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BACKGROUND: Smoking of illicit drugs may lead to more rapid TB disease progression or late treatment presentation, yet research on this topic is scant. We examined the association between smoked drug use and bacterial burden among patients newly initiated on drug-susceptible TB (DS-TB) therapy.METHODS: Data from 303 participants initiating DS-TB treatment in the Western Cape Province, South Africa, were analyzed. Smoked drug use was defined as self-reported or biologically verified methamphetamine, methaqualone and/or cannabis use. Proportional hazard and logistic regression models (adjusted for age, sex, HIV status and tobacco use) examined associations between smoked drug use and mycobacterial time to culture positivity (TTP), acid-fast bacilli sputum smear positivity and lung cavitation.RESULTS: People who smoked drugs (PWSD) comprised 54.8% (n = 166) of the cohort. TTP was faster for PWSD (hazard ratio 1.48, 95% CI 1.10–1.97; P = 0.008). Smear positivity was higher among PWSD (OR 2.28, 95% CI 1.22–4.34; P = 0.011). Smoked drug use (OR 1.08, 95% CI 0.62–1.87; P = 0.799) was not associated with increased cavitation.CONCLUSIONS: PWSD had a higher bacterial burden at diagnosis than those who do not smoke drugs. Screening for TB among PWSD in the community may facilitate earlier linkage to TB treatment and reduce community transmission.

Snake ownership is popular; however, housing and care may not always satisfy the animal's welfare needs. For example, snakes are often kept in environmental conditions that restrict their ability to stretch out fully or move around, using rectilinear locomotion. To date, little empirical data exist on the housing and husbandry of captive snakes and how these impact welfare. This study analyses survey responses from 744 snake owners worldwide and explores potential welfare concerns for snakes kept within private homes. It documents the most common housing and husbandry methods and compares the three most common families (Pythonids, Boids and Colubrids). Owner-reported data were used to derive scores for two potential welfare indicators: number of clinical signs of ill health and the number of reported negative (abnormal) behaviours. Using these indicators, associations were tested with snake-keeping variables, such as enclosure size, level of enrichment, temperature and humidity. Owners reported that 90.7% (n = 675) of snakes adopted rectilinear (straight-line or near straight-line) positions or movements. Snakes kept in enclosures > 1 snake length tended to have more enrichment types and were reported with fewer clinical signs of ill health. Some snakes were housed at unknown temperature (7.7%) or humidity (48.1%) ranges or in environmental conditions not in keeping with current recommended guidelines. Corn snakes (Pantherophis guttatus) were the most likely species to be kept at a humidity which did not match recommendations which may present a welfare concern. This study's results can be used to target husbandry guidance for future recommendations and care manuals.

Livestock guarding dogs (LGDs) are used all over the world to help in carnivore conservation by mitigating human-wildlife conflict. In Namibia, LGDs are used in cheetah conservation to prevent depredation of stock and reduce retaliatory killings. However, behavioral problems in the dogs, such as chasing wildlife and harassing livestock, exist leading to poor dog performance and farmer dissatisfaction. In most other types of working dogs, behavior tests for suitability are reported and/or validated within the scientific literature. To date this has not been done for LGDs. In this paper, we design a composite behavioral test and a questionnaire to rate the dogs’ effectiveness as an LGD. This test was used on 14 LGDs, 7 of which were operational and 7 of which were being used as breeding stock. In total, 16 behavioral variables were measured. A Principal Components Analysis reduced these to 5 underlying personality traits: “Playfulness,” “Trainability,” “Independence,” “Sociability with people” and “Reactivity.” When 14 dogs were tested 3 times, 20 days apart, the traits “Playfulness,” “Trainability” and “Independence” were found to be consistent. “Trainability” was negatively correlated to dog age. Dogs with a higher “Trainability” and lower “Reactivity” showed a tendency to be rated as more effective by their herdsman. Dogs scoring higher for “Playfulness” were more likely to be reported to harass stock, and dogs that chased a moving object under experimental conditions were generally rated higher for tendency to chase predator wildlife when working. This study suggests that there are personality attributes which can be measured and are consistent across time in LGDs. Several of these are linked to better performance in trained dogs. Whether these are predictive of later performance in untrained dogs, is yet to be ascertained.

Interactive clinical skills models have been demonstrated to be useful for teaching medical and veterinary clinical skills, yet to date, very few exist for teaching skills relevant to zoological companion animals and wildlife species including birds. This two-part study aimed to create, develop, and validate a model. Interviews and a survey were conducted using veterinary and wildlife professionals to select an avian clinical skill that is challenging and performed frequently. Tube/gavage feeding, or “crop tubing” satisfied both criteria; on average it was performed 71 times a year by surveyed respondents was rated 3.4/9 for difficulty of teaching and 3.5/9 for difficulty of learning. Therefore, a new model of a bird, made from a soft toy, silicone, and 3D printed parts, was designed to train students to perform this technique. Forty-two participants were recruited and divided into two groups; one used the model the other watched an instructional video on crop tubing. The students completed a self-evaluated confidence questionnaire, before and after, using either resource. They then performed the technique on a dead bird and their proficiency at 10 different actions that comprised the technique was evaluated by two assessors. The model group performed significantly better than the video group on all evaluated actions ( U ≤ 143.5, p ≤ .0031), and reported significantly higher confidence ( U = 129.5, p = 0.018). In conclusion, the newly developed model in combination with an instruction booklet offers an effective and inexpensive alternative way to teach crop tubing in a teaching environment, without compromising animal welfare.

Purpose Dietary micronutrient intakes of iron, folate and vitamin B12 are known to influence hemoglobin. Low maternal hemoglobin (maternal anemia) has been linked to low birthweight and other adverse health outcomes in the fetus and infant. Our primary aim was to explore relationships between maternal dietary micronutrient intakes, maternal full blood count (FBC) parameters and fetal abdominal circumference (AC) and estimated fetal weight (EFW) growth trajectories. Secondarily, we aimed to assess relationships between maternal dietary micronutrient intakes, maternal hemoglobin values and placental weight and birthweight. Methods Mother–child pairs (n = 759) recruited for the ROLO study were included in this analysis. Maternal dietary micronutrient intakes were calculated from food diaries completed during each trimester of pregnancy. FBC samples were collected at 13- and 28-weeks’ gestation. Fetal ultrasound measurements were recorded at 20- and 34-weeks’ gestation. Growth trajectories for AC and EFW were estimated using latent class trajectory mixture models. Results Dietary intakes of iron and folate were deficient for all trimesters. Mean maternal hemoglobin levels were replete at 13- and 28-weeks’ gestation. Dietary iron, folate and vitamin B12 intakes showed no associations with fetal growth trajectories, placental weight or birthweight. Lower maternal hemoglobin concentrations at 28 weeks’ gestation were associated with faster rates of fetal growth and larger placental weights and birthweights. Conclusion The negative association between maternal hemoglobin at 28 weeks’ gestation and accelerated fetal and placental growth may be due to greater consumption of maternal iron and hemoglobin by fetuses’ on faster growth trajectories in addition to placental biochemical responses to lower oxygen states.

We cross-match and compare characteristics of galaxy clusters identified in observations from two sky surveys using two completely different techniques. One sample is optically selected from the analysis of three years of Dark Energy Survey observations using the redMaPPer cluster detection algorithm. The second is X-ray selected from XMM observations analysed by the XMM Cluster Survey. The samples comprise a total area of 57.4 deg$^2$, bounded by the area of 4 contiguous XMM survey regions that overlap the DES footprint. We find that the X-ray selected sample is fully matched with entries in the redMaPPer catalogue, above $\lambda>$20 and within 0.1$< z, Comment: Accepted for publication to MNRAS

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy of the skin. Its incidence is increasing with half of cases involving the head and neck. To the best of our knowledge, few large studies have been published in the UK, and to date this is the largest reported series of head and neck MCC. We retrospectively reviewed the outcomes of patients with MCC in three hospitals in the south-east of England over a 12-year period (2008–2019). Diagnosis was based on histological data following biopsy. Overall survival and disease-specific survival were calculated using Kaplan–Meier and log-rank tests. Fifty-eight patients met the inclusion criteria (24 stage I, 22 stage II, 9 stage III, and 3 unclassified). Median disease-free survival was 36 months (95% CI 0 to 77.2) and median overall survival 50 months (95% CI 29.9 to 70). Overall five-year survival was 34.4% (95% CI 17% to 52%) with two-year survival at 62% (95% CI 48% to 76%). Five-year disease-free survival was 26.7% (95% CI 17 to 52%) with two-year disease-free survival at 54% (95% CI 40% to 68%). To date, this is the largest UK based study reporting overall and disease-free survival associated with MCC of the head and neck. Half the patients presented late, and surgery was the mainstay of treatment, augmented by adjuvant radiotherapy. There is a need to better stratify patients at risk of developing metastatic disease, with the use of sentinel lymph node biopsy and positron-emission tomography-computed tomography (PET-CT), as immunotherapy and targeted agents are now available to treat advanced disease.

Despite increased attention devoted to diversity, equity, and inclusion (DEI) within academic medicine, representation, lack of workforce and leadership diversity, and bias within medicine remain persistent problems. The purpose of the current study was to understand the current efforts and attention to DEI within academic departments of surgery in the United States. 251 department of surgery websites were reviewed, using a standardized data collection form and scoring procedure, accompanied by a 10 percent fidelity check by an independent reviewer. Only 16% of departments of surgery included DEI-specific information, such as a DEI mission statement or initiatives on their departmental sites, with less than seven percent of departments reporting a DEI committee. Such public information may have implications for recruitment and retention of diverse faculty and trainees, downstream effects for patient care, and could be critical to public accountability to improve diversity and create a culture of equity and inclusion.

Air pollution in urban environments has been shown to have a negative impact on air quality and human health, particularly in megacities. Over recent decades, Delhi, India, has suffered high atmospheric pollution, with significant particulate matter (PM) concentrations as a result of anthropogenic activities. Organic aerosols (OAs) are composed of thousands of different chemical species and are one of the main constituents of submicron particles. However, quantitative knowledge of OA composition, their sources and their processes in urban environments is still limited. This is important particularly in India, as Delhi is a massive, inhomogeneous conurbation, where we would expect the apportionment and concentrations to vary depending on where in Delhi the measurements/source apportionment is performed, indicating the need for multisite measurements. This study presents the first multisite analysis carried out in India over different seasons, with a focus on identifying OA sources. The measurements were taken during 2018 at two sites in Delhi, India. One site was located at the India Meteorological Department, New Delhi (ND). The other site was located at the Indira Gandhi Delhi Technical University for Women, Old Delhi (OD). Non-refractory submicron aerosol (NR-PM1) concentrations (ammonium, nitrate, sulfate, chloride and organic aerosols) of four aerosol mass spectrometers were analysed. Collocated measurements of volatile organic compounds, black carbon, NOx and CO were performed. Positive matrix factorisation (PMF) analysis was performed to separate the organic fraction, identifying a number of conventional factors: hydrocarbon-like OAs (HOAs) related to traffic emissions, biomass burning OAs (BBOAs), cooking OAs (COAs) and secondary OAs (SOAs). A composition-based estimate of PM1 is defined by combining black carbon (BC) and NR-PM1 (C-PM1= BC + NR-PM1). No significant difference was observed in C-PM1 concentrations between sites, OD (142 ± 117 µg m−3) compared to ND (123 ± 71 µg m3), from post-monsoon measurements. A wider variability was observed between seasons, where pre-monsoon and monsoon showed C-PM1 concentrations lower than 60 µg m−3. A seasonal variation in C-PM1 composition was observed; SO42- showed a high contribution over pre-monsoon and monsoon seasons, while NO3- and Cl− had a higher contribution in winter and post-monsoon. The main primary aerosol source was from traffic, which is consistent with the PMF analysis and Aethalometer model analysis. Thus, in order to reduce PM1 concentrations in Delhi through local emission controls, traffic emission control offers the greatest opportunity. PMF–aerosol mass spectrometer (AMS) mass spectra will help to improve future aerosol source apportionment studies. The information generated in this study increases our understanding of PM1 composition and OA sources in Delhi, India. Furthermore, the scientific findings provide significant information to strengthen legislation that aims to improve air quality in India.

Air pollution in urban environments has been shown to have a negative impact on air quality and human health, particularly in megacities. Over recent decades, Delhi, India, has suffered high atmospheric pollution, with significant particulate matter (PM) concentrations as a result of anthropogenic activities. Organic aerosols (OAs) are composed of thousands of different chemical species and are one of the main constituents of submicron particles. However, quantitative knowledge of OA composition, their sources and their processes in urban environments is still limited. This is important particularly in India, as Delhi is a massive, inhomogeneous conurbation, where we would expect the apportionment and concentrations to vary depending on where in Delhi the measurements/source apportionment is performed, indicating the need for multisite measurements. This study presents the first multisite analysis carried out in India over different seasons, with a focus on identifying OA sources. The measurements were taken during 2018 at two sites in Delhi, India. One site was located at the India Meteorological Department, New Delhi (ND). The other site was located at the Indira Gandhi Delhi Technical University for Women, Old Delhi (OD). Non-refractory submicron aerosol (NR-PM1) concentrations (ammonium, nitrate, sulfate, chloride and organic aerosols) of four aerosol mass spectrometers were analysed. Collocated measurements of volatile organic compounds, black carbon, NOx and CO were performed. Positive matrix factorisation (PMF) analysis was performed to separate the organic fraction, identifying a number of conventional factors: hydrocarbon-like OAs (HOAs) related to traffic emissions, biomass burning OAs (BBOAs), cooking OAs (COAs) and secondary OAs (SOAs). A composition-based estimate of PM1 is defined by combining black carbon (BC) and NR-PM1 (C-PM1= BC + NR-PM1). No significant difference was observed in C-PM1 concentrations between sites, OD (142 ± 117 µg m−3) compared to ND (123 ± 71 µg m3), from post-monsoon measurements. A wider variability was observed between seasons, where pre-monsoon and monsoon showed C-PM1 concentrations lower than 60 µg m−3. A seasonal variation in C-PM1 composition was observed; SO42- showed a high contribution over pre-monsoon and monsoon seasons, while NO3- and Cl− had a higher contribution in winter and post-monsoon. The main primary aerosol source was from traffic, which is consistent with the PMF analysis and Aethalometer model analysis. Thus, in order to reduce PM1 concentrations in Delhi through local emission controls, traffic emission control offers the greatest opportunity. PMF–aerosol mass spectrometer (AMS) mass spectra will help to improve future aerosol source apportionment studies. The information generated in this study increases our understanding of PM1 composition and OA sources in Delhi, India. Furthermore, the scientific findings provide significant information to strengthen legislation that aims to improve air quality in India.

Mesophotic (30–150 m) reef fish assemblages in the 'Au'au Channel, between the Hawaiian Islands of Maui and Lanai, were compared visually with neighboring shallow (

Objectives To gain insight into veterinary nurse knowledge of pain recognition and control in rabbits. Materials and methods We used a survey to establish current attitudes amongst veterinary nurses towards pain management in pet rabbits and factors that might shape those attitudes. The survey was advertised at national and international veterinary conferences, in veterinary publications and on social media. Results A total of 284 questionnaires (95% from the UK) were completed and analysed. The majority of respondents (78%) nursed 1-10 rabbits per month and 5.6% of the respondents reported regularly running a rabbit clinic. The respondents were regularly involved in nursing during common procedures such as castration and ovariohysterectomy. Responsibility for post-operative pain assessment was reported to be by "nurses only" (50%), "nurses and vets" (42%) and occasionally by "vets only" (3%). The majority of respondents reported that they did not use a pain scale but often relied on behavioural indicators, while 20% used the Rabbit Grimace Scale. The majority of the respondents reported being "fairly confident" at recognising pain in rabbits. Clinical significance Veterinary nurses are involved in many aspects of rabbit care, and they are generally confident at nursing this species. This survey also suggests the need for more data on the use of pain assessment tools in rabbits and the importance of teamwork between nurses and veterinarians.

BackgroundThere are few studies on the physiology and haematology of rescued bearded capuchin monkeys. These are necessary to better understand the health and welfare status of the animals, including when performing reintroductions, and to avoid zoonoses.MethodsWe aimed to obtain physiological and haematological values, morphometry and parasitological status of 26 bearded capuchins in two rescue centres in Northeast Brazil.ResultsWe found sex- and age-related differences in respiratory rate, body weight and body mass index, but not haematology. The haematological values obtained were significantly different from published data but within the reference intervals for the species. Animals infected with Ancylostoma spp. had significantly lower values in the parameters: haemoglobin concentration, mean corpuscular volume and mean corpuscular haemoglobin concentration than non-infected individuals.ConclusionPhysiological and haematological values of rescued capuchins were similar to those found in previous studies. Ancylostomiasis appears to cause alterations to haematological values of this species.

The authors have withdrawn their manuscript as they are reviewing the study and the manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have anyquestions, please contact the corresponding author.

In this paper we present the X-ray analysis of SDSS DR8 redMaPPer (SDSSRM) clusters using data products from the $XMM$ Cluster Survey (XCS). In total, 1189 SDSSRM clusters fall within the $XMM$-Newton footprint. This has yielded 456 confirmed detections accompanied by X-ray luminosity ($L_{X}$) measurements. Of the detected clusters, 382 have an associated X-ray temperature measurement ($T_{X}$). This represents one of the largest samples of coherently derived cluster $T_{X}$ values to date. Our analysis of the X-ray observable to richness ($\lambda$) scaling relations has demonstrated that scatter in the $T_{X}-\lambda$ relation is roughly a third of that in the $L_{X}-\lambda$ relation, and that the $L_{X}-\lambda$ scatter is intrinsic, i.e. will not be significantly reduced with larger sample sizes. Our analysis of the scaling relation between $L_{X}$ and $T_{X}$ has shown that the fits are sensitive to the selection method of the sample, i.e. whether the sample is made up of clusters detected "serendipitously" compared to those deliberately targeted by $XMM$. These differences are also seen in the $L_{X}-\lambda$ relation and, to a lesser extent, in the $T_{X}-\lambda$ relation. Exclusion of the emission from the cluster core does not make a significant impact to the findings. A combination of selection biases is a likely, but as yet unproven, reason for these differences. Finally, we have also used our data to probe recent claims of anisotropy in the $L_{X}-T_{X}$ relation across the sky. We find no evidence of anistropy, but stress that this may be masked in our analysis by the incomplete declination coverage of the SDSS DR8 sample., Comment: 23 pages, 20 figures, Accepted for publication to MNRAS

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

In December 1919 the U.S. government, in the wake of the famed mail bombings (including to Attorney General A. Mitchell Palmer) and the earlier Seattle General Strike, took a dramatic step. As a part of the broader anti-radical campaign under the Espionage and Sedition Acts, 249 known leftists and many Russians swept up in the famed Palmer Raids - specifically socialists and anarchists - boarded the Buford and set sail for Europe. Among the passengers were notable radicals like Emma Goldman and Alexander Berkman. This work by the Departments of Justice and Labor stands is an important, though underexplored, physical act and moment that institutionalized the first American “Red Scare,” and revealed the broader tensions surrounding “loyalty,” the immigrant population, and anti-radicalism.

Objective This open-label, controlled, randomized study assessed the safety, tolerability, and efficacy of StrataGraft tissue compared to autograft in the treatment of deep partial-thickness (DPT) burns. Methods Thirty subjects with DPT thermal burns (3%–43% total body surface area) were treated with StrataGraft tissue as follows: cohort 1, ≤220 cm2 refrigerated tissue; cohort 2, ≤440 cm2 refrigerated tissue; and cohort 3, ≤440 cm2 cryopreserved tissue. On each subject, two comparable areas of DPT burn were randomized to receive StrataGraft tissue or autograft. Coprimary end points were the percent area of the StrataGraft tissue treatment site undergoing salvage autografting by Day 28 and wound closure of treatment sites by 3 months. Results By Day 28, no StrataGraft tissue treatment sites underwent autografting. By 3 months, 93% and 100% of the StrataGraft tissue and autograft treatment sites achieved complete wound closure, respectively. No significant differences in observer total and overall opinion POSAS scores between StrataGraft tissue and autograft treatment sites were observed at any timepoint. The most common adverse event was pruritus (17%). Conclusions StrataGraft tissue treatment of DPT thermal burns reduced the need for autograft, resulted in wound closure and treatment-site cosmesis comparable to that of autograft, and was well tolerated.

Graphical abstract, The dose emission from DPIs can be affected by the inspiratory parameters achieved by the patient as well as the device in-use. Conventional in-vitro dose emission methodology was used, but instead of using inhalation volume (Vin) of 2 or 4 L and peak inhalation flow (PIF) corresponding to 4 kPa, a range of PIFs (28.3, 60, 90 and 120 L min−1) and Vins (0.5, 0.75, 1, 1.5, 2, and 4 L) were used. The formulation was composed of spray dried Theophylline as a model drug with Lactohale® α lactose monohydrate carrier. The formulation was aerosolised using two DPIs; a low resistance Breezhaler® and high resistance Handihaler®. The formulation showed a consistent dose content uniformity with a Coefficient of Variation (CV) of 1.70%. The drug distribution on the surface of the carrier was obvious from the SE micrographs with some drug particles lodged into lactose crevices. The dose emission after the first inhalation (ED1) and total emitted dose (TED) of theophylline increased with PIF and Vin, irrespective of the inhaler device. However, the dose delivered was superior for the Handihaler® compared to Breezhaler®. Drug retention in the capsule and device was high at low PIFs and Vins and reduced after the second inhalation. Therefore, our study supports the recommendations for patients who cannot achieve sufficient PIF and Vin to inhale twice for each dose to ensure the better clinical outcome.

Periodontal disease is one of the most common conditions affecting dogs worldwide and is reported to be particularly prevalent in racing greyhounds. A range of potential risk factors have been hypothesised. Previous research has suggested that regular tooth brushing can reduce both calculus and gingivitis, but the frequency required is unclear. Here, we report a controlled blinded in situ trial, in which kennel staff brushed 160 racing greyhounds’ teeth (living at six kennel establishments), either weekly, daily or never over a two-month period. All of the visible teeth were scored for calculus and gingivitis, using previously validated scales. We calculated average scores for each of the three teeth groups and overall whole mouth scores, averaging the teeth groups. Changes were compared to the baseline. After two months, the total calculus scores (controlling for baseline) were significantly different in the three treatment groups, (F(2,129) = 10.76, p &lt, 0.001) with both weekly and daily brushing resulting in significant reductions. Gingivitis was also significantly different between groups (F(2,128) = 4.57, p = 0.012), but in this case, only daily brushing resulted in a significant reduction. Although the dogs in different kennels varied significantly in their levels of both calculus (F(5,129) = 8.64, p &lt, 0.001) and gingivitis (F(5,128) = 3.51 p = 0.005), the intervention was similarly effective in all of the establishments. The teeth groups varied, and the incisors were not significantly affected by the treatment. Since the trainers implementing the routine, reported a minimal time commitment and positive experiences, we suggest that daily brushing is recommended for racing greyhounds, and that any instructions or demonstrations should include attention to all teeth groups including the incisors. Similar trials need to be conducted with retired greyhounds since these have been shown to present particularly high levels of periodontal disease.

A species-specific composite pain scale is a prerequisite for adequate pain assessment. The aim of this study was to develop a multidimensional pain scale specific to rabbits (Oryctolagus cuniculus) called the Bristol Rabbit Pain Scale (BRPS). The scale was developed over five phases using a unique combination of methods: focus groups and behavioural observation. The first two phases aimed at identifying descriptors to describe a rabbit in pain, and then reducing their number, both using focus groups. A total of 72 pain descriptors were grouped under six categories (Demeanour, Posture, Facial expression, Attention to the painful area, Audible and Other) and ‘No pain’ descriptors were added. The third phase aimed to confirm, through video observation of rabbits, the categories and descriptors previously described, to reject those terms that were ambiguous, and identify any new descriptors that had not been included in the previous list of descriptors. This led to the rejection of the categories Audible and Attention to the painful area and of 34 descriptors. Seven new descriptors were identified. The last two phases constructed the final format of the BRPS by refining the categories, ranking the descriptors on an ordinal scale and testing the internal reliability of the scale using Cronbach’s alpha test. This led to a composite pain scale of six categories (Demeanour, Posture, Locomotion, Ears, Eyes and Grooming) with four intensities of pain (0, 1, 2, and 3), a total score of 0–18, and a high Cronbach’s alpha coefficient (alpha = 0.843). This BRPS fills an important gap in the field of rabbit medicine and has the potential to improve the assessment and management of pain in rabbits providing veterinary professionals with a novel multidimensional pain assessment tool. Further studies will investigate the clinical utility, validity and reliability of the BRPS.

The growing body of working dog literature includes many examples of scales robustly developed to measure aspects of dog behavior. However, when comparing behavior to working dog ability, most studies rely on training organizations' own long-established ratings of performance, or simply pass/fail at selection or certification as measures of success. Working ability is multifaceted, and it is likely that different aspects of ability are differentially affected by external factors. In order to understand how specific aspects of selection, training, and operations influence a dog's working ability, numerous facets of performance should be considered. An accurate and validated method for quantifying multiple aspects of performance is therefore required. Here, we describe the first stages of formulating a meaningful performance measurement tool for two types of working search dogs. The systematic methodology used was: (1) interviews and workshops with a representative cross-section of stakeholders to produce a shortlist of behaviors integral to current operational performance of vehicle (VS) and high assurance (HAS) search dogs; (2) assessing the reliability and construct validity of the shortlisted behavioral measures (at the behavior and the individual rater level) using ratings of diverse videoed searches by experienced personnel; and (3) selecting the most essential and meaningful behaviors based on their reliability/validity and importance. The resulting performance measurement tool was composed of 12 shortlisted behaviors, most of which proved reliable and valid when assessed by a group of raters. At the individual rater level, however, there was variability between raters in the ability to use and interpret behavioral measures, in particular, more abstract behaviors such as Independence. This illustrates the importance of examining individual rater scores rather than extrapolating from group consensus (as is often done), especially when designing a tool that will ultimately be used by single raters. For ratings to be practically valuable, individual rater reliability needs to be improved, especially for behaviors deemed as essential (e.g., control and confidence). We suggest that the next steps are to investigate why individuals vary in their ratings and to undertake efforts to increase the likelihood that they reach a common conceptualization of each behavioral construct. Plausible approaches are improving the format in which behaviors are presented, e.g., by adding benchmarks and utilizing rater training.

Background: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. Patients and methods: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma. © 2020 European Society for Medical Oncology

SummaryZoonotic infections, such as COVID-19, reside in animal hosts before jumping species to humans. The Carnivora, like mink, carry many zoonoses yet how diversity in host immune genes across species impact upon pathogen carriage are poorly understood. Here we describe a progressive evolutionary downregulation of pathogen sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerisation domain leucine rich repeat receptors (NLRs), acquisition of a unique caspase−1/−4 effector fusion protein that processes gasdermin D pore formation without inducing lytic cell death and the formation of an NLRP3-caspase-8 containing inflammasome that inefficiently processes interleukin-1β (IL-1β). Inflammasomes regulate gut immunity, but the carnivorous diet is antimicrobial suggesting a tolerance to the loss of these immune pathways. The consequences of systemic inflammasome downregulation, however, can reduce the host sensing of specific pathogens such that they can reside undetected in the Carnivora.

Increasing emissions from sources such as construction and burning of biomass from crop residues, roadside and municipal solid waste have led to a rapid increase in the atmospheric concentrations of fine particulate matter (≤2.5 μm; PM2.5) over many Indian cities. Analyses of their chemical profiles are important for receptor models to accurately estimate the contributions from different sources. We have developed chemical source profiles for five important pollutant sources - construction (CON), paved road dust (PRD), roadside biomass burning (RBB), solid waste burning (SWB), and crop residue burning (CPB) - during three intensive campaigns (winter, summer and post-monsoon) in and around Delhi. We obtained chemical characterisations of source profiles incorporating carbonaceous material such as organic carbon (OC) and elemental carbon (EC), water-soluble ions (F−, Cl−, NO2−, NO3−, SO42−, PO43−, Na+ and NH4+), and elements (Mg, Al, Si, P, S, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Br, Rb, Sr, Ba, and Pb). CON was dominated by the most abundant elements, K, Si, Fe, Al, and Ca. PRD was also dominated by crustal elements, accounting for 91% of the total analysed elements. RBB, SWB and CPB profiles were dominated by organic matter, which accounted for 94%, 86.2% and 86% of the total PM2.5, respectively. The database of PM emission profiles developed from the sources investigated can be used to assist source apportionment studies for accurate quantification of the causes of air pollution and hence assist governmental bodies in formulating relevant countermeasures.

Background Carcinoid heart disease (CHD) often complicates neuroendocrine tumours (NET). The prognosis of CHD without intervention is poor; 3 year survival is estimated at 31%. Surgical valve replacement is the only treatment for CHD, but is associated with high 30-day mortality (10–15%). Purpose The aim is to identify pre-operative transthoracic echocardiogram (PTTE) findings that could determine which patients have a high likelihood of post-surgical mortality at 1 year. Methods This retrospective observational cohort study recruited 88 patients with a confirmed diagnosis of CHD between 2005–19 at University Hospital Birmingham; 49 (56%) of these were treated surgically. Indications for surgery: stable NET, symptomatic severe valvular dysfunction, progressive RV dilatation or RV dysfunction, no significant comorbidities. All patients underwent a standard PTTE. PTTE parameters assessed: right ventricular (RV) size, RV function (qualitative), TAPSE, RV fractional area change, RV S wave velocity, left ventricular (LV) size, LV ejection fraction and valve velocities. Surgery was performed by a single surgical team with bioprosthetic valve replacements. Results Patients were followed up for a median of 15 months (IQR: 6–59) after surgery, during which time there were 33 deaths, giving a median survival time of 30 months (IQR: 7–85). Increasingly severe RV dilatation was significantly associated with shorter survival (p=0.032). The estimated survival rate at three years was 67% in those with normal RV size, compared to 24% in the severe RV group (Figure 1). RV basal diameter was assessed used ROC curve analysis for the outcome of one year survival and returned an area under the curve of 0.66 (SE=0.10). Youden's index identified RV diameter >4.8cm to be the optimal cut-off for identifying high-risk patients. One year mortality rates were 26% (7/27) vs. 75% (9/12) in those with RV basal diameter of ≤4.8 vs. >4.8cm (p=0.006). Conclusion A pre-operative right ventricular basal diameter >4.8cm is associated with a near three-fold increase in post-operative mortality at one year. These findings highlight the importance of regular imaging in order to optimise the timing of surgery in patients with CHD. Figure 1. Kaplan-Meier curve of post-op survival Funding Acknowledgement Type of funding source: None

Self-assessments of performance are commonly used in the human workplace, although compared to peer or supervisor ratings, they may be subject to positive biases or leniency. The use of subjective ratings scales in animal sciences is also common, although little consideration is usually given to possible rater bias. Dog handlers, for example, work very closely, and form strong relationships, with their dogs but are also best placed to monitor dog performance since they often work in isolation. Previous work found ratings of search dog performance correlated well between experienced dog trainers, instructors, and scientists; but until now, there has been no investigation into ratings made by a dog’s own handler. We compared handlers’ subjective assessment of their own dog’s search performance to scores given by other handlers and in a second study, to scores made by impartial raters. We found that handlers generally showed leniency; for example scoring their own dogs more favourably for Control (responsiveness to commands) and MotivationStrength of Indication. But the degree of bias varied with the trait being scored and between raters. Such differences may be attributable to greater desirability or importance of favourable scores for certain traits, or a lack of clarity of their precise meaning. Handlers may vary in susceptibility to bias due to differing levels of experience and the extent to which they view their dog’s ability as dependent on their own. The exact causes require further investigation. We suggest working dog agencies provide rater-training to overcome leniency, improve reliability and validity, and to increase handler’s motivation to provide accurate assessments. This study represents one of a series of steps to formulate robust, validated and evidence- based performance rating systems and has relevance to any situation where raters assess their own performance or others (particularly where they may have a vested interest in, or loyalty towards, the ratee).

Toxoplasma gondii is an obligate intracellular parasite that can invade any nucleated cell of any warm-blooded animal. In a previous screen to identify virulence determinants, disruption of gene TgME49_305140 generated a T. gondii mutant that could not establish a chronic infection in mice. The protein product of TgME49_305140, here named TgPL3, is a 277 kDa protein with a patatin-like phospholipase (PLP) domain and a microtubule binding domain. Antibodies generated against TgPL3 show that it is localized to the apical cap. Using a rapid selection FACS-based CRISPR/Cas-9 method, a TgPL3 deletion strain (ΔTgPL3) was generated. ΔTgPL3 parasites have defects in host cell invasion, which may be caused by reduced rhoptry secretion. We generated complementation clones with either wild type TgPL3 or an active site mutation in the PLP domain by converting the catalytic serine to an alanine, ΔTgPL3::TgPL3S1409A (S1409A). Complementation of ΔTgPL3 with wild type TgPL3 restored all phenotypes, while S1409A did not, suggesting that phospholipase activity is necessary for these phenotypes. ΔTgPL3 and S1409A parasites are also virtually avirulent in vivo but induce a robust antibody response. Vaccination with ΔTgPL3 and S1409A parasites protected mice against subsequent challenge with a lethal dose of Type I T. gondii parasites, making ΔTgPL3 a compelling vaccine candidate. These results demonstrate that TgPL3 has a role in rhoptry secretion, host cell invasion and survival of T. gondii during acute mouse infection., Author summary Toxoplasma gondii is a eukaryotic parasite commonly found in warm-blooded animals worldwide. Successful replication of T. gondii within the host relies on its sophisticated cell invasion mechanism. Previous studies found that disruption of the T. gondii gene TgME49_305140 generated a mutant that could not establish a chronic infection in mice. The protein product of this gene, named TgPL3, is large with both patatin-like phospholipase and microtubule binding domains. Here we show that TgPL3 is localized to the apical end of T. gondii, which is used for invasion. A mutant T. gondii strain with a deletion of TgPL3 (ΔTgPL3) was generated. ΔTgPL3 parasites are defective for host cell invasion and do not cause disease in mice, even at high doses. Complementation of the TgPL3 gene back into ΔTgPL3 parasites repairs the invasion and mice infection defects. Moreover, complementation of ΔTgPL3 with a point mutation in the active site of the phospholipase domain (S1409A) did not rescue the invasion and mouse infection defects, suggesting the PLP domain is responsible for these phenotypes. Vaccination of mice with ΔTgPL3 and S1409A parasites protected them against lethal challenge with T. gondii, highlighting the potential of ΔTgPL3 as a vaccine strain.

Fatigue, a frequent and disabling symptom for people with multiple sclerosis (PwMS), inconsistently correlates with white matter (WM) pathology. Network-based analysis, accounting for the manner in which lesions disrupt networks of structurally connected gray matter (GM) regions, may provide additional insight.To identify patterns of WM tract disruption which explain self-reported fatigue severity in PwMS.137 PwMS and 50 age- and sex-matched healthy controls (HC) underwent fatigue assessment and brain MRI. Lesion maps were applied to determine the severity of WM tract disruption between pairs of GM regions. Then, the Network-Based-Statistics tool was applied to identify structural networks whose disruption explained fatigue severity. To determine whether these networks explain unique variance above conventional MRI measures and depression, regressions were applied controlling for age, sex, brain volume, T2-lesion volume, and depression.Patient-perceived fatigue in PwMS was positively associated with overall lesion burden (β = 0.563, p-value 0.001). In contrast, localized disruptions in WM tracts between regions including the amygdala, insula, hippocampus, putamen, temporal pole, caudal-middle-frontal gyrus, rostral-middle-frontal gyrus, inferior-parietal gyrus, and banks of the superior temporal sulcus were significantly negatively correlated with fatigue in PwMS (β = -0.586, p-value 0.001). Average disruption within this specific, localized network explained significant additional variance in fatigue above what was otherwise explained by depression and conventional MRI measures of neuropathology (ΔRAlthough overall lesion burden correlates positively with fatigue in PwMS, localized WM damage between the amygdala, temporal pole, and other connected structures is associated with lower severity of patient-perceived fatigue.

Training new medical odors presents challenges in procuring sufficient target samples, and suitably matched controls. Organizations are often forced to choose between using fewer samples and risking dogs learning individuals or using differently sourced samples. Even when aiming to standardize all aspects of collection, processing, storage and presentation, this risks there being subtle differences which dogs use to discriminate, leading to artificially high performance, not replicable when novel samples are presented. We describe lessons learnt during early training of dogs to detect prostate cancer from urine. Initially, six dogs were trained to discriminate between hospital-sourced target and externally-sourced controls believed to be processed and stored the same way. Dogs performed well: mean sensitivity 93.5% (92.2–94.5) and specificity 87.9% (78.2–91.9). When training progressed to include hospital-sourced controls, dogs greatly decreased in specificity 67.3% (43.2–83.3). Alerted to a potential issue, we carried out a methodical, investigation. We presented new strategically chosen samples to the dogs and conducted a logistic regression analysis to ascertain which factor most affected specificity. We discovered the two sets of samples varied in a critical aspect, hospital-processed samples were tested by dipping the urinalysis stick into the sample, whilst for externally sourced samples a small amount of urine was poured onto the stick. Dogs had learnt to distinguish target aided by the odor of this stick. This highlights the importance of considering every aspect of sample processing even when using urine, often believed to be less susceptible to contamination than media like breath.