THE TRANSPORT AND FATE OF FLUOXETINE HYDROCHLORIDE, DIAZEPAM AND THEIR HUMAN METABOLITES IN SEWAGE SLUDGE-AMENDED SOIL

The European Union (EU) banned disposal of sewage sludge (SS) at sea in 1998. Since that time the application rate of SS to land has risen significantly and is set to rise further. Fifty-two percent of SS was disposed to land in the UK in 2000. Land application is thus possibly an important transport route for SS-associated organic chemicals into the environment. There are now over 3000 different pharmaceutical ingredients in use in the EU and the last decade has also seen an increase in reports of pharmacologically active compounds in the environment (e.g. in watercourses, open ocean, soil). Regardless of this there is still a significant lack of knowledge as regards the transport and fate of pharmaceuticals in the environment, particularly in soils. The present project therefore investigated the biotic fate of the selective serotonin re-uptake inhibitor (SSRI), Prozac® (Fluoxetine HCI), and the 1,4-benzodiazepine, Valium® (Diazepam) and their major human metabolites Norfluoxetine HCI, Temazepam, Oxazepam and Nordiazepam in a UK SS-amended soil. Extraction techniques, such as solid phase extraction, for the analytes from a range of matrices (water, soil and plant material) were developed, which allowed subsequent analysis using developed high performance liquid chromatography - electrospray ionization - multistage mass spectrometry (HPLC-ESI-MS") techniques. Ratio calibration using deuterated internal standards allowed the generation of quantitative data. The pharmaceuticals were found to be resistant to biodegradation in both liquid culture studies (60 days), and even after prolonged exposure in SS-amended soil (>200 days; Fluoxetine HCI only). Oxazepam was the only 1,4- benzodiazepine studied which underwent biotic transformation(- 80%) in liquid culture studies. Evidence to support the theory that the transformation product seen was a 1,4- benzodiazepine tautomer, is presented. Results of what is believed to be one of the first examples of research into pharmaceutical uptake by plants are presented. In a preliminary tissue culture study the translocation of Fluoxetine HCI into Brassica stems (5% uptake) and leaves (3% uptake) confirmed that plant uptake of some pharmaceuticals may be a potential transport route in the environment. The stability of the pharmaceuticals under environmentally relevant conditions has implications for the consequent accumulation in SS-amended soils and possible subsequent uptake into plants grown on the soils.The Biotechnology and Biological Sciences Research Council and AstraZeneca, Brixham Environmental Laborator

The supply of steroids and other performance and image enhancing drugs (PIEDs) in one English city: Fakes, counterfeits, supplier trust, common beliefs and access

As with other illicit drugs, such as heroin or cocaine, illicit steroids and other performance and image enhancing drugs (PIED) have for some time been assumed to involve an inherent degree of danger and risk. This is due to the unknown and potentially dangerous substances present in them; fakes and counterfeits are of particular concern. Many of these ‘risks’ are unknown and unproven. In addition, a tendency to abstract these risks by reference to forensic data tends to negate the specific risks related to local PIED markets, and this in turn has led to much being missed regarding the broader nature of those markets and how buyers and suppliers interact and are situated within them. This article reports on research that sought to explore each of these issues in one mid-sized city in South West England. A snapshot image is provided of what the steroids and other image or performance enhancing drugs market ‘looked like’ in this particular city in 2013: how it operated; how different users sought out and purchased their PIED; the beliefs they held about the PIED they sourced; and the methods they employed to feel confident in the authenticity of their purchases. A forensic analysis was undertaken of a sample of user-sourced PIED as a complementary approach. The results showed almost all of these drugs to be poor-quality fakes and/or counterfeits. The level of risk cannot be ‘read off’ from forensic findings, and poor-quality fakes/counterfeits cannot simply be considered an attempt to defraud. Users believed they had received genuine PIED that were efficacious, and employed a range of basic approaches to try to ensure genuine purchases. Many, if not most, transactions at the ‘street’ level were akin to ‘social supply’ rather than commercial in nature.Arts, Education & Law Group, Key Centre for Ethics, Law, Justice and GovernanceFull Tex

Paradigmatic Approaches to Studying Environment and Human Health: (Forgotten) Implications for Interdisciplinary Research

Copyright © 2013 ElsevierInterdisciplinary research is increasingly promoted in a wide range of fields, especially so in the study of relationships between the environment and human health. However, many projects and research teams struggle to address exactly how researchers from a multitude of disciplinary and methodological backgrounds can best work together to maximize the value of this approach to research. In this paper, we briefly review the role of interdisciplinary research, and emphasize that it is not only our discipline and methods, but our research paradigms, that shape the way that we work. We summarize three key research paradigms - positivism, postpositivism and interpretivism - with an example of how each might approach a given environment-health research issue. In turn, we argue that understanding the paradigm from which each researcher operates is fundamental to enabling and optimizing the integration of research disciplines, now argued by many to be necessary for our understanding of the complexities of the interconnections between human health and our environment as well as their impacts in the policy arena. We recognize that a comprehensive interrogation of research approaches and philosophies would require far greater length than is available in a journal paper. However, our intention is to instigate debate, recognition, and appreciation of the different worlds inhabited by the multitude of researchers involved in this rapidly expanding field

Interventions, outcomes and outcome measurement instruments in stillbirth care research: A systematic review to inform the development of a core outcome set

Background: A core outcome set could address inconsistent outcome reporting and improve evidence for stillbirth care research, which has been identified as an important research priority. Objectives To identify outcomes and outcome measurement instruments reported by studies evaluating interventions after the diagnosis of a stillbirth. Search strategy Amed, BNI, CINAHL, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO, and WHO ICTRP from 1998 to August 2021. Selection criteria Randomised and non-randomised comparative or non-comparative studies reporting a stillbirth care intervention. Data collection and analysis Interventions, outcomes reported, definitions and outcome measurement tools were extracted. Main results 40 randomised and 200 non-randomised studies were included. 58 different interventions were reported, labour and birth care (52 studies), hospital bereavement care (28 studies), clinical investigations (116 studies), care in a multiple pregnancy (2 studies), psychosocial support (28 studies) and care in a subsequent pregnancy (14 studies). 391 unique outcomes were reported and organised into 14 outcome domains: labour and birth; postpartum; delivery of care; investigations; multiple pregnancy; mental health; emotional functioning; grief and bereavement; social functioning; relationship; whole person; subsequent pregnancy; subsequent children and siblings and economic. 242 outcome measurement instruments were used, with 0-22 tools per outcome. Conclusions: Heterogeneity in outcome reporting, outcome definition and measurement tools in care after stillbirth exists. Considerable research gaps on specific intervention types in stillbirth care were identified. A core outcome set is needed to standardise outcome collection and reporting for stillbirth care research

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant