A survey of dog behavior modification practice in the UK: Who is offering it, what methods are they using and how effective do their clients perceive practitioners to be?

Thousands of dogs are relinquished each year in the UK owing to behavioral problems. Hence, there is a clear role for behavior modification therapy in the mitigation of this canine welfare risk. Since statutory regulation and a universal register of canine professionals (CPs) does not yet exist in the UK, it remains unclear who is offering such therapy, which behaviors are being treated, what types of approaches various CPs may be taking and the success (or otherwise) CPs are having. This study aimed to provide some insight into these issues from the perspective of pet dog owners (clients).An online survey of 235 participants showed that the primary reason for seeking behavior help from a CP was related to aggression, although often more than one issue was reported. Regardless of the behavior problem, no significant differences were found for the type of CP consulted (dog trainer versus behaviorist). Furthermore, in the client's opinion, there were no significant differences between CP types in their ability to improve their dog's unwanted behavior. Interestingly, behaviorists were significantly more likely than dog trainers to use ‘reward-based’ methods over ‘balanced training’ (balanced being a mix of reward and punishment; =8.226, df=1, p=0.004).In conclusion, in the current UK vacuum of statutory regulation, clients are just as likely to employ a trainer as a behaviorist, regardless of their dog's unwanted behavior. However, both CP types were equally able to facilitate behavior improvement, as reported by the client, regardless of the type of training methods (reward-based versus balanced) adopted. This study raises further questions to be explored including the client's opinion of the extent to which the ends (behavior outcomes) justify the means (e.g. punitive training methods which are likely to be aversive for the dog). Also, the general public's understanding of the potential welfare implications of the type of behavior modification plan they may or may not choose to follow

A survey of dog behavior modification practice in the UK: Who is offering it, what methods are they using and how effective do their clients perceive practitioners to be?

Thousands of dogs are relinquished each year in the UK owing to behavioral problems. Hence, there is a clear role for behavior modification therapy in the mitigation of this canine welfare risk. Since statutory regulation and a universal register of canine professionals (CPs) does not yet exist in the UK, it remains unclear who is offering such therapy, which behaviors are being treated, what types of approaches various CPs may be taking and the success (or otherwise) CPs are having. This study aimed to provide some insight into these issues from the perspective of pet dog owners (clients). An online survey of 235 participants showed that the primary reason for seeking behavior help from a CP was related to aggression, although often more than one issue was reported. Regardless of the behavior problem, no significant differences were found for the type of CP consulted (dog trainer versus behaviorist). Furthermore, in the client's opinion, there were no significant differences between CP types in their ability to improve their dog's unwanted behavior. Interestingly, behaviorists were significantly more likely than dog trainers to use ‘reward-based’ methods over ‘balanced training’ (balanced being a mix of reward and punishment; =8.226, df=1, p=0.004). In conclusion, in the current UK vacuum of statutory regulation, clients are just as likely to employ a trainer as a behaviorist, regardless of their dog's unwanted behavior. However, both CP types were equally able to facilitate behavior improvement, as reported by the client, regardless of the type of training methods (reward-based versus balanced) adopted. This study raises further questions to be explored including the client's opinion of the extent to which the ends (behavior outcomes) justify the means (e.g. punitive training methods which are likely to be aversive for the dog). Also, the general public's understanding of the potential welfare implications of the type of behavior modification plan they may or may not choose to follow

The contribution of geology and groundwater studies to city-scale ground source heat network strategies: a case study from Cardiff, Wales, UK

The development of integrated heat network strategies involving exploitation of the shallow subsurface requires knowledge of ground conditions at the feasibility stage, and throughout the life of the system. We describe an approach to the assessment of ground constraints and energy opportunities in data-rich urban areas. Geological and hydrogeological investigations have formed a core component of the strategy development for sustainable thermal use of the subsurface in Cardiff, UK. We present findings from a 12 month project titled ‘Ground Heat Network at a City Scale’, which was co-funded by NERC/BGS and the UK Government through the InnovateUK Energy Catalyst grant in 2015-16. The project examined the technical feasibility of extracting low grade waste heat from a shallow gravel aquifer using a cluster of open loop ground source heat pumps. Heat demand mapping was carried out separately. The ground condition assessment approach involved the following steps: (1) city-wide baseline groundwater temperature mapping in 2014 with seasonal monitoring for at least 12 months prior to heat pump installation (Patton et al 2015); (2) desk top and field-based investigation of the aquifer system to determine groundwater levels, likely flow directions, sustainable pumping yields, water chemistry, and boundary conditions; (3) creation of a 3D geological framework model with physical property testing and model attribution; (4) use steps 1-3 to develop conceptual ground models and production of maps and GIS data layers to support scenario planning, and initial heat network concept designs; (5) heat flow modelling in FEFLOW software to analyse sustainability and predict potential thermal breakthrough in higher risk areas; (6) installation of a shallow open loop GSHP research observatory with real-time monitoring of groundwater bodies to provide data for heat flow model validation and feedback for system control. In conclusion, early ground condition modelling and subsurface monitoring have provided an initial indication of ground constraints and opportunities supporting development of aquifer thermal energy systems in Cardiff. Ground models should consider the past and future anthropogenic processes that influence and modify the condition of the ground. These include heat losses from buildings, modification of the groundwater regime by artificial pumping, sewers, and other GSH schemes, and construction hazards such as buried infrastructure, old foundations, land contamination and un-exploded ordnance. This knowledge base forms the foundation for a ‘whole life’ approach for sustainable thermal use of the subsurface. Benefits of the approach include; timely and easy to understand information for land use and financial resource planning, reduced financial risk for developers and investors, clear evidence to help improve public perception of GSHP technology, and provision of independent environmental data to satisfy the needs of the regulator

Cyclic-AMP and bacterial cyclic-AMP receptor proteins revisited: adaptation for different ecological niches.

Escherichia coli cyclic-AMP receptor protein (CRP) represents one of the paradigms of bacterial gene regulation. Yet despite decades of intensive study, new information continues to emerge that prompts reassessment of this classic regulatory system. Moreover, in recent years CRPs from several other bacterial species have been characterized, allowing the general applicability of the CRP paradigm to be tested. Here the properties of the E. coli, Mycobacterium tuberculosis and Pseudomonas putida CRPs are considered in the context of the ecological niches occupied by these bacteria. It appears that the cyclic-AMP-CRP regulatory system has been adapted to respond to distinct external and internal inputs across a broad sensitivity range that is, at least in part, determined by bacterial lifestyles

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Mycobacterium tuberculosis cAMP Receptor Protein (Rv3676) Differs from the Escherichia coli Paradigm in Its cAMP Binding and DNA Binding Properties and Transcription Activation Properties*

The pathogen Mycobacterium tuberculosis produces a burst of cAMP upon infection of macrophages. Bacterial cyclic AMP receptor proteins (CRP) are transcription factors that respond to cAMP by binding at target promoters when cAMP concentrations increase. Rv3676 (CRPMt) is a CRP family protein that regulates expression of genes (rpfA and whiB1) that are potentially involved in M. tuberculosis persistence and/or emergence from the dormant state. Here, the CRPMt homodimer is shown to bind two molecules of cAMP (one per protomer) at noninteracting sites. Furthermore, cAMP binding by CRPMt was relatively weak, entropy driven, and resulted in a relatively small enhancement in DNA binding. Tandem CRPMt-binding sites (CRP1 at −58.5 and CRP2 at −37.5) were identified at the whiB1 promoter (PwhiB1). In vitro transcription reactions showed that CRP1 is an activating site and that CRP2, which was only occupied in the presence of cAMP or at high CRPMt concentrations in the absence of cAMP, is a repressing site. Binding of CRPMt to CRP1 was not essential for open complex formation but was required for transcription activation. Thus, these data suggest that binding of CRPMt to the PwhiB1 CRP1 site activates transcription at a step after open complex formation. In contrast, high cAMP concentrations allowed occupation of both CRP1 and CRP2 sites, resulting in inhibition of open complex formation. Thus, M. tuberculosis CRP has evolved several distinct characteristics, compared with the Escherichia coli CRP paradigm, to allow it to regulate gene expression against a background of high concentrations of cAMP