Findings of the International Subarachnoid Aneurysm Trial and the National Study of Subarachnoid Haemorrhage in context.

Concern has been expressed about the applicability of the findings of the International Subarachnoid Aneurysm Trial (ISAT) with respect to the relative effects on outcome of coiling and clipping. It has been suggested that the findings of the National Study of Subarachnoid Haemorrhage may have greater relevance for neurosurgical practice. The objective of this paper was to interpret the findings of these two studies in the context of differences in their study populations, design, execution and analysis. Because of differences in design and analysis, the findings of the two studies are not directly comparable. The ISAT analysed all randomized patients by intention-to-treat, including some who did not undergo a repair, and obtained the primary outcome for 99% of participants. The National Study only analysed participants who underwent clipping or coiling, according to the method of repair, and obtained the primary outcome for 91% of participants. Time to repair was also considered differently in the two studies. The comparison between coiling and clipping was susceptible to confounding in the National Study, but not in the ISAT. The two study populations differed to some extent, but inspection of these differences does not support the view that coiling was applied inappropriately in the National Study. Therefore, there are many reasons why the two studies estimated different sizes of effect. The possibility that there were real, systematic differences in practice between the ISAT and the National Study cannot be ruled out, but such explanations must be seen in the context of other explanations relating to chance, differences in design or analysis, or confounding

Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis

Background: Neuropsychiatric symptoms are common in Parkinson’s disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy. // Methods: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model. // Results: We identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI −0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=−0.02, 95% CI −0.43 to 0.39). // Conclusion: Reward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes

An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly

Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL

Improving access to emergent spinal care through knowledge translation : an ethnographic study

Background: For patients and family members, access to timely specialty medical care for emergent spinal conditions is a significant stressor to an already serious condition. Timing to surgical care for emergent spinal conditions such as spinal trauma is an important predictor of outcome. However, few studies have explored ethnographically the views of surgeons and other key stakeholders on issues related to patient access and care for emergent spine conditions. The primary study objective was to determine the challenges to the provision of timely care as well as to identify areas of opportunities to enhance care delivery. Methods: An ethnographic study of key administrative and clinical care providers involved in the triage and care of patients referred through CritiCall Ontario was undertaken utilizing standard methods of qualitative inquiry. This comprised 21 interviews with people involved in varying capacities with the provision of emergent spinal care, as well as qualitative observations on an orthopaedic/neurosurgical ward, in operating theatres, and at CritiCall Ontario’s call centre. Results: Several themes were identified and organized into categories that range from inter-professional collaboration through to issues of hospital-level resources and the role of relationships between hospitals and external organizations at the provincial level. Underlying many of these issues is the nature of the medically complex emergent spine patient and the scientific evidentiary base upon which best practice care is delivered. Through the implementation of knowledge translation strategies facilitated from this research, a reduction of patient transfers out of province was observed in the one-year period following program implementation. Conclusions: Our findings suggest that competing priorities at both the hospital and provincial level create challenges in the delivery of spinal care. Key stakeholders recognized spinal care as aligning with multiple priorities such as emergent/critical care, medical through surgical, acute through rehabilitative, disease-based (i.e. trauma, cancer), and wait times initiatives. However, despite newly implemented strategies, there continues to be increasing trends over time in the number of spinal CritiCall Ontario referrals. This reinforces the need for ongoing inter-professional efforts in care delivery that take into account the institutional contexts that may constrain individual or team efforts

Free-ocean CO2 enrichment (FOCE) systems: present status and future developments

Free-ocean CO2 enrichment (FOCE) systems are designed to assess the impact of ocean acidification on biological communities in situ for extended periods of time (weeks to months). They overcome some of the drawbacks of laboratory experiments and field observations by enabling (1) precise control of CO2 enrichment by monitoring pH as an offset of ambient pH, (2) consideration of indirect effects such as those mediated through interspecific relationships and food webs, and (3) relatively long experiments with intact communities. Bringing perturbation experiments from the laboratory to the field is, however, extremely challenging. The main goal of this paper is to provide guidelines on the general design, engineering, and sensor options required to conduct FOCE experiments. Another goal is to introduce xFOCE, a community-led initiative to promote awareness, provide resources for in situ perturbation experiments, and build a user community. Present and existing FOCE systems are briefly described and examples of data collected presented. Future developments are also addressed as it is anticipated that the next generation of FOCE systems will include, in addition to pH, options for oxygen and/or temperature control. FOCE systems should become an important experimental approach for projecting the future response of marine ecosystems to environmental change

Assessment of interprofessional competence in undergraduate health professions education: protocol for a systematic review of self-report instruments

Background Health practitioners from different professions, and with differing competencies, need to collaborate to provide quality care. Competencies in interprofessional working need developing in undergraduate educational preparation. This paper reports the protocol for a systematic review of self-report instruments to assess interprofessional learning in undergraduate health professionals’ education. Methods We will search PubMed, Web of Science, CINAHL and ERIC from January 2010 onwards. A combination of search terms for interprofessional learning, health professions, psychometric properties, assessment of learning and assessment tools will be used. Two reviewers will independently screen all titles, abstracts and full-texts. Potential conflicts will be resolved through discussion. Quantitative and mixed-methods studies evaluating interprofessional learning in undergraduate health professions education (e.g. medicine, nursing, occupational and physical therapy, pharmacy and psychology) will be included. Methodological quality of each reported instrument, underpinning theoretical frameworks, and the effects of reported interventions will be assessed. The overall outcome will be the effectiveness of instruments used to assess interprofessional competence. Primary outcomes will be the psychometric properties (e.g. reliability, discriminant and internal validity) of instruments used. Secondary outcomes will include time from intervention to assessment, how items relate to specific performance/competencies (or general abstract constructs) and how scores are used (e.g. to grade students, to improve courses or research purposes). Quantitative summaries in tabular format and a narrative synthesis will allow recommendations to be made on the use of self-report instruments in practice. Discussion Many studies use self-report questionnaires as tools for developing meaningful interprofessional education activities and assessing students’ interprofessional competence. This systematic review will evaluate both the benefits and limitations of reported instruments and help educators and researchers (i) choose the most appropriate existing self-report instruments to assess interprofessional competence and (ii) inform the design and conduct of interprofessional competency assessment using self-report instruments. Systematic review registration Open Science Framework [https://osf.io/vrfjn]

Cardiovascular magnetic resonance in emergency patients with multivessel disease or unobstructed coronary arteries: A cost-effectiveness analysis in the UK

Objective To identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway. Design Economic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK. Setting Usual care (with or without CMR) in the NHS. Participants Patients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries. Interventions Model 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone. Main outcome measures Key drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. Results In both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: -£64 (95% CI -£232 to £187)/FFR: £360 (95% CI -£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI -0.0076 to 0.0093)) and (£98 (95% CI -£199 to £488) and 0.0005 QALYs (95% CI -0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups. Conclusions If CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Copper Chaperone for Cu/Zn Superoxide Dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc

BACKGROUND: Small increases in zinc (Zn) consumption above recommended amounts have been shown to reduce copper (Cu) status in experimental animals and humans. Recently, we have reported that copper chaperone for Cu/Zn superoxide dismutase (CCS) protein level is increased in tissues of overtly Cu-deficient rats and proposed CCS as a novel biomarker of Cu status. METHODS: Weanling male Wistar rats were fed one of four diets normal in Cu and containing normal (30 mg Zn/kg diet) or moderately high (60, 120 or 240 mg Zn/kg diet) amounts of Zn for 5 weeks. To begin to examine the clinical relevance of CCS, we compared the sensitivity of CCS to mild Cu deficiency, induced by moderately high intakes of Zn, with conventional indices of Cu status. RESULTS: Liver and erythrocyte CCS expression was significantly (P < 0.05) increased in rats fed the Zn-60 and/or Zn-120 diet compared to rats fed normal levels of Zn (Zn-30). Erythrocyte CCS expression was the most sensitive measure of reduced Cu status and was able to detect a decrease in Cu nutriture in rats fed only twice the recommended amount of Zn. Liver, erythrocyte and white blood cell CCS expression showed a significant (P < 0.05) inverse correlation with plasma and liver Cu concentrations and caeruloplasmin activity. Unexpectedly, rats fed the highest level of Zn (Zn-240) showed overall better Cu status than rats fed a lower level of elevated Zn (Zn-120). Improved Cu status in these rats correlated with increased duodenal mRNA expression of several Zn-trafficking proteins (i.e. MT-1, ZnT-1, ZnT-2 and ZnT-4). CONCLUSION: Collectively, these data show that CCS is a sensitive measure of Zn-induced mild Cu deficiency and demonstrate a dose-dependent biphasic response for reduced Cu status by moderately high intakes of Zn