A 10-year retrospective review of Salmonella infections at the Children\u27s Hospital in London, Ontario

OBJECTIVES: To describe Salmonella infections in children presenting to the Children\u27s Hospital (London Health Sciences Centre, London, Ontario), to assess risk factors for infection and to examine whether younger children, particularly infants younger than 12 weeks of age, experience higher morbidity than older children. METHODS: A 10-year retrospective review of children with Salmonella infections at the Children\u27s Hospital was conducted. Patient demographics, risk factors for infection, clinical characteristics, bacteriology and outcome were collected from the hospital charts and laboratory records. Data were separated into groups based on age and recent use of antibiotics to analyze differences in outcomes. RESULTS: Sixty-six children with Salmonella infections presented to the Children\u27s Hospital over a 10-year period. Common risk factors for Salmonella infection included having sick contacts, living in a rural area, recent travel, contact with pets (especially reptiles) and exposure to local water. Younger age was associated with an increased likelihood of admission to hospital, treatment with antibiotics and a longer course of antibiotic therapy. This was true when comparing older infants with those younger than 12 weeks of age. Patients recently treated with antibiotics and those with significant underlying medical conditions were more likely to be admitted. CONCLUSIONS: A wider knowledge of the epidemiological risk factors for Salmonella infection may improve diagnosis. Higher admission rates were expected in children younger than 12 weeks of age, those recently treated with antibiotics and those who had a significant underlying medical condition. A prospective, multicentre study is needed to further address questions regarding increased illness severity and appropriate management of Salmonella infections in children younger than 12 weeks of age. ©2010 Pulsus Group Inc. All rights reserved

Acute outcome after a single cryoballoon ablation: Comparison between Arctic Front Advance and Arctic Front Advance PRO

BACKGROUND: The novel fourth-generation cryoballoon (CB4) potentially allows for enhanced catheter maneuverability and more frequent capture of pulmonary vein (PV) potentials which can be used to monitor real-time PV isolation (PVI). The aim of our study is to compare the acute procedural endpoints between the CB4 and second-generation cryoballoon (CB2). METHODS: A single-center retrospective chart review was used to examine 50 consecutive patients with drug-refractory atrial fibrillation undergoing CB4-based PVI. Procedural data and acute success of these patients were compared to 50 propensity-matched controls who underwent cryoballoon ablation procedure using CB2. RESULTS: Procedures performed with the CB4 showed significant shorter fluoroscopy time (14.8 \ub1 5.5 vs 18.0 \ub1 6.5 minutes, P = .04), shorter procedure time (58.3 \ub1 15.7 vs 65.3 \ub1 21 minutes, P = .13), and shorter total ablation time (10.8 \ub1 1.5 vs 13.8 \ub1 1.9 minutes, P = .42). The real-time PVI visualization rate was 33.3% in the CB2 group and 74.7% in the CB4 group (P < .001). CB4 was correlated to significant increase of acute real-time recordings with regard to all the single PV (left superior PV: 58% vs 84%, P = .02; left inferior PV: 26% vs 71%, P = .001; right superior PV 29% vs 61%, P = .01; and right inferior PV 19% vs 58%, P = .002). CONCLUSION: The CB4 was more often able to capture real-time recordings of PV potentials and the subsequent acute PV isolation

Models, Brains, and Scientific Realism

Prediction Error Minimization theory (PEM) is one of the most promising attempts to model perception in current science of mind, and it has recently been advocated by some prominent philosophers as Andy Clark and Jakob Hohwy. Briefly, PEM maintains that “the brain is an organ that on average and over time continually minimizes the error between the sensory input it predicts on the basis of its model of the world and the actual sensory input” (Hohwy 2014, p. 2). An interesting debate has arisen with regard to which is the more adequate epistemological interpretation of PEM. Indeed, Hohwy maintains that given that PEM supports an inferential view of perception and cogni-tion, PEM has to be considered as conveying an internalist epistemological perspective. Contrary to this view, Clark maintains that it would be incorrect to interpret in such a way the indirectness of the link between the world and our inner model of it, and that PEM may well be combined with an externalist epistemological perspective. The aim of this paper is to assess those two opposite interpretations of PEM. Moreover, it will be suggested that Hohwy’s position may be considerably strengthened by adopting Carlo Cellucci’s view on knowledge (2013)

Improved Selective Class i HDAC and Novel Selective HDAC3 Inhibitors: Beyond Hydroxamic Acids and Benzamides

The application of class I HDAC inhibitors as cancer therapies is well established, but more recently their development for nononcological indications has increased. We report here on the generation of improved class I selective human HDAC inhibitors based on an ethylketone zinc binding group (ZBG) in place of the hydroxamic acid that features the majority of HDAC inhibitors. We also describe a novel set of HDAC3 isoform selective inhibitors that show stronger potency and selectivity than the most commonly used HDAC3 selective tool compound RGFP966. These compounds are again based on an alternative ZBG with respect to the ortho-anilide that is featured in HDAC3 selective compounds reported to date

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies

Mathematical practice, crowdsourcing, and social machines

The highest level of mathematics has traditionally been seen as a solitary endeavour, to produce a proof for review and acceptance by research peers. Mathematics is now at a remarkable inflexion point, with new technology radically extending the power and limits of individuals. Crowdsourcing pulls together diverse experts to solve problems; symbolic computation tackles huge routine calculations; and computers check proofs too long and complicated for humans to comprehend. Mathematical practice is an emerging interdisciplinary field which draws on philosophy and social science to understand how mathematics is produced. Online mathematical activity provides a novel and rich source of data for empirical investigation of mathematical practice - for example the community question answering system {\it mathoverflow} contains around 40,000 mathematical conversations, and {\it polymath} collaborations provide transcripts of the process of discovering proofs. Our preliminary investigations have demonstrated the importance of "soft" aspects such as analogy and creativity, alongside deduction and proof, in the production of mathematics, and have given us new ways to think about the roles of people and machines in creating new mathematical knowledge. We discuss further investigation of these resources and what it might reveal. Crowdsourced mathematical activity is an example of a "social machine", a new paradigm, identified by Berners-Lee, for viewing a combination of people and computers as a single problem-solving entity, and the subject of major international research endeavours. We outline a future research agenda for mathematics social machines, a combination of people, computers, and mathematical archives to create and apply mathematics, with the potential to change the way people do mathematics, and to transform the reach, pace, and impact of mathematics research.Comment: To appear, Springer LNCS, Proceedings of Conferences on Intelligent Computer Mathematics, CICM 2013, July 2013 Bath, U

Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis

Objective: To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p < 0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p = 0.011). Interpretation: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis.

OBJECTIVE: To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). METHODS: After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). RESULTS: Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. CONCLUSION: These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients

How to think about informal proofs

This document is the Accepted Manuscript version of the following article: Brendan Larvor, ‘How to think about informal proofs’, Synthese, Vol. 187(2): 715-730, first published online 9 September 2011. The final publication is available at Springer via doi:10.1007/s11229-011-0007-5It is argued in this study that (i) progress in the philosophy of mathematical practice requires a general positive account of informal proof; (ii) the best candidate is to think of informal proofs as arguments that depend on their matter as well as their logical form; (iii) articulating the dependency of informal inferences on their content requires a redefinition of logic as the general study of inferential actions; (iv) it is a decisive advantage of this conception of logic that it accommodates the many mathematical proofs that include actions on objects other than propositions; (v) this conception of logic permits the articulation of project-sized tasks for the philosophy of mathematical practice, thereby supplying a partial characterisation of normal research in the fieldPeer reviewedFinal Accepted Versio