Nasopharyngeal Carriage of Pneumococcus in Children in England up to 10 Years After 13-Valent Pneumococcal Conjugate Vaccine Introduction: Persistence of Serotypes 3 and 19A and Emergence of 7C.

BACKGROUND: Monitoring changes in pharyngeal carriage of pneumococcus in children following 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the United Kingdom in 2010 informs understanding of patterns of invasive pneumococcal disease (IPD) incidence. METHODS: Nasopharyngeal swabs from healthy children vaccinated with PCV13 according to schedule (2, 4, and 12 months) were cultured and serotyped. Results for children aged 13-48 months were compared between 2014-2015 and 2017-2019 and with children aged 6-12 months (2017-2020). Blood was obtained from a subset of children for pneumococcal serotype-specific immunoglobulin G (IgG). RESULTS: Total pneumococcal carriage at 13-48 months was 47.9% (473/988) in 2014-2015 and 51.8% (412/795) in 2017-2019 (P = .10); at age 6-12 months this value was 44.6% (274/615). In 2017-2019, 2.9% (95% confidence interval, 1.8%-4.3%) of children aged 13-48 months carried PCV13 serotypes (mainly 3 [1.5%] and 19A [0.8%]) and >20% carried the additional 20-valent PCV (PCV20) serotypes. Similar proportions of children had IgG ≥0.35 IU/mL for each serotype in 2014-2015 and 2017-2019. Serotype 7C carriage increased significantly (P < .01) between 2014-2015 and 2017-2019. Carriage of PCV20 serotypes 8 and 12F, both major causes of IPD, was rare. CONCLUSIONS: Introduction of PCV20, if licensed for children, could significantly change the composition of pneumococcal serotypes carried in the pharynx of UK children. CLINICAL TRIALS REGISTRATION: NCT03102840.

Shaping EU medicines regulation in the post COVID-19 era.

The EU Medicines Regulatory Network (EMRN), comprised of the European Medicines Agency (EMA), the medicines regulatory authorities of the Member States and the European Commission (EC), is operating amid a complex crisis that has positioned regulators centre stage due to their key role in the development, approval and safety monitoring of vaccines and treatments for COVID-19. Here we consider the EMA's and EMRN's response to the pandemic and some of the early learnings that will help reshape medicines regulation in the post COVID-19 era. We also reflect on how some of these learnings will be formally followed up under revised EU legislation to extend EMA's mandate, reinforcing its role in crisis preparedness and response.

Communicating to and engaging with the public in regulatory science.

This paper presents selected highlights from the 'Engaging with society' session of EFSA's third Scientific Conference 'Science, Food and Society' (Parma, Italy, 18-21 September 2018). The social dimension for scientific advisory bodies largely concerns science communication and public engagement. The political, economic and technological transformation of contemporary societies is challenging conventional structures and approaches in these areas. The disintermediation of communication and the proliferation of misinformation, it is argued, herald the onset of the post-truth society. A better understanding of the way individuals consume information today has led to the development of tools to guide mediators such as journalists and communication specialists in countering these trends. Public engagement can reinforce confidence in regulatory bodies and potentially contribute to the quality of the scientific process. Scientific advisory bodies in Europe have created strategies and mechanisms to engage the public that are designed to increase transparency and representativeness. To be effective, several engagement mechanisms are needed, although factors such as resource constraints, institutional culture and public/stakeholder attitudes may limit their development. In conclusion, a more vigorous role for social research is needed to place scientific risk assessment within broader socio-economic and political contexts. Social science expertise can help to define more impactful public information strategies and to explore the potential opportunities that engaged stakeholders and citizens can make to sustain and strengthen regulatory science.

The GABAB receptor agonist, baclofen, contributes to three distinct varieties of amnesia in the human brain - A detailed case report.

We describe a patient in whom long-term, therapeutic infusion of the selective gamma-amino-butyric acid type B (GABAB) receptor agonist, baclofen, into the cerebrospinal fluid (CSF) gave rise to three distinct varieties of memory impairment: i) repeated, short periods of severe global amnesia, ii) accelerated long-term forgetting (ALF), evident over intervals of days and iii) a loss of established autobiographical memories. This pattern of impairment has been reported in patients with temporal lobe epilepsy (TLE), in particular the subtype of Transient Epileptic Amnesia (TEA). The amnesic episodes and accelerated forgetting remitted on withdrawal of baclofen, while the autobiographical amnesia (AbA) persisted. This exceptional case highlights the occurrence of 'non-standard' forms of human amnesia, reflecting the biological complexity of memory processes. It suggests a role for GABAB signalling in the modulation of human memory over multiple time-scales and hints at its involvement in 'epileptic amnesia'.

Mixed halogenated dioxins/furans (PXDD/Fs) and biphenyls (PXBs) in food: occurrence and toxic equivalent exposure using specific relative potencies.

The occurrence of nineteen mixed halogenated (bromo-chloro) dibenzo-p-dioxins, dibenzofurans (PXDD/Fs) and biphenyls (PXBs) in a range of foods (n>100) was investigated. The analytical methodology used dual activated carbon column fractionation with high resolution mass spectrometric measurement (13,500-15,000 res). Occurrence was observed in most commonly consumed foods but the most frequent detections of these environmental contaminants were made in shellfish and offal. The concentrations of the individual compounds were condensed into toxic equivalents (TEQs) using recently reported relative potency values. Although representing only a small subset of the full range of toxic PXDD/Fs and PXBs, the TEQs estimated for these compounds ranged from 0.2% to approximately 15% (depending on the food matrix) of the corresponding TEQ for the fully chlorinated analogues. This finding is of great toxicological importance as it implies that a potentially greater magnitude of TEQ could be associated with the full range of toxic PXDD/Fs and PXBs, thus making a significant contribution to dioxin-like toxicity from the diet, to human exposure.

Regulatory structures for gene therapy medicinal products in the European Union.

Taking into account the complexity and technical specificity of advanced therapy medicinal products: (gene and cell therapy medicinal products and tissue engineered products), a dedicated European regulatory framework was needed. Regulation (EC) No. 1394/2007, the "ATMP Regulation" provides tailored regulatory principles for the evaluation and authorization of these innovative medicines. The majority of gene or cell therapy product development is carried out by academia, hospitals, and small- and medium-sized enterprises (SMEs). Thus, acknowledging the particular needs of these types of sponsors, the legislation also provides incentives for product development tailored to them. The European Medicines Agency (EMA) and, in particular, its Committee for Advanced Therapies (CAT) provide a variety of opportunities for early interaction with developers of ATMPs to enable them to have early regulatory and scientific input. An important tool to promote innovation and the development of new medicinal products by micro-, small-, and medium-sized enterprises is the EMA's SME initiative launched in December 2005 to offer financial and administrative assistance to smaller companies. The European legislation also foresees the involvement of stakeholders, such as patient organizations, in the development of new medicines. Considering that gene therapy medicinal products are developed in many cases for treatment of rare diseases often of monogenic origin, the involvement of patient organizations, which focus on rare diseases and genetic and congenital disorders, is fruitful. Two such organizations are represented in the CAT. Research networks play another important role in the development of gene therapy medicinal products. The European Commission is funding such networks through the EU Sixth Framework Program.

Mixed brominated/chlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls: Simultaneous congener-selective determination in food.

Of the 4600 individual poly-halogenated (bromo-chloro) dibenzo-p-dioxins, dibenzo-furans (PXDD/Fs) and 9180 poly-halogenated biphenyls (PXBs), 19 compounds were selected for analysis in food, based on current toxicological knowledge, chemical configuration, type and degree of halogenation, and the limited knowledge on environmental occurrence levels. The selection was also tempered by the availability of reliable analytical standards. The analytical methodology designed to allow simultaneous determination of PXDD/Fs and PXBs, was based on internal standardisation with (13)C(12) labelled compounds and high resolution mass spectrometry and involved a new separation procedure using dual activated carbon column fractionation. In order to unambiguously measure these compounds a practical, higher mass resolution (13,500-15,000 res) was used, coupled with a judicious choice of analyte ions and relative ion ratios. Further specificity was incorporated by exploiting the differences in chromatographic retention from those of potential interferants. The methodology was validated and used to measure occurrence levels of these contaminants in different matrices such as milk, meat, fish, eggs, offal, shellfish and soil. The limits of detection achieved by this methodology ranged from 0.005 to 0.02ngkg(-1) fat for foods. The analyses revealed the presence of both PXDD/Fs and PXBs, with the latter occurring to a greater extent, followed by PXDFs. This work represents the first targeted approach to measuring a range of individual PXDD/Fs and PXBs simultaneously.

Polychlorinated naphthalenes (PCNs): congener specific analysis, occurrence in food, and dietary exposure in the UK.

Information on the occurrence of toxicologically significant polychlorinated naphthalenes (PCNs) in food, or on human exposure, is sparse. In this work, PCN congeners (PCNs 52, 53, 66/67, 68, 69, 71/72, 73, 74, and 75) were selected for analysis, based on the available literature on current occurrence and toxicology, and limited by the commercial availability of reference standards. The analytical methodology used cold solvent extraction of prehydrolyzed samples fortified with internal standards ((13)C(10) labeled PCNs), activated carbon and basic alumina purification, and measurement by HRGC-HRMS. The investigation showed PCN occurrence in all studied foods: meat, milk, fish, dairy and meat products, eggs, poultry, vegetables, fruits, etc. The most frequently detected congeners were PCN 52, PCNs 66/67, and PCN 73. The highest concentrations were observed in fish (maximum value of 37 ng/kg w.w. for the sum of the measured congeners). The dioxin-like toxicity (PCN TEQ) associated with these concentrations is 1-2 orders of magnitude lower than those reported for chlorinated dioxins or PCBs in food and, on the basis of dietary intakes estimated using very conservative assumptions regarding concentrations of these contaminants in the UK, the levels of PCNs alone in food do not suggest any toxicological concerns.

Evaluation of constructed wetland treatment performance for winery wastewater.

Rapid expansion of wineries in rural California during the past three decades has created contamination problems related to winery wastewater treatment and disposal; however, little information is available about performance of on-site treatment systems. Here, the project objective was to determine full-scale, subsurface-flow constructed wetland retention times and treatment performance through assessment of water quality by daily sampling of total dissolved solids, pH, total suspended solids, chemical oxygen demand (COD), tannins, nitrate, ammonium, total Kjeldahl nitrogen, phosphate, sulfate, and sulfide across operating systems for winery wastewater treatment. Measurements were conducted during both the fall crush season of heavy loading and the spring following bottling and racking operations at the winery. Simple decay model coefficients for these constituents as well as COD and tannin removal efficiencies from winery wastewater in bench-scale reactors are also determined. The bench-scale study used upward-flow, inoculated attached-growth (pea-gravel substrate) reactors fed synthetic winery wastewater. Inlet and outlet tracer studies for determination of actual retention times were essential to analyses of treatment performance from an operational subsurface-flow constructed wetland that had been overloaded due to failure to install a pretreatment system for suspended solids removal. Less intensive sampling conducted at a smaller operational winery wastewater constructed wetland that had used pretreatment suspended solids removal and aeration indicated that the constructed wetlands were capable of complete organic load removal from the winery wastewater.