International links between Streptococcus pneumoniae vaccine serotype 4 sequence type (ST) 801 in Northern European shipyard outbreaks of invasive pneumococcal disease.

BACKGROUND: Pneumococcal disease outbreaks of vaccine preventable serotype 4 sequence type (ST)801 in shipyards have been reported in several countries. We aimed to use genomics to establish any international links between them. METHODS: Sequence data from ST801-related outbreak isolates from Norway (n = 17), Finland (n = 11) and Northern Ireland (n = 2) were combined with invasive pneumococcal disease surveillance from the respective countries, and ST801-related genomes from an international collection (n = 41 of > 40,000), totalling 106 genomes. Raw data were mapped and recombination excluded before phylogenetic dating. RESULTS: Outbreak isolates were relatively diverse, with up to 100 SNPs (single nucleotide polymorphisms) and a common ancestor estimated around the year 2000. However, 19 Norwegian and Finnish isolates were nearly indistinguishable (0-2 SNPs) with the common ancestor dated around 2017. CONCLUSION: The total diversity of ST801 within the outbreaks could not be explained by recent transmission alone, suggesting that harsh environmental and associated living conditions reported in the shipyards may facilitate invasion of colonising pneumococci. However, near identical strains in the Norwegian and Finnish outbreaks does suggest that transmission between international shipyards also contributed to those outbreaks. This indicates the need for improved preventative measures in this working population including pneumococcal vaccination.

Using genomics to examine the persistence of Streptococcus pneumoniae serotype 19A in Ireland and the emergence of a sub-clade associated with vaccine failures.

BACKGROUND: Streptococcus pneumoniae serotype 19A remains a significant cause of invasive pneumococcal disease (IPD) in Ireland despite the successful introduction of a 13-valent pneumococcal conjugate vaccine (PCV13) in 2010 which reduced the overall incidence of IPD in children. METHODS: Invasive Streptococcus pneumoniae serotype 19A isolates from the Irish reference laboratory between 2007-08 and 2017-18 were analysed using whole genome sequencing (WGS) to investigate the persistence of this vaccine-preventable serotype. We compared the entire national 19A collection to other international collections using a standardised nomenclature of Global Pneumococcal Sequencing Clusters (GPSC). RESULTS: Expansion of GPSCs and clonal complexes (CCs) may have been associated with vaccine introduction and antimicrobial prescribing policies. A sub-clade of GPSC1-CC320 (n = 25) unique to Ireland, included five of the ten vaccine failures/breakthrough cases identified (p = 0.0086). This sub-clade was not observed in a global GPSC1-CC320 collection. All isolates within the sub-clade (n = 25) contained a galE gene variant rarely observed in a global pneumococcal collection (n = 37/13454, p < 0.001) nor within GPSC1-CC320 (n = 19/227) (p < 0.001). The sub-clade was estimated to have emerged at the start of the PCV-vaccine era (ancestral origin 2000, range 1995-2004) and expanded in Ireland, with most isolated after PCV13 introduction (n = 24/25). CONCLUSIONS: The identification of a sub-clade/variant of serotype 19A highlights the benefit of using WGS to analyse genotypes associated with persistence of a preventable serotype of S. pneumoniae. Particularly as this sub-clade identified was more likely to be associated with IPD in vaccinated children than other 19A genotypes. It is possible that changes to the galE gene, which is involved in capsule production but outside of the capsular polysaccharide biosynthesis locus, may affect bacterial persistence within the population. Discrete changes associated with vaccine-serotype persistence should be further investigated and may inform vaccine strategies.

Strain features and distributions in pneumococci from children with invasive disease before and after 13-valent conjugate vaccine implementation in the USA.

The effect of second-generation pneumococcal conjugate vaccines on invasive pneumococcal disease (IPD) strain distributions have not yet been well described. We analysed IPD isolates recovered from children aged <5 years through Active Bacterial Core surveillance before (2008-2009; n = 828) and after (2011-2013; n = 600) 13-valent pneumococcal conjugate vaccine (PCV13) implementation. We employed conventional testing, PCR/electrospray ionization mass spectrometry and whole genome sequence (WGS) analysis to identify serotypes, resistance features, genotypes, and pilus types. PCV13, licensed in February 2010, effectively targeted all major 19A and 7F genotypes, and decreased antimicrobial resistance, primarily owing to removal of the 19A/ST320 complex. The strain complex contributing most to the remaining ß-lactam resistance during 2011-2013 was 35B/ST558. Significant emergence of non-vaccine clonal complexes was not evident. Because of the removal of vaccine serotype strains, positivity for one or both pilus types (PI-1 and PI-2) decreased in the post-PCV13 years 2011-2013 relative to 2008-2009 (decreases of 32-55% for PI-1, and >95% for PI-2 and combined PI-1 + PI-2). ß-Lactam susceptibility phenotypes correlated consistently with transpeptidase region sequence combinations of the three major penicillin-binding proteins (PBPs) determined through WGS analysis. Other major resistance features were predictable by DNA signatures from WGS analysis. Multilocus sequence data combined with PBP combinations identified progeny, serotype donors and recipient strains in serotype switch events. PCV13 decreased the frequency of all PCV13 serotype clones and concurrently decreased the frequency of strain subsets with resistance and/or adherence features conducive to successful carriage. Our results serve as a reference describing key features of current paediatric IPD strains in the USA after PCV13 implementation.

Genetic stability of pneumococcal isolates during 35 days of human experimental carriage.

BACKGROUND: Pneumococcal carriage is a reservoir for transmission and a precursor to pneumococcal disease. The experimental human pneumococcal carriage model provides a useful tool to aid vaccine licensure through the measurement of vaccine efficacy against carriage (VEcol). Documentation of the genetic stability of the experimental human pneumococcal carriage model is important to further strengthen confidence in its safety and conclusions, enabling it to further facilitate vaccine licensure through providing evidence of VEcol. METHODS: 229 isolates were sequenced from 10 volunteers in whom experimental human pneumococcal carriage was established, sampled over a period of 35 days. Multiple isolates from within a single volunteer at a single time provided a deep resolution for detecting variation. HiSeq data from the isolates were mapped against a PacBio reference of the inoculum to call variable sites. RESULTS: The observed variation between experimental carriage isolates was minimal with the maximum SNP distance between any isolate and the reference being 3 SNPs. CONCLUSION: The low-level variation described provides evidence for the stability of the experimental human pneumococcal carriage model over 35 days, which can be reliably and confidently used to measure VEcol and aid future progression of pneumococcal vaccination.

Millennial-scale variability in Antarctic ice-sheet discharge during the last deglaciation.

Our understanding of the deglacial evolution of the Antarctic Ice Sheet (AIS) following the Last Glacial Maximum (26,000-19,000 years ago) is based largely on a few well-dated but temporally and geographically restricted terrestrial and shallow-marine sequences. This sparseness limits our understanding of the dominant feedbacks between the AIS, Southern Hemisphere climate and global sea level. Marine records of iceberg-rafted debris (IBRD) provide a nearly continuous signal of ice-sheet dynamics and variability. IBRD records from the North Atlantic Ocean have been widely used to reconstruct variability in Northern Hemisphere ice sheets, but comparable records from the Southern Ocean of the AIS are lacking because of the low resolution and large dating uncertainties in existing sediment cores. Here we present two well-dated, high-resolution IBRD records that capture a spatially integrated signal of AIS variability during the last deglaciation. We document eight events of increased iceberg flux from various parts of the AIS between 20,000 and 9,000 years ago, in marked contrast to previous scenarios which identified the main AIS retreat as occurring after meltwater pulse 1A and continuing into the late Holocene epoch. The highest IBRD flux occurred 14,600 years ago, providing the first direct evidence for an Antarctic contribution to meltwater pulse 1A. Climate model simulations with AIS freshwater forcing identify a positive feedback between poleward transport of Circumpolar Deep Water, subsurface warming and AIS melt, suggesting that small perturbations to the ice sheet can be substantially enhanced, providing a possible mechanism for rapid sea-level rise.

Sampling methods for the study of pneumococcal carriage: a systematic review.

Streptococcus pneumoniae is an important pathogen worldwide. Accurate sampling of S. pneumoniae carriage is central to surveillance studies before and following conjugate vaccination programmes to combat pneumococcal disease. Any bias introduced during sampling will affect downstream recovery and typing. Many variables exist for the method of collection and initial processing, which can make inter-laboratory or international comparisons of data complex. In February 2003, a World Health Organisation working group published a standard method for the detection of pneumococcal carriage for vaccine trials to reduce or eliminate variability. We sought to describe the variables associated with the sampling of S. pneumoniae from collection to storage in the context of the methods recommended by the WHO and those used in pneumococcal carriage studies since its publication. A search of published literature in the online PubMed database was performed on the 1st June 2012, to identify published studies that collected pneumococcal carriage isolates, conducted after the publication of the WHO standard method. After undertaking a systematic analysis of the literature, we show that a number of differences in pneumococcal sampling protocol continue to exist between studies since the WHO publication. The majority of studies sample from the nasopharynx, but the choice of swab and swab transport media is more variable between studies. At present there is insufficient experimental data that supports the optimal sensitivity of any standard method. This may have contributed to incomplete adoption of the primary stages of the WHO detection protocol, alongside pragmatic or logistical issues associated with study design. Consequently studies may not provide a true estimate of pneumococcal carriage. Optimal sampling of carriage could lead to improvements in downstream analysis and the evaluation of pneumococcal vaccine impact and extrapolation to pneumococcal disease control therefore further in depth comparisons would be of value.

Continued control of pneumococcal disease in the UK - the impact of vaccination.

Streptococcus pneumoniae, also known as the pneumococcus, is an important cause of morbidity and mortality in the developed and developing world. Pneumococcal conjugate vaccines were first introduced for routine use in the USA in 2000, although the seven-valent pneumococcal conjugate vaccine (PCV7) was not introduced into the UK's routine childhood immunization programme until September 2006. After its introduction, a marked decrease in the incidence of pneumococcal disease was observed, both in the vaccinated and unvaccinated UK populations. However, pneumococci are highly diverse and serotype prevalence is dynamic. Conversely, PCV7 targets only a limited number of capsular types, which appears to confer a limited lifespan to the observed beneficial effects. Shifts in serotype distribution have been detected for both non-invasive and invasive disease reported since PCV7 introduction, both in the UK and elsewhere. The pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV, Synflorix; GlaxoSmithKline) and 13-valent pneumococcal conjugate vaccine (PCV13, Prevenar 13; Pfizer) have been newly licensed. The potential coverage of the 10- and 13-valent conjugate vaccines has also altered alongside serotype shifts. Nonetheless, the mechanism of how PCV7 has influenced serotype shift is not clear-cut as the epidemiology of serotype prevalence is complex. Other factors also influence prevalence and incidence of pneumococcal carriage and disease, such as pneumococcal diversity, levels of antibiotic use and the presence of risk groups. Continued surveillance and identification of factors influencing serotype distribution are essential to allow rational vaccine design, implementation and continued effective control of pneumococcal disease.

Response of the Io plasma torus to comet Shoemaker-Levy 9.

Spectroscopic and imaging observations of the Io plasma torus were made in June and July 1994 in conjunction with the encounter of periodic comet Shoemaker-Levy 9 with Jupiter. Characteristic emissions from sulfur and oxygen ions showed a decline of about 30 percent in the extreme ultraviolet and an increase of about 40 percent in the far ultraviolet relative to preimpact observations. Changes in the extreme ultraviolet may be indicative of small changes in the torus electron temperature as a result of quenching of electrons by dust associated with the comet passage. However, no new emission features indicative of fragment dust within the torus were detected. The characteristic torus morphology seen in ground-based imaging was typical of that observed in the past.

Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy.

OBJECTIVE: To compare pregnancy outcome prospectively after phenytoin and carbamazepine monotherapy with outcome in matched mother-child pairs exposed to nonteratogens to evaluate the relative fetal safety of these drugs. DESIGN: A prospective, controlled, and blinded observational study. PATIENTS: Thirty-six mother-child pairs exposed to carbamazepine monotherapy and 34 pairs exposed to phenytoin monotherapy, all prospectively studied, were compared with mother-child pairs exposed to nonteratogens. The controls were matched for maternal age, time of consultation, obstetric history, and socioeconomic status. MAIN OUTCOME MEASURE: The primary end point of interest was the children's global IQ measured by either the Bayley or the McCarthy scale according to their ages. SETTING: A teratology consultation program and two neurology services in Toronto, Ontario. RESULTS: Children exposed to phenytoin in utero had a mean (+/- SD) global IQ 10 points lower (95% confidence interval, 4.9 to 15.8 points) than their matched controls (113.4 +/- 13.1 and 103.1 +/- 25.1; P = .038). The Reynell language development scores followed a similar trend, with children exposed to phenytoin scoring significantly lower than their controls. Phenytoin-exposed children had a global IQ of 84 or less significantly more often than the control group (P < .01). Children exposed in utero to carbamazepine did not differ from their controls on any of the neurobehavioral tests. CONCLUSIONS: Our study suggests a clinically important negative effect of phenytoin on neurobehavioral development, independent of maternal or environmental factors, causing a substantial number of children to achieve a lower score than expected on cognitive tests. No similar effects could be shown after gestational use of carbamazepine.

Subarachnoid hemorrhage due to a spinal cord hemangioblastoma: case report.

A case of solitary spinal hemangioblastoma with spontaneous subarachnoid hemorrhage is presented. There was no features to distinguish the subarachnoid hemorrhage in this case from that due to an intracranial lesion. However, mild sensory symptoms involving the left arm and leg had preceded the hemorrhage by several months. The lesion was detected by cerebral angiography and computed tomographic scanning, and the diagnosis was confirmed at operation. A small syrinx was noted, and the lesion was totally removed without causing any deficit, despite its origin from the dorsum of the spinal cord. The tumor contained a false aneurysm, which had been visualized angiographically.