Metabolism-based category formation for the prioritisation of genotoxicity hazard assessment for plant protection product residues (Part 4): α-Chloroacetamides.

In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 69 α-chloroacetamide herbicides for which either Ames, chromosomal aberration or micronucleus test results are publicly available. A set of structural space alerts were defined, each linked to a key metabolic transformation present in the α-chloroacetamide metabolic space. The structural space alerts were combined with covalent chemistry profiling to develop categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data individual groups of plant protection products as the basis for the development of the structural space alerts.

IDEA tool: Establishing a prioritisation matrix for oral health improvement interventions.

Initial impetus for action: Oral health is not equitably distributed. More deprived areas experience appreciably worse oral health outcomes. Oral health improvement programmes in Local Authorities (LA) seek to reduce these inequalities but have diminished in recent years following the COVID-19 pandemic. LAs have also endured funding cuts to public health budgets, placing a greater emphasis on the need for establishing a clear prioritisation matrix for oral health improvement interventions. Solution: A prioritisation matrix that considered both the importance and do-ability of oral health improvement interventions was developed. Both are composite measures. The importance comprised evidence of benefit, impact on inequalities, alignment with national/local priorities and cost-effectiveness of the intervention. The do-ability considered the available support from stakeholders, building/equipment requirements, workforce issues and investment funding. A working group was necessary to inform the do-ability aspect of the prioritisation matrix. Scores were assigned to each criterion, the sum of the scores informed whether the intervention was eliminated, aspirational or implemented based on predetermined thresholds. Outcome: The prioritisation matrix ensured a transparent and systematic approach for intervention selection, which reflected local resources and priorities. Moreover, this tool should help ensure the most effective, equitable, practical and sustainable interventions are chosen having the greatest impact on improving oral health outcomes.

Development of an adverse outcome pathway network for nephrotoxicity.

Adverse outcome pathways (AOPs) were introduced in modern toxicology to provide evidence-based representations of the events and processes involved in the progression of toxicological effects across varying levels of the biological organisation to better facilitate the safety assessment of chemicals. AOPs offer an opportunity to address knowledge gaps and help to identify novel therapeutic targets. They also aid in the selection and development of existing and new in vitro and in silico test methods for hazard identification and risk assessment of chemical compounds. However, many toxicological processes are too intricate to be captured in a single, linear AOP. As a result, AOP networks have been developed to aid in the comprehension and placement of associated events underlying the emergence of related forms of toxicity-where complex exposure scenarios and interactions may influence the ultimate adverse outcome. This study utilised established criteria to develop an AOP network that connects thirteen individual AOPs associated with nephrotoxicity (as sourced from the AOP-Wiki) to identify several key events (KEs) linked to various adverse outcomes, including kidney failure and chronic kidney disease. Analysis of the modelled AOP network and its topological features determined mitochondrial dysfunction, oxidative stress, and tubular necrosis to be the most connected and central KEs. These KEs can provide a logical foundation for guiding the selection and creation of in vitro assays and in silico tools to substitute for animal-based in vivo experiments in the prediction and assessment of chemical-induced nephrotoxicity in human health.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Metabolism-based category formation for the prioritisation of genotoxicity hazard assessment for plant protection product residues (part 3): Strobilurins.

In dietary risk assessment of plant protection products, residues of active ingredients and their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity, in terms of metabolism, a metabolic similarity profiling scheme has been developed from an analysis of 46 chemicals of strobilurin fungicides and their metabolites for which either Ames, chromosomal aberration or micronucleus test results are publicly available. This profiling scheme consists of a set of ten sub-structures, each linked to a key metabolic transformation present in the strobilurin metabolic space. This metabolic similarity profiling scheme was combined with covalent chemistry profiling and physico-chemistry properties to develop chemical categories suitable for chemical prioritisation via read-across. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for metabolism data and individual groups of plant protection products as the basis for the development of such profiling schemes.

Detailed analysis of in-hospital transmission of SARS-CoV-2 using whole genome sequencing.

BACKGROUND: Hospital transmission of SARS-CoV-2 has proved difficult to control, with healthcare-associated infections troublesome throughout. AIM: To understand factors contributing to hospital transmission of infections, which is necessary for containing spread. METHODS: An outbreak of 56 staff and patient cases of COVID-19 over a 31-day period in a tertiary referral unit is presented, with at least a further 29 cases identified outside of the unit and the hospital by whole genome sequencing (WGS). FINDINGS: Transmission is documented from staff to staff, staff to patients, and patients to staff, showing disruption of a tertiary referral service, despite implementation of nationally recommended control measures, superior ventilation, and use of personal protective equipment. There was extensive spread from the index case, despite this patient spending only 10 h bed bound on the ward in strict cubicle isolation and with an initial single target low level (CT = 32) polymerase chain reaction test. CONCLUSION: This investigation highlights how effectively and rapidly SARS-CoV-2 can spread in certain circumstances. It raises questions about infection control measures in place at the time and calls into question the premise that transmissibility can be reliably detected by using lower sensitivity rapid antigen lateral flow tests. We also highlight the value of early intervention in reducing impact as well as the value of WGS in understanding outbreaks.

Sub-structure-based category formation for the prioritisation of genotoxicity hazard assessment for pesticide residues (part 2): Triazoles.

In dietary risk assessment, residues of pesticidal ingredients or their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity and to identify structural alerts associated with genotoxic concern, a set of chemical sub-structures was derived for an example dataset of 66 triazole agrochemicals for which either Ames, chromosomal aberration or micronucleus test results are publicly available. This analysis resulted in a set of ten structural alerts that define the chemical space, in terms of the common parent and metabolic scaffolds, associated with the triazole chemical class. An analysis of the available profiling schemes for DNA and protein reactivity shows the importance of investigating the predictivity of such schemes within a well-defined area of structural space. Structural space alerts, covalent chemistry profiling and physico-chemistry properties were combined to develop chemical categories suitable for chemical prioritisation. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for pesticide-class specific metabolism data as the basis for structural space alert development.

Sub-structure-based category formation for the prioritisation of genotoxicity hazard assessment for pesticide residues: Sulphonyl ureas.

In dietary risk assessment, residues of pesticidal ingredients or their metabolites need to be evaluated for their genotoxic potential. The European Food Safety Authority recommend a tiered approach focussing assessment and testing on classes of similar chemicals. To characterise similarity and to identify structural alerts associated with genotoxic concern, a set of chemical sub-structures was derived for an example dataset of 74 sulphonyl urea agrochemicals for which either Ames, chromosomal aberration or micronucleus test results are publicly available. This analysis resulted in a set of seven structural alerts that define the chemical space, in terms of the common parent and metabolic scaffolds, associated with the sulphonyl urea chemical class. An analysis of the available profiling schemes for DNA and protein reactivity shows the importance of investigating the predictivity of such schemes within a well-defined area of structural space. Structural space alerts, covalent chemistry profiling and physico-chemistry properties were combined to develop chemical categories suitable for chemical prioritisation. The method is a robust and reproducible approach to such read-across predictions, with the potential to reduce unnecessary testing. The key challenge in the approach was identified as being the need for pesticide-class specific metabolism data as the basis for structural space alert development.

COSMOS next generation - A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals.

The COSMOS Database (DB) was originally established to provide reliable data for cosmetics-related chemicals within the COSMOS Project funded as part of the SEURAT-1 Research Initiative. The database has subsequently been maintained and developed further into COSMOS Next Generation (NG), a combination of database and in silico tools, essential components of a knowledge base. COSMOS DB provided a cosmetics inventory as well as other regulatory inventories, accompanied by assessment results and in vitro and in vivo toxicity data. In addition to data content curation, much effort was dedicated to data governance - data authorisation, characterisation of quality, documentation of meta information, and control of data use. Through this effort, COSMOS DB was able to merge and fuse data of various types from different sources. Building on the previous effort, the COSMOS Minimum Inclusion (MINIS) criteria for a toxicity database were further expanded to quantify the reliability of studies. COSMOS NG features multiple fingerprints for analysing structure similarity, and new tools to calculate molecular properties and screen chemicals with endpoint-related public profilers, such as DNA and protein binders, liver alerts and genotoxic alerts. The publicly available COSMOS NG enables users to compile information and execute analyses such as category formation and read-across. This paper provides a step-by-step guided workflow for a simple read-across case, starting from a target structure and culminating in an estimation of a NOAEL confidence interval. Given its strong technical foundation, inclusion of quality-reviewed data, and provision of tools designed to facilitate communication between users, COSMOS NG is a first step towards building a toxicological knowledge hub leveraging many public data systems for chemical safety evaluation. We continue to monitor the feedback from the user community at support@mn-am.com.

Impact of Reducing Water Fluoride on Dental Caries and Fluorosis.

Guidance intended to reduce fluoride toothpaste ingestion in early childhood was introduced in Ireland in 2002. In 2007, water fluoride concentration was adjusted from 0.8-1.0 to 0.6-0.8 ppm. The objective of this study was to determine the difference in caries and fluorosis levels following introduction of these 2 policy measures. A before-and-after study compared caries and fluorosis in random samples of 8-y-olds in Dublin (n = 707) and Cork-Kerry (n = 1148) in 2017 with 8-y-olds in Dublin (n = 679) and Cork-Kerry (n = 565) in 2002. Dentinal caries experience (primary teeth, d3vcmft(cde)) and fluorosis (permanent teeth, Dean's index of very mild or higher) were clinically measured. Lifetime exposure to community water fluoridation (CWF) was classified as "full CWF"/"no CWF." Effect of examination year on caries prevalence and severity and fluorosis prevalence was assessed using multivariate regression adjusting for other explanatory variables. There was little change in commencement of fluoride toothpaste use at ≤24 mo following introduction of toothbrushing guidance. Among children with full CWF, there was no statistically significant difference in caries prevalence or severity between 2017 and 2002. In 2017, caries prevalence was 55% in Dublin (full CWF) and 56% in Cork-Kerry (full CWF), and mean d3vcmft(cde) among children with caries was 3.4 and 3.7, respectively. Caries severity was less in 2017 (mean 4.2) than 2002 (mean 4.9) among children with no CWF (P = 0.039). The difference in caries severity between children with full CWF and no CWF was less in 2017 than in 2002 (interaction P = 0.013), suggesting a reduced benefit for CWF in 2017. In 2017, fluorosis prevalence was 18% in Dublin (full CWF) and 12% in Cork-Kerry (full CWF). Fluorosis was predominantly "very mild" with no statistically significant difference between 2017 and 2002. CWF at 0.6 to 0.8 ppm is an effective caries-preventive measure. Results suggested low uptake of toothbrushing guidance, a reduced caries-preventive effect for CWF in primary teeth, and no reduction in fluorosis following introduction of the policy measures.

An RCT of atraumatic restorative treatment for older adults: 5 year results.

OBJECTIVES: to compare the survival of ART and a conventional restorative technique (CT) for restoring carious lesions in older adults after 5 years. METHODS: In this parallel randomised controlled clinical trial, 219 independently-living adults were recruited from a dental hospital/community and a geriatric day hospital. Ninety-nine patients who met the inclusion criteria and presented with carious lesions were randomly allocated to receive either ART or conventional restorations (anaesthesia, rotary instruments and resin-modified glass ionomer). The status of restorations was assessed 6 months, 1, 2 and 5 years after restoration placement. Estimates of cumulative survival were calculated for each interval between assessments and a Cox Proportional Hazards (PH) model was fitted to the interval-censored survival time. RESULTS: Three hundred restorations (ART n=142; CT n=158) were placed on 99 patients, 46 males and 53 females, with a mean age of 73.2, SD: 6.8 (65-90 yrs). After 5 years, ART and CT presented cumulative probability of survival of 85% and 79% (p=0.8095), respectively. CONCLUSIONS: ART presents survival rates comparable to a conventional technique, when treating older adults after 5 years. The ART approach could be a useful tool to provide dental care for older adults particularly in the nonclinical setting. (Trial Registration number: ISRCTN 76299321). CLINICAL RELEVANCE: This study shows that ART presents survival rates comparable to conventional techniques to treat carious lesions in older patients after 5 years. It is well accepted by this age cohort, and therefore could be an alternative to treat the elderly, especially those who are homebound or cannot attend the dentist.

Molecular fingerprint-derived similarity measures for toxicological read-across: Recommendations for optimal use.

Computational approaches are increasingly used to predict toxicity due, in part, to pressures to find alternatives to animal testing. Read-across is the "new paradigm" which aims to predict toxicity by identifying similar, data rich, source compounds. This assumes that similar molecules tend to exhibit similar activities i.e. molecular similarity is integral to read-across. Various of molecular fingerprints and similarity measures may be used to calculate molecular similarity. This study investigated the value and concordance of the Tanimoto similarity values calculated using six widely used fingerprints within six toxicological datasets. There was considerable variability in the similarity values calculated from the various molecular fingerprints for diverse compounds, although they were reasonably concordant for homologous series acting via a common mechanism. The results suggest generic fingerprint-derived similarities are likely to be optimally predictive for local datasets, i.e. following sub-categorisation. Thus, for read-across, generic fingerprint-derived similarities are likely to be most predictive after chemicals are placed into categories (or groups), then similarity is calculated within those categories, rather than for a whole chemically diverse dataset.

Fascial layers influence the spread of injectate during ultrasound-guided infraclavicular brachial plexus block: a cadaver study.

BACKGROUND: Fascial layers of the neurovascular sheath containing the brachial plexus influence distribution of local anaesthetic, hence increasing the risk of block failure when performing infraclavicular brachial plexus block (ICB). METHODS: Ultrasound-guided infraclavicular brachial plexus block was performed on cadavers using a single injection technique with dye (20-30 ml). After injection, we carried out consecutive dissection of the neurovascular bundle to study dye injectate spread and identify the presence of fascial layers. Ultrasound video images (scout scan and injection) and recordings of dissections were evaluated by independent experts (regional anaesthetists and anatomists). RESULTS: Well defined fascial layers were identified at dissection in seven out of 12 infraclavicular spaces studied. These fascial layers impeded the spread of dye injectate substantially in six cases and partially in one case. No fascial layers were identified at dissection in five cases, in each of which the spread of injectate was complete throughout the neurovascular bundle. The sensitivity and specificity of ultrasonography and haptic sensation for detection of fascial layers were poor. CONCLUSIONS: When fascial layers are present in the neurovascular sheath, they impede the spread of injectate during infraclavicular brachial plexus block. Ultrasound detection of these fascial layers is unreliable in cadavers. These findings support the use of greater volumes of injectate or a multiple injection technique when performing this block.

Characterisation of data resources for in silico modelling: benchmark datasets for ADME properties.

INTRODUCTION: The cost of in vivo and in vitro screening of ADME properties of compounds has motivated efforts to develop a range of in silico models. At the heart of the development of any computational model are the data; high quality data are essential for developing robust and accurate models. The characteristics of a dataset, such as its availability, size, format and type of chemical identifiers used, influence the modelability of the data. Areas covered: This review explores the usefulness of publicly available ADME datasets for researchers to use in the development of predictive models. More than 140 ADME datasets were collated from publicly available resources and the modelability of 31 selected datasets were assessed using specific criteria derived in this study. Expert opinion: Publicly available datasets differ significantly in information content and presentation. From a modelling perspective, datasets should be of adequate size, available in a user-friendly format with all chemical structures associated with one or more chemical identifiers suitable for automated processing (e.g. CAS number, SMILES string or InChIKey). Recommendations for assessing dataset suitability for modelling and publishing data in an appropriate format are discussed.

Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens.

Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.

The debate continues: a prospective, randomised, single-blind study comparing Coblation and bipolar tonsillectomy techniques.

OBJECTIVES: Tonsillectomy is a common procedure with significant post-operative pain. This study was designed to compare post-operative pain, returns to a normal diet and normal activity, and duration of regular analgesic use in Coblation and bipolar tonsillectomy patients. METHODS: A total of 137 patients, aged 2-50 years, presenting to a single institution for tonsillectomy or adenotonsillectomy were recruited. Pain level, diet, analgesic use, return to normal activity and haemorrhage data were collected. RESULTS: Coblation tonsillectomy was associated with significantly less pain than bipolar tonsillectomy on post-operative days 1 (p = 0.005), 2 (p = 0.006) and 3 (p = 0.010). Mean pain scores were also significantly lower in the Coblation group (p = 0.039). Coblation patients had a significantly faster return to normal activity than bipolar tonsillectomy patients (p < 0.001). CONCLUSION: Coblation tonsillectomy is a less painful technique compared to bipolar tonsillectomy in the immediate post-operative period and in the overall post-operative period. This allows a faster return to normal activity and decreased analgesic requirements.

A Retrospective Audit of In-Hospital 30-day Mortality from Acute Myocardial Infarction in Connolly Hospital Blanchardstown.

In 2015, The Department of Health published the first annual report of the "National Healthcare Quality Reporting System." Connolly Hospital was reported to a mortality rate within 30 days post-Acute Myocardial Infarction (AMI) of 9.87 per 100 cases which was statistically significantly higher than the national rate. We carried out a retrospective audit of patients who were HIPE-coded as having died within 30 days of AMI from 2011-2013 and identified 42 patients. On review, only 23 patients (54.8%) were confirmed as having had an AMI. We identified 12 patients who had AMI included on death certificate without any evidence for same. If the 22 patients incorrectly coded were excluded, the mortality rate within 30 days post-AMI in CHB would fall to 4.14 deaths per 100 cases, well below the national average. Inaccuracies of data collection can lead to erroneous conclusions when examining healthcare data.

Potential emigration of Siberian cattle germplasm on Chirikof Island, Alaska.

Feral cattle residing in Chirikof Island, Alaska, are relatively distinct from breeds used in commercial production in North America. However, preliminary evidence suggested that they exhibit substantial genetic relationship with cattle from Yakutian region of Siberia. Thus, our objective was to further elucidate quantify the origins, admixture and divergence of the Chirikof Island cattle relative to cattle from Siberia and USA. Subject animals were genotyped at 15 microsatellite loci. Compared with Turano-Mongolian and North American cattle, Chirikof Island cattle had similar variation, with slightly less observed heterozygosity, fewer alleles per locus and a positive fixation index. Analysis of the genetic distances revealed two primary clusters; one that contained the North American breeds and the Kazakh White head, and a second that contained the Yakutian and Kalmyk breeds, and the Chirikof population. Thus, it is suggested that Chirikof Island cattle may be a composite of British breeds emanating from North America and Turano-Mongolian cattle. A potential founder effect, consistent with historical records of the Russian-American period, may contribute to the adaptation of the Chirikof Island cattle to their harsh high-latitude environment. Further study of adaptive mechanisms manifest by these cattle is warranted.

Acute otitis media associated bilateral sudden hearing loss: case report and literature review.

BACKGROUND: Sudden sensorineural hearing loss is a rare otological condition with potential for dire outcomes including permanent hearing loss. Although the majority of cases are deemed idiopathic, bilateral sudden sensorineural hearing loss represents a rare subset typically related to systemic conditions, with higher morbidity and mortality. A controversial association with acute otitis media has been reported, with few bilateral cases published in the literature. CASE REPORT: A very rare case of bilateral sudden sensorineural hearing loss associated with acute otitis media is described, with a review of the literature. CONCLUSION: The limited evidence available suggests that acute otitis media with tinnitus and/or bacterial pathology may have an increased risk of sudden sensorineural hearing loss, which is consistent with the case described. Although there is no sufficiently powered published evidence to provide definitive treatment guidelines, the literature reviewed suggests that early myringotomy and antibiotics may greatly improve treatment outcomes.