Risk based testing for Mycobacterium bovis following a clinical case in a zoological garden

This document is the version of a published work that appeared in final form in Journal of Zoo and Aquarium Research. To access the final edited and published work see http://dx.doi.org/10.19227/jzar.v2i1.62Mycobacterium bovis is a strictly controlled disease. Outbreaks in zoos result in animal movement bans, disease investigation and euthanasia of infected animals. Both specific tuberculosis legislation and European Directive 92/65, often known as the "Balai" directive, require zoos to be free from tuberculosis in order to import and export animals. This paper describes the use of a risk based targeted testing programme for tuberculosis following a confirmed case of disease. This regime ensured a comprehensive but proportionate disease investigation developed through close co-operation with government veterinary officials, therefore limiting the impact of anaesthetic procedures and animal handling required to complete the necessary testing

Becoming collaborative: a study of intra-organisational relational dynamics

The intra-organisational relationships of through-life support services providers are complex, especially given the multifaceted nature of the provision required. For example, capabilities within the UK highways maintenance arena must support engineering design, routine maintenance and the ongoing management of the network. While collaboration in construction projects has formed a major research focus in recent years, there is a paucity of work examining collaboration in-flight. Through a micro-practices approach two contracts delivering highway infrastructure maintenance and renewal services are examined to explore the intra-organisational relationships that determine the quality of service delivered. Despite the rhetoric of collaboration and integrated working that pervades the contemporary project discourse, there was a clear focus on addressing immediate technical and commercial concerns rather than on creating the conditions for integrated working to flourish. On the occasions where the collaborative environment was prioritised a more integrated service was delivered. In contrast to other accounts of the ways collaborative working shapes performance, this research reveals an acute need for a sustained collaborative effort; as soon as ‘collaborative working’ was normalised, the level of integration and seamlessness of service was diminished. This questions normative notions of what defines collaborative working in projects, and suggests a need for re-framing it as an ongoing accomplishment of actors involved. Such a perspective resonates with notions of ‘organizational becoming’, particularly in that attempts to foster collaboration are themselves constitutive of the unfolding and shifting nature of intra-organizational relationships that emerge in complex contractual arrangements

Contracts, collaboration and conflict resolution: Forging relationships in the face of adversity

Contracts have traditionally been used to coordinate expectations and structure relations, with clients using them to define and manage commercial relationships with suppliers. Whilst extant literature is concerned with large capital projects of a ‘one-off’ nature, this research is concerned with individual contracts within ‘on-going’ strategic infrastructure maintenance programmes. Whereas relational contracting strategies are associated with better client-supplier relations, ‘on-going’ strategic infrastructure maintenance programmes tend not to use such contracts. This presents a problematic contextual backdrop for the successful delivery of such programmes. This research seeks to understand the conditions under which collaborative working arrangements can be achieved within non-collaborative commercial frameworks. An in-depth case study is used to explore collaboration within transactional lump-sum arrangements. The research reveals how the interpretation of a lump-sum contract led to the prioritisation of cost savings over quality and initially stimulated behaviours that inhibited collaboration. However, over time informal working practices and a collaborative working philosophy emerged reminiscent of that expected under relational contracts. Collaboration was established in an informal project culture that ran counter to a persistent adversarial commercial framework. Formal performance measures were resolved and performance appeared satisfactory to the client, even though it was enabled by informal working practices running counter to the client’s chosen contract. Contra much previous work that deterministically positions relationships as a product of the contract, this study reveals that collaborative behaviours can thrive even in unfavourable contractual conditions. This, in turn, calls for a re-theorisation of the relationship between contracts and behaviours within long-term programme arrangements

Patient-reported outcome measures for clinical decision-making in outpatient follow-up: validity and reliability of a renal disease questionnaire

Background Patient-reported outcome measures are increasingly used by clinicians to support communication in telephone- or face-to-face consultations with patients. A renal disease questionnaire has been developed, but not sufficiently evaluated through clinimetrics in clinical setting. Hence, we aimed to evaluate the content validity, construct validity and the test–retest reliability of a renal disease questionnaire to be used for clinical decision-making. Methods A content, construct validity and test–retest reliability study was conducted in 3 nephrology outpatient clinics in Central Denmark Region, Denmark. Content validity (face validity, comprehensibility and relevance) was assessed among 8 patients and 6 clinicians. Reliability was assessed by asking outpatients with chronic kidney disease to complete the questionnaire twice. Reliability was assessed by kappa statistics and agreement by percentage. Construct validity was determined using 4 a priori defined hypotheses and comparing 2 known groups. Results Five new domains emerged, 6 items were rephrased and 3 items were removed following the content validity test. A total of 160 patients completed the questionnaire with median 8 days (IQR 2 days) between assessments. The test–retest reliability parameters of the single items in the questionnaire were substantial to almost perfect as all the observed weighted kappa values ranged from 0.61 to 0.91, 95% CI (0.34 to 0.95). In total, 61% of the single items showed almost perfect agreement. In total, 3 of the 4 hypotheses were accepted and 44% of the items showed satisfying known-group discriminative validity. Conclusion A renal disease questionnaire used for clinical decision-making in outpatient follow-up showed acceptable content validity and substantial to almost perfect reliability. Sufficient construct validity was not established. Incorporating the questionnaire into routine clinical practice may improve the evaluation of disease burden in patients with chronic kidney disease

Shifts of criteria or neural timing? The assumptions underlying timing perception studies

In timing perception studies, the timing of one event is usually manipulated relative to another, and participants are asked to judge if the two events were synchronous, or to judge which of the two events occurred first. Responses are analyzed to determine a measure of central tendency, which is taken as an estimate of the timing at which the two events are perceptually synchronous. When these estimates do not coincide with physical synchrony, it is often assumed that the sensory signals are asynchronous, as though the transfer of information concerning one input has been accelerated or decelerated relative to the other. Here we show that, while this is a viable interpretation, it is equally plausible that such effects are driven by shifts in the criteria used to differentiate simultaneous from asynchronous inputs. Our analyses expose important ambiguities concerning the interpretation of simultaneity judgement data, which have hitherto been underappreciated

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, PPeer reviewe

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe