% vs 51.4%, p<0.001). P/R treated patients with the IL28B CC genotype achieved higher SVR rate, as compared to patients with CT (58.6% vs 40.8%, p=0.002). The prevalence of IL10R -1087 GG genotype was lower in patients than in controls (31.8 % vs 52.2%, p<0.001). Among patients achieving SVR, the IL10R -1087 GG genotype occurred with higher frequency than the AA (32.0% vs 17.4%, p=0.013). The IL28B T allele plus IL10R A allele combination was found with higher prevalence in patients than in controls (52% vs 20.7%, p<0.001). The IL28B CC plus IL10R A allele combination occurred with higher frequency among patients with SVR than in non-responders (21.3% vs 12.8%, p=0.026). Both the IL28B CC plus IL10R GG and the IL28B CC plus IL10R A allele combinations occurred with lower frequency in patients than in controls. CONCLUSIONS: In our HCV1 patients, both the IL28B CC and IL10R GG genotypes are associated with clearance of HCV. Moreover, distinct IL28B and IL10R allele combinations appear to be protective against chronic HCV1 infection and predictors of response to P/R therapy

Positive selection inhibits gene mobilization and transfer in soil bacterial communities

Horizontal gene transfer (HGT) between bacterial lineages is a fundamental evolutionary process that accelerates adaptation. Sequence analyses show that conjugative plasmids are principal agents of HGT in natural communities. However, we lack understanding of how the ecology of bacterial communities and their environments affect the dynamics of plasmid-mediated gene mobilization and transfer. Here we show, in simple experimental soil bacterial communities containing a conjugative mercury resistance plasmid, the repeated, independent mobilization of transposon-borne genes from chromosome to plasmid, plasmid to chromosome and, in the absence of mercury selection, interspecific gene transfers from the chromosome of one species to the other via the plasmid. By reducing conjugation, positive selection for plasmid-encoded traits, like mercury resistance, can consequently inhibit HGT. Our results suggest that interspecific plasmid-mediated gene mobilization is most likely to occur in environments where plasmids are infectious, parasitic elements rather than those where plasmids are positively selected, beneficial elements

MOST: a modified MLST typing tool based on short read sequencing

Multilocus sequence typing (MLST) is an effective method to describe bacterial populations. Conventionally, MLST involves Polymerase Chain Reaction (PCR) amplification of housekeeping genes followed by Sanger DNA sequencing. Public Health England (PHE) is in the process of replacing the conventional MLST methodology with a method based on short read sequence data derived from Whole Genome Sequencing (WGS). This paper reports the comparison of the reliability of MLST results derived from WGS data, comparing mapping and assembly-based approaches to conventional methods using 323 bacterial genomes of diverse species. The sensitivity of the two WGS based methods were further investigated with 26 mixed and 29 low coverage genomic data sets from Salmonella enteridis and Streptococcus pneumoniae. Of the 323 samples, 92.9% (n = 300), 97.5% (n = 315) and 99.7% (n = 322) full MLST profiles were derived by the conventional method, assembly- and mapping-based approaches, respectively. The concordance between samples that were typed by conventional (92.9%) and both WGS methods was 100%. From the 55 mixed and low coverage genomes, 89.1% (n = 49) and 67.3% (n = 37) full MLST profiles were derived from the mapping and assembly based approaches, respectively. In conclusion, deriving MLST from WGS data is more sensitive than the conventional method. When comparing WGS based methods, the mapping based approach was the most sensitive. In addition, the mapping based approach described here derives quality metrics, which are difficult to determine quantitatively using conventional and WGS-assembly based approaches

Dietary factors impact on the association between CTSS variants and obesity related traits.

Cathepsin S, a protein coded by the CTSS gene, is implicated in adipose tissue biology--this protein enhances adipose tissue development. Our hypothesis is that common variants in CTSS play a role in body weight regulation and in the development of obesity and that these effects are influenced by dietary factors--increased by high protein, glycemic index and energy diets

Evolution of Streptococcus pneumoniae Serotype 3 in England and Wales: A Major Vaccine Evader.

Despite its inclusion in pneumococcal conjugate vaccine 13 (PCV13), Streptococcus pneumoniae serotype 3 remains a major cause of invasive pneumococcal disease in England and Wales. Previous studies have indicated that there are distinct lineages within serotype 3 clonal complex 180 and the clade distributions have shifted in recent years with the emergence of clade II. We undertook whole genome sequencing and genomic analysis of 616 serotype 3 isolates from England and Wales between 2003 and 2018, including invasive and carriage isolates. Our investigations showed that clade II has expanded since 2014 and now represents 50% of serotype 3 invasive pneumococcal disease (IPD) isolates in England and Wales. Genomic analysis of antibiotic resistance and protein antigen genes showed that distinct profiles are present within the clades which could account for the recent emergence of this clade. This investigation highlights the importance and utility of routine whole genome sequencing and its ability to identify new and emerging variation at the single nucleotide level which informs surveillance and will impact future vaccine development

Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605

BACKGROUND: The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. METHODS: We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. RESULTS: A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. CONCLUSION: These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation