Microglia Regulate Pruning of Specialized Synapses in the Auditory Brainstem.

The assembly of uniquely organized sound localization circuits in the brainstem requires precise developmental mechanisms. Glial cells have been shown to shape synaptic connections in the retinogeniculate system during development, but their contributions to specialized auditory synapses have not been identified. Here we investigated the role of microglia in auditory brainstem circuit assembly, focusing on the formation and pruning of the calyx of Held in the medial nucleus of the trapezoid body (MNTB). Microglia were pharmacologically depleted in mice early in development using subcutaneous injections of an inhibitor of colony stimulating factor 1 receptor, which is essential for microglia survival. Brainstems were examined prior to and just after hearing onset, at postnatal days (P) 8 and P13, respectively. We found that at P13 there were significantly more polyinnervated MNTB neurons when microglia were depleted, consistent with a defect in pruning. Expression of glial fibrillary acidic protein (GFAP), a mature astrocyte marker that normally appears in the MNTB late in development, was significantly decreased in microglia-depleted mice at P13, suggesting a delay in astrocyte maturation. Our results demonstrate that monoinnervation of MNTB neurons by the calyx of Held is significantly disrupted or delayed in the absence of microglia. This finding may reflect a direct role for microglia in synaptic pruning. A secondary role for microglia may be in the maturation of astrocytes in MNTB. These findings highlight the significant function of glia in pruning during calyx of Held development

Unlearning and patient safety

This chapter adds to the growing body of literature on unlearning by contributing a model applicable to the context of professional organisations, and more specifically to healthcare and patient safety. An overview of the global patient safety agenda is described and a gap in implementing sustained safety improvement identified. The UK’s efforts to bridge this gap in patient safety by transforming their NHS into a ‘learning organisation’ are discussed. The unlearning literature is reviewed and an updated model of unlearning conceptualized that contains three dimensions relevant to the study of professionals: cognitive, cultural and political. As a research agenda, this chapter provides a starting point for thinking about how unlearning can be studied in organisations; establishing a theoretical foundation for future study

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Maxwell’s defense of revolution, or how academia can help transform and save the world

Review of Maxwell, N. (2014) Global philosophy: What philosophy ought to be? Exeter, UK: Imprint-Academic, Societas – Essays in Political & Cultural Criticism. (Pb, pp.192. ISBN 9781845407674).In his recent book, Nicholas Maxwell revisits for the most part ideas, arguments, and positions he has been defending quite forcefully for the past 40 years or so. These include his conceptions of what philosophy ought to be, about the nature of science and its progress-making features, how to best construe empiricism and rationality, his take on the history and philosophy of science, on philosophy and the history of philosophy, the nature of (academic) inquiry, and finally, his position about the role of education and the university more generally in view of his rather pessimistic yet compellingly realistic diagnosis of the problems and challenges confronting our world at this point in our history

Clusters' last stand: Toward a theory of the process of meaning-making in science

The nature of the process of meaning-making in science has been one of the central problems in the philosophy of science of the 20th century. Yet, in spite of strenuous efforts by many able philosophers and historians of science over the past three decades or so, our understanding of this process continues to be unsatisfactory and fragmented at best. The need for an adequate account has been particularly exacerbated by the "infamous" and often misinterpreted problem of incommensurability (of meaning), and its alleged consequence, the incomparability of scientific theories--which presumably threatens the rationality, objectivity, and progress of science. In this project, I argue that a new and revised cluster theory can be articulated, which meets the objections typically raised against (i) traditional (contextual or cluster) theories of meaning (Carnap, Kuhn, Gasking, Putnam, Achinstein) and (ii) theories of reference (Scheffler, Putnam, Kitcher). Such a theory is not only based on more plausible assumptions and principles, but, in addition, it satisfies the main adequacy requirements formulated by proponents of a "cognitive-historical approach" (Shapere, Nersessian, Kuhn). I am thus concerned not just with refuting "the entering wedge" of the argument against a defense of cluster theory, but with offering a relatively developed theory, sufficiently fleshed out to permit appreciation of its distinctiveness and evaluation of its merits. I argue that the new cluster theory provides not only an adequate account of the process of meaning-making in science, but also a nuanced and context-sensitive one, which exhibits the fine-structure of the history of science. It is thus capable of accounting for the different kinds and degrees of meaning and reference changes in science. Furthermore, when applied in a case-study of the "chemical revolution," it accounts for that which has escaped change without discontinuity, or even, as result of (and simply within) a broader framework of continuous conceptual change. The new cluster theory constitutes a proposal showing how the comparability of scientific theories is possible, how we have in fact been comparing them all along, despite "local incommensurabilities" of various kinds and degrees. Such a theory offers new insights into the developments of the chemical revolution in particular, but also into the structure and process of scientific revolutions in general. In short, it gives us a new framework for understanding the rationality, objectivity, and progress of science

Review of Maxwell, N. (2014) Global philosophy: Whatphilosophy ought to be?

Review of Maxwell, N. (2014) Global philosophy: What philosophy ought to be? Exeter, UK: Imprint-Academic, Societas – Essays in Political Cultural Criticism. (Pb, pp.192. ISBN 9781845407674).In his recent book, Nicholas Maxwell revisits for the most part ideas, arguments, and positions he has been defending quite forcefully for the past 40 years or so. These include his conceptions of what philosophy ought to be, about the nature of science and its progress-making features, how to best construe empiricism and rationality, his take on the history and philosophy of science, on philosophy and the history of philosophy, the nature of (academic) inquiry, and finally, his position about the role of education and the university more generally in view of his rather pessimistic yet compellingly realistic diagnosis of the problems and challenges confronting our world at this point in our history.Resenha de / Review of Maxwell, N. (2014) Global philosophy: Whatphilosophy ought to be? Exeter, UK: Imprint­Academic, Societas – Essays in Political CulturalCriticism. (Pb, pp.192. ISBN 9781845407674)Este texto trata de uma resenhado livro de Nicholas Maxwell (2014),Global philosophy: What philosophyought to be? Exeter, UK: Imprint­Academic, Societas – Essays in Political Cultural Criticism. Neste livro,Nicholas Maxwell rediscute a maior partedas ideias, argumentos e positções que eletem defendido com muito esforço nosúltimos 40 anos. Neste programa,podemos ler sobre suas concepções de oque a filosofia devia ser, sobre a naturezada ciência e seu progresso, como melhortratar do emprirismo e da racionalidade,sua visão sobre a história e a filosofia daciência, sobre a filosofia e a história dafilosofia, e a natureza da pesquisa(acadêmica), entre outras