Recurrent, life-threatening PE in the setting of popliteal vein aneurysm in pregnancy: a case report.

BACKGROUND: Popliteal vein aneurysms (PVA) are a rare clinical entity with unknown etiology that pose a significant risk for venous thromboembolic events (VTE). The current literature supports anticoagulation and operative management. There are few case reports of PVA in pregnancy. We present a unique case of a pregnant patient with recurrent pulmonary embolism (PE) in the setting of PVA with intra-aneurysmal thrombosis who ultimately underwent surgical excision. CASE PRESENTATION: A previously healthy 34-year-old G2P1 at 30 weeks gestation presented to the emergency department with shortness of breath and chest pain. She was diagnosed with PE and subsequently required intensive care unit (ICU) admission and thrombolysis for a massive PE. While on a therapeutic dose of tinzaparin she had recurrence of PE in the post-partum period. She was treated with supratherapeutic tinzaparin and subsequently transitioned to warfarin. She was found to have a PVA and ultimately underwent successful PVA ligation. She remains on anticoagulation for secondary prevention of VTE. CONCLUSIONS: PVA are a rare but potentially fatal source of VTE. Patients most commonly present with symptoms of PE. The risk of VTE is elevated in the pro-thrombotic states of pregnancy and the post-partum period due to both physiologic and anatomical changes. The recommended management of PVA with PE is anticoagulation and surgical resection of the aneurysm, however this can be complicated in the setting of pregnancy. We demonstrated that pregnant patients with PVA can be temporized with medical management to avoid surgical intervention during pregnancy, but require close symptom monitoring and serial imaging to reassess the PVA, with high index of suspicion for recurrent VTE. Ultimately, patients with PVA and PE should undergo surgical resection to reduce the risk of recurrence and long-term complications. The ideal duration of post-operative anticoagulation remains unclear, and should likely be decided on based on risks, benefits, values, and shared decision making with the patient and their care provider.

The impulsive horse: Comparing genetic, physiological and behavioral indicators to those of human addiction.

Stress and genotype elicit changes in impulse control in a range of species that are attributable to adaptations in both the central and peripheral nervous system. We examined aspects of this mechanism in the horse by assessing the effect of a dopamine receptor genotype (DRD4) and central dopaminergic tone (measured via spontaneous blink rate [SBR] and behavioral initiation rate [BIR]), on measures of impulsivity, compulsivity (3-choice serial reaction time task) and sympathetic/ parasympathetic system balance (heart rate variability [HRV]). Genotype did not have a significant effect on any of the parameters measured. SBR but not BIR correlated significantly with levels of impulsivity. There was no clear association of HRV parameters with either measures of central dopaminergic activity or impulsivity/compulsivity. Overall, some elements of the data suggest that the horse may be a useful animal model for assessing the genetic and environmental factors that lead to the physiological and behavioral phenotype of human addiction, particularly when considering the relationship between central dopaminergic tone and impulsivity.

Survival after inpatient or outpatient pulmonary rehabilitation in patients with fibrotic interstitial lung disease: a multicentre retrospective cohort study.

BACKGROUND: The impact of pulmonary rehabilitation (PR) on survival in patients with fibrotic interstitial lung disease (ILD) is unknown. Given the challenges conducting a large randomised controlled trial, we aimed to determine whether improvement in 6-minute walk distance (6MWD) was associated with better survival. METHODS: This retrospective, international cohort study included patients with fibrotic ILD participating in either inpatient or outpatient PR at 12 sites in 5 countries. Multivariable models were used to estimate the association between change in 6MWD and time to death or lung transplantation accounting for clustering by centre and other confounders. RESULTS: 701 participants (445 men and 256 women) with fibrotic ILD were included. The mean±SD ages of the 196 inpatients and 505 outpatients were 70±11 and 69±12 years, respectively. Baseline/changes in 6MWD were 262±128/55±83 m for inpatients and 358±125/34±65 m for outpatients. Improvement in 6MWD during PR was associated with lower hazard rates for death or lung transplant on adjusted analysis for both inpatient (HR per 10 m 0.94, 95% CI 0.91 to 0.97, p<0.001) and outpatient PR (HR 0.97, 95% CI 0.95 to 1.00, p=0.042). Participation in ≥80% of planned outpatient PR sessions was associated with a 33% lower risk of death (95% CI 0.49% to 0.92%). CONCLUSIONS: Patients with fibrotic ILD who improved physical performance during PR had better survival compared with those who did not improve performance. Confirmation of these hypothesis-generating findings in a randomised controlled trial would be required to definitely change clinical practice, and would further support efforts to improve availability of PR for patients with fibrotic ILD.

A massive rock and ice avalanche caused the 2021 disaster at Chamoli, Indian Himalaya.

On 7 February 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. More than 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27 × 106 cubic meters of rock and glacier ice collapsed from the steep north face of Ronti Peak. The rock and ice avalanche rapidly transformed into an extraordinarily large and mobile debris flow that transported boulders greater than 20 meters in diameter and scoured the valley walls up to 220 meters above the valley floor. The intersection of the hazard cascade with downvalley infrastructure resulted in a disaster, which highlights key questions about adequate monitoring and sustainable development in the Himalaya as well as other remote, high-mountain environments.

Psoriasis: The Skin I'm In. Development of a behaviour change tool to improve the care and lives of people with psoriasis.

BACKGROUND: Psoriasis is a long-term skin condition associated with considerable life impairment. Extensive literature regarding the needs of patients with psoriasis is not translated into clinical practice. AIM: To explore and communicate the experience of living with psoriasis and interacting with healthcare professionals (HCPs). METHODS: In total, 21 patients attending a tertiary adult psoriasis service were interviewed individually. Interviews were recorded and transcribed, then the transcripts were examined and thematic analyses and qualitative content analysis performed. The results were communicated via a short film. RESULTS: Three key themes were identified: comparison with cancer, misalignment of response with need and fear of social exclusion. Cancer comparison subthemes included poorer services, lack of awareness and trivialization of psoriasis compared with cancer. Misalignment subthemes related to lack of knowledge and inappropriate response of HCPs and society towards psoriasis. Fear of social exclusion subthemes included erroneous belief of psoriasis being contagious and the expectation of rejection. Consequent emotions of fear, shame and anxiety resulted in avoidant behaviours, which perpetuated social exclusion. Participants valued active listening, shared decision-making and communication of hope regarding treatment by HCPs. CONCLUSION: Despite extensive research into psoriasis and the availability of effective treatment for many patients, people with psoriasis live unnecessarily impaired lives and have unsatisfactory healthcare experiences. Storytelling techniques provide a method to communicate scientific information in a way that may drive change in delivery of healthcare and improve the lives of patients.

Skeletal muscle mitoflashes, pH, and the role of uncoupling protein-3.

Mitochondrial reactive oxygen species (ROS) are important cellular signaling molecules, but can cause oxidative damage if not kept within tolerable limits. An important proximal form of ROS in mitochondria is superoxide. Its production is thought to occur in regulated stochastic bursts, but current methods using mitochondrial targeted cpYFP to assess superoxide flashes are confounded by changes in pH. Accordingly, these flashes are generally referred to as 'mitoflashes'. Here we provide regulatory insights into mitoflashes and pH fluctuations in skeletal muscle, and the role of uncoupling protein-3 (UCP3). Using quantitative confocal microscopy of mitoflashes in intact muscle fibers, we show that the mitoflash magnitude significantly correlates with the degree of mitochondrial inner membrane depolarization and ablation of UCP3 did not affect this correlation. We assessed the effects of the absence of UCP3 on mitoflash activity in intact skeletal muscle fibers, and found no effects on mitoflash frequency, amplitude or duration, with a slight reduction in the average size of mitoflashes. We further investigated the regulation of pH flashes (pHlashes, presumably a component of mitoflash) by UCP3 using mitochondrial targeted SypHer (mt-SypHer) in skeletal muscle fibers. The frequency of pHlashes was significantly reduced in the absence of UCP3, without changes in other flash properties. ROS scavenger, tiron, did not alter pHlash frequency in either WT or UCP3KO mice. High resolution respirometry revealed that in the absence of UCP3 there is impaired proton leak and Complex I-driven respiration and maximal coupled respiration. Total cellular production of hydrogen peroxide (H2O2) as detected by Amplex-UltraRed was unaffected. Altogether, we demonstrate a correlation between mitochondrial membrane potential and mitoflash magnitude in skeletal muscle fibers that is independent of UCP3, and a role for UCP3 in the control of pHlash frequency and of proton leak- and Complex I coupled-respiration in skeletal muscle fibers. The differential regulation of mitoflashes and pHlashes by UCP3 and tiron also indicate that the two events, though may be related, are not identical events.

Bayesian latent class estimation of sensitivity and specificity parameters of diagnostic tests for bovine tuberculosis in chronically infected herds in Northern Ireland.

In the European Union, the recommended ante-mortem diagnostic methods for bovine tuberculosis (bTB) include the single intradermal cervical comparative tuberculin (SICCT) test and the interferon-gamma (IFN-γ) test as an ancillary test. The SICCT test has a moderate sensitivity (Se) and high specificity (Sp), while the IFN-γ test has good Se, but a lower Sp than the SICCT test. A retrospective Bayesian latent class analysis was conducted on 71,185 cattle from 806 herds chronically infected with bTB distributed across Northern Ireland (NI) to estimate the Se and Sp of the common ante-mortem tests and meat inspection. Analyses were also performed on data stratified by farming type and herd location to explore possible differences in test performance given the heterogeneity in the population. The mean estimates in chronically infected herds were: (1) 'standard' SICCT: Se 40.5-57.7%, Sp 96.3-99.7%; (2) 'severe' SICCT: Se 49.0%-60.6%, Sp 94.4-99.4%; (3) IFN-γ(bovine-avian) using a NI optical density (OD) cut-off difference of 0.05: IFN-γ(B-A)NI: Se 85.8-93.0%, Sp 75.6-96.2%; (4) IFN-γ(bovine-avian) using a standard 'commercial' OD cut-off difference of 0.1: IFN-γ(B-A)0.1: Se 83.1-92.1%, Sp 83.1-97.3%; and (5) meat inspection: Se 49.0-57.1% Se, Sp 99.1-100%. Se estimates were lower in cattle from dairy farms than from beef farms. There were no notable differences in estimates by location of herds. Certain population characteristics, such as production type, might influence the ability of bTB tests to disclose truly infected cases.

An analysis of effects of heterozygosity in dairy cattle for bovine tuberculosis resistance.

Genetic selection of cattle more resistant to bovine tuberculosis (bTB) may offer a complementary control strategy. Hypothesising underlying non-additive genetic variation, we present an approach using genome-wide high density markers to identify genomic loci with dominance effects on bTB resistance and to test previously published regions with heterozygote advantage in bTB. Our data comprised 1151 Holstein-Friesian cows from Northern Ireland, confirmed bTB cases and controls, genotyped with the 700K Illumina BeadChip. Genome-wide markers were tested for associations between heterozygosity and bTB status using marker-based relationships. Results were tested for robustness against genetic structure, and the genotypic frequencies of a significant locus were tested for departures from Hardy-Weinberg equilibrium. Genomic regions identified in our study and in previous publications were tested for dominance effects. Genotypic effects were estimated through ASReml mixed models. A SNP (rs43032684) on chromosome 6 was significant at the chromosome-wide level, explaining 1.7% of the phenotypic variance. In the controls, there were fewer heterozygotes for rs43032684 (P < 0.01) with the genotypic values suggesting that heterozygosity confers a heterozygote disadvantage. The region surrounding rs43032684 had a significant dominance effect (P < 0.01). SNP rs43032684 resides within a pseudogene with a parental gene involved in macrophage response to infection and within a copy-number-variation region previously associated with nematode resistance. No dominance effect was found for the region on chromosome 11, as indicated by a previous candidate region bTB study. These findings require further validation with large-scale data.

Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows.

BACKGROUND: Susceptibility to Mycobacterium bovis infection in cattle is governed in part by host genetics. However, cattle diagnosed as infected with M. bovis display varying signs of pathology. The variation in host response to infection could represent a continuum since time of exposure or distinct outcomes due to differing pathogen handling. The relationships between host genetics and variation in host response and pathological sequelae following M. bovis infection were explored by genotyping 1966 Holstein-Friesian dairy cows at 538,231 SNPs with three distinct phenotypes. These were: single intradermal cervical comparative tuberculin (SICCT) test positives with visible lesions (VLs), SICCT-positives with undetected visible lesions (NVLs) and matched controls SICCT-negative on multiple occasions. RESULTS: Regional heritability mapping identified three loci associated with the NVL phenotype on chromosomes 17, 22 and 23, distinct to the region on chromosome 13 associated with the VL phenotype. The region on chromosome 23 was at genome-wide significance and candidate genes overlapping the mapped window included members of the bovine leukocyte antigen class IIb region, a complex known for its role in immunity and disease resistance. Chromosome heritability analysis attributed variance to six and thirteen chromosomes for the VL and NVL phenotypes, respectively, and four of these chromosomes were found to explain a proportion of the phenotypic variation for both the VL and NVL phenotype. By grouping the M. bovis outcomes (VLs and NVLs) variance was attributed to nine chromosomes. When contrasting the two M. bovis infection outcomes (VLs vs NVLs) nine chromosomes were found to harbour heritable variation. Regardless of the case phenotype under investigation, chromosome heritability did not exceed 8% indicating that the genetic control of bTB resistance consists of variants of small to moderate effect situated across many chromosomes of the bovine genome. CONCLUSIONS: These findings suggest the host genetics of M. bovis infection outcomes is governed by distinct and overlapping genetic variants. Thus, variation in the pathology of M. bovis infected cattle may be partly genetically determined and indicative of different host responses or pathogen handling. There may be at least three distinct outcomes following M. bovis exposure in dairy cattle: resistance to infection, infection resulting in pathology or no detectable pathology.

Assessment of concurrent infection with bovine viral diarrhoea virus (BVDV) and Mycobacterium bovis: A herd-level risk factor analysis from Northern Ireland.

Bovine viral diarrhoea virus (BVDV) is a significant pathogen of cattle, leading to severe economic and animal-welfare impacts. Furthermore, the pathogen has been associated with impacting the progression or spread of other pathogens (e.g. Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB)). During this study we investigated (i) risk factors for BVDV at a herd-level and (ii) whether there was any association between BVDV and herd-level bTB risk. The data for this study were gathered from a voluntary BVDV control programme in Northern Ireland (2013-2015) based on the identification of virus positive animals through tissue tag testing of calves. We assigned a herd-level BVDV status to 2827 participating herds, where a herd was assumed "infected" if one or more animals tested positive for BVDV. Two model suites were developed. Firstly, we assessed risk factors for BVDV herd status using multivariable logit random-effects modelling, aggregating to the calendar year level (2013-2015; n=4828; model 1). Secondly, we aggregated data across the three years of the study to give an overall status for the whole study period (n=2827; logistic model 2). Risk factors included year, herd-type, herd size, number of births, inward trade moves, calf mortality, and region. Furthermore, the herd-level bovine tuberculosis status (based on the single intradermal comparative cervical tuberculin (SICCT) test outcomes, or confirmation at post-mortem), or the size of bTB breakdowns (number of SICCT test positive animals), of herds was also investigated to assess whether there was an association (co-infection) with herd BVDV status. The final models suggested that BVDV herd status was positively associated with increased levels of calf mortality, herd size, number of births, the number of BVDV tests undertaken and the number of animals introduced to the herd. There was a significant univariable positive association between BVDV status, and SICCT breakdown risk, breakdown size and confirmed bTB status in model 2. However, there was no evidence of significant associations between bTB status (using SICTT status, confirmed status or herd breakdown size) and BVDV status in final multivariable models when controlling for other significant confounders. These results provide information for action for the future control and eradication of BVDV in Northern Ireland, though these data provide little support for the hypothesised association between BVDV and bTB status at herd-level. Further animal-level analyses are necessary to investigate whether there is support for a BVD-bTB co-infection association, including the impact of co-infection on the severity of infection.

An exploratory study using framework analysis to investigate health-seeking behaviour in patients with psoriasis.

BACKGROUND: Psoriasis is a long-term inflammatory skin disorder, with negative effects on employment, relationships and social function, frequently causing reduced quality of life. People with psoriasis often present to secondary care late into their condition but the reasons for this are unknown. OBJECTIVES: To examine the patient pathway, health-seeking behaviour and drivers for referral to secondary care in patients with psoriasis. METHODS: Sixteen patients with mild-to-severe psoriasis, newly referred to secondary care participated in a semi-structured interview. Scripts were analysed by a thematic framework. RESULTS: The median duration of time living with psoriasis was 15 years at referral. Drivers of secondary care referral included rapid deterioration or extremis, development of comorbidities, knowledge of treatment options, and influence of partners and friends. Reasons for late presentation to secondary care include familial experience of psoriasis, lack of follow-up after the initiation of treatments, beliefs that psoriasis is incurable and must be tolerated, and that psoriasis is not life threatening and therefore not worthy of medical help and difficulty in obtaining a secondary care referral. A common pathway from seeking help at psoriasis onset, evolving into the development of delayed health seeking later in the pathway, was identified. CONCLUSIONS: Identifying the causes of delay in presentation to secondary care and effective treatment ascertains key areas to target. Health seeking early in the disease pathway provides a 'window of opportunity' for intervention, which may enable people with psoriasis to obtain early, effective treatment and achieve their full life potential.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

Biological Features of Human Papillomavirus-related Head and Neck Cancers Contributing to Improved Response.

Head and neck squamous cell carcinomas (HNSCC) are the sixth most common malignancy globally, and an increasing proportion of oropharyngeal HNSCCs are associated with the human papillomavirus (HPV). Patients with HPV-associated tumours have markedly improved overall and disease-specific survival compared with their HPV-negative counterparts when treated with chemoradiation. Although the difference in outcomes between these two groups is clearly established, the mechanism underlying these differences remains an area of investigation. Data from preclinical, clinical and genomics studies have started to suggest that an increase in radio-sensitivity of HPV-positive HNSCC may be responsible for improved outcomes, the putative mechanisms of which we will review here. The Cancer Genome Atlas and others have recently documented a multitude of molecular differences between HPV-positive and HPV-negative tumours. Preclinical investigations by multiple groups have explored possible mechanisms of increased sensitivity to therapy, including examining differences in DNA repair, hypoxia and the immune response. In addition to differences in the response to therapy, some groups have started to investigate phenotypic differences between the two diseases, such as tumour invasiveness. Finally, we will conclude with a brief review of ongoing clinical trials that are attempting to de-escalate treatment to minimise long-term toxicity while maintaining cure rates. New insights from preclinical and genomic studies may eventually lead to personalised treatment paradigms for HPV-positive patients.

Understanding the concept of a reflective surface: can sheep improve navigational ability through the use of a mirror?

Mirror image-induced stimulation and the ability to use the mirror to improve navigational ability for the purpose of object location are considered measures of animal cognitive ability. The purpose of this study was to assess these cognitive abilities in sheep (Ovis aries) as part of a larger programme profiling the cognitive ability of this animal species. Three separate groups of sheep [(n = 29); 10 Welsh Mountain, 8 Norfolk Horned and 11 Borderdale] were trained (≥80 % criterion) to locate a salient object (yellow bucket containing cereal-based food) in one of two possible positions, from one of two possible starting points. Each group of sheep was then divided into two sub-groups. One sub-group was exposed to a mirror over a period of 15 days (mirror exposed), whilst the other group remained mirror naïve. All animals were then retested within the choice maze using the mirror, where two out of the possible four bucket positions were now 'apparent' (as reflections in the mirror), in order to assess whether mirror-exposed animals had a more accurate representation of the real bucket position. Sheep exhibited two out of the three archetypal stages of mirror-induced behaviour, namely social/exploratory and contingency behaviour, with differences existing between breeds. Welsh Mountain sheep spent significantly more time fixating on the self-image and touching the self-image with their muzzle than the other two breeds. During the test phase, no overall differences in performance were observed between the mirror-exposed and mirror-naïve groups. However, Welsh Mountain sheep did perform significantly more correct responses overall, compared to the other two breeds. Although the data did not convincingly demonstrate that sheep could use a reflective surface to improve their navigational ability, the observed differences between groups suggests that some breeds of sheep may demonstrate better navigational ability as well as having a greater engagement with the self-image than others.

Enteric fever in the Pacific: a regional retrospective study from Auckland, New Zealand.

BACKGROUND: There are limited clinical data on enteric fever in the Pacific and New Zealand (NZ) compared with the Indian subcontinent (ISC) and South-East Asia (SEA). Our objective was to describe enteric fever in Auckland - a large Pacific city, focusing on disease acquired in these regions. METHODS: We reviewed enteric fever cases hospitalised in Auckland from January 2005 to December 2010. RESULTS: Microbiologically confirmed EF was identified in 162 patients. Travel regions: Pacific, 40 cases (25%) (Samoa, 38; Fiji, two), ISC, 72 (44%), SEA, seven (4%), other, three (2%), no travel, 40 (25%). Enteric fever rates for Auckland resident travellers were: India 50.3/100 000; Samoa 19.7/100 000.All Pacific cases were Salmonella Typhi. Of local isolates (without travel history), 38 were S. Typhi (36 fully susceptible, one multi-drug resistant (MDR) + nalidixic acid resistant (NAR), one unknown) and two S. Paratyphi (both NAR). Of non-Pacific travel, 56/82 (69%) isolates were S. Typhi, the remainder S. Paratyphi (15 isolates were fully susceptible, only 1% were MDR). Significant associations of serotype and antibiotic resistance with different travel regions and similarity of phage types (local and Pacific) were observed. Headache, vomiting and acute kidney injuries were more frequent with Pacific travel, while abdominal distension and cholecystitis with local disease. Shorter duration of treatment in the Pacific group was seen despite length of stay in hospital not being reduced. Local cases were associated with longer hospital admissions. CONCLUSIONS: One half of cases in Auckland are acquired either from Pacific or locally. Similarities mean that disease acquired locally is likely of Pacific origin.

Psoriasis: snapshots of the unspoken: using novel methods to explore patients' personal models of psoriasis and the impact on well-being.

BACKGROUND: People with psoriasis report high levels of undermanaged distress. This is compounded by the problem that some patients find it difficult to discuss their emotions. Distress prevents optimal self-management, which may exacerbate psoriasis flares, thereby creating a vicious cycle. OBJECTIVES: To offer people with psoriasis a novel way of expressing their personal models of psoriasis in order to gain a better understanding of their experiences of living with the condition. METHODS: We used a qualitative technique - asking people with psoriasis to complete a postcard entitled 'Dear Psoriasis...' - to collect survey data on their personal models of psoriasis. RESULTS: One hundred and four returned postcards provided new insights into the extent of and reasons for distress in psoriasis. Seven dominant themes emerged: identity and relationships; battleground; control; emotional consequences; hypervigilance; coping; treatment burden. CONCLUSIONS: Reports of distress were common, and for many it was long-standing. Some reported low self-esteem and self-denigration bordering on self-loathing, and described being hypervigilant and in a constant battle with their skin. Many people did not expect to have intimate relationships, resulting in reduced social support for patients in the future. This research underscores the need for patient support and psychological treatment to be made available as part of routine care.

Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis.

Tuberculosis (TB) caused by Mycobacterium bovis is a re-emerging disease of livestock that is of major economic importance worldwide, as well as being a zoonotic risk. There is significant heritability for host resistance to bovine TB (bTB) in dairy cattle. To identify resistance loci for bTB, we undertook a genome-wide association study in female Holstein-Friesian cattle with 592 cases and 559 age-matched controls from case herds. Cases and controls were categorised into distinct phenotypes: skin test and lesion positive vs skin test negative on multiple occasions, respectively. These animals were genotyped with the Illumina BovineHD 700K BeadChip. Genome-wide rapid association using linear and logistic mixed models and regression (GRAMMAR), regional heritability mapping (RHM) and haplotype-sharing analysis identified two novel resistance loci that attained chromosome-wise significance, protein tyrosine phosphatase receptor T (PTPRT; P=4.8 × 10(-7)) and myosin IIIB (MYO3B; P=5.4 × 10(-6)). We estimated that 21% of the phenotypic variance in TB resistance could be explained by all of the informative single-nucleotide polymorphisms, of which the region encompassing the PTPRT gene accounted for 6.2% of the variance and a further 3.6% was associated with a putative copy number variant in MYO3B. The results from this study add to our understanding of variation in host control of infection and suggest that genetic marker-based selection for resistance to bTB has the potential to make a significant contribution to bTB control.