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The understanding of selectivity in reactions exhibiting nonstatistical dynamics is impeded by the limitations of trajectory studies with regard to nuclear quantum effects, especially tunneling. We described here the use of ring-polymer molecular dynamics (RPMD) to account for an unusual regiochemical isotope effect on the regioselectivity of hydroborations of alkenes with BH 3 /BD 3 . RPMD is able to account for the experimental observation, while statistical approaches and classical trajectories fail. The combination of experiment and RPMD trajectories suggests that tunneling in the initial collision of reactants is the major source of the nonstatistical selectivity.

Background: Ticks are an important driver of veterinary health care, causing irritation and sometimes infection to their hosts. We explored epidemiological and geo-referenced data from > 7 million electronic health records (EHRs) from cats and dogs collected by the Small Animal Veterinary Surveillance Network (SAVSNET) in Great Britain (GB) between 2014 and 2021 to assess the factors affecting tick attachment in an individual and at a spatiotemporal level., Methods: EHRs in which ticks were mentioned were identified by text mining; domain experts confirmed those with ticks on the animal. Tick presence/absence records were overlaid with a spatiotemporal series of climate, environment, anthropogenic and host distribution factors to produce a spatiotemporal regression matrix. An ensemble machine learning spatiotemporal model was used to fine-tune hyperparameters for Random Forest, Gradient-boosted Trees and Generalized Linear Model regression algorithms, which were then used to produce a final ensemble meta-learner to predict the probability of tick attachment across GB at a monthly interval and averaged long-term through 2014-2021 at a spatial resolution of 1 km. Individual host factors associated with tick attachment were also assessed by conditional logistic regression on a matched case-control dataset., Results: In total, 11,741 consultations were identified in which a tick was recorded. The frequency of tick records was low (0.16% EHRs), suggesting an underestimation of risk. That said, increased odds for tick attachment in cats and dogs were associated with younger adult ages, longer coat length, crossbreeds and unclassified breeds. In cats, males and entire animals had significantly increased odds of recorded tick attachment. The key variables controlling the spatiotemporal risk for tick attachment were climatic (precipitation and temperature) and vegetation type (Enhanced Vegetation Index). Suitable areas for tick attachment were predicted across GB, especially in forests and grassland areas, mainly during summer, particularly in June., Conclusions: Our results can inform targeted health messages to owners and veterinary practitioners, identifying those animals, seasons and areas of higher risk for tick attachment and allowing for more tailored prophylaxis to reduce tick burden, inappropriate parasiticide treatment and potentially TBDs in companion animals and humans. Sentinel networks like SAVSNET represent a novel complementary data source to improve our understanding of tick attachment risk for companion animals and as a proxy of risk to humans., (© 2024. The Author(s).)

Introduction: Systemically-administered antimicrobials are often prescribed in canine and feline gastrointestinal clinical presentations. Responsible use of antimicrobials, particularly those considered Highest Priority Critically Important Antimicrobials (HPCIAs) is vital to tackle antimicrobial resistance. Although practice-level prescription guidance is available, further strategies based on a greater understanding of antimicrobial prescription at the population-level are needed. Here, we used a mixed-methods approach, harnessing veterinary electronic health records (EHRs) to characterise the use of antimicrobials in canine and feline gastrointestinal presentations, and to explore justification and reasoning around antimicrobial prescribing, particularly of HPCIAs., Methods: This observational study used 23,337 EHRs complemented with veterinary practitioner-completed questionnaires, from canine and feline gastrointestinal consultations from 225 volunteer UK veterinary practices between April 2014 and September 2018., Results: A total of 83.4% (95% confidence interval (CI) 82.6-84.3) gastrointestinal presentations were reported as mild, with non-haemorrhagic diarrhoea and vomiting the most frequently reported clinical signs. Systemically-administered antimicrobials occurred in 28.6% of canine (95% CI 26.9-30.3) and 22.4% of feline (95% CI 20.4-24.4) gastrointestinal consultations, with HPCIA prescription occurring more frequently in cats. Results of multivariable analysis showed the presence of non-haemorrhagic diarrhoea (canine Odds Ratio (OR) 2.1, 95% CI 1.9-2.3; feline OR 1.8, 95% CI 1.5-2.1), haemorrhagic diarrhoea (canine OR 4.2, 95% CI 3.8-4.7; feline OR 3.1, 95% CI 2.4-3.8), and moderate/severe presentations (canine OR 1.9, 95% CI 1.7-2.8; feline OR 2.0, 95% CI 1.7-2.5) were positively associated with receiving a systemically-administered antimicrobial. Thematic analysis of clinical narrative content of 516 gastrointestinal consultations where HPCIAs were prescribed allowed the identification of ten factors underpinning reasoning or decision-making for HPCIA prescription: perceived animal/owner compliance; owner's expectations; perceived risk of infection; clinical signs; recent clinical history; perceived positive previous response to antimicrobial therapy; geriatric patients and euthanasia; concomitant conditions; diagnostic testing and the behavioral trend to trial antimicrobial therapy empirically in gastrointestinal cases. No explicit justification for HPCIA prescription was recorded in 77% of cases., Discussion: Improving recorded justification represents a clear target for stewardship programmes. By utilising a complementary mixed-methods approach to EHRs, this study unlocks previously untapped data recorded within EHRs. These results can help inform targeted interventions, contributing towards enhanced antimicrobial stewardship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fins, Singleton, Radford, Sánchez-Vizcaíno and Pinchbeck.)

The intersection of human, animal, and ecosystem health at One Health interfaces is recognised as being of key importance in the evolution and spread of antimicrobial resistance (AMR) and represents an important, and yet rarely realised opportunity to undertake vital AMR surveillance. A working group of international experts in pathogen genomics, AMR, and One Health convened to take part in a workshop series and online consultation focused on the opportunities and challenges facing genomic AMR surveillance in a range of settings. Here we outline the working group's discussion of the potential utility, advantages of, and barriers to, the implementation of genomic AMR surveillance at One Health interfaces and propose a series of recommendations for addressing these challenges. Embedding AMR surveillance at One Health interfaces will require the development of clear beneficial use cases, especially in low-income and middle-income countries. Evidence of directionality, risks to human and animal health, and potential trade implications were also identified by the working group as key issues. Addressing these challenges will be vital to enable genomic surveillance technology to reach its full potential for assessing the risk of transmission of AMR between the environment, animals, and humans at One Health interfaces., Competing Interests: Declaration of interests DMM reports funding from the British Society for Antimicrobial Chemotherapy. EJ had partial salary cover from the Wellcome Trust over the course of this work. SJP is a member of the Scientific Advisory Board of Next Gen Diagnostics and was supported by Illumina to attend the European Congress of Clinical Microbiology and Infectious Diseases conference. NAF reports funding from the Bill & Melinda Gates Foundation, UK Research and Innovation, and National Institute for Health Research (NIHR). KSB reports funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council (MRC) and partial salary cover from the Wellcome Trust and the UK Health Security Agency over the course of this work. RNZ reports funding from the MRC. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Fleas in the genus Ctenocephalides are the most clinically important parasitic arthropods of dogs and cats worldwide yet risk factors that might increase the risk of infestation in small animals remains unclear. Here we developed a supervised text mining approach analysing key aspects of flea epidemiology using electronic health records from domestic cats and dogs seen at a sentinel network of 191 voluntary veterinary practices across Great Britain between March 2014 and July 2020. Our methods identified fleas as likely to have been present during 22,276 of 1,902,016 cat consultations (1.17%) and 12,168 of 4,844,850 dog consultations (0.25%). Multivariable logistic regression modelling found that animals originating from areas of least deprivation were associated with 50% reductions in odds of veterinary-recorded flea infestation compared to the most deprived regions in England. Age of the animal was significantly associated with flea presentation in both cats and dogs, with cases peaking before animals reached 12 months. Cases were recorded through each study years, peaking between July and October, with fluctuations between each year. Our findings can be used towards healthcare messaging for veterinary practitioners and owners., (© 2023 The Authors. Medical and Veterinary Entomology published by John Wiley & Sons Ltd on behalf of Royal Entomological Society.)

Background: This study aimed to describe the management of cases of suspected and confirmed canine multicentric lymphoma (ML) in first opinion practice (FOP) and investigate whether socioeconomic factors are associated with initial management., Methods: Clinical narratives from electronic health records collected by the Small Animal Veterinary Surveillance Network (SAVSNET) were searched to identify dogs with peripheral lymphadenomegaly in which ML was the major differential. Cases were grouped as either ML confirmed (ML-C) or ML suspected but not confirmed (ML-S). Associations between initial management and socioeconomic factors were assessed via multivariable logistic regression., Results: Two hundred and sixty-four cases with ML-C and 410 with ML-S were identified. There was an increased probability that owners of ML-C cases resided in less deprived areas. Moreover, a diagnosis was made more commonly in insured dogs. Only insured pets were more likely to be treated with chemotherapy following diagnosis. The majority of dogs in both groups were treated with corticosteroids alone (ML-S, n = 256/410; ML-C, n = 123/264). A small minority were referred (n = 30/674)., Conclusion: Socioeconomic inequalities appear to be associated with the diagnosis and management of dogs with suspected or confirmed ML in FOP. Most dogs with suspected multicentric lymphoma (in the UK) are managed in FOP (n = 644/674). Consequently, expanding the knowledge base relevant to this setting offers an opportunity to improve the management of canine lymphoma., (© 2022 British Veterinary Association.)

This mixed-method study explored the impacts of the COVID-19 pandemic on owners' veterinary healthcare seeking, with particular focus on dogs with chronic conditions. A convenience sample of 719 UK dog owners completed an online survey (December 2020-January 2021). Differences in treatment provision and respondents' decisions to seek care across acute, preventative, chronic conditions and for end-of-life care were explored. Multivariable logistic regression models were used to identify factors associated with seeking care for any health issue compared to deciding against it, and urgency to seek care given symptom that could indicate chronic conditions. Open-ended questions were analyzed by thematic analysis. Significant (p-value < 0.05) differences in care seeking decisions were identified regarding access to veterinary care and the way treatment was provided across all health issues. The top reasons for not seeking care across all health issues were a lack of access to a veterinarian (30%, n = 56/187) and a reluctance for a dog to go to the clinic unaccompanied (20%, n = 38/187). Variables related to stronger dog-owner relationship, higher confidence in seeking care, perception of: benefits of veterinary care, dog's high susceptibility to illness and high severity of dog's condition, increased the odds of seeking, and urgency to seek, care. A dog's chronic illness diagnosis reduced the odds of seeking care during the pandemic, reportedly due to difficulties in accessing care for non-urgent issues. Qualitative analysis showed that limited access to routine consultations, delays in test results and restricted access to complementary treatments, led some owners of dogs with chronic conditions to believe that their dog's welfare had deteriorated during the pandemic. Pandemic control measures necessitated changes to how consultations were run. These changes were often viewed favorably, but dog-client separation during consultations were considered problematic, sometimes delaying veterinary advice-seeking, including for euthanasia. Separating owners from their dogs during veterinary consultations should be avoided wherever possible due to impacts on dogs, owners and healthcare seeking. Interventions to improve veterinary healthcare seeking could target attitudes toward benefits of seeking care, improve owners' self-efficacy and capitalize on the dog-owner bond. Such interventions should be implemented alongside interventions aimed at removing structural barriers to accessing healthcare., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Owczarczak-Garstecka, Furtado, Graham, Lloyd, Singleton, Wallis and Westgarth.)

Introduction/objectives: Canine cardiovascular (CV) diseases are often managed in primary care settings. The objectives were to describe CV therapeutic agent (CVTA) prescribing patterns in primary care practices in the United Kingdom (UK) and to evaluate recorded clinical signs, diagnostic tests and justifications for use of torasemide, a recently marketed and authorised loop-diuretic in the UK., Animals, Materials and Methods: Electronic health records (EHRs) describing 3,579,420 consultations (1,043,042 unique dogs) were collated (1 April 2014 and 31 December 2018) by the Small Animal Veterinary Surveillance Network from 270 veterinary practices. Consultations prescribing at least one CVTA were identified. Annual variation in individual CVTA prescriptions was analysed using mixed-effects binomial regression models. Free-text clinical narratives were manually read to determine the first-prescribing event for torasemide., Results: Twenty-nine thousand and seven consultations (0.81% of all consultations, 95% confidence interval [CI], 0.76-0.86) prescribed CVTA in 14,148 (1.36%) dogs. Furosemide (52.8% of CV-prescribing consultations, 95% CI 50.7-54.9) and pimobendan (51.9%, 95% CI 50.1-53.7) were most prescribed. Longitudinal analysis (2014-2018) showed a significant negative temporal trend for angiotensin-converting enzyme inhibitors (p < 0.001), and furosemide (p = 0.003) and a positive temporal trend for pimobendan (p = 0.020) and torasemide (p < 0.001). First prescriptions of torasemide were identified in 16.5% of torasemide-prescribing consultations. Where justification for prescription of torasemide was identified (32.5%), furosemide resistance was the most common (92.0%)., Conclusions: EHRs can be used to temporally monitor prescribing habits, including responses to market authorisations. Despite authorisation in the UK for torasemide use as a first-line diuretic, it was most commonly prescribed after furosemide resistance., Competing Interests: Conflicts of Interest Statement Small Animal Veterinary Surveillance Network (including Alan Radford and David Singleton) was funded by the Biotechnology and Biological Research Council and Dogs Trust during this study and has received prior funding from the Veterinary Medicines Directorate and the British Small Animal Veterinary Association. Funding has also been received from various pharmaceutical companies in the past, but no funding was received for the work presented here. The other authors (EFB, EM and HHG) have no conflicts of interest to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Transmissable venereal tumour (TVT) is a tumour transplanted by physical contact between dogs. Lesions typically affect the genitalia. TVT is not considered enzootic in the United Kingdom (UK), with cases seen in imported dogs. We sought to determine the patient characteristics, temporal and spatial distribution and country of origin of affected dogs in the UK., Methods: Electronic pathology records (EPRs) from four UK veterinary diagnostic laboratories collected between 2010 and 2019 were searched for the terms 'venereal' or 'TVT'. Reports were reviewed for statements confirming a TVT and descriptive statistics collated., Results: Of 182 EPRs matching the search terms, a diagnosis of TVT was confirmed in 71. Country of origin was noted in 36 cases (50.7%) with Romania being the most common (n = 29). Cases were reported in each UK constituent country, with the majority being in England (64, 90.1%). The incidence of TVT diagnosis increased over the last decade (z = 2.78, p = 0.005)., Conclusion: The incidence of TVT diagnosed in the UK is increasing. The majority of cases were known to have been imported. Autochthonous transmission cannot be excluded due to study design. Vets are encouraged to carefully examine the genitalia of dogs imported to the UK from countries with enzootic TVT., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Grass seed foreign bodies (GSFBs) are a familiar presentation, especially in dogs, associated with a variety of clinical signs depending on site of penetration and extent of migration. Seasonality and risk factors for GSFB occurrence were investigated using electronic health records from a sentinel voluntary network of 245 veterinary practices in the United Kingdom between 17th March 2014 and 18th September 2020. Clinical narrative text mining of 4,580,503 canine consultations produced a final case dataset of 1,037 consultations where GSFBs had been recorded in individual dogs. Cases of GSFBs were recorded in all months, with 940 (90.6 %) recorded between June and September. In particular, the odds of GSFBs in July was almost 176 times more than that of January (Odds ratio, OR, 175.6, 95 % Confidence interval, CI, 43.5-707.7, P < 0.001). Compared to the retriever breed type, spaniel breed types were 7.7 times more likely to present with a GSFB (CI 5.4-11.0, P < 0.001). Other significant risk factors associated with recorded GSFBs for this population included being male (OR = 1.4, CI 1.2-1.6, P < 0.001), and geographical location. When compared to the South East of England, risk was lowest in Wales (OR = 0.1, CI 0.0-0.3, P=<0.001), and highest in the East of England (OR = 1.9, 1.2-2.9, P = 0.003), and overall risk in urban areas was reduced (OR = 0.8, CI 0.7-1.0, P = 0.024). These observations provide a number of areas for temporally targeted health campaigns at specific types of dogs, to reduce the impact of GSFBs on canine welfare., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cancer is a major reason for veterinary consultation, especially in companion animals. Cancer surveillance plays a key role in prevention but opportunities for such surveillance in companion animals are limited by the lack of suitable veterinary population health infrastructures. In this paper we describe a pathology-based animal tumour registry (PTR) developed within the Small Animal Veterinary Surveillance Network (SAVSNET) built from electronic pathology records (EPR) submitted to this network. From an original collection of 180232 free text (non-structured) EPRs reported between April 2018 and June 2019, we used specific text-mining methodologies to identify 109895 neoplasias. These data were normalized to describe both the tumour (type and location) and the animal (breed, neutering status and veterinary practice postcode). The resulting PTR, the largest of its kind for companion animals to date, is an important research resource being able to facilitate a wide array of research in areas including surveillance, clinical decision making and comparative cancer biology., (© 2021. The Author(s).)

Background: Antimicrobial resistance (AMR) is a globally important one health threat. The impact of resistant infections on companion animals, and the potential public health implications of such infections, has not been widely explored, largely due to an absence of structured population-level data., Objectives: We aimed to efficiently capture and repurpose antimicrobial susceptibility test (AST) results data from several veterinary diagnostic laboratories (VDLs) across the United Kingdom to facilitate national companion animal clinical AMR surveillance. We also sought to harness and genotypically characterize isolates of potential AMR importance from these laboratories., Methods: We summarized AST results for 29,330 canine and 8,279 feline Enterobacteriaceae isolates originating from companion animal clinical practice, performed between April 2016 and July 2018 from four VDLs, with submissions from 2,237 United Kingdom veterinary practice sites., Results: Escherichia coli ( E. coli ) was the most commonly isolated Enterobacteriaceae in dogs (69.4% of AST results, 95% confidence interval, CI, 68.7-70.0) and cats (90.5%, CI 89.8-91.3). Multi-drug resistance was reported in 14.1% (CI 13.5-14.8) of canine and 12.0% (CI 11.1-12.9) of feline E. coli isolates. Referral practices were associated with increased E. coli 3rd generation ≤ cephalosporin resistance odds (dogs: odds ratio 2.0, CI 1.2-3.4). We selected 95 E. coli isolates for whole genome analyses, of which seven belonged to sequence type 131, also carrying the plasmid-associated extended spectrum β-lactamase gene bla CTX-M- 15 . The plasmid-mediated colistin resistance gene mcr-9 was also identified for the first time in companion animals., Conclusions: Linking clinical AMR data with genotypic characterization represents an efficient means of identifying important resistance trends in companion animals on a national scale., Competing Interests: MJ and LR were employed by the veterinary diagnostic company IDEXX Laboratories Ltd. StS was employed by the veterinary diagnostic company NationWide Laboratories/CAPL Ltd. Although employed by the University of Liverpool, DT held primary responsibility for managing a commercial veterinary diagnostic laboratory within the university. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Singleton, Pongchaikul, Smith, Bengtsson, Baker, Timofte, Steen, Jones, Roberts, Sánchez-Vizcaíno, Dawson, Noble, Radford, Pinchbeck and Williams.)

13 C kinetic isotope effects (KIEs) for the photoredox-promoted [2 + 2] cycloaddition of enones were determined in homocoupling and heterocoupling examples. The only significant KIEs were observed at the β carbon, indicating that C β -C β bond formation is irreversible. However, these KIEs were much lower than computational predictions, suggesting that product selectivity is determined in part by a step prior to C β -C β bond formation. The results are explained as arising from a competition between C-C bond formation and electron exchange between substrate alkenes. This idea is supported by a relatively small substituent effect on substrate selectivity. The possible rates for electron transfer and bond-forming steps are analyzed, and the competition appears plausible, particularly if the mechanism involves a complex between reduced and neutral enone molecules.

Background: Backyard poultry ownership is of keen interest in the United Kingdom. However, despite this, little is known about veterinary care engagement and outcomes of visits in this group of species., Methods: This study described and characterised veterinary practice-visiting backyard poultry, utilising electronic health record data supplied by veterinary practices voluntarily participating in the Small Animal Veterinary Surveillance Network between 1st April 2014 and 31st March 2019., Results: In total, 4424 recorded poultry consultations originating from 197 veterinary practices (352 sites) were summarised. Chicken consultation (n = 3740) peak incidence was in early summer (April-June), relative to all recorded species. More chickens resided in rural (incident rate ratio = 2.5, confidence interval [CI] 2.3-2.6, p <0.001) or less deprived areas. Non-specific clinical signs were commonly recorded (17.6% of chicken consultations, CI 15.9-19.2), as were those indicative of advanced disease. This latter finding was reflected in prescribed management strategies, with euthanasia comprising 29.8% (CI 27.0-32.6) of consultations. Antimicrobials were commonly prescribed (33.0% of consultations, CI 29.8-36.2), 43.8% of which included antimicrobials considered 'highest priority critically important' by the World Health Organisation., Conclusion: Our findings indicate a need to tailor antimicrobial prescription guidance to the backyard poultry setting. In addition, late presentation of disease, vague clinical descriptions in clinical narratives and high euthanasia rates show that disease identification, management and knowledge of poultry health and welfare among owners and veterinary surgeons can be improved., (© 2021 British Veterinary Association.)

The initial energy in a reactive intermediate is derived from the transition state before the intermediate but can affect selectivity after the intermediate. In this way an observable selectivity can report on a prior, kinetically hidden mechanistic step. This new type of mechanistic probe is demonstrated here for the oxidation of 1-methylcyclobutanol by phthaloyl peroxide/Bu 4 N + Br - , and it supports a hypobromite chain mechanism in place of the previously proposed hydrogen atom transfer mechanism.

Robust evidence supporting strategies for companion animal antimicrobial stewardship is limited, despite frequent prescription of highest priority critically important antimicrobials (HPCIA). Here we describe a randomised controlled trial where electronic prescription data were utilised (August 2018-January 2019) to identify above average HPCIA-prescribing practices (n = 60), which were randomly assigned into a control group (CG) and two intervention groups. In March 2019, the light intervention group (LIG) and heavy intervention group (HIG) were notified of their above average status, and were provided with educational material (LIG, HIG), in-depth benchmarking (HIG), and follow-up meetings (HIG). Following notification, follow-up monitoring lasted for eight months (April-November 2019; post-intervention period) for all intervention groups, though HIG practices were able to access further support (i.e., follow-up meetings) for the first six of these months if requested. Post-intervention, in the HIG a 23.5% and 39.0% reduction in canine (0.5% of total consultations, 95% confidence interval, 0.4-0.6, P = 0.04) and feline (4.4%, 3.4-5.3, P < 0.001) HPCIA-prescribing consultations was observed, compared to the CG (dogs: 0.6%, 0.5-0.8; cats: 7.4%, 6.0-8.7). The LIG was associated with a 16.7% reduction in feline HPCIA prescription (6.1% of total consultations, 5.3-7.0, P = 0.03). Therefore, in this trial we have demonstrated effective strategies for reducing veterinary HPCIA prescription.

The lack of population health surveillance for companion animal populations leaves them vulnerable to the effects of novel diseases without means of early detection. We present evidence on the effectiveness of a system that enabled early detection and rapid response a canine gastroenteritis outbreak in the United Kingdom. In January 2020, prolific vomiting among dogs was sporadically reported in the United Kingdom. Electronic health records from a nationwide sentinel network of veterinary practices confirmed a significant increase in dogs with signs of gastroenteric disease. Male dogs and dogs living with other vomiting dogs were more likely to be affected. Diet and vaccination status were not associated with the disease; however, a canine enteric coronavirus was significantly associated with illness. The system we describe potentially fills a gap in surveillance in neglected populations and could provide a blueprint for other countries.

Large intramolecular 13 C kinetic isotope effects (KIEs) for the di-π-methane rearrangement of benzobarrelene fit with statistical expectations from heavy-atom tunneling when a low-energy sensitizer is employed, but much lower KIEs are observed with higher-energy sensitizers. These results in combination with trajectory studies suggest that the excess vibrational energy available from triplet energy transfer leads to hot and nonstatistical dynamics in the rearrangement.

Antimicrobial stewardship is a cornerstone of efforts to curtail antimicrobial resistance. To determine factors potentially influencing likelihood of prescribing antimicrobials for animals, we analyzed electronic health records for unwell dogs (n = 155,732 unique dogs, 281,543 consultations) and cats (n = 69,236 unique cats, 111,139 consultations) voluntarily contributed by 173 UK veterinary practices. Using multivariable mixed effects logistic regression, we found that factors associated with decreased odds of systemic antimicrobial prescription were client decisions focused on preventive health: vaccination (dogs, odds ratio [OR] 0.93, 95% CI, 0.90-0.95; cats, OR 0.92, 95% CI 0.89-0.95), insurance (dogs, OR 0.87, 95% CI 0.84-0.90; cats, OR 0.82, 95% CI 0.79-0.86), neutering of dogs (OR 0.90, 95% CI 0.88-0.92), and practices accredited by the Royal College of Veterinary Surgeons (OR 0.79, 95% 95% CI 0.68-0.92). This large multicenter companion animal study demonstrates the potential of preventive healthcare and client engagement to encourage responsible antimicrobial drug use.

Additions of acids to 1,3-dienes are conventionally understood as involving discrete intermediates that undergo an ordinary competition between subsequent pathways to form the observed products. The combined experimental, computational, and dynamic trajectory study here suggests that this view is incorrect, and that solvation dynamics plays a critical role in the mechanism. While implicit solvent models were inadequate, QM/QM' trajectories in explicit solvent provide an accurate prediction of the experimental selectivity in the addition of HCl to 1,3-pentadiene. Trajectories initiated from a protonation saddle point on the potential of mean force surface are predominantly unproductive due to a gating effect of solvation that allows diene protonation only when the incipient ion pair is neither too solvent-stabilized nor too little. Protonation then leads to relatively unsolvated ion pairs, and a majority of these collapse rapidly to the 1,2-product, without barrier and without achieving equilibrium solvation as intermediates. The remainder decay slowly, at a rate consistent with equilibrium solvation as true intermediates, affording a mixture of addition products. Overall, an accurate description of the nature and pathway selectivity of the ion pair intermediates in carbocation reactions must allow for species lacking equilibrium solvation. Potential reinterpretations of a series of historically notable observations in carbocation reactions are discussed.

Myxomatosis is a highly contagious, frequently fatal viral disease affecting both wild and domesticated European rabbits across many areas of the world. Here we used electronic health records (EHRs) collected from pet rabbits attending a sentinel voluntary network of 191 veterinary practices across Great Britain (GB) between March 2014 and June 2019 to identify new features of this disease's epidemiology. From a total of 89,408 rabbit consultations, text mining verified by domain experts identified 207 (0.23 %) cases where myxomatosis was the only differential diagnosis recorded by the attending practitioner. Cases occurred in all months but February and were distributed across the country. Consistent with studies in wild rabbits, the majority of cases occurred between August and November. However, there was also evidence for considerable variation between years. A nested case control study identified important risk factors for myxomatosis within this pet animal population including season, sex, age, vaccination status and distance to likely wild rabbit habitats. Female entire rabbits were twice as likely to be a case (odds ratio (OR) 1.98, 95 % confidence interval (CI) 1.26-3.13, p = 0.003), suggesting a novel role for behaviour in driving transmission from wild to domesticated rabbits. Vaccination had the largest protective effect with vaccinated rabbits being 8.3 times less likely to be a case than unvaccinated rabbits (OR = 0.12, 95 % CI 0.06-0.21, p = <0.001)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The carboborative ring contraction of cyclohexenes exhibits an abnormal selectivity pattern in which a formally concerted double migration gives rise to predominant but not exclusive inversion products. In dynamic trajectories, the inversion and retention products are formed from the same transition state, and the trajectories accurately account for the experimental product ratios. The unusual origin of the selectivity is the dynamically retained non-equivalence of newly formed versus pre-existing bonds after the first bond migration.

Canine acute diarrhoea is frequently observed in first opinion practice, though little is known about commonly used diagnostic or therapeutic management plans, including use of antimicrobials. This retrospective observational study utilised electronic health records augmented with practitioner-completed questionnaires from 3,189 cases (3,159 dogs) collected from 179 volunteer veterinary practices between April 2014 and January 2017. We used multivariable analysis to explore factors potentially associated with pharmaceutical agent prescription, and resolution of clinical signs by 10 days post-initial presentation. Use of bacteriological and/or parasitological diagnostic tests were uncommon (3.2% of cases, 95% confidence interval, CI, 2.4-4.0), though systemic antimicrobials were the most commonly prescribed pharmaceutical agents (49.7% of cases, 95% CI 46.1-53.2). Such prescription was associated with haemorrhagic diarrhoea (odds ratio, OR, 4.1; 95% CI 3.4-5.0), body temperature in excess of 39.0°C, or moderate/severe cases (OR 1.3, 95% CI 1.1-1.7). Gastrointestinal agents (e.g., antacids) were prescribed to 37.7% of cases (95% CI 35.4-39.9), and were most frequently prescribed to vomiting dogs regardless of presence (OR 46.4, 95% CI 19.4-110.8) or absence of blood (OR 17.1, 95% CI 13.4-21.9). Endoparasiticides/endectocides were prescribed to 7.8% of cases (95% CI 6.8-9.0), such prescription being less frequent for moderate/severe cases (OR 0.5, 95% CI 0.4-0.7), though more frequent when weight loss was recorded (OR 3.4, 95% CI 1.3-9.0). Gastrointestinal nutraceuticals (e.g., probiotics) were dispensed to 60.8% of cases (95% CI 57.1-64.6), these cases less frequently presenting with moderate/severe clinical signs (OR 0.6, 95% CI 0.5-0.8). Nearly a quarter of cases were judged lost to follow-up ( n =754). Insured (OR 0.7, 95% CI 0.5-0.9); neutered (OR 0.4, 95% CI 0.3-0.5), or vaccinated dogs (OR 0.3, 95% CI 0.3-0.4) were less commonly lost to follow-up. Of remaining dogs, clinical signs were deemed resolved in 95.4% of cases (95% CI 94.6-96.2). Provision of dietary modification advice and gastrointestinal nutraceuticals alone were positively associated with resolution (OR 2.8, 95% CI 1.3-6.1); no such associations were found for pharmaceutical agents, including antimicrobials. Hence, this study supports the view that antimicrobials are largely unnecessary for acute diarrhoea cases; this being of particular importance when considering the global threat posed by antimicrobial resistance.

Díaz-Urrutia and Ott (Reports, 22 March 2019, p. 1326) report a selective conversion of methane to methanesulfonic acid that is proposed to occur by a cationic chain reaction in which CH 3 + adds to sulfur trioxide (SO 3 ) to form CH 3 -S(O) 2 O + This mechanism is not plausible because of the solvent reactivity of CH 3 + , the non-nucleophilicity of the sulfur atom of SO 3 , and the high energy of CH 3 -S(O) 2 O^{., (Copyright © 2019, American Association for the Advancement of Science.)}

Pharmaceutical agents (PAs) are commonly prescribed in companion animal practice in the United Kingdom. However, little is known about PA prescription on a population-level, particularly with respect to PAs authorised for human use alone prescribed via the veterinary cascade; this raises important questions regarding the efficacy and safety of PAs prescribed to companion animals. This study explored new approaches for describing PA prescription, diversity and co-prescription in dogs, cats and rabbits utilising electronic health records (EHRs) from a sentinel network of 457 companion animal-treating veterinary sites throughout the UK over a 2-year period (2014-2016). A novel text mining-based identification and classification methodology was utilised to semi-automatically map practitioner-defined product descriptions recorded in 918,333 EHRs from 413,870 dogs encompassing 1,242,270 prescriptions; 352,730 EHRs from 200,541 cats encompassing 491,554 prescriptions, and 22,526 EHRS from 13,398 rabbits encompassing 18,490 prescriptions respectively. PA prescription as a percentage of booked consultations was 65.4% (95% confidence interval, CI, 64.6-66.3) in dogs; in cats it was 69.1% (95% CI, 67.9-70.2) and in rabbits, 56.3% (95% CI, 54.7-57.8). Vaccines were the most commonly prescribed PAs in all three species, with antibiotics, antimycotics, and parasiticides also commonly prescribed. PA prescription utilising products authorised for human use only (hence, 'human-authorised') comprised 5.1% (95% CI, 4.7-5.5) of total canine prescription events; in cats it was 2.8% (95% CI, 2.6-3.0), and in rabbits, 7.8% (95% CI, 6.5-9.0). The most commonly prescribed human-authorised PA in dogs was metronidazole (antibiotic); in cats and rabbits it was ranitidine (H 2 histamine receptor antagonist). Using a new approach utilising the Simpson's Diversity Index (an ecological measure of relative animal, plant etc. species abundance), we identified differences in prescription based on presenting complaint and species, with rabbits generally exposed to a less diverse range of PAs than dogs or cats, potentially reflecting the paucity of authorised PAs for use in rabbits. Finally, through a novel application of network analysis, we demonstrated the existence of three major co-prescription groups (preventive health; treatment of disease, and euthanasia); a trend commonly observed in practice. This study represents the first time PA prescription has been described across all pharmaceutical families in a large population of companion animals, encompassing PAs authorised for both veterinary and human-only use. These data form a baseline against which future studies could be compared, and provides some useful tools for understanding PA comparative efficacy and risks when prescribed in the varied setting of clinical practice., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Vaccination remains a mainstay of companion animal population health. However, how vaccine use at a population level complies with existing guidelines is unknown. Here we use electronic health records to describe vaccination in dogs, cats and rabbits attending a large sentinel network of UK veterinary practices. In total, 77.9% (95% CI: 77.6-78.1) of animals had recorded vaccinations. The percentage of animals with recorded vaccinations was higher in dogs, neutered animals, in insured dogs and cats and in purebred dogs. Vaccination rates varied in different regions of Great Britain in all species. Dogs and cats belonging to owners living in less deprived areas of England and Scotland were more likely to be recorded as vaccinated. In the vaccinated population, cats received more core vaccines per year of life (0.86) than dogs (0.75), with feline leukaemia vaccines almost as frequent as core vaccines. In dogs, leptospira vaccines were more frequent than core vaccines. This descriptive study suggests a substantial proportion of animals are not benefiting from vaccine protection. For the first time, we identify potential factors associated with variations in recorded vaccination frequency, providing a critical baseline against which to monitor future changes in companion animal vaccination and evidence to inform future targeted health interventions.

Blowfly strike is a devastating and often rapidly fatal disease in rabbits. In Great Britain (GB), Lucilia sericata is the primary causative species. Despite its severity, there has been minimal investigatory work into the disease in rabbits. Here we used text mining to screen electronic health records (EHRs) from a large sentinel network of 389 veterinary practices in GB between March 2014 and April 2017 for confirmed cases of blowfly strike in rabbits. Blowfly strike was identified in 243 of 42,226 rabbit consultations (0.6%), affecting 205 individual rabbits. The anatomical site of recorded blowfly strike lesions was overwhelmingly the perineal area (n = 109, 52.4%). Less commonly lesions were observed affecting other areas of the body (n = 9, 4.3%) and head (n = 8, 3.8%); in 83 consultations (39.9%), the affected area was not specified. Of the rabbits presenting with blowfly strike, 44.7% were recorded as being euthanized or died. A case control study was used to identify risk factors for blowfly strike in this population. Whilst sex and neuter status in isolation were not significantly associated with blowfly strike, entire female rabbits showed a 3.3 times greater odds of being a case than neutered female rabbits. Rabbits five years of age and over were more than 3.8 times likely to present for blowfly strike. For every 1 °C rise in environmental temperature between 4.67 °C and 17.68 °C, there was a 33% increase risk of blowfly strike, with cases peaking in July or August. Overall blowfly strike cases started earlier and peaked higher in the south of Great Britain. The most northerly latitude studied was at lower risk of blowfly strike than the most southerly (OR = 0.50, p < 0.001). There appeared to be no significant relationship between blowfly strike in rabbits and either the sheep density or rural and urban land coverage types. The results presented here can be used for targeted health messaging to reduce the impact of this deadly disease for rabbits. We propose that real-time temporal and spatial surveillance of the rabbit disease may also help inform sheep control, where the seasonal profile is very similar, and where routine surveillance data is also not available. Our results highlight the value of sentinel databases based on EHRs for research and surveillance., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Any long-lived chemical structure in solution is subject to statistical energy equilibration, so the history of any specific structure does not affect its subsequent reactions. This is not true for very short-lived intermediates because energy equilibration takes time. Here, this idea is applied to achieve the 'energy labelling' of a reactive intermediate. The selectivity of the ring-opening α-cleavage reaction of the 1-methylcyclobutoxy radical is found here to vary broadly depending on how the radical was formed. Reactions that provide little excess energy to the intermediate lead to a high selectivity in the subsequent cleavage (measured as a kinetic isotope effect), whereas reactions that provide more excess energy to the intermediate exhibit a lower selectivity. Accounting for the expected excess energy allows the prediction of the observed product ratios and, in turn, the product ratios can be used to determine the energy present in an intermediate.

Our previous work found that canonical forms of transition state theory incorrectly predict the regioselectivity of the hydroboration of propene with BH 3 in solution. In response, it has been suggested that alternative statistical and nonstatistical rate theories can adequately account for the selectivity. This paper uses a combination of experimental and theoretical studies to critically evaluate the ability of these rate theories, as well as dynamic trajectories and newly developed localized statistical models, to predict quantitative selectivities and qualitative trends in hydroborations on a broader scale. The hydroboration of a series of terminally substituted alkenes with BH 3 was examined experimentally, and a classically unexpected trend is that the selectivity increases as the alkyl chain is lengthened far from the reactive centers. Conventional and variational transition state theories can predict neither the selectivities nor the trends. The canonical competitive nonstatistical model makes somewhat better predictions for some alkenes but fails to predict trends, and it performs poorly with an alkene chosen to test a specific prediction of the model. Added nonstatistical corrections to this model make the predictions worse. Parametrized Rice-Ramsperger-Kassel-Marcus (RRKM)-master equation calculations correctly predict the direction of the trend in selectivity versus alkene size but overpredict its magnitude, and the selectivity with large alkenes remains unpredictable with any parametrization. Trajectory studies in explicit solvent can predict selectivities without parametrization but are impractical for predicting small changes in selectivity. From a lifetime and energy analysis of the trajectories, "localized RRKM-ME" and "competitive localized noncanonical" rate models are suggested as steps toward a general model. These provide the best predictions of the experimental observations and insight into the selectivities.

Several formal heteroborylative cyclization reactions have been recently reported, but little physical-organic and mechanistic data are known. We now investigate the catalyst-free formal thioboration reaction of alkynes to gain mechanistic insight into B-chlorocatecholborane (ClBcat) in its new role as an alkynophilic Lewis acid in electrophilic cyclization/dealkylation reactions. In kinetic studies, the reaction is second-order globally and first-order with respect to both the 2-alkynylthioanisole substrate and the ClBcat electrophile, with activation parameters of ΔG ‡ = 27.1 ± 0.1 kcal mol -1 at 90 °C, ΔH ‡ = 13.8 ± 1.0 kcal mol -1 , and ΔS ‡ = -37 ± 3 cal mol -1 K -1 , measured over the range 70-90 °C. Carbon kinetic isotope effects supported a rate-determining Ad E 3 mechanism wherein alkyne activation by neutral ClBcat is concerted with cyclative attack by nucleophilic sulfur. A Hammett study found a ρ + of -1.7, suggesting cationic charge buildup during the cyclization and supporting rate-determining concerted cyclization. Studies of the reaction with tris(pentafluorophenyl)borane (B(C 6 F 5 ) 3 ), an activating agent capable of cyclization but not dealkylation, resulted in the isolation of a postcyclization zwitterionic intermediate. Kinetic studies via UV-vis spectroscopy with this boron reagent found second-order kinetics, supporting the likely relevancy of intermediates in this system to the ClBcat system. Computational studies comparing ClBcat with BCl 3 as an activating agent showed why BCl 3 , in contrast to ClBcat, failed to mediate the complete the cyclization/demethylation reaction sequence by itself. Overall, the results support a mechanism in which the ClBcat reagent serves a bifunctional role by sequentially activating the alkyne, despite being less electrophilic than other known alkyne-activating reagents and then providing chloride for post-rate-determining demethylation/neutralization of the resulting zwitterionic intermediate.

A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C-H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it. From further computational work a second generation, in silico designed catalyst emerged, where replacing Bpin with Beg (eg = ethylene glycolate) was predicted to significantly improve ortho selectivity. Experimentally, reactions employing B 2 eg 2 gave ortho selectivities > 99%. Adding triethylamine significantly improved conversions. This ligand-substrate electrostatic interaction provides a unique control element for selective C-H functionalization.

Antimicrobial resistance is an increasingly important global health threat and the use of antimicrobial agents is a key risk factor in its development. This study describes antimicrobial agent prescription (AAP) patterns over a 2year period using electronic health records (EHRs) from booked consultations in a network of 457 sentinel veterinary premises in the United Kingdom. A semi-automated classification methodology was used to map practitioner defined product codes in 918,333 EHRs from 413,870 dogs and 352,730 EHRs from 200,541 cats, including 289,789 AAPs. AAP as a proportion of total booked consultations was more frequent in dogs (18.8%, 95% confidence interval, CI, 18.2-19.4) than cats (17.5%, 95% CI 16.9-18.1). Prescription of topical antimicrobial agents was more frequent in dogs (7.4%, 95% CI 7.2-7.7) than cats (3.2%, 95% CI 3.1-3.3), whilst prescription of systemic antimicrobial agents was more frequent in cats (14.8%, 95% CI 14.2-15.4) than dogs (12.2%, 95% CI 11.7-12.7). A decreasing temporal pattern was identified for prescription of systemic antimicrobial agents in dogs and cats. Premises which prescribed antimicrobial agents frequently for dogs also prescribed frequently for cats. AAP was most frequent during pruritus consultations in dogs and trauma consultations in cats. Clavulanic acid potentiated amoxicillin was the most frequently prescribed antimicrobial agent in dogs (28.6% of prescriptions, 95% CI 27.4-29.8), whereas cefovecin, a third generation cephalosporin, was the most frequently prescribed antimicrobial agent in cats (36.2%, 95% CI 33.9-38.5). This study demonstrated patterns in AAP over time and for different conditions in a population of companion animals in the United Kingdom., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)