Expanding access to veterinary clinical decision support in resource-limited settings: a scoping review of clinical decision support tools in medicine and antimicrobial stewardship.

Introduction: Digital clinical decision support (CDS) tools are of growing importance in supporting healthcare professionals in understanding complex clinical problems and arriving at decisions that improve patient outcomes. CDS tools are also increasingly used to improve antimicrobial stewardship (AMS) practices in healthcare settings. However, far fewer CDS tools are available in lowerand middle-income countries (LMICs) and in animal health settings, where their use in improving diagnostic and treatment decision-making is likely to have the greatest impact. The aim of this study was to evaluate digital CDS tools designed as a direct aid to support diagnosis and/or treatment decisionmaking, by reviewing their scope, functions, methodologies, and quality. Recommendations for the development of veterinary CDS tools in LMICs are then provided. Methods: The review considered studies and reports published between January 2017 and October 2023 in the English language in peer-reviewed and gray literature. Results: A total of 41 studies and reports detailing CDS tools were included in the final review, with 35 CDS tools designed for human healthcare settings and six tools for animal healthcare settings. Of the tools reviewed, the majority were deployed in high-income countries (80.5%). Support for AMS programs was a feature in 12 (29.3%) of the tools, with 10 tools in human healthcare settings. The capabilities of the CDS tools varied when reviewed against the GUIDES checklist. Discussion: We recommend a methodological approach for the development of veterinary CDS tools in LMICs predicated on securing sufficient and sustainable funding. Employing a multidisciplinary development team is an important first step. Developing standalone CDS tools using Bayesian algorithms based on local expert knowledge will provide users with rapid and reliable access to quality guidance on diagnoses and treatments. Such tools are likely to contribute to improved disease management on farms and reduce inappropriate antimicrobial use, thus supporting AMS practices in areas of high need.

Targets in the Tumour Matrisome to Promote Cancer Therapy Response.

The extracellular matrix (ECM) is composed of complex fibrillar proteins, proteoglycans, and macromolecules, generated by stromal, immune, and cancer cells. The components and organisation of the matrix evolves as tumours progress to invasive disease and metastasis. In many solid tumours, dense fibrotic ECM has been hypothesised to impede therapy response by limiting drug and immune cell access. Interventions to target individual components of the ECM, collectively termed the matrisome, have, however, revealed complex tumour-suppressor, tumour-promoter, and immune-modulatory functions, which have complicated clinical translation. The degree to which distinct components of the matrisome can dictate tumour phenotypes and response to therapy is the subject of intense study. A primary aim is to identify therapeutic opportunities within the matrisome, which might support a better response to existing therapies. Many matrix signatures have been developed which can predict prognosis, immune cell content, and immunotherapy responses. In this review, we will examine key components of the matrisome which have been associated with advanced tumours and therapy resistance. We have primarily focussed here on targeting matrisome components, rather than specific cell types, although several examples are described where cells of origin can dramatically affect tumour roles for matrix components. As we unravel the complex biochemical, biophysical, and intracellular transduction mechanisms associated with the ECM, numerous therapeutic opportunities will be identified to modify tumour progression and therapy response.

The mediating role of reflective functioning and general psychopathology in the relationship between childhood conduct disorder and adult aggression among offenders.

BACKGROUND: The nature of the pathway from conduct disorder (CD) in adolescence to antisocial behavior in adulthood has been debated and the role of certain mediators remains unclear. One perspective is that CD forms part of a general psychopathology dimension, playing a central role in the developmental trajectory. Impairment in reflective functioning (RF), i.e., the capacity to understand one's own and others' mental states, may relate to CD, psychopathology, and aggression. Here, we characterized the structure of psychopathology in adult male-offenders and its role, along with RF, in mediating the relationship between CD in their adolescence and current aggression. METHODS: A secondary analysis of pre-treatment data from 313 probation-supervised offenders was conducted, and measures of CD symptoms, general and specific psychopathology factors, RF, and aggression were evaluated through clinical interviews and questionnaires. RESULTS: Confirmatory factor analyses indicated that a bifactor model best fitted the sample's psychopathology structure, including a general psychopathology factor (p factor) and five specific factors: internalizing, disinhibition, detachment, antagonism, and psychoticism. The structure of RF was fitted to the data using a one-factor model. According to our mediation model, CD significantly predicted the p factor, which was positively linked to RF impairments, resulting in increased aggression. CONCLUSIONS: These findings highlight the critical role of a transdiagnostic approach provided by RF and general psychopathology in explaining the link between CD and aggression. Furthermore, they underscore the potential utility of treatments focusing on RF, such as mentalization-based treatment, in mitigating aggression in offenders with diverse psychopathologies.

Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function.

Crosstalk between cancer and stellate cells is pivotal in pancreatic cancer, resulting in differentiation of stellate cells into myofibroblasts that drives tumour progression. To assess cooperative mechanisms in a 3D context, we generated chimeric spheroids using human and mouse cancer and stellate cells. Species-specific deconvolution of bulk-RNA sequencing data revealed cell type-specific transcriptomes underpinning invasion. This dataset highlighted stellate-specific expression of transcripts encoding the collagen-processing enzymes ADAMTS2 and ADAMTS14. Strikingly, loss of ADAMTS2 reduced, while loss of ADAMTS14 promoted, myofibroblast differentiation and invasion independently of their primary role in collagen-processing. Functional and proteomic analysis demonstrated that these two enzymes regulate myofibroblast differentiation through opposing roles in the regulation of transforming growth factor ß availability, acting on the protease-specific substrates, Serpin E2 and fibulin 2, for ADAMTS2 and ADAMTS14, respectively. Showcasing a broader complexity for these enzymes, we uncovered a novel regulatory axis governing malignant behaviour of the pancreatic cancer stroma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

"It's a habit. They've been doing it for decades and they feel good and safe.": A qualitative study of barriers and opportunities to changing antimicrobial use in the Indonesian poultry sector.

Interventions to change antimicrobial use (AMU) practices can help mitigate the risk of antimicrobial resistance (AMR) development. However, changing AMU practices can be challenging due to the complex nature of the factors influencing AMU-related behaviours. This study used a qualitative approach to explore the factors that influenced decision-making on AMU by farmers and other actors in the Indonesian poultry sector. Thirty-five semi-structured interviews were conducted with farmers, technical services staff from the private sector, and representatives of associations, universities, and international organisations in Central Java, West Java, and East Java. Thematic analysis identified three patterns of influence on AMU: how farmers used information to make AMU-related decisions, the importance of farmers' social and advisory networks, and the motivations driving changes in AMU behaviours. Key barriers identified included a lack of shared understanding around when to use antibiotics, financial pressures in the poultry sector, and a lack of engagement with government veterinary services. Potential opportunities identified included high farmer awareness of AMU, identification of private sector actors and peer networks as the stakeholders with established relationships of trust with farmers, and the importance of farmers' conceptions of good farming practices, which could be engaged with to improve AMU practices.

The Future of Precision Oncology.

Our understanding of the molecular mechanisms underlying cancer development and evolution have evolved rapidly over recent years, and the variation from one patient to another is now widely recognized. Consequently, one-size-fits-all approaches to the treatment of cancer have been superseded by precision medicines that target specific disease characteristics, promising maximum clinical efficacy, minimal safety concerns, and reduced economic burden. While precision oncology has been very successful in the treatment of some tumors with specific characteristics, a large number of patients do not yet have access to precision medicines for their disease. The success of next-generation precision oncology depends on the discovery of new actionable disease characteristics, rapid, accurate, and comprehensive diagnosis of complex phenotypes within each patient, novel clinical trial designs with improved response rates, and worldwide access to novel targeted anticancer therapies for all patients. This review outlines some of the current technological trends, and highlights some of the complex multidisciplinary efforts that are underway to ensure that many more patients with cancer will be able to benefit from precision oncology in the near future.

TGFß-mediated MMP13 secretion drives myoepithelial cell dependent breast cancer progression.

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFß - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.

INVESTIGATING BLOOD LACTATE CONCENTRATION AS A PROGNOSTIC INDICATOR FOR BIRDS PRESENTING WITH BREVETOXICOSIS: 2020-2021.

Large blooms of the dinoflagellate Karenia brevis cause annual harmful algal bloom events, or "red tides" on Florida's Gulf Coast. Each year, the Clinic for the Rehabilitation of Wildlife (CROW) is presented with hundreds of cases of aquatic birds that exhibit neurologic clinical signs due to brevetoxicosis. Double-crested cormorants (Phalacrocorax auratus) are the most common species seen, and typically present with a combination of ataxia, head tremors, knuckling, and/or lagophthalmos. Blood lactate levels are known to increase in mammals for a variety of reasons, including stress, hypoxia, sepsis, and trauma, but there is limited literature on blood lactate values in avian species. The objective of this study was to determine the prognostic value of blood lactate concentration on successful rehabilitation and release of birds presenting with clinical signs consistent with brevetoxicosis. Blood lactate levels were collected on intake, the morning after presentation and initial therapy, and prior to disposition (release or euthanasia) from 194 birds (including 98 cormorants) representing 17 species during the 2020-2021 red tide season. Overall, mean blood lactate at intake, the morning after intake, and predisposition was 2.9, 2.8, and 3.2 mmol/L, respectively, for released birds across all species (2.9, 2.9, and 3.2 mmol/L for released cormorants); 3.4, 3.4, and 6.5 mmol/L for birds that died (4.0, 3.5, and 7.9 mmol/L for cormorants that died); and 3.1, 3.5, and 4.7 mmol/L for birds that were euthanized (3.5, 4.7, and 4.9 mmol/L for cormorants that were euthanized). On average, birds that died or were euthanized had an elevated lactate at all time points as compared to those that were released, but these results were not statistically significant (P = 0.13). These results indicate that blood lactate levels do not appear to be useful as a prognostic indicator for successful release of birds, including double-crested cormorants, affected by brevetoxicosis.

PKN2 deficiency leads both to prenatal 'congenital' cardiomyopathy and defective angiotensin II stress responses.

The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the expansion of mesoderm, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The specific role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established. We used mice with cardiomyocyte-directed knockout of PKN2 or global PKN2 haploinsufficiency to assess cardiac development and function using high resolution episcopic microscopy, MRI, micro-CT and echocardiography. Biochemical and histological changes were also assessed. Cardiomyocyte-directed PKN2 knockout embryos displayed striking abnormalities in the compact myocardium, with frequent myocardial clefts and diverticula, ventricular septal defects and abnormal heart shape. The sub-Mendelian homozygous knockout survivors developed cardiac failure. RNASeq data showed up-regulation of PKN2 in patients with dilated cardiomyopathy, suggesting an involvement in adult heart disease. Given the rarity of homozygous survivors with cardiomyocyte-specific deletion of PKN2, the requirement for PKN2 in adult mice was explored using the constitutive heterozygous PKN2 knockout. Cardiac hypertrophy resulting from hypertension induced by angiotensin II was reduced in these haploinsufficient PKN2 mice relative to wild-type littermates, with suppression of cardiomyocyte hypertrophy and cardiac fibrosis. It is concluded that cardiomyocyte PKN2 is essential for heart development and the formation of compact myocardium and is also required for cardiac hypertrophy in hypertension. Thus, PKN signalling may offer therapeutic options for managing congenital and adult heart diseases.

Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets.

Cancer-associated fibroblasts (CAFs) have conflicting roles in the suppression and promotion of cancer. Current research focuses on targeting the undesirable properties of CAFs, while attempting to maintain tumour-suppressive roles. CAFs have been widely associated with primary or secondary therapeutic resistance, and strategies to modify CAF function have therefore largely focussed on their combination with existing therapies. Despite significant progress in preclinical studies, clinical translation of CAF targeted therapies has achieved limited success. Here we will review our emerging understanding of heterogeneous CAF populations in tumour biology and use examples from pancreatic ductal adenocarcinoma to explore why successful clinical targeting of protumourigenic CAF functions remains elusive. Single-cell technologies have allowed the identification of CAF subtypes with a differential impact on prognosis and response to therapy, but currently without clear consensus. Identification and pharmacological targeting of CAF subtypes associated with immunotherapy response offers new hope to expand clinical options for pancreatic cancer. Various CAF subtype markers may represent biomarkers for patient stratification, to obtain enhanced response with existing and emerging combinatorial therapeutic strategies. Thus, CAF subtyping is the next frontier in understanding and exploiting the tumour microenvironment for therapeutic benefit. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Targeting the HER3 pseudokinase domain with small molecule inhibitors.

HER3 is a potent oncogenic growth factor receptor belonging to the human epidermal growth factor (HER/EGFR) family of receptor tyrosine kinases. In contrast to other EGFR family members, HER3 is a pseudokinase, lacking functional kinase activity. As such, efforts to develop small molecule tyrosine kinase inhibitors against this family member have been limited. In response to HER3-specific growth factors such as neuregulin (NRG, also known as heregulin or HRG), HER3 must couple with catalytically active family members, including its preferred partner HER2. Dimerization of the intracellular HER2:HER3 kinase domains is a critical part of the activation mechanism and HER3 plays a specialized role as an allosteric activator of the active HER2 kinase partner. Intriguingly, many pseudokinases retain functionally important nucleotide binding capacity, despite loss of kinase activity. We demonstrated that occupation of the nucleotide pocket of the pseudokinase HER3 retains functional importance for growth factor signaling through oncogenic HER2:HER3 heterodimers. Mutation of the HER3 nucleotide pocket both disrupts signaling and disrupts HER2:HER3 dimerization. Conversely, ATP competitive drugs which bind to HER3, but not HER2, can stabilize HER2:HER3 dimers, induce signaling and promote cell growth in breast cancer models. This indicates a nucleotide-dependent conformational role for the HER3 kinase domain. Critically, our recent proof-of-concept work demonstrated that HER3-directed small molecule inhibitors can also disrupt HER2:HER3 dimerization and signaling, supporting the prospect that HER3 can be a direct drug target despite its lack of intrinsic activity. In this chapter we will describe methods for identifying and validating small molecule inhibitors against the HER3 pseudokinase.

Orbital compartment syndrome secondary to subperiosteal abscess initiated by barotrauma.

This case report demonstrates an unusual complication of bacterial rhinosinusitis, causing orbital compartment syndrome from a presumed barotrauma. We postulate that the patient developed unilateral optic neuropathy, as a result of orbital compartment syndrome, secondary to orbital subperiosteal abscess following direct communication with the ethmoid sinus initiated by barotrauma. It is supported by evidence of a bony dehiscence on the lamina papyracea of the medial orbital wall with sudden onset of pain, proptosis and visual symptoms during flight.

Electronic information systems for One Health surveillance of antimicrobial resistance: a systematic scoping review.

INTRODUCTION: Electronic information systems (EIS) that implement a 'One Health' approach by integrating antimicrobial resistance (AMR) data across the human, animal and environmental health sectors, have been identified as a global priority. However, evidence on the availability, technical capacities and effectiveness of such EIS is scarce. METHODS: Through a qualitative synthesis of evidence, this systematic scoping review aims to: identify EIS for AMR surveillance that operate across human, animal and environmental health sectors; describe their technical characteristics and capabilities; and assess whether there is evidence for the effectiveness of the various EIS for AMR surveillance. Studies and reports between 1 January 2000 and 21 July 2021 from peer-reviewed and grey literature in the English language were included. RESULTS: 26 studies and reports were included in the final review, of which 27 EIS were described. None of the EIS integrated AMR data in a One Health approach across all three sectors. While there was a lack of evidence of thorough evaluations of the effectiveness of the identified EIS, several surveillance system effectiveness indicators were reported for most EIS. Standardised reporting of the effectiveness of EIS is recommended for future publications. The capabilities of the EIS varied in their technical design features, in terms of usability, data display tools and desired outputs. EIS that included interactive features, and geospatial maps are increasingly relevant for future trends in AMR data analytics. CONCLUSION: No EIS for AMR surveillance was identified that was designed to integrate a broad range of AMR data from humans, animals and the environment, representing a major gap in global efforts to implement One Health approaches to address AMR.

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion.

In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

Systematic review of the status of veterinary epidemiological research in two species regarding the FAIR guiding principles.

BACKGROUND: The FAIR (Findable, Accessible, Interoperable, Reusable) principles were proposed in 2016 to set a path towards reusability of research datasets. In this systematic review, we assessed the FAIRness of datasets associated with peer-reviewed articles in veterinary epidemiology research published since 2017, specifically looking at salmonids and dairy cattle. We considered the differences in practices between molecular epidemiology, the branch of epidemiology using genetic sequences of pathogens and hosts to describe disease patterns, and non-molecular epidemiology. RESULTS: A total of 152 articles were included in the assessment. Consistent with previous assessments conducted in other disciplines, our results showed that most datasets used in non-molecular epidemiological studies were not available (i.e., neither findable nor accessible). Data availability was much higher for molecular epidemiology papers, in line with a strong repository base available to scientists in this discipline. The available data objects generally scored favourably for Findable, Accessible and Reusable indicators, but Interoperability was more problematic. CONCLUSIONS: None of the datasets assessed in this study met all the requirements set by the FAIR principles. Interoperability, in particular, requires specific skills in data management which may not yet be broadly available in the epidemiology community. In the discussion, we present recommendations on how veterinary research could move towards greater reusability according to FAIR principles. Overall, although many initiatives to improve data access have been started in the research community, their impact on the availability of datasets underlying published articles remains unclear to date.

West Nile Virus Seroprevalence in an Outdoor Nonhuman Primate Breeding Colony in South Florida.

West Nile virus (WNV) was first detected in Florida in July 2001, with 404 human cases reported to the Centers for Disease Control and Prevention as of February 2020. The subtropical climate of Florida is ideal for the mosquitoes that transmit WNV. We investigated the WNV seroprevalence in 3 NHP species housed outdoors at The Mannheimer Foundation in South Florida. From January to December 2016, 520 3 to 30 y old NHP were sampled at our 2 closed sites in Homestead and LaBelle: 200 rhesus macaques (Macaca mulatta), 212 cynomolgus macaques (Macaca fascicularis), and 108 hamadryas baboons (Papio hamadryas hamadryas). The presence of WNV IgG antibodies in these animals was determined by serum neutralization assays, which found a total seroprevalence of 14%. Seroprevalence was significantly higher in the baboons (29%) than the rhesus (11%) and cynomolgus (9%) macaques. The probability of seropositivity significantly increased with age, but sex and site did not significantly affect seroprevalence. The frequency of WNV seropositivity detected in these outdoor-housed NHP suggests that screening for WNV and other vector-borne diseases may be necessary prior to experimental use, particularly for infectious disease studies in which viremia or viral antibodies could confound results, and especially for populations housed outdoors in warm, wet climates. As no seropositive subjects demonstrated clinical signs of WNV and WNV exposure did not appear to significantly impact colony health, routine testing is likely unnecessary for most NHP colonies. However, WNV infection should still be considered as a differential diagnosis for any NHP presenting with nonspecific neurologic signs. Mosquito abatement plans and vigilant sanitation practices to further decrease mosquito and avian interaction with research NHP should also be considered.

Risk-based early detection system of African Swine Fever using mortality thresholds.

African swine fever (ASF) is an infectious disease of swine causing major losses in the swine industry worldwide. Early detection of ASF is challenging because of the wide range of non-specific clinical signs produced and its relatively low contagiousness. Monitoring pig mortality is a promising approach for early detection of ASF, but such approach has been associated with delay in disease detection in large pig farms. The purpose of this study was to compare the effectiveness and suitability of early detection strategies for ASF in large commercial pig farms using mortality monitoring at the pen, room or barn level. The within-barn spread of the disease was modelled including the non-homogeneous probabilities of transmission within pens, between pens and between rooms. The performances of early detection surveillance based on mortality thresholds established for different epidemiological units were compared in terms of sensitivity, time to detection and number of false alarms per year. A barn with a capacity of 3,200 pigs divided into 8 rooms with 10 pens each containing 40 pigs per pen was used as an example. Our results show that using room- or pen-based mortality thresholds provided a time to detection of 8 days post-disease introduction. Similar detection performances could be achieved with barn-level mortality threshold but at the cost of an increased number of pigs to be tested each year. The different scenarios tested also show that barn characteristics such as baseline mortality rate and pen size had a limited impact on the pen-level mortality thresholds required for disease early detection. These results offer strong support for using mortality data for early detection of ASF not only in small pig herds but also in large commercial barns. Furthermore, the mortality thresholds defined in this study might be relevant to a wide range of pig production sites.

Mentalization for Offending Adult Males (MOAM): study protocol for a randomized controlled trial to evaluate mentalization-based treatment for antisocial personality disorder in male offenders on community probation.

BACKGROUND: Antisocial personality disorder (ASPD), although associated with very significant health and social burden, is an under-researched mental disorder for which clinically effective and cost-effective treatment methods are urgently needed. No intervention has been established for prevention or as the treatment of choice for this disorder. Mentalization-based treatment (MBT) is a psychotherapeutic treatment that has shown some promising preliminary results for reducing personality disorder symptomatology by specifically targeting the ability to recognize and understand the mental states of oneself and others, an ability that is compromised in people with ASPD. This paper describes the protocol of a multi-site RCT designed to test the effectiveness and cost-effectiveness of MBT for reducing aggression and alleviating the wider symptoms of ASPD in male offenders subject to probation supervision who fulfil diagnostic criteria for ASPD. METHODS: Three hundred and two participants recruited from a pool of offenders subject to statutory supervision by the National Probation Service at 13 sites across the UK will be randomized on a 1:1 basis to 12 months of probation plus MBT or standard probation as usual, with follow-up to 24 months post-randomization. The primary outcome is frequency of aggressive antisocial behaviour as assessed by the Overt Aggression Scale - Modified. Secondary outcomes include violence, offending rates, alcohol use, drug use, mental health status, quality of life, and total service use costs. Data will be gathered from police and criminal justice databases, NHS record linkage, and interviews and self-report measures administered to participants. Primary analysis will be on an intent-to-treat basis; per-protocol analysis will be undertaken as secondary analysis. The primary outcome will be analysed using hierarchical mixed-effects linear regression. Secondary outcomes will be analysed using mixed-effects linear regression, mixed-effects logistic regression, and mixed-effects Poisson models for secondary outcomes depending on whether the outcome is continuous, binary, or count data. A cost-effectiveness and cost-utility analysis will be undertaken. DISCUSSION: This definitive, national, multi-site trial is of sufficient size to evaluate MBT to inform policymakers, service commissioners, clinicians, and service users about its potential to treat offenders with ASPD and the likely impact on the population at risk. TRIAL REGISTRATION: ISRCTN 32309003 . Registered on 8 April 2016.

Evidence That Higher Temperatures Are Associated With a Marginally Lower Incidence of COVID-19 Cases.

Seasonal variations in COVID-19 incidence have been suggested as a potentially important factor in the future trajectory of the pandemic. Using global line-list data on COVID-19 cases reported until 17th of March 2020 and global gridded weather data, we assessed the effects of air temperature and relative humidity on the daily incidence of confirmed COVID-19 local cases at the subnational level (first-level administrative divisions). After adjusting for surveillance capacity and time since first imported case, average temperature had a statistically significant, negative association with COVID-19 incidence for temperatures of -15°C and above. However, temperature only explained a relatively modest amount of the total variation in COVID-19 cases. The effect of relative humidity was not statistically significant. These results suggest that warmer weather may modestly reduce the rate of spread of COVID-19, but anticipation of a substantial decline in transmission due to temperature alone with onset of summer in the northern hemisphere, or in tropical regions, is not warranted by these findings.