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

Characteristics of Invasive Pneumococcal Disease Caused by Emerging Serotypes After the Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in England: A Prospective Observational Cohort Study, 2014-2018.

BACKGROUND: England is experiencing a rapid increase in invasive pneumococcal disease (IPD) caused by serotypes 8, 12F, and 9N; their clinical characteristics and outcomes have not been described. METHODS: Public Health England conducts national IPD surveillance. Cases due to emerging serotypes were compared with those included in the 13-valent pneumococcal conjugate vaccine (PCV13) and the remaining non-PCV13 serotypes. RESULTS: There were 21 592 IPD cases during 2014-15 to 2017-18, including 20 108 (93.1%) with serotyped isolates and 17 450 (86.8%) with completed questionnaires. PCV13 serotypes were responsible for 20.1% (n = 4033), while serotype 8 (3881/20 108 [19.3%]), 12F (2365/20 108 [11.8%]), and 9N (1 296/20 108 [6.4%]) were together responsible for 37.5% of cases. Invasive pneumonia was the most common presentation (11 424/16 346 [69.9%]) and, overall, 67.0% (n = 11 033) had an underlying comorbidity. The median age (interquartile range) at IPD due to serotypes 8 (59 [45-72] years) and 12F (56 [41-70] years) was lower than serotype 9N (67 [53-80] years), PCV13 serotypes (68 [52-81] years), and remaining non-PCV13 serotypes (70 [53-82] years). Serotype 9N IPD cases also had higher comorbidity prevalence (748/1087 [68.8%]) compared to serotype 8 (1901/3228 [58.9%]) or 12F (1042/1994 [52.3%]), and higher case fatality (212/1128 [18.8%]) compared to 8.6% (291/3365) or 10.0% (209/2086), respectively. CONCLUSIONS: Serotypes 8 and 12F were more likely to cause IPD in younger, healthier individuals and less likely to be fatal, while serotype 9N affected older adults with comorbidities and had higher case fatality

Trends in invasive Haemophilus influenzae serotype a disease in England from 2008–09 to 2021–22: a prospective national surveillance study

Background Invasive Haemophilus influenzae serotype a (Hia) disease is rare, with most cases reported among Indigenous populations in North America. In England, national surveillance was enhanced following an increase in laboratory-confirmed invasive Hia disease since the 2016–17 epidemiological year. This study aimed to describe the epidemiological trends, clinical characteristics of cases, and assess potential genomic drivers. Methods Hospital laboratories in England routinely submit invasive H influenzae isolates to the UK Health Security Agency for confirmation and serotyping. In this prospective national surveillance study we contacted the general practitioners and clinicians of all patients with laboratory-confirmed invasive Hia from the 2008–09 to the 2021–22 epidemiological year to complete a clinical questionnaire on demographics, underlying conditions, clinical presentation, complications, outcomes, and travel history of the patient. All Hia invasive isolates from residents in England were included in the study; non-invasive isolates were excluded. Multilocus sequence typing (MLST), whole genome single-nucleotide polymorphism, and k-mer-based analysis of bacterial isolates were performed following Illumina whole-genome sequencing (WGS). Outcomes included epidemiological trends, clinical characteristics of confirmed Hia cases, and genomic analyses. Findings From the 2008–09 to the 2021–22 epidemiological years, there were 52 cases of invasive infection with H influenzae serotype a in England (25 [48%] in female patients and 27 [52%] in male patients). There were zero to two annual Hia cases (accounting for <0·5% of serotyped H influenzae isolates) until 2015–16, after which cases increased across England to 19 cases in 2021–22 (incidence 0·03 cases per 100 000), when Hia accounted for 19 (4%) of 484 serotyped H influenzae isolates, 19 (19%) of 100 capsulated cases, and 37% (19 of 52) of all H influenzae cases between 2008–09 and 2021–22. Most of the recent increase in cases occurred among individuals aged 65 years and older (17 [33%] of 52), who typically presented with bacteraemic pneumonia (13 [76%] of 17), and infants younger than 1 year, who had the highest incidence and were more likely to present with meningitis (five [50%] of ten). Overall case fatality rate was 7·7% (95% CI 2·1–19·7; four of 52 patients). WGS found that closely related MLST sequence types ST1511 (20 [39%] of 51), ST23 (13 [25%] of 51), and ST56 (seven [14%] of 51) accounted for most cases, with no evidence of serotype b strains switching capsule to Hia. Duplication of the capsule operon, associated with more severe disease, was present in 32 (80%) of 40 of these sequence types. Analysis of the core and accessory genome content grouped most isolates into a single strain. Interpretation The persistent increase in invasive Hia cases across England and across all age groups suggests widespread transmission, consistent with reports from other European countries, and will require close monitoring. Funding UK Health Security Agency

Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Invasive Pneumococcal Disease and Risk of Pneumococcal Coinfection With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): Prospective National Cohort Study, England.

BACKGROUND: Streptococcus pneumoniae coinfection with influenza results in synergistic lethality, but there are limited data on pneumococcal coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Public Health England conducts invasive pneumococcal disease (IPD) and SARS-CoV-2 surveillance in England. IPD trends during 2000/2001-2019/2020 epidemiological years were analyzed and cases during February-June 2020 linked with laboratory-confirmed SARS-CoV-2 infections. Multivariable logistic regression was used to assess risk factors for death. RESULTS: IPD incidence in 2019/2020 (7.6/100 000; n = 3964) was 30% (IRR, .70; 95% CI, .18-2.67) lower compared with 2018/2019 (10.9/100 000; n = 5666), with large reductions observed across all age groups during March-June 2020. There were 160 886 SARS-CoV-2 and 1137 IPD cases during February-June 2020, including 40 IPD/coronavirus disease 2019 (COVID-19) co-infections (.025% [95% CI, .018-.034] of SARS-CoV-2 infections; 3.5% [2.5-4.8] of IPD cases), 21 with COVID-19 diagnosed 3-27 days after IPD, and 27 who developed COVID-19 ≥28 days after IPD. Case-fatality rates (CFRs) were 62.5 (25/40), 47.6% (10/21), and 33.3% (9/27), respectively (P < .001). In addition to an independent association with increasing age and serotype group, CFR was 7.8-fold (95% CI, 3.8-15.8) higher in those with IPD/COVID-19 coinfection and 3.9-fold (95% CI, 1.4-10.7) higher in patients who developed COVID-19 3-27 days after IPD compared with patients with IPD only. CONCLUSIONS: Large declines in IPD were observed following COVID-19 lockdown. IPD/COVID-19 coinfections were rare but associated with high CFR, mainly in older adults. The rarity, age and serotype distribution of IPD/COVID-19 coinfections do not support wider extension of pneumococcal vaccination

Excellent capability in degrading azo dyes by MgZn-based metallic glass powders

The lack of new functional applications for metallic glasses hampers further development of these fascinating materials. In this letter, we report for the first time that the MgZn-based metallic glass powders have excellent functional ability in degrading azo dyes which are typical organic water pollutants. Their azo dye degradation efficiency is about 1000 times higher than that of commercial crystalline Fe powders, and 20 times higher than the Mg-Zn alloy crystalline counterparts. The high Zn content in the amorphous Mg-based alloy enables a greater corrosion resistance in water and higher reaction efficiency with azo dye compared to crystalline Mg. Even under complex environmental conditions, the MgZn-based metallic glass powders retain high reaction efficiency. Our work opens up a new opportunity for functional applications of metallic glasses

Functional MRI of Auditory Responses in the Zebra Finch Forebrain Reveals a Hierarchical Organisation Based on Signal Strength but Not Selectivity

BACKGROUND: Male songbirds learn their songs from an adult tutor when they are young. A network of brain nuclei known as the 'song system' is the likely neural substrate for sensorimotor learning and production of song, but the neural networks involved in processing the auditory feedback signals necessary for song learning and maintenance remain unknown. Determining which regions show preferential responsiveness to the bird's own song (BOS) is of great importance because neurons sensitive to self-generated vocalisations could mediate this auditory feedback process. Neurons in the song nuclei and in a secondary auditory area, the caudal medial mesopallium (CMM), show selective responses to the BOS. The aim of the present study is to investigate the emergence of BOS selectivity within the network of primary auditory sub-regions in the avian pallium. METHODS AND FINDINGS: Using blood oxygen level-dependent (BOLD) fMRI, we investigated neural responsiveness to natural and manipulated self-generated vocalisations and compared the selectivity for BOS and conspecific song in different sub-regions of the thalamo-recipient area Field L. Zebra finch males were exposed to conspecific song, BOS and to synthetic variations on BOS that differed in spectro-temporal and/or modulation phase structure. We found significant differences in the strength of BOLD responses between regions L2a, L2b and CMM, but no inter-stimuli differences within regions. In particular, we have shown that the overall signal strength to song and synthetic variations thereof was different within two sub-regions of Field L2: zone L2a was significantly more activated compared to the adjacent sub-region L2b. CONCLUSIONS: Based on our results we suggest that unlike nuclei in the song system, sub-regions in the primary auditory pallium do not show selectivity for the BOS, but appear to show different levels of activity with exposure to any sound according to their place in the auditory processing stream

Alternative organizing in times of crisis : resistance assemblages and socio-spatial solidarity

This paper draws on research conducted in Greece, where, during the last seven years, an acute socio-economic crisis has led to the emergence of a number of alternative organizational forms. By foregrounding the term drasis, the unexpected unfolding of an event in a specific space and time, we discuss how these alternative forms assemble differential capacities in order to resist the neoliberal ordering of socio-spatial and economic relations. In particular, we focus on two self-organized spaces, namely, a social centre and a squatted public garden and discuss two concrete instances of drasis. We propose that drasis instigates the establishment and evolution of transformative, prefigurative organizing through three interrelated processes, namely, the formation of resistance assemblages, social learning and socio-spatial solidarity. The paper offers three propositions, suggesting that drasis provides the socio-material conditions through which new resistance formations challenge the established productive forces of society and co-produce alternative forms of civic life.© 2017 published by SAGE. This is an author produced version of a paper published in European Urban and Regional Studies, uploaded in accordance with the publisher’s self- archiving policy. The final published version (version of record) is available online at http://journals.sagepub.com/doi/10.1177/0969776416683001. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it

Endogenous laminin is required for human airway smooth muscle cell maturation

BACKGROUND: Airway smooth muscle (ASM) contraction underlies acute bronchospasm in asthma. ASM cells can switch between a synthetic-proliferative phenotype and a contractile phenotype. While the effects of extracellular matrix (ECM) components on modulation of ASM cells to a synthetic phenotype have been reported, the role of ECM components on maturation of ASM cells to a contractile phenotype in adult lung is unclear. As both changes in ECM components and accumulation of contractile ASM are features of airway wall remodelling in asthma, we examined the role of the ECM protein, laminin, in the maturation of contractile phenotype in human ASM cells. METHODS: Human ASM cells were made senescence-resistant by stable expression of human telomerase reverse transcriptase. Maturation to a contractile phenotype was induced by 7-day serum deprivation, as assessed by immunoblotting for desmin and calponin. The role of laminin on ASM maturation was investigated by comparing the effects of exogenous laminin coated on culture plates, and of soluble laminin peptide competitors. Endogenous expression of laminin chains during ASM maturation was also measured. RESULTS: Myocyte binding to endogenously expressed laminin was required for ASM phenotype maturation, as laminin competing peptides (YIGSR or GRGDSP) significantly reduced desmin and calponin protein accumulation that otherwise occurs with prolonged serum deprivation. Coating of plastic cell culture dishes with different purified laminin preparations was not sufficient to further promote accumulation of desmin or calponin during 7-day serum deprivation. Expression of α2, β1 and γ1 laminin chains by ASM cells was specifically up-regulated during myocyte maturation, suggesting a key role for laminin-2 in the development of the contractile phenotype. CONCLUSION: While earlier reports suggest exogenously applied laminin slows the spontaneous modulation of ASM to a synthetic phenotype, we show for the first time that endogenously expressed laminin is required for ASM maturation to the contractile phenotype. As endogenously expressed laminin chains α2, β1 and γ1 are uniquely increased during myocyte maturation, these laminin chains may be key in this process. Thus, human ASM maturation appears to involve regulated endogenous expression of a select set of laminin chains that are essential for accumulation of contractile phenotype myocytes

Lung development in laminin γ2 deficiency: abnormal tracheal hemidesmosomes with normal branching morphogenesis and epithelial differentiation

BACKGROUND: Laminin γ2 (Lamc2), one of the polypeptides in laminin-332 (laminin-5), is prominent in the basement membrane of alveolar walls and airways of developing and adult lung. Laminins are important for lung morphogenesis and based on its localization, a function for laminin γ2 in lung development has been hypothesized. Targeted deletion of the laminin γ2 gene in mice results in skin blistering and neonatal death at 3–5 days after birth due to failure to thrive. METHODS: Examination of lung development in Lamc2-/- mice through 1–2 days postnatal was accomplished by morphometric analysis, lung bud culture, electron microscopy, immunohistochemical and immunofluorescence staining. RESULTS: Compared to littermate controls, Lamc2-/- lungs were similar in morphology during embryonic life. At post-natal day 1–2, distal saccules were mildly dilated by chord length measurements. Epithelial differentiation as evaluated by immunohistochemical staining for markers of ciliated cells, Clara cells, alveolar type I cells and alveolar type II cells did not reveal a difference between Lamc2-/- and littermate control lungs. Likewise, vascular development, smooth muscle cell differentiation, and elastic fiber formation looked similar, as did airway basement membrane ultrastructure. Branching morphogenesis by lung bud culture was similar in Lamc2-/- and littermate control lungs. Since laminin-332 is important for hemidesmosome formation, we examined the structure of tracheal hemidesmosomes by transmission electron microscopy. Compared to littermate controls, Lamc2-/- tracheal hemidesmosomes were less organized and lacked the increased electron density associated with the basement membrane abutting the hemidesmosome. CONCLUSION: These findings indicate that laminin γ2 and laminin-332, despite their prominence in the lung, have a minimal role in lung development through the saccular stage

The T1405N Carbamoyl Phosphate Synthetase Polymorphism Does Not Affect Plasma Arginine Concentrations in Preterm Infants

A C-to-A nucleotide transversion (T1405N) in the gene that encodes carbamoyl-phosphate synthetase 1 (CPS1) has been associated with changes in plasma concentrations of L-arginine in term and near term infants but not in adults. In preterm infants homozygosity for the CPS1 Thr1405 variant (CC genotype) was associated with an increased risk of having necrotizing enterocolitis (NEC). Plasma L-arginine concentrations are decreased in preterm infants with NEC.To examine the putative association between the CPS1 T1405N polymorphism and plasma arginine concentrations in preterm infants.Prospective multicenter cohort study. Plasma and DNA samples were collected from 128 preterm infants (<30 weeks) between 6 and 12 hours after birth. Plasma amino acid and CPS1 T1405N polymorphism analysis were performed.Distribution of genotypes did not differ between the preterm (CC:CA:AA = 55.5%:33.6%:10.9%, n = 128) and term infants (CC:CA:AA = 54.2%:35.4%:10.4%, n = 96). There was no association between the CPS1 genotype and plasma L-arginine or L-citrulline concentration, or the ornithine to citrulline ratio, which varies inversely with CPS1 activity. Also the levels of asymmetric dimethylarginine, and symmetric dimethylarginine were not significantly different among the three genotypes.The present study in preterm infants did not confirm the earlier reported association between CPS1 genotype and L-arginine levels in term infants