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Key factors such as stage of lactation, parity, and body fat reserves have been associated with the digital cushion thickness (DCT), however, there are discrepancies between the results of previously published studies. The objective of this study was to examine the association of stage of lactation, body fat reserves, parity, and lesion incidence with DCT in a large cohort of intensively monitored cows. Across 4 UK farms, 2,352 cows were prospectively enrolled and assessed at 4 time points: before calving (T1-Precalving), immediately after calving (T2-Calving), in early lactation (T3-Early), and in late lactation (T4-Late). At each time point, BCS was recorded, the presence of sole lesions (sole ulcers and sole hemorrhage) and white line lesions was assessed by veterinarians, and an ultrasound image was taken to retrospectively measure the backfat thickness (BFT) in the pelvic region and the digital cushion on the hind left lateral claw. Mixed effects multivariable linear regression models, with the cow as a random effect, were fit to examine the association between the explanatory variables and DCT. The explanatory variables tested were farm, parity, stage of lactation, BCS, BFT, height, the presence of a lesion at the time of measurement, the chronicity of a lesion during early lactation, the predicted maximum daily milk yield, and the rate of milk production rise in early lactation. Stage of lactation and farm were both associated with DCT; however, an interaction was present, and this DCT pattern of change was farm-dependent. Two distinct patterns emerged; one indicated the nadir to occur shortly after calving, the other indicated the nadir to occur during early lactation. Neither BFT nor BCS were significantly associated with DCT. Heifers displayed thinner digital cushions compared with multiparous cows; however, this effect was dependent on the stage of lactation, with heifers having a thinner digital cushion up until late lactation, by which time DCT was commensurate with multiparous animals. Sole lesions and white line lesions at the time of measurement were associated with DCT (sole lesion: estimate = -0.07 mm, 95% CI = -0.14-0.00; white line lesion: estimate = 0.28 mm, 95% CI = 0.15-0.42)., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Digital dermatitis (DD) is a polybacterial disease endemic to most UK dairy farms. It poses a major financial and welfare threat and is characterized by high incidence and recurrence rates. We aimed to investigate the association between the UK EBV for resistance to digital dermatitis, the digital dermatitis index (DDI), and the frequency of DD, heel horn erosion (HHE), and interdigital hyperplasia (IH) in a population of Holstein dairy cows. We enrolled and genotyped 2,352 cows from 4 farms in a prospective cohort study. Foot lesion records were recorded by veterinary surgeons for each animal at 4 time points during a production cycle, starting at approximately 2 mo before calving and ending in late lactation. Importantly, these records were not used in the calculation of the DDI. Lesion records were matched to the animal's own DDI (n = 2,101) and their sire's DDI (n = 1,812). Digital dermatitis index values in our study population ranged from -1.41 to +1.2 and were transformed to represent distance from the mean expressed in SD. The relationship between the DDI and the presence of DD was investigated using a logistic regression model, with farm, parity, and a farm-parity interaction fitted as covariates. A multivariable logistic regression model was fitted to evaluate the relationship between HHE and DDI with farm fitted as a covariate. Finally, a univariable logistic regression model with DDI as explanatory variable was used to investigate the relationship between IH and DDI. The odds ratio of an animal being affected by DD was 0.69 for 1 SD increase in the animal's DDI (95% CI = 0.63-0.76). The odds of HHE and IH were 0.69 (95% CI = 0.62-0.76) and 0.58 (95% CI = 0.49-0.68) respectively for 1 SD increase in DDI. The adjusted probability of DD was 32% (95% CI = 27-36%) for cows with mean DDI value of 0, while it was 24% (95% CI = 20-29%) in cows with a DDI value of +1. Sire DDI breeding values were standardized in the same way and then binned into terciles creating an ordinal variable representing bulls of high, medium, and low genetic merit for DD resistance. The daughters of low genetic merit bulls were at 2.05 (95% CI = 1.60-2.64), 1.96 (95% CI = 1.53-2.50), and 2.85 (95% CI = 1.64-5.16) times greater odds of being affected by DD, HHE, and IH, respectively, compared with the daughters of high genetic merit bulls. The results of this study highlight the potential of digital dermatitis genetic indexes to aid herd management of DD, and suggest that breeding for resistance to DD, alongside environmental and management control practices, could reduce the prevalence of the disease., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Foot characteristics have been linked to the development of sole lesions (sole hemorrhage and sole ulcers) and white line lesions, also known as claw horn disruption lesions (CHDL). The objective of this study was to examine the association of claw anatomy and sole temperature with the development of CHDL. A cohort of 2,352 cows was prospectively enrolled from 4 UK farms and assessed at 3 time points: before calving (T1-precalving), immediately after calving (T2-calving), and in early lactation. At each time point body condition score was recorded, a thermography image of each foot was taken for sole temperature measurement, the presence of CHDL was assessed by veterinary surgeons, and an ultrasound image was taken to retrospectively measure the digital cushion and sole horn thickness. Additionally, at the postcalving time point, foot angle and heel depth were recorded. Four multivariable logistic regression models were fit to separately examine the relationship of precalving and postcalving explanatory variables with the development of either white line lesions or sole lesions. Explanatory variables tested included digital cushion thickness, sole horn thickness, sole temperature, foot angle, and heel depth. Farm, parity, body condition score, and presence of lesion at the time of measurement were also included in the models. A thicker digital cushion shortly after calving was associated with decreased odds of cows developing sole lesions during early lactation (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.65-0.84). No association was found between digital cushion thickness and development of white line lesions. Sole temperature after calving was associated with increased odds of the development of sole lesions (OR: 1.03, 95% CI: 1.02-1.05), and sole temperature before and after calving was associated with the development of white line lesions (T1-precalving OR: 1.04, 95% CI: 1.01-1.07; T2-calving OR: 0.96, 95% CI: 0.93-0.99). Neither foot angle nor heel depth was associated with the development of either lesion type. However, an increased sole horn thickness after calving reduced the odds of cows developing sole lesions during early lactation (OR: 0.88, 95% CI: 0.83-0.93), highlighting the importance of maintaining adequate sole horn when foot trimming. Before calving, animals with a lesion at the time of measurement and a thicker sole were more likely to develop a sole lesion (OR: 1.23, 95% CI: 1.09-1.40), compared with those without a sole lesion. The results presented here suggest that white line and sole lesions may have differing etiopathogenesis. Results also confirm the association between the thickness of the digital cushion and the development of sole lesions, highlight the association between sole horn thickness and sole lesions, and challenge the potential importance of foot angle and heel depth in the development of CHDL., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Abstract: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The NASA Perseverance rover discovered light-toned float rocks scattered across the surface of Jezero crater that are particularly rich in alumina ( ~ 35 wt% Al 2 O 3 ) and depleted in other major elements (except silica). These unique float rocks have heterogeneous mineralogy ranging from kaolinite/halloysite-bearing in hydrated samples, to spinel-bearing in dehydrated samples also containing a dehydrated Al-rich phase. Here we describe SuperCam and Mastcam-Z observations of the float rocks, including the first in situ identification of kaolinite or halloysite on another planet, and dehydrated phases including spinel and apparent partially dehydroxylated kaolinite. The presence of spinel in these samples is likely detrital in origin, surviving kaolinitization, pointing to an ultramafic origin. However, the association of low hydration with increased Al 2 O 3 abundances suggests heating-induced dehydration which could have occurred during the lithification or impact excavation of these rocks. Given the orbital context of kaolinite-bearing megabreccia in the Jezero crater rim, we propose an origin for these rocks involving intense aqueous alteration of the parent material, followed by dehydration/lithification potentially through impact processes, and dispersion into Jezero crater through flood or impact-related processes., Competing Interests: Competing interestsThe authors declare no competing interests. C. Bedford is an Editorial Board Member for Communications Earth & Environment, but was not involved in the editorial review of, nor the decision to publish this article., (© The Author(s) 2024.)

Introduction: Evidence suggests that standards for resistance of furniture to ignition may lead to an increase in use of chemical flame retardants (CFRs). This is motivating the development of new approaches that maintain high levels of fire safety while facilitating a reduction in use of CFRs. However, reconciling potential fire risk with use of CFRs in relation to specific policy objectives is challenging., Objectives: To inform the development of a new policy in the UK for the fire safety of furniture, we developed for domestic furniture quantitative models of fire risk and potential for CFR exposure. We then combined the models to determine if any lower fire risk, higher CFR exposure categories of furniture were identifiable., Methods: We applied a novel mixed-methods approach to modelling furniture fire risk and CFR exposure in a data-poor environment, using literature-based concept mapping, qualitative research, and data visualisation methods to generate fire risk and CFR exposure models and derive furniture product rankings., Results: Our analysis suggests there exists a cluster of furniture types including baby and infant products and pillows that have comparable overall properties in terms of lower fire risk and higher potential for CFR exposure., Discussion: There are multiple obstacles to reconciling fire risk and CFR use in furniture. In particular, these include a lack of empirical data that would allow absolute fire risk and exposure levels to be quantified. Nonetheless, it seems that our modelling method can potentially yield meaningful product clusters, providing a basis for further research., Competing Interests: PW declares they are a self-employed consultant who provides research, training, and editorial services on a contracted basis for industry, NGO, academic, and publishing clients. Given the controversial nature of the issues researched in this project, the way the work is received could affect their prospects for securing future contracts in this area. However, they do not identify any specific financial interests that would be directly affected at this time. For non-financial interests, they declare involvement in environmental advocacy for over 15 years and being motivated by a perceived need for significant improvement in identification and management of potential risks to health posed by the environment in which humans live. They have written several papers and held public positions, such as developing and/or signing consensus statements, about the need for improved regulation and scientific assessment of chemical substances with flame retardants as an example. They are actively involved with NGOs, particularly in the UK, who are advocating for reforms to chemical regulation. Being prominently involved as a Research Fellow in the Evidence-Based Toxicology Collaboration, their views could be perceived as upholding that organisation’s views. They are also Editor-in-Chief of Evidence-Based Toxicology, a new journal concerned with promoting improved research and publishing practices in toxicology and environmental health. While these financial and non-financial interests are pertinent to the manuscript, PW does not believe them to have compromised the integrity of the work undertaken. SW declares scientific consultancy services in fields unrelated to the topic of research in this manuscript. The way the work is received could affect their prospects of future employment. CB declares employment at the University of Central Lancashire in the Centre for Fire and Hazards Sciences as part of a team who examine the toxicity of flammable materials. CB is also a trade union representative at the University. As a result of previous work in their current role, CB declares an awareness of the potential hazards presented by both flammable materials and flame retardants, and the belief that it is important to accurately assess hazards and strive to protect people from them as much as possible. They do not think that this conviction has affected their ability to contribute objectively to this work. NB declares employment by Oakdene Hollins at the time the research was carried out. Oakdene Hollins is a sustainability consultancy that works with private and public sector clients on reducing their environmental impacts. SH declares being an academic researcher. Given the controversial nature of the issues we have researched in this project, the way the work is received could affect their prospects for securing future research grants and contracts, as well external consultancy work in this area. However, they cannot identify any specific financial interests that would be directly affected at this time. For non-financial interests, their extensive previous research into human exposure to a wide range of chemical contaminants including flame retardants inherently influences the submitted publication. They declare being a current member of the UK government’s Hazardous Substances Advisory Committee; while this manuscript may be perceived as reflecting the views of this committee, it has not to date involved consideration of human exposure to flame retardants and moreover SH’s views are purely their own and not those of the committee. While these financial and non-financial interests are pertinent to the manuscript, SH does not believe them to have compromised the integrity of the work undertaken. NJ declares employment as a Post Doctoral Researcher at the University of Central Lancashire at the time the research was carried out. TK declares they are currently employed by the Department for Business and Trade (formerly the Department for Business, Energy, and Industrial Strategy at the time this research was completed), and that they commissioned this work on behalf of the Office for Product Safety and Standards under the science division (Research, Evidence and Dissemination team) within OPSS. They were involved in setting the objectives and the design of the research. TK’s role in this context was to provide scientific and technical advice to policy makers, and they were not themselves a decision-maker or policy lead. As a civil servant they state they are impartial to the findings of the research, and that the research does not necessarily represent the views of the department. DN declares being employed by OPSS during the conduct of the study, as Head of the Science Strategy team overseeing research projects in the science division (Research, Evidence and Dissemination team) within OPSS. DN’s role in this context was to provide scientific and technical advice to policy makers, and they were not themselves a decision-maker or policy lead. EP declares employment by Oakdene Hollins at the time the research was carried out. Oakdene Hollins is a sustainability consultancy that works with private and public sector clients on reducing their environmental impacts. EW declares employment by the University of Central Lancashire at the time the research was carried out. RH declares employment as a Professor of Chemistry and Fire Science by the University of Central Lancashire since 2007. They do not have any secondary employment, consultancy, board membership, patents or patent applications. They have received research funding from external organisations: in 2018, £15,000 by Silentnight Beds Ltd., to undertake four large scale fire tests and assess the smoke toxicity; in 2019, £161,000 from Innovate UK and Silentnight Beds Ltd., to support a Knowledge Transfer Partnership aimed at helping Silentnight reduce their fire retardant use, the smoke toxicity, and the recyclability of their products, in order to improve their access to the wider mainland European market (Silentnight Beds had no involvement in the current BEIS project, nor in the authorship of this paper); funding from Fire Safe Europe to support a PhD student investigating smoke toxicity of construction products; and funding from the Construction Products Group, Europe to develop fire protective coatings for structural steel. RH has also supported their colleague Prof Anna Stec in their role as an expert witness to the United Kingdom’s Grenfell Tower Inquiry, and is a member of the BEIS Expert Advisory Panel for the revision of the English Furniture Flammability Regulations. RH does not believe they have any interests that compete with those of the research described in the manuscript., (Copyright: © 2023 Whaley et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sole hemorrhage and sole ulcers, referred to as sole lesions, are important causes of lameness in dairy cattle. We aimed to compare the serum metabolome of dairy cows that developed sole lesions in early lactation with that of cows that remained unaffected. We prospectively enrolled a cohort of 1,169 Holstein dairy cows from a single dairy herd and assessed animals at 4 time points: before calving, immediately after calving, early lactation, and late lactation. Sole lesions were recorded by veterinary surgeons at each time point, and serum samples were collected at the first 3 time points. Cases were defined by the presence of sole lesions in early lactation and further subdivided by whether sole lesions had been previously recorded; unaffected controls were randomly selected to match cases. Serum samples from a case-control subset of 228 animals were analyzed with proton nuclear magnetic resonance spectroscopy. Spectral signals, corresponding to 34 provisionally annotated metabolites and 51 unlabeled metabolites, were analyzed in subsets relating to time point, parity cohort, and sole lesion outcome. We used 3 analytic methods (partial least squares discriminant analysis, least absolute shrinkage and selection operator regression, and random forest) to determine the predictive capacity of the serum metabolome and identify informative metabolites. We applied bootstrapped selection stability, triangulation, and permutation to support the inference of variable selection. The average balanced accuracy of class prediction ranged from 50 to 62% depending on the subset. Across all 17 subsets, 20 variables had a high probability of being informative; those with the strongest evidence of being associated with sole lesions corresponded to phenylalanine and 4 unlabeled metabolites. We conclude that the serum metabolome, as characterized by proton nuclear magnetic resonance spectroscopy, does not appear able to predict sole lesion presence or future development of lesions. A small number of metabolites may be associated with sole lesions although, given the poor prediction accuracies, these metabolites are likely to explain only a small proportion of the differences between affected and unaffected animals. Future metabolomic studies may reveal underlying metabolic mechanisms of sole lesion etiopathogenesis in dairy cows; however, the experimental design and analysis need to effectively control for interanimal and extraneous sources of spectral variation., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Lameness in dairy cattle is primarily caused by foot lesions including the claw horn lesions (CHL) of sole haemorrhage (SH), sole ulcers (SU), and white line disease (WL). This study investigated the genetic architecture of the three CHL based on detailed animal phenotypes of CHL susceptibility and severity. Estimation of genetic parameters and breeding values, single-step genome-wide association analyses, and functional enrichment analyses were performed., Results: The studied traits were under genetic control with a low to moderate heritability. Heritability estimates of SH and SU susceptibility on the liability scale were 0.29 and 0.35, respectively. Heritability of SH and SU severity were 0.12 and 0.07, respectively. Heritability of WL was relatively lower, indicating stronger environmental influence on the presence and development of WL than the other two CHL. Genetic correlations between SH and SU were high (0.98 for lesion susceptibility and 0.59 for lesion severity), whereas genetic correlations of SH and SU with WL also tended to be positive. Candidate quantitative trait loci (QTL) were identified for all CHL, including some on Bos taurus chromosome (BTA) 3 and 18 with potential pleiotropic effects associated with multiple foot lesion traits. A genomic window of 0.65 Mb on BTA3 explained 0.41, 0.50, 0.38, and 0.49% of the genetic variance for SH susceptibility, SH severity, WL susceptibility, and WL severity, respectively. Another window on BTA18 explained 0.66, 0.41, and 0.70% of the genetic variance for SH susceptibility, SU susceptibility, and SU severity, respectively. The candidate genomic regions associated with CHL harbour annotated genes that are linked to immune system function and inflammation responses, lipid metabolism, calcium ion activities, and neuronal excitability., Conclusions: The studied CHL are complex traits with a polygenic mode of inheritance. Most traits exhibited genetic variation suggesting that animal resistance to CHL can be improved with breeding. The CHL traits were positively correlated, which will facilitate genetic improvement for resistance to CHL as a whole. Candidate genomic regions associated with lesion susceptibility and severity of SH, SU, and WL provide insights into a global profile of the genetic background underlying CHL and inform genetic improvement programmes aiming at enhancing foot health in dairy cattle., (© 2023. The Author(s).)

Sole hemorrhage and sole ulcers, referred to as sole lesions, are important causes of lameness in dairy cattle. The objective of this study was to estimate the genetic parameters of a novel trait reflecting how well cows recovered from sole lesions and the genetic correlation of this trait with overall susceptibility to sole lesions. A cohort of Holstein dairy cows was prospectively enrolled on 4 farms and assessed at 4 timepoints: before calving, immediately after calving, in early lactation, and in late lactation. At each timepoint, sole lesions were recorded at the claw level by veterinary surgeons and used to define 2 binary traits: (1) susceptibility to sole lesions-whether animals were affected with sole lesions at least once during the study or were unaffected at every assessment, and (2) sole lesion recovery-whether sole lesions healed between early and late lactation. Animals were genotyped and pedigree details extracted from the national database. Analyses were conducted with BLUPF90 software in a single-step framework; genetic parameters were estimated from animal threshold models using Gibbs sampling. The genetic correlation between both traits was approximated as the correlation between genomic estimated breeding values, adjusting for their reliabilities. A total of 2,025 animals were used to estimate the genetic parameters of sole lesion susceptibility; 44% of animals recorded a sole lesion at least once during the study period. The heritability of sole lesion susceptibility, on the liability scale, was 0.25 (95% highest density interval = 0.16-0.34). A total of 498 animals were used to estimate the genetic parameters of sole lesion recovery; 71% of animals had recovered between the early and late lactation assessments. The heritability of sole lesion recovery, on the liability scale, was 0.27 (95% highest density interval = 0.02-0.52). The approximate genetic correlation between each trait was -0.11 (95% confidence interval = -0.20 to -0.02). Our results indicate that recovery from sole lesions is heritable. If this finding is corroborated in further studies, it may be possible to use selective breeding to reduce the frequency of chronically lame cows. As sole lesion recovery appears to be weakly genetically related to sole lesion susceptibility, successful genetic improvement of sole lesion recovery would benefit from selection on this trait directly., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: The study aim was to characterise issues faced by farmers and veterinary surgeons when making end-of-life decisions for dairy cattle., Methods: Online surveys were distributed to British dairy farmers and veterinary surgeons for 20 weeks from November 2020., Results: There were 83 responses (37 farmers, 46 veterinary surgeons). Among youngstock, the risk of unassisted/natural death (2.6% ± 0.3%) was almost double the risk of euthanasia (1.4% ± 0.3%; p = 0.003). The opposite, however, was true in the milking herd: the risk of euthanasia (2.3% ± 0.3%) was greater than unassisted/natural death (1.6% ± 0.2%; p = 0.05). A fallen stock collector (62%) typically performed euthanasia and most farms (66%) did not have anyone trained to perform euthanasia. Most deaths within the milking herd were attributed to 'unknown or not recorded' (median 15% of deaths). The factors that farmers most frequently reported as strongly influencing their decision of when to euthanase an animal relative to the onset of disease were 'failure to respond to treatment' (89%), 'veterinary advice' (89%) and 'severity of disease' (88%). On average, veterinarians had moderate or high confidence that 60% of dairy farm clients 'are performing euthanasia in a timely manner so as to prevent unnecessary suffering'. Veterinary surgeons had variable agreement on the time to euthanasia for various conditions., Conclusions: The survey highlighted end-of life decision-making successes and areas for improvement on dairy farms. An evidence-based, decision-support framework may help end-of-life decision-making, particularly for complex diseases., Competing Interests: The authors declare they have no conflicts of interest., (© 2022 The Authors. Veterinary Record Open published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

The digital cushion is linked to the development of claw horn lesions (CHL) in dairy cattle. The objectives of this study were to (1) estimate genetic parameters for digital cushion thickness (DCT), (2) estimate the genetic correlation between DCT and CHL, and (3) identify candidate genes associated with DCT. A cohort of 2,352 Holstein dairy cows were prospectively enrolled on 4 farms and assessed at 4 time points: before calving, immediately after calving, in early lactation, and in late lactation. At each time point, CHL was recorded by veterinary surgeons, and ultrasonographic images of the digital cushion were stored and retrospectively measured at 2 anatomical locations. Animals were genotyped and pedigree details extracted from the national database. Genetic parameters were estimated following a single-step approach implemented in AIREMLF90. Four traits were analyzed: the 2 DCT measurements, sole lesions (sole hemorrhage and sole ulcers), and white line lesions. All traits were analyzed with univariate linear mixed models; bivariate models were fit to estimate the genetic correlation between traits within and between time points. Single-marker and window-based genome-wide association analyses of DCT traits were conducted at each time point; candidate genes were mapped near (<0.2 Mb) or within the genomic markers or windows with the largest effects. Heritability estimates of DCT ranged from 0.14 to 0.44 depending on the location of DCT measurement and assessment time point. The genetic correlation between DCT and sole lesions was generally negative, notably between DCT immediately after calving and sole lesions in early or late lactation, and between DCT in early or late lactation and sole lesion severity in early or late lactation. Digital cushion thickness was not genetically correlated with white line lesions. A polygenic background to DCT was found; genes associated with inflammation, fat metabolism, and bone development were mapped near or within the top markers and windows. The moderate heritability of DCT provides an opportunity to use selective breeding to change DCT in a population. The negative genetic correlation between DCT and sole lesions at different stages of production lends support to current hypotheses of sole lesion pathogenesis. Highlighted candidate genes provide information regarding the complex genetic background of DCT in Holstein cows, but further studies are needed to explore and corroborate these findings., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: This study aimed to determine the association between the lameness advantage genetic index and four outcomes: sole haemorrhage (SH), sole ulcers (SU), white line lesions (WL), and lameness during mobility scoring., Methods: We enrolled 2352 Holstein cows from four predominantly housed dairy herds in the UK. Cows were mobility scored and foot lesions recorded at four time points from before calving to late lactation. Cows were genotyped and genetic indexes were assigned to each cow following national genetic evaluations. Lameness records and genetic indexes were matched for 2107 cows. Four separate multivariable logistic regression models, which included farm and parity as covariables, were used to quantify the association between the lameness advantage index and whether animals were affected by SH, SU, WL, or lameness., Results: The odds ratios (95% confidence intervals) for one-point increases in the lameness advantage index were 0.79 (0.72-0.86), 0.68 (0.59-0.78), 0.94 (0.84-1.04), and 0.82 (0.74-0.91) for SH, SU, WL, and lameness, respectively. The same trends were present when the sire's lameness advantage index was evaluated in place of the animal's own, although the strength of this association was generally weaker., Conclusion: The lameness advantage index is associated with SH, SU, and lameness, therefore selection on the lameness advantage index could be considered in herds aiming to reduce lameness. Where genomic testing of heifers is not conducted, sire lameness advantage index may still be effective to reduce SH and SU incidence., (© 2022 British Veterinary Association.)

Background: The objective of this study was to investigate the association between (sub)clinical mastitis (CM) in the first 30 days in milk (DIM) and the presence of sole ulcers (SU) later in lactation., Methods: Holstein cows and heifers were examined for presence of sole haemorrhage and SU before calving, in the first 14 days postcalving and in early lactation (after 30 DIM). CM episodes and somatic cell counts (SCC) measurements were obtained from farm records. Multivariable logistic regression was used for data analysis., Results: Odds of SU in early lactation were 2.44 times greater (95% confidence interval [CI] 0.97-5.54) in cows that had CM in the first 30 DIM compared to cows that did not have CM in the first 30 DIM. When cows that had SU precalving or at the calving check were excluded from the dataset, an association of CM in the first 30 DIM with later presence of SU was no longer statistically significant but the same numeric trend still existed (odds ratio [OR] 2.25, 95% CI 0.81-5.34). The odds of SU in early lactation were 1.70 times greater in cows that had high SCC compared to cows that did not have high SCC in the first 100 DIM (95% CI 1.13-2.55)., Conclusion: An association was found between CM in the first 30 DIM and presence of SU in early lactation (after 30 DIM). Elucidating the mechanism behind this relationship could improve our understanding of the aetiopathogenesis of both diseases and lead to new preventive strategies., (© 2022 British Veterinary Association.)

Background: The objective of this study was to evaluate the benefits of administering ketoprofen to cows suffering from active digital dermatitis (DD)., Methods: 158 cows presented with active DD (M1, M2 or M4.1 stage) were randomly allocated to either the control or the treatment group. All cows were treated with topical application of oxytetracycline spray. The treatment group also received an intramuscular injection of ketoprofen (3 mg/kg, Ketofen 10%, Ceva Animal Health). Cows were mobility scored just before they were treated and then again one week later. Information regarding their daily milk production was also collected., Results: Animals in the control group were at 2.57 (95% confidence interval (CI): 0.82-8.01, p = 0.10) times higher odds to be lame at the second evaluation compared to those that received ketoprofen as well. This was a numeric but not statistically significant difference. When only cows that were lame prior to treatment were considered, cows that did not receive ketoprofen were at 20.20 (95% CI: 1.40-291.29, p = 0.03) higher odds of remaining lame week post-treatment comparing to cows that did receive ketoprofen. Freshly calved and lame at enrolment cows in the treatment group produced 58.38 ± 1.85 kg per day the week after treatment comparing to freshly calved and lame at enrolment controls that produced 47.89 ± 1.81 kg per day (p < 0.05)., Conclusion: The addition of ketoprofen in the treatment of active DD lesions may be beneficial for animal welfare and for animal productivity., (© 2021 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Our aims were to (1) determine how interdigital skin temperature (IST), measured using infrared thermography, was associated with different stages of digital dermatitis (DD) lesions and (2) develop and validate models that can use IST measurements to identify cows with an active DD lesion. Between March 2019 and March 2020, infrared thermographic images of hind feet were taken from 2,334 Holstein cows across 4 farms. We recorded the maximum temperature reading from infrared thermographic images of the interdigital skin between the heel bulbs on the hind feet. Pregnant animals were enrolled approximately 1 to 2 mo precalving, reassessed 1 wk after calving, and again at approximately 50 to 100 d postpartum. At these time points, IST and the clinical stage of DD (M-stage scoring system: M1-M4.1) were recorded in addition to other data such as the ambient environmental temperature, height, body condition score, parity, and the presence of other foot lesions. A mixed effect linear regression model with IST as the dependent variable was fitted. Interdigital skin temperature was associated with DD lesions; compared to healthy feet, IST was highest in feet with M2 lesions, followed by M1 and M4.1 lesions. Subsequently, the capacity of IST measurements to detect the presence or absence of an active DD lesion (M1, M2, or M4.1) was explored by fitting logistic regression models, which were tested using 10-fold validation. A mixed effect logistic regression model with the presence of active DD as the dependent variable was fitted first. The average area under the curve for this model was 0.80 when its ability to detect presence of active DD was tested on 10% of the data that were not used for the model's training; an average sensitivity of 0.77 and an average specificity of 0.67 was achieved. This model was then restricted so that only explanatory variables that could be practically recorded in a nonresearch, external setting were included. Validation of this model demonstrated an average area under the curve of 0.78, a sensitivity of 0.88, and a specificity of 0.66 for 1 of the time points (precalving). Lower sensitivity and specificity were achieved for the other 2 time points. Our study adds further evidence to the relationship between DD and foot skin temperature using a large data set with multiple measurements per animal. Additionally, we highlight the potential for infrared thermography to be used for routine on-farm diagnosis of active DD lesions., (Copyright © 2021 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Objectives : Research on dissociative symptomatology in the context of Posttraumatic Stress Disorder (PTSD) has been gaining traction, with dissociation being studied as a set of complex symptoms following trauma exposure and as a specific subtype of PTSD. The aims of this review are to summarize the literature as it stands, examine the efficacy of existing interventions in treating dissociative symptomatology within the context of PTSD, and offer potential suggestions for future research. Methods : A systematic approach was taken to locate empirical studies on PTSD that included dissociation as an outcome in the PubMed, Scopus, and PsycINFO databases. Recent experimental designs with adult subjects (18+ years) in the English language were included, yielding 103 potentially eligible studies. Thirty-three full-text articles were screened with 17 articles meeting criteria for inclusion in the systematic review. Results : Designs, populations, treatments, and inventories were extremely diverse. Most therapies did not target dissociation specifically, although the results of this review suggest that PTSD patients who experience dissociative symptoms could benefit from trauma-focused treatments, which often significantly reduced dissociative and trauma-related symptoms. Conclusion : Future work should consider the evaluation of dissociation as a unique outcome to gain understanding about the nature of traumatic stress and to develop treatment options for its many presentations. The current literature displays limited generalizability to the treatment of individuals with high dissociation, which is a line of inquiry that should be explored. More RCTs are needed.

While debates have raged over the relationship between trance and rock art, unambiguous evidence of the consumption of hallucinogens has not been reported from any rock art site in the world. A painting possibly representing the flowers of Datura on the ceiling of a Californian rock art site called Pinwheel Cave was discovered alongside fibrous quids in the same ceiling. Even though Native Californians are historically documented to have used Datura to enter trance states, little evidence exists to associate it with rock art. A multianalytical approach to the rock art, the quids, and the archaeological context of this site was undertaken. Liquid chromatography-mass spectrometry (LC-MS) results found hallucinogenic alkaloids scopolamine and atropine in the quids, while scanning electron microscope analysis confirms most to be Datura wrightii Three-dimensional (3D) analyses of the quids indicate the quids were likely masticated and thus consumed in the cave under the paintings. Archaeological evidence and chronological dating shows the site was well utilized as a temporary residence for a range of activities from Late Prehistory through Colonial Periods. This indicates that Datura was ingested in the cave and that the rock painting represents the plant itself, serving to codify communal rituals involving this powerful entheogen. These results confirm the use of hallucinogens at a rock art site while calling into question previous assumptions concerning trance and rock art imagery., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Heterolithic, boulder-containing, pebble-strewn surfaces occur along the lower slopes of Aeolis Mons ("Mt. Sharp") in Gale crater, Mars. They were observed in HiRISE images acquired from orbit prior to the landing of the Curiosity rover. The rover was used to investigate three of these units named Blackfoot, Brandberg, and Bimbe between sols 1099 and 1410. These unconsolidated units overlie the lower Murray formation that forms the base of Mt. Sharp, and consist of pebbles, cobbles and boulders. Blackfoot also overlies portions of the Stimson formation, which consists of eolian sandstone that is understood to significantly postdate the dominantly lacustrine deposition of the Murray formation. Blackfoot is elliptical in shape (62 × 26 m), while Brandberg is nearly circular (50 × 55 m), and Bimbe is irregular in shape, covering about ten times the area of the other two. The largest boulders are 1.5-2.5 m in size and are interpreted to be sandstones. As seen from orbit, some boulders are light-toned and others are dark-toned. Rover-based observations show that both have the same gray appearance from the ground and their apparently different albedos in orbital observations result from relatively flat sky-facing surfaces. Chemical observations show that two clasts of fine sandstone at Bimbe have similar compositions and morphologies to nine ChemCam targets observed early in the mission, near Yellowknife Bay, including the Bathurst Inlet outcrop, and to at least one target (Pyramid Hills, Sol 692) and possibly a cap rock unit just north of Hidden Valley, locations that are several kilometers apart in distance and tens of meters in elevation. These findings may suggest the earlier existence of draping strata, like the Stimson formation, that would have overlain the current surface from Bimbe to Yellowknife Bay. Compositionally these extinct strata could be related to the Siccar Point group to which the Stimson formation belongs. Dark, massive sandstone blocks at Bimbe are chemically distinct from blocks of similar morphology at Bradbury Rise, except for a single float block, Oscar (Sol 516). Conglomerates observed along a low, sinuous ridge at Bimbe consist of matrix and clasts with compositions similar to the Stimson formation, suggesting that stream beds likely existed nearly contemporaneously with the dunes that eventually formed the Stimson formation, or that they had the same source material. In either case, they represent a later pulse of fluvial activity relative to the lakes associated with the Murray formation. These three units may be local remnants of infilled impact craters (especially circular-shaped Brandberg), decayed buttes, patches of unconsolidated fluvial deposits, or residual mass-movement debris. Their incorporation of Stimson and Murray rocks, the lack of lithification, and appearance of being erosional remnants suggest that they record erosion and deposition events that post-date the exposure of the Stimson formation.

Objectives: Posttraumatic stress disorder (PTSD) and pain often co-occur, introducing clinical challenges and economic burden. Psychological treatments are considered effective for each condition, yet it is not known which therapies have the potential to concurrently address PTSD and pain-related symptoms., Materials and Methods: To conduct a systematic review and meta-analysis, databases were searched for articles published between January 2007 and December 2017 describing results from clinical trials of interventions addressing PTSD and pain-related symptoms in adults. Two independent reviewers finalized data extraction and risk of bias assessments. A random-effects model was used for meta-analysis and to calculate pooled and subgroup effect sizes (ESs) of psychological-only (single modality) and multimodal interventions., Results: Eighteen trials (7 uncontrolled, 11 randomized controlled trials, RCTs), totaling 1583 participants, were included in the systematic review. RCT intervention types included exposure-based, cognitive-behavioral, and mindfulness-based therapies. Data from 10 RCTs (N=1, 35) were available for meta-analysis, which demonstrated moderate effect for reduced PTSD severity (ES=-0.55, confidence interval [CI]: -0.83, -0.26) and nonsignificant effect for pain intensity (ES=-0.14, CI: -0.43, 0.15) and pain interference (ES=-0.07, CI: -0.35, 0.20) outcomes. Findings from uncontrolled trials supported meta-analytic results from RCTs. Using GRADE assessment, the quality of evidence was deemed as moderate for RCTs and low for non-RCTs., Discussion: Findings indicated that the majority of the interventions appeared to have a greater impact on reducing PTSD rather than pain-related symptoms. There remains a need to further develop interventions that consistently impact PTSD and pain-related outcomes when these 2 conditions co-occur.

The Grenfell Tower fire in central London, started within a flat, engulfed the whole 24 storey building in flames, killed 72 people and spread toxic effluent via the plume and particulate deposits. Soil samples from 6 locations up to 1,2 km from the Tower, together with semi-burnt fire debris and char samples, were collected 1 and 6 months after the fire. Additionally, dust samples and condensates were collected from a flat 160 m away from the Tower after 17 months. Samples were analysed for common potentially toxic components of fire effluents and synthetic vitreous fibres. Samples collected within 140 m of the Tower showed, amongst other toxicants, polychlorinated dibenzo-p-dioxin concentrations 60 times greater than UK urban reference soil levels; benzene levels were 40 times greater; levels of 6 key polycyclic aromatic hydrocarbons (PAHs) were approximately 160 times greater. PAHs levels are approximately 20 times greater than those reported from nearby Hyde Park before the fire. To explain the presence of these pyrogenic contaminants char and partially burnt debris were also collected and analysed. Benzene, PAHs, isocyanates and phosphorus flame retardants were found. Hydrogen cyanide and synthetic vitreous fibres were present in both soil and debris. Particulate and pyrogenic contamination in the immediate vicinity is clearly evident, and may have leached out of fire debris, char and dust. Further analysis of the area around the Tower is necessary to understand potential health risks., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Bovine herpesvirus-4 (BoHV-4) and bovine viral diarrhea virus (BVDV) infect the uterus of cattle, often resulting in reduced fertility, or abortion of the fetus, respectively. Here, exposure of primary bovine endometrial cells to BoHV-4 or BVDV modulated the production of inflammatory mediators. Viral pathogen-associated molecular patterns (PAMPs) are detected via pattern-recognition receptors (PRRs). However, the relative contribution of specific PRRs to innate immunity, during viral infection of the uterus, is unclear. Endometrial epithelial and stromal cells constitutively express the PRR Toll-like receptor (TLR)-3, but, the status of retinoic acid-inducible gene I (RIG-I), a sensor of cytosolic nucleic acids, is unknown. Primary endometrial epithelial and stromal cells had low expression of RIG-I, which was increased in stromal cells after 12 h transfection with the TLR3 ligand Poly(I:C), a synthetic analog of double-stranded RNA. Furthermore, short interfering RNA targeting TLR3 , or interferon (IFN) regulatory transcription factor 3, an inducer of type I IFN transcription, reduced Poly(I:C)-induced RIG-I protein expression and reduced inflammatory mediator secretion from stromal cells. We conclude that antiviral defense of endometrial stromal cells requires coordinated recognition of PAMPs, initially via TLR3 and later via inducible RIG-I.

Human cytomegalovirus (HCMV) strains that have been passaged in vitro rapidly acquire mutations that impact viral growth. These laboratory-adapted strains of HCMV generally exhibit restricted tropism, produce high levels of cell-free virus, and develop susceptibility to natural killer cells. To permit experimentation with a virus that retained a clinically relevant phenotype, we reconstructed a wild-type (WT) HCMV genome using bacterial artificial chromosome technology. Like clinical virus, this genome proved to be unstable in cell culture; however, propagation of intact virus was achieved by placing the RL13 and UL128 genes under conditional expression. In this study, we show that WT-HCMV produces extremely low titers of cell-free virus but can efficiently infect fibroblasts, epithelial, monocyte-derived dendritic, and Langerhans cells via direct cell-cell transmission. This process of cell-cell transfer required the UL128 locus, but not the RL13 gene, and was significantly less vulnerable to the disruptive effects of IFN, cellular restriction factors, and neutralizing antibodies compared with cell-free entry. Resistance to neutralizing antibodies was dependent on high-level expression of the pentameric gH/gL/gpUL128-131A complex, a feature of WT but not passaged strains of HCMV., Competing Interests: The authors declare no conflict of interest.

Voltage-gated Ca(2+) (CaV) channels enable Ca(2+) influx in response to membrane depolarization. CaV2.1 channels are localized to the presynaptic membrane of many types of neurons where they are involved in triggering neurotransmitter release. Several signaling proteins have been identified as important CaV2.1 regulators including protein kinases, G-proteins and Ca(2+) binding proteins. Recently, we discovered that leucine rich repeat kinase 2 (LRRK2), a protein associated with inherited Parkinson's disease, interacts with specific synaptic proteins and influences synaptic transmission. Since synaptic proteins functionally interact with CaV2.1 channels and synaptic transmission is triggered by Ca(2+) entry via CaV2.1, we investigated whether LRRK2 could impact CaV2.1 channel function. CaV2.1 channel properties were measured using whole cell patch clamp electrophysiology in HEK293 cells transfected with CaV2.1 subunits and various LRRK2 constructs. Our results demonstrate that both wild type (wt) LRRK2 and the G2019S LRRK2 mutant caused a significant increase in whole cell Ca(2+) current density compared to cells expressing only the CaV2.1 channel complex. In addition, LRRK2 expression caused a significant hyperpolarizing shift in voltage-dependent activation while having no significant effect on inactivation properties. These functional changes in CaV2.1 activity are likely due to a direct action of LRRK2 as we detected a physical interaction between LRRK2 and the β3 CaV channel subunit via coimmunoprecipitation. Furthermore, effects on CaV2.1 channel function are dependent on LRRK2 kinase activity as these could be reversed via treatment with a LRRK2 inhibitor. Interestingly, LRRK2 also augmented endogenous voltage-gated Ca(2+) channel function in PC12 cells suggesting other CaV channels could also be regulated by LRRK2. Overall, our findings support a novel physiological role for LRRK2 in regulating CaV2.1 function that could have implications for how mutations in LRRK2 contribute to Parkinson's disease pathophysiology.

Objectives: Previously we have reported that endothelin receptor A and B antagonists elicit differential effects on cerebral blood flow and cellular damage. In summary, endothelin receptor A antagonists restore microcirculation and diminish cellular damage after injury, while endothelin receptor B antagonists had no effect on either parameter. However, what is not known is the effect of either antagonist on behavioral outcome. Therefore, this work was designed to test the effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury (TBI)., Methods: A total of 48 male Sprague-Dawley rats (400-450 g) were used in this study. Four groups (n = 12 per group) were generated as follows: sham operation, trauma+vehicle (0·9% saline), trauma+40 nmol BQ-123 (a selective endothelin receptor A antagonist) and trauma +20 nmol BQ-788 (a selective endothelin receptor B antagonist). All treatments were delivered via intracerebroventricular injection. Trauma was induced using a weight acceleration impact device. Twenty-four hours post-injection animals were tested for 21 days on a radial arm maze task to determine cognitive outcome., Results: Our data indicated that endothelin receptor A antagonism significantly reduced the extent of behavioral deficits following TBI while endothelin receptor B and vehicle injection had no effect., Conclusion: The results suggest that endothelin receptor A, but not endothelin receptor B, antagonism improves behavioral outcome following TBI. Furthermore, these data provide a functional correlate to previously published findings in our laboratory showing that endothelin receptor A antagonism improves both blood flow and cellular outcome following TBI. In a broader sense, this work demonstrates that hypoperfusion following TBI likely contributes to poor outcome following head injury.

Objectives: The purpose of this study was to test the efficacy of a novel endothelin receptor A antagonist on blood flow and behavioral outcome given 30 minutes following traumatic brain injury., Methods: Male Sprague-Dawley rats (400-450 g) were used in this study. All animals were scanned for initial blood flow using arterial spin labeling magnetic resonance imaging (n = 72 total). Half were subjected to traumatic brain injury using a weight acceleration impact device (n = 36 total). Sham operated animals were used as control (n = 36 total). Thirty minutes following traumatic brain injury, animals were given one intravenous injection of vehicle (0·9% saline) or 1·0 mg/kg clazosentan, a novel endothelin receptor A antagonist, for a total of four groups. At 4, 24, and 48 hours post-traumatic brain injury, blood flow determination continued. On the second day post-traumatic brain injury/sham operation, behavioral testing commenced using a radial arm maze to assess cognitive function., Results: Our results indicate that 1·0 mg/kg clazosentan was effective in ameliorating hypoperfusion seen after traumatic brain injury. Saline had no effect. Furthermore, clazosentan treatment was effective in significantly improving behavioral outcome following traumatic brain injury., Conclusion: Collectively, these results indicate that clazosentan, given at 30 minutes post-traumatic brain injury, is effective in improving outcome following injury.

Background: Cancer care is increasingly specialized. Relationships between pancreatic cancer care, mortality and patterns of clinical practice among the full spectrum of patients, including those with irresectable tumours, are not well understood., Methods: A cohort of 782 patients diagnosed prospectively with pancreatic cancer in 29 acute hospitals in England and Wales over 1 year were followed for 2-3 years. The effects of doctors' and hospitals' specialization, indicated by annual patient volumes, on operative mortality rates, survival times, and test and treatment provision were studied. Multiple logistic and Cox regression models were used to control for prognostic factors and treatments, providing adjusted odds and hazard ratios associated with a higher volume of ten patients annually., Results: Patients managed by higher-volume hospitals survived significantly longer (hazard ratio 0.88 (95 per cent confidence interval (c.i.) 0.83 to 0.93); P < 0.001). They were more likely to undergo cytological examination (odds ratio (OR) 1.21 (95 per cent c.i. 1.01 to 1.35)), resection (OR 1.44 (1.17 to 1.79)) and biliary stenting (OR 1.17 (1.02 to 1.34)), and were less likely to have bypass surgery (OR 0.66 (0.55 to 0.78)). Patients of higher-volume doctors were more likely to undergo endoscopic retrograde cholangiopancreatography (OR 1.59 (1.19 to 2.11)), percutaneous transhepatic cholangiography (OR 1.50 (1.12 to 2.00)), laparoscopy (OR 1.81 (1.07 to 3.06)), resection (OR 1.84 (1.29 to 2.61)) and bypass surgery (1.71 (1.25 to 2.33))., Conclusion: Specialization appears to improve survival and to promote more thorough investigation.

Objectives: To measure the geographical variation in prevalence of cardiovascular disease, risk factors, and their control in a nationally representative sample of older British women., Methods: Baseline survey using general practitioner record review, a self completed questionnaire, research nurse interview, and physical examination in a randomly selected sample of women aged 60-79 drawn from 23 towns in England, Scotland, and Wales., Results: Of 7,173 women invited and eligible to participate, information was obtained on 4,286 (60%). One in five women had a doctor diagnosis of any one of myocardial infarction, angina, heart failure, stroke, or peripheral vascular disease. Fifty per cent of women were hypertensive, 12% smoked, and over one quarter were obese. Fifty per cent had a total cholesterol level greater than 6.5 mmol/l, though only 3% had low high density lipoprotein concentrations. Cardiovascular disease prevalence varied by geographical region being highest in Scotland: age adjusted prevalence (95% confidence intervals) 25.0% (21.5% to 28.8%) and lowest in South England: age adjusted prevalence (95% confidence intervals) 15.4% (13.5% to 17.6%). The geographical variations in cardiovascular disease prevalence were attenuated by adjustment for risk factors and socioeconomic position; further adjustment for health service use (as indicated by aspirin or statin use) reduced the differences further. However, variation remained even after full adjustment for these factors: odds ratio (95% confidence intervals) comparing Midlands and Wales to South England 1.15 (0.82 to 1.61) and comparing Scotland to South England 1.53 (1.08 to 2.14). Of women with cardiovascular disease, 12% were current smokers, a third had uncontrolled hypertension, a third were obese, and 90% had a blood cholesterol over 5 mmol/l. Only 41% were taking antiplatelet drugs and 22% were taking a statin., Conclusions: Older British women have a higher prevalence of cardiovascular disease and risk factors than previously documented. The workload consequences of attempting to control risk factors and ensure optimal secondary prevention for older British women are considerable. Geographical variations in cardiovascular disease prevalence in older women are somewhat, but not fully, explained by variations in major risk factors, socioeconomic position, and health service utilisation.

Background: To evaluate specialization in National Health Service (NHS) cancer care, volume-outcome relationships were examined., Methods: This was a cohort study of 1512 patients with oesophageal or gastric cancer in 23 acute NHS hospitals. Outcomes were survival time and operative (30 day) mortality. Multiple regression analysis was performed, adjusted for diagnoses, prognoses and treatments., Results: For oesophageal cancer, the operative mortality rate decreased by 40 per cent (odds ratio 0.60 (95 per cent confidence interval (c.i.) 0.36 to 0.99 per cent); P = 0.047) for each increase of ten patients in doctors' annual surgical caseloads, and the risk of death decreased by 8 per cent (hazard ratio 0.92 (95 per cent c.i. 0.85 to 0.99); P = 0.021) for each increase of ten patients in doctors' annual caseloads. For gastric cancer, the operative mortality rate decreased by 41 per cent (odds ratio 0.59 (95 per cent c.i. 0.32 to 1.07)) for each increase of ten patients in doctors' annual surgical caseloads, and the risk of death decreased by 7 per cent (hazard ratio 0.93 (95 per cent c.i. 0.89 to 0.98); P = 0.009) for each increase of ten patients in hospitals' annual caseloads. Patients of higher-volume doctors were more likely to receive most investigations and treatments, independently of presenting features., Conclusion: The study supports concentration of services for oesophageal and gastric cancers. Specialization of doctors and their teams is at least as important as specialization of hospitals.

Objective: To determine the prevalence of achieving new recommended levels of physical activity, the types of activity involved, and their determinants among elderly British women., Design: National cross sectional survey., Participants: 2341 women aged 60 to 79 from 15 British towns., Main Outcome Measures: Prevalence of subjects achieving recommended levels of physical activity., Results: Over two thirds of the participants were active at new recommended levels. This was mainly achieved through participation in heavy housework. If domestic activities were excluded only 21% were regularly active. Women who participated in brisk walking for at least 2.5 hours per week had reduced odds of being overweight: odds ratio (95% confidence intervals) 0.5 (0.3 to 0.6) after adjustment for other forms of activity, health status, smoking, and socioeconomic position. Participating in at least 2.5 hours of heavy housework was not associated with reduced odds of being overweight 1.1 (0.8 to 1.4). Age, self reported poor health status, coronary heart disease, and respiratory disease were independently associated with reduced odds of participating in all types of activity. In addition participation in brisk walking and physical exercise were less likely in current smokers, those from the lowest socioeconomic class, and those living in the north of the country. Participation in heavy housework was less likely in women reporting depression but was not associated with smoking, socioeconomic class, or area of residence., Conclusions: If new physical activity recommendations, which include domestic activities, are used to assess population levels of physical activity then it seems that the majority of elderly women are sufficiently active. Heavy housework is not associated with reduced levels of being overweight and prospective studies are necessary to demonstrate an independent health benefit of participating in domestic activities.

Background: previous studies of the accuracy of self-reported weight have been criticised for using inadequate methods and have included only young or middle aged adults. Self-report is more likely to be relied upon in both clinical and research practice in older age groups. The cultural pressures that may cause the tendency among younger women to underestimate their weight, particularly when they are overweight, may operate differently in older women., Objective: to determine the accuracy of self-reported weight among older women., Methods: national cross sectional survey of women aged 60-79 from 9 towns across England, Scotland and Wales. Self-reported weight from a participant questionnaire was compared to measured weight at examination., Results: of 2729 women who were invited, 1636 (60%) returned the questionnaire (of whom 1549 gave a self-reported weight) and 1384 (51%) attended for examination (of whom 1381 were weighed). In total there were 1310 (48% of the total invited sample) with complete self-report and measured weight. Self-reported and measured weight were highly correlated (Pearson's correlation coefficient, 0.982 95% confidence interval, 0.979-0.983) and self-reported weight differed from measured weight by only 1.0 kg (95% confidence interval 0.8 kg, 1.1 kg) on average. However, a difference plot, with limits of agreement at -4.0 kg to +6.0 kg (95% confidence intervals: lower limit -4.3 kg, -3.8 kg; upper limit +5.7 kg, +6.2 kg) revealed poor agreement between methods. Obese individuals, in particular, were more likely to underestimate their weight., Conclusions: though self-report of weight by women in their 60s and 70s is highly correlated, at an individual level differences between self-report and measured weight are frequently large. Obese individuals, in particular, tend to underestimate their weight. Self-report of weight should not be relied upon in prospective epidemiological studies or clinical practice when accuracy at the level of the individual is required.

Low dose aspirin is effective, safe, and economical in the secondary prevention of cardiovascular disease. We have found that only one-third of post-menopausal women with cardiovascular disease are using aspirin and that the majority of women who are using aspirin are doing so for primary prevention. Improvements in this area of medical practice are both necessary and feasible.

The recently synthesized compounds 4, 4-bis(difluoramino)-1-nitropiperidine (I), 1,4,4-trinitropiperidine (II), 1,1,4,4-tetranitrocyclohexane (III), 1,1,4, 4-tetrakis(difluoramino)cyclohexane (IV) and 3,3,7, 7-tetrakis(difluora-mino)octahydro-1,5-dinitro-1,5-diazocine (HNFX, V) are being considered as potential energetic materials. The mass spectra of these compounds were studied using electron ionization (EI) mass spectrometry. A collision-induced dissociation (CID) study of the major EI peaks was carried out using a Finnigan TSQ 700 tandem mass spectrometer. The mass fragmentation pathways are constructed and discussed. The decomposition of HNFX (V), under EI, appeared to parallel the thermal decomposition of nitramines where N-NO(2) cleavage is often the first step. However, the two nitramines with a six-membered ring structure (I and II) underwent initial loss of a geminal substituent; loss of a nitramine nitro group was the secondary step. The two cyclohexane structures (III and IV) showed similar initial fragmentation pathways, featuring successive losses of nitro or difluoramino groups. Copyright 2000 John Wiley & Sons, Ltd.

Laccase, purified from Coriolus versicolor, removed pentachlorophenol (PCP) from solution at pH 5, depending on initial PCP concentration and amount of laccase. With 100 units of laccase, 100% of 25 microg ml(-1) PCP and 60% of 200 microg ml(-1) PCP were removed respectively over 72 h. No free chloride was released in the reaction. In reaction with 100 microg PCP, products were primarily polymers (about 80,000 MW) with only 2-3 pg of o- and p-chloranils formed. Polymers were stable to acid hydrolysis and no release of PCP, or other low-molecular-weight products, was detected over several weeks. Laccase has a potential use in the biotreatment of aqueous effluents containing PCP, with polymerised products being removed from solution due to their high molecular weight.

Tracing and treating contacts (partner notification, PN) is a crucial part of the control of sexually transmitted infections but few studies have quantified its outcome. A retrospective national study obtained information from 155 clinics on 1308 patients with gonorrhoea, 59% of all UK patients attending in January to March 1995. These gave 1887 contacts (1:1.5) of whom 621 attended, 75% being found to be infected. The ratio of contacts attending to index patients was 0.5 (621/1260). The ratio was not influenced by gender or ethnicity, but was affected by orientation, being 0.5 for contacts of male heterosexuals, 0.3 for contacts of male homosexuals (P <0.001). PN outcome was less good in metropolitan (0.3) than provincial clinics (0.5), suggesting that further research is necessary on the reasons for this difference. Reliable ongoing outcome audit will require good communication between clinics to verify that contacts have attended. The contact:index ratio is suitable for evaluation of PN as it relates to actual outcome rather than to the patient's account of contact numbers. Local work can be assessed against these national figures.

The methods of assay in body fluids of 1-beta-alkyl, 1-beta-phenyl and 1-beta-acyl glucuronic acids ("glucuronide conjugates") have been reviewed. Most of the 78 references cited (from the literature of the period 1990-1997) concern the glucuronide conjugates of drug metabolites, and these have been considered, for reasons of accessibility, within sections of individual drug classes such as analgesics, anti-cancer agents and opioids. Other glucuronide conjugates are considered under "miscellaneous compounds". A few gas chromatography and capillary electrophoresis methods are described, but the major technique of assay (62 citations) is reversed-phase high-performance liquid chromatography.

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19-55, duration 3-36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks' run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00-07.00). Biochemical hypoglycaemia (<3.5 mmol l(-1)) was observed on 39 of the 80 patient-nights studied (48.75%). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA1 (H 9.8 +/- 0.3%, P 10.0 +/- 0.3%, p = 0.32) and daily insulin doses (H 0.63 +/- 0.04 units kg(-1) day(-1) vs P 0.63 +/- 0.05 units kg(-1) day(-1), p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 +/- 7.8 vs 61.4 +/- 5.3 mmol.h l(-1), p < 0.05) but not porcine insulin (AUC 70.7 +/- 7.2 vs 70.1 +/- 7.5 mmol.h l(-1), p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia.

Objective: 1. To audit the management of cervical carcinoma in the South West Region with the aim of identifying and addressing deficiencies. 2. To determine whether recent NHS restructuring has affected the provision of cancer care., Design: Retrospective review of hospital case notes., Setting: All hospitals in the South West Region of England., Population: Three hundred and twenty-four women with a diagnosis of cervical carcinoma: 191 were diagnosed in 1989 and 133 in 1993., Main Outcome Measures: Documentation of patient assessment and management., Results: There was a mean delay of 17 days (range 0-66) from cervical smear to cytology report and 34 days (range 1-380) from general practitioner referral to attendance at a hospital clinic. Overall, 175 women (54%) had evidence of cytological assessment prior to treatment and 137 (42%) had a colposcopic assessment; 49% had cytological assessment and 37% had colposcopy in 1989, compared with 60% and 50%, respectively, in 1993. Excluding 49 cases of micro-invasive carcinoma, 238 case notes (86%) contained evidence of clinical examination; 195 women (71%) had had an examination under anaesthesia, 115 (42%) a chest radiograph, 123 (45%) an intravenous urogram or renal ultrasound, and 92 (33%) cystoscopy. One hundred and forty-seven women (53%) had FIGO staging recorded in the notes. As first line treatment, 69 had conservative surgery (39 for Stage IA), 138 had radiotherapy, and 107 had radical surgery. Ten had radical surgery for Stage IA but eight had a > 3 mm invasion or lymphatic/vascular spread. Thirty-one had Stage IB treated with radiotherapy of whom 14 were younger than 50 years of age. Following radical surgery 30% had evidence of sampling > or = 10 nodes, and 9% had tumour extending to the resection margins., Conclusions: Record keeping was inadequate but appeared to indicate inconsistent cytological, clinical, colposcopic and radiological assessment, leading to inappropriate clinical delays and conservative surgery. Radical surgery often appeared inadequate, but poor node sampling rates may also reflect insufficient histopathological preparation or reporting. There was a reduction in the number of new cases of cervical carcinoma diagnosed in 1993, perhaps reflecting an observed increase in cytological surveillance. No other alterations in clinical practice were observed over the four-year period. We feel it is imperative to standardise assessment throughout the region with a minimum clinical and histopathological dataset.

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l-1 for 30 min and lowered it to 2.9 mmol l-1 for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 +/- 4 vs 77 +/- 15 mU l-1 (mean +/- SEM) (mean difference 29 mU l-1, 95% CI -22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 +/- 3.5 vs 21.0 +/- 4.0 mU l-1 (mean difference 85 mU l-1, 95% CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 +/- 14 vs 128 +/- 7 ng l-1 (mean difference -4, 95% CI -39 to 31; p = NS) and adrenaline: 2.9 +/- 0.4 vs 2.8 +/- 0.3 nmol l-1, (mean difference 0.1, 95% CI -0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 +/- 1.4 vs 19.6 +/- 2.2 (mean difference -1.0, 95% CI -3.8 to 1.8; p = NS) and autonomic: 8.9 +/- 0.9 vs. 9.9 +/- 1.3 (mean difference -1.1, 95% CI -5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.

Objective: To evaluate the present management of muscle-invasive bladder cancer in the South West Region and to assess the workload resulting from the rationalization of treatment in specific centres., Methods: A retrospective survey was undertaken in all the hospitals in the South West Region, to assess the management of all patients presenting with muscle-invasive bladder cancer in the years 1989 and 1993. Data were collected from histopathology records and hospital in-patients' notes. The optimum standard of assessment and treatment were defined by a panel of specialists in urological tumours. The management of patients was compared against these defined standards., Results: A total of 186 and 199 patients in 1989 and 1993, respectively, were evaluated. When comparing their assessment against the defined standard, only 69% of patients in 1989 and 58% in 1993 had an intravenous urogram, with 7% and 4%, respectively, having no upper tract imaging (the remainder undergoing ultrasonography). Evidence from an examination under anaesthetic (EUA) was found for 80% of patients in 1989 and 84% of patients in 1993. Only 23% of patients in 1989 and 36% in 1993 were staged by either computed tomography or magnetic resonance imaging. In both 1989 and 1993, 54% of patients had definitive treatment, 31% had an endoscopic follow-up only and 15% had no treatment; there were no differences in age or co-morbidity among these groups. The median time elapsed between referral and diagnosis was 59 days (1989) and 52 days (1993), and the median delay to definitive treatment was 114 and 96 days, respectively., Conclusion: There was insufficient upper tract imaging, poor clinical staging in the EUA and too few investigations for staging. The low rate of definitive treatment may be a consequence of the delays in management, allowing the tumour to progress, and suggesting the need for a more rapid assessment of haematuria.

Recent studies have reported reduced endocrine and symptomatic responses to hypoglycaemia 18-24 h after antecedent hypoglycaemia in both non-diabetic subjects and those with insulin-dependent diabetes mellitus. We examined these and peripheral physiological responses in eight non-diabetic subjects aged 23-35 years in the week following antecedent hypoglycaemia. Blood glucose levels were held at plateaus of 5 mmol/l and 2.5 mmol/l for 30 min during hyperinsulinaemic (60 mU x m-2x min-1) morning clamps on days 1, 3 and 8 of two study periods separated by at least 4 weeks. Measurements were made at time 0, 15 and 30 min of each plateau on each day. One the afternoon of Day 1 we also induced either euglycaemia with a blood glucose level of 5 mmol/l (control week) or hypoglycaemia of 2.9 mmol/l (hypo week) for 2 h in random order. The adrenaline response to morning hypoglycaemia (p<0.001 on all days) was attenuated on Day 3 (p<0.05) and Day 8 (p<0.05) compared to Day 1 of hypo week only. Sweating was also attenuated on Day 3 (p<0.05) and Day 8 (p<0.02) of hypo week only. Noradrenaline levels and tremor increased during hypoglycaemia on each study day (p<0.05) but did not differ between days in either week. During hypo week only, the total symptom score response to hypoglycaemia was attenuated on Day 3 (p<0.03) but not Day 8 (p=0.10). Autonomic symptoms were similarly affected. In summary, the physiological responses to hypoglycaemia are affected differentially by antecedent hypoglycaemia with sweating and adrenaline responses remaining impaired for at least adrenaline responses remaining impaired for at least 5 days.

The pH-rate profile for the hydrolysis of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) in aqueous solution has been measured. Comparison with other data suggests that hydrolysis occurs by almost complete unimolecular elimination of sulfur trioxide, with weak involvement of a molecule of water in the transition state. The catalytic power (kcat/kuncat) of the sulfotransferases is estimated to be in the order of 10(10)-10(12). Amines--exemplified by morpholine--react spontaneously with PAPS in water at 39 degrees C by attack at both sulfuryl and (5')phosphoryl groups in a ratio of 2:3. The mechanism of activation of the coenzyme, PAPS, by the sulfotransferases that catalyse N-sulfation must involve suppression of its native N-phosphorylating reactivity and specific enhancement of its N-sulfating reactivity. Studies of the aminolysis of the coenzyme in aprotic solvent-water mixtures suggest how this might be accomplished.

Two unrelated children with a severe form of juvenile hyaline fibromatosis are described. In addition to painful flexion contractures of all of the large joints, oral and skin lesions, and typical radiologic appearance of osteolytic defects, both girls had marked growth retardation and recurrent infections. Both children died in early infancy of overwhelming infection.

A series of quaternary salt derivatives of 2-[(hydroxyimino)methyl]-1-methylimidazole incorporating various side chains bearing ether, silyl, nitrile, ester, halogen, nitro, sulfone, amino, or aminosulfonyl substituents was prepared and evaluated in vivo for the treatment of anticholinesterase intoxication. Test results in the mouse revealed that the type and location of the side-chain substituent both have a significant influence on the toxicity and antidotal effectiveness of the compounds. Some of the more active examples represent the most potent therapeutics to date against intoxication by the powerful cholinesterase inhibitors soman and tabun. Significantly, the antidotal effectiveness of the compounds was not dependent on the inhibiting agent nor was there any correlation between in vivo efficacy and in vitro reactivation of ethyl (4-nitrophenyl)methylphosphonate inhibited human acetylcholinesterase. These observation suggested that the main mode of antidotal protection by the compounds is something other than enzyme reactivation.