Publications by authors named "Michael J Carter"

50 Publications

Degradation of the Endothelial Glycocalyx Contributes to Metabolic Acidosis in Children Following Cardiopulmonary Bypass Surgery.

Pediatr Crit Care Med 2021 May 4. Epub 2021 May 4.

Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, United Kingdom. Thrombosis and Vascular Biology Research Group, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Institute of Women and Children's Health, King's College London, St Thomas' Hospital, London, United Kingdom. Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. Department of Intensive Care, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

Objectives: Cardiopulmonary bypass surgery is complicated by metabolic acidosis, microvascular dysfunction, and capillary leak. The glycocalyx-a layer of proteins and sugars lining the vascular endothelium-is degraded during cardiopulmonary bypass. We aimed to describe the kinetics of glycocalyx degradation during and following cardiopulmonary bypass. We hypothesized that cleavage of negatively charged fragments of the glycocalyx would directly induce metabolic acidosis through changes in the strong ion gap (defined using Stewart's physicochemical approach to acid-base chemistry). We also investigated whether glycocalyx degradation was associated with failure of endothelial function and cardiovascular dysfunction.

Design: Single-center prospective cohort study.

Setting: Twenty-two bed surgical/medical PICU.

Patients: Twenty-seven term infants and children requiring cardiopulmonary bypass surgery for the correction/palliation of congenital heart disease.

Interventions: None.

Measurements And Main Results: We recruited 27 patients, 5 days to 57 months old. We prospectively sampled plasma prior to, during, and following cardiopulmonary bypass at predefined time points. We measured plasma concentrations of interleukin-6 (inflammatory marker), heparan sulfate (negatively charged glycocalyx glycosaminoglycan), and syndecan-1 (neutrally charged glycocalyx protein). We defined the following outcome measures: metabolic acidosis (strong ion gap), renal dysfunction (fold change in creatinine), capillary leak (fluid bolus volume), cardiovascular dysfunction (Vasoactive Inotropic Score), and length of ventilation. In linear regression models, maximum measured heparan sulfate concentration (negatively charged) was associated with metabolic acidosis (p = 0.016), renal dysfunction (p = 0.009), and length of ventilation (p = 0.047). In contrast, maximum measured syndecan-1 concentration (neutrally charged) was not associated with these clinical endpoints (p > 0.30 for all).

Conclusions: Our data show that metabolic acidosis (increased strong ion gap) is associated with plasma concentration of heparan sulfate, a negatively charged glycosaminoglycan cleaved from the endothelial glycocalyx during cardiopulmonary bypass. In addition, cleavage of heparan sulfate was associated with renal dysfunction, capillary leak, and global markers of cardiovascular dysfunction. These data highlight the importance of designing translational therapies to protect the glycocalyx in cardiopulmonary bypass.
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http://dx.doi.org/10.1097/PCC.0000000000002746DOI Listing
May 2021

Coronary aneurysms, myocardial dysfunction, and shock in a COVID-19 child, role of ECMO, immunomodulation, and cardiac CT.

Cardiol Young 2021 Jan 28:1-5. Epub 2021 Jan 28.

Paediatric Cardiac Surgery Department, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Coronary artery aneurysms in children were observed as a rare complication associated with coronavirus disease 2019 (COVID-19). This case report describes the severe end of the spectrum of the new multisystem inflammatory syndrome in a 12-year-old child with coronary aneurysms, myocardial dysfunction, and shock, managed successfully with extracorporeal membrane oxygenation support and immunomodulation therapy. This report also highlights the additional benefits of cardiac CT in the diagnosis and follow-up of coronary aneurysms.
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http://dx.doi.org/10.1017/S1047951121000147DOI Listing
January 2021

Paediatric Inflammatory Multisystem Syndrome Temporally-Associated with SARS-CoV-2 Infection: An Overview.

Intensive Care Med 2021 01 14;47(1):90-93. Epub 2020 Oct 14.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.

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http://dx.doi.org/10.1007/s00134-020-06273-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556601PMC
January 2021

Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection.

Nat Med 2020 11 18;26(11):1701-1707. Epub 2020 Aug 18.

Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-multisystem inflammatory syndrome in children (MIS-C)-which comprises multiorgan dysfunction and systemic inflammation. We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections, and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4CCR7 T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness and appears distinct from Kawasaki disease.
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http://dx.doi.org/10.1038/s41591-020-1054-6DOI Listing
November 2020

Assessment of an Antibody-in-Lymphocyte Supernatant Assay for the Etiological Diagnosis of Pneumococcal Pneumonia in Children.

Front Cell Infect Microbiol 2019 17;9:459. Epub 2020 Jan 17.

Patan Academy of Health Sciences, Kathmandu, Nepal.

New diagnostic tests for the etiology of childhood pneumonia are needed. We evaluated the antibody-in-lymphocyte supernatant (ALS) assay to detect immunoglobulin (Ig) G secretion from peripheral blood mononuclear cell (PBMC) culture, as a potential diagnostic test for pneumococcal pneumonia. We enrolled 348 children with pneumonia admitted to Patan Hospital, Kathmandu, Nepal between December 2015 and September 2016. PBMCs sampled from participants were incubated for 48 h before harvesting of cell culture supernatant (ALS). We used a fluorescence-based multiplexed immunoassay to measure the concentration of IgG in ALS against five conserved pneumococcal protein antigens. Of children with pneumonia, 68 had a confirmed etiological diagnosis: 12 children had pneumococcal pneumonia (defined as blood or pleural fluid culture-confirmed; or plasma CRP concentration ≥60 mg/l and nasopharyngeal carriage of serotype 1 pneumococci), and 56 children had non-pneumococcal pneumonia. Children with non-pneumococcal pneumonia had either a bacterial pathogen isolated from blood (six children); or C-reactive protein <60 mg/l, absence of radiographic consolidation and detection of a pathogenic virus by multiplex PCR (respiratory syncytial virus, influenza viruses, or parainfluenza viruses; 23 children). Concentrations of ALS IgG to all five pneumococcal proteins were significantly higher in children with pneumococcal pneumonia than in children with non-pneumococcal pneumonia. The concentration of IgG in ALS to the best-performing antigen discriminated between children with pneumococcal and non-pneumococcal pneumonia with a sensitivity of 1.0 (95% CI 0.73-1.0), specificity of 0.66 (95% CI 0.52-0.78) and area under the receiver-operating characteristic curve (AUROCC) 0.85 (95% CI 0.75-0.94). Children with pneumococcal pneumonia were older than children with non-pneumococcal pneumonia (median 5.6 and 2.0 years, respectively, < 0.001). When the analysis was limited to children ≥2 years of age, assay of IgG ALS to pneumococcal proteins was unable to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia (AUROCC 0.67, 95% CI 0.47-0.88). This method detected spontaneous secretion of IgG to pneumococcal protein antigens from cultured PBMCs. However, when stratified by age group, assay of IgG in ALS to pneumococcal proteins showed limited utility as a test to discriminate between pneumococcal and non-pneumococcal pneumonia in children.
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http://dx.doi.org/10.3389/fcimb.2019.00459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988833PMC
September 2020

Nanostructured fibers as a versatile photonic platform: radiative cooling and waveguiding through transverse Anderson localization.

Light Sci Appl 2018 18;7:37. Epub 2018 Jul 18.

1Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY 10027 USA.

Broadband high reflectance in nature is often the result of randomly, three-dimensionally structured materials. This study explores unique optical properties associated with one-dimensional nanostructures discovered in silk cocoon fibers of the comet moth, . The fibers are populated with a high density of air voids randomly distributed across the fiber cross-section but are invariant along the fiber. These filamentary air voids strongly scatter light in the solar spectrum. A single silk fiber measuring ~50 μm thick can reflect 66% of incoming solar radiation, and this, together with the fibers' high emissivity of 0.88 in the mid-infrared range, allows the cocoon to act as an efficient radiative-cooling device. Drawing inspiration from these natural radiative-cooling fibers, biomimetic nanostructured fibers based on both regenerated silk fibroin and polyvinylidene difluoride are fabricated through wet spinning. Optical characterization shows that these fibers exhibit exceptional optical properties for radiative-cooling applications: nanostructured regenerated silk fibers provide a solar reflectivity of 0.73 and a thermal emissivity of 0.90, and nanostructured polyvinylidene difluoride fibers provide a solar reflectivity of 0.93 and a thermal emissivity of 0.91. The filamentary air voids lead to highly directional scattering, giving the fibers a highly reflective sheen, but more interestingly, they enable guided optical modes to propagate along the fibers through transverse Anderson localization. This discovery opens up the possibility of using wild silkmoth fibers as a biocompatible and bioresorbable material for optical signal and image transport.
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http://dx.doi.org/10.1038/s41377-018-0033-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107007PMC
July 2018

Examining the impact of error estimation on the effects of self-controlled feedback.

Hum Mov Sci 2019 Feb 20;63:182-198. Epub 2018 Dec 20.

School of Human Kinetics, University of Ottawa, Montpetit Hall, 125 University, Room 232, Ottawa, ON K1N 6N5, Canada. Electronic address:

Two experiments were conducted that examined the motivational and informational perspectives concerning learning advantages from self-controlled practice. Three groups were tasked with learning a novel skill; self-controlled (SC), yoked traditional (YT), and yoked with error estimation required during the acquisition phase (YE). Results from the delayed learning measures showed the YE group performed better than the SC and YT groups, for Expt. 1. A similar pattern emerged for Expt. 2, albeit, this was not significant. While there were no motivation differences across the groups in either experiment, a strong correlation in Expt. 2 was shown between error estimation capabilities, which were best for the YE group, and learning. These combined results suggest that informational processes contribute more to the self-controlled feedback learning advantage, relative to motivational contributions.
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http://dx.doi.org/10.1016/j.humov.2018.12.002DOI Listing
February 2019

Identification and treatment of paediatric sepsis: getting the balance right.

Arch Dis Child 2018 12 25;103(12):1185-1186. Epub 2018 May 25.

Children and Young People's Services, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/archdischild-2018-314865DOI Listing
December 2018

Laboratory and molecular surveillance of paediatric typhoidal Salmonella in Nepal: Antimicrobial resistance and implications for vaccine policy.

PLoS Negl Trop Dis 2018 04 23;12(4):e0006408. Epub 2018 Apr 23.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford and the NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.

Background: Children are substantially affected by enteric fever in most settings with a high burden of the disease, including Nepal. However pathogen population structure and transmission dynamics are poorly delineated in young children, the proposed target group for immunization programs. Here we present whole genome sequencing and antimicrobial susceptibility data on 198 S. Typhi and 66 S. Paratyphi A isolated from children aged 2 months to 15 years of age during blood culture surveillance at Patan Hospital, Nepal, 2008-2016.

Principal Findings: S. Typhi was the dominant agent and comprised several distinct genotypes, dominated by 4.3.1 (H58). The heterogeneity of genotypes in children under five was reduced compared to data from 2005-2006, attributable to ongoing clonal expansion of H58. Most isolates (86%) were non-susceptible to fluoroquinolones, associated mainly with S. Typhi H58 lineage II and S. Paratyphi A harbouring mutations in the quinolone resistance-determining region (QRDR); non-susceptible strains from these groups accounted for 50% and 25% of all isolates. Multi-drug resistance (MDR) was rare (3.5% of S. Typhi, 0 S. Paratyphi A) and restricted to chromosomal insertions of resistance genes in H58 lineage I strains. Temporal analyses revealed a shift in dominance from H58 Lineage I to H58 Lineage II, with the latter being significantly more common after 2010. Comparison to global data sets showed the local S. Typhi and S. Paratyphi A strains had close genetic relatives in other South Asian countries, indicating regional strain circulation. Multiple imports from India of ciprofloxacin-resistant H58 lineage II strains were identified, but these were rare and showed no evidence of clonal replacement of local S. Typhi.

Significance: These data indicate that enteric fever in Nepal continues to be a major public health issue with ongoing inter- and intra-country transmission, and highlights the need for regional coordination of intervention strategies. The absence of a S. Paratyphi A vaccine is cause for concern, given its prevalence as a fluoroquinolone resistant enteric fever agent in this setting.
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http://dx.doi.org/10.1371/journal.pntd.0006408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933809PMC
April 2018

Predicting the severity of dengue fever in children on admission based on clinical features and laboratory indicators: application of classification tree analysis.

BMC Pediatr 2018 03 13;18(1):109. Epub 2018 Mar 13.

Department of Tropical Hygiene (Biomedical and Health Informatics), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

Background: Dengue fever is a re-emerging viral disease commonly occurring in tropical and subtropical areas. The clinical features and abnormal laboratory test results of dengue infection are similar to those of other febrile illnesses; hence, its accurate and timely diagnosis for providing appropriate treatment is difficult. Delayed diagnosis may be associated with inappropriate treatment and higher risk of death. Early and correct diagnosis can help improve case management and optimise the use of resources such as hospital staff, beds, and intensive care equipment. The goal of this study was to develop a predictive model to characterise dengue severity based on early clinical and laboratory indicators using data mining and statistical tools.

Methods: We retrieved data from a study of febrile illness in children at Angkor Hospital for Children, Cambodia. Of 1225 febrile episodes recorded, 198 patients were confirmed to have dengue. A classification and regression tree (CART) was used to construct a predictive decision tree for severe dengue, while logistic regression analysis was used to independently quantify the significance of each parameter in the decision tree.

Results: A decision tree algorithm using haematocrit, Glasgow Coma Score, urine protein, creatinine, and platelet count predicted severe dengue with a sensitivity, specificity, and accuracy of 60.5%, 65% and 64.1%, respectively.

Conclusions: The decision tree we describe, using five simple clinical and laboratory indicators, can be used to predict severe cases of dengue among paediatric patients on admission. This algorithm is potentially useful for guiding a patient-monitoring plan and outpatient management of fever in resource-poor settings.
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http://dx.doi.org/10.1186/s12887-018-1078-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850907PMC
March 2018

Assessment and Translation of the Antibody-in-Lymphocyte Supernatant (ALS) Assay to Improve the Diagnosis of Enteric Fever in Two Controlled Human Infection Models and an Endemic Area of Nepal.

Front Microbiol 2017 23;8:2031. Epub 2017 Oct 23.

Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.

New diagnostic tests for enteric fever are urgently needed to assist with timely antimicrobial treatment of patients and to measure the efficacy of prevention measures such as vaccination. In a novel translational approach, here we use two recently developed controlled human infection models (CHIM) of enteric fever to evaluate an antibody-in-lymphocyte supernatant (ALS) assay, which can detect recent IgA antibody production by circulating B cells in mononuclear cell culture. We calculated the discriminative ability of the ALS assay to distinguish diagnosed cases in the two CHIM studies in Oxford, prior to evaluating blood culture-confirmed diagnoses of patients presenting with fever to hospital in an endemic areas of Kathmandu, Nepal. Antibody responses to membrane preparations and lipopolysaccharide provided good sensitivity (>90%) for diagnosing systemic infection after oral challenge with Typhi or . Paratyphi A. Assay specificity was moderate (~60%) due to imperfect sensitivity of blood culture as the reference standard and likely unrecognized subclinical infection. These findings were augmented through the translation of the assay into the endemic setting in Nepal. Anti-MP IgA responses again exhibited good sensitivity (86%) but poor specificity (51%) for detecting blood culture-confirmed enteric fever cases (ROC AUC 0.79, 95%CI 0.70-0.88). Patients with anti-MP IgA ALS titers in the upper quartile exhibited a clinical syndrome synonymous with enteric fever. While better reference standards are need to assess enteric fever diagnostics, routine use of this ALS assay could be used to rule out infection and has the potential to double the laboratory detection rate of enteric fever in this setting over blood culture alone.
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http://dx.doi.org/10.3389/fmicb.2017.02031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660281PMC
October 2017

Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Proteome Array.

Front Microbiol 2017 19;8:1794. Epub 2017 Sep 19.

Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, and the Oxford National Institutes for Health Research Biomedical Research Centre, University of OxfordOxford, United Kingdom.

Current diagnostic tests for typhoid fever, the disease caused by Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 . Typhi antigens in sera from 41 participants challenged with oral . Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort ( = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid ( = 100) from other febrile bacteremia ( = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.
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http://dx.doi.org/10.3389/fmicb.2017.01794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609549PMC
September 2017

Response preparation and execution during intentional bimanual pattern switching.

J Neurophysiol 2017 09 28;118(3):1720-1731. Epub 2017 Jun 28.

School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada

During continuous bimanual coordination, in-phase (IP; 0° relative phase) and anti-phase (AP; 180° relative phase) patterns can be stably performed without practice. Paradigms in which participants are required to intentionally switch between these coordination patterns have been used to investigate the interaction between the performer's intentions and intrinsic dynamics of the body's preferred patterns. The current study examined the processes associated with switching preparation and execution through the use of a startling acoustic stimulus (SAS) as the switch stimulus. A SAS is known to involuntarily trigger preprogrammed responses at a shortened latency and, thus, can be used to probe advance preparation. Participants performed cyclical IP and AP bimanual elbow extension-flexion movements in which they were required to switch patterns in response to an auditory switch cue, which was either nonstartling (80 dB) or a SAS (120 dB). Results indicated that reaction time to the switch stimulus (i.e., switch onset) was significantly reduced on startle trials, indicative of advance preparation of the switch response. Similarly, switching time was reduced on startle trials, which was attributed to increased neural activation caused by the SAS. Switching time was also shorter for AP to IP trials, but only when the switching stimulus occurred at either the midpoint or reversal locations within the movement cycle, suggesting that the switch location may affect the intrinsic dynamics of the system. The current study provides novel information regarding preparation and execution of intentional switching between in-phase and anti-phase bimanual coordination patterns. Using a startling acoustic stimulus, we provide strong evidence that the switching response is prepared before the switch stimulus, and switch execution is accelerated by the startling stimulus. In addition, the time required to switch between patterns and relative limb contribution is dependent upon where in the movement cycle the switch stimulus occurred.
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http://dx.doi.org/10.1152/jn.00323.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596139PMC
September 2017

The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications.

Front Immunol 2017 1;8:630. Epub 2017 Jun 1.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom.

Despite the availability of advances in molecular diagnostic testing for infectious disease, there is still a need for tools that advance clinical care and public health. Current methods focus on pathogen detection with unprecedented precision, but often lack specificity. In contrast, the host immune response is highly specific for the infecting pathogen. Serological studies are rarely helpful in clinical settings, as they require acute and convalescent antibody testing. However, the B cell response is much more rapid and short-lived, making it an optimal target for determining disease aetiology in patients with infections. The performance of tests that aim to detect circulating antigen-specific antibody-secreting cells (ASCs) has previously been unclear. Test performance is reliant on detecting the presence of ASCs in the peripheral blood. As such, the kinetics of the ASC response to infection, the antigen specificity of the ASC response, and the methods of ASC detection are all critical. In this review, we summarize previous studies that have used techniques to enumerate ASCs during infection. We describe the emergence, peak, and waning of these cells in peripheral blood during infection with a number of bacterial and viral pathogens, as well as malaria infection. We find that the timing of antigen-specific ASC appearance and disappearance is highly conserved across pathogens, with a peak response between day 7 and day 8 of illness and largely absent following day 14 since onset of symptoms. Data show a sensitivity of ~90% and specificity >80% for pathogen detection using ASC-based methods. Overall, the summarised work indicates that ASC-based methods may be very sensitive and highly specific for determining the etiology of infection and have some advantages over current methods. Important areas of research remain, including more accurate definition of the timing of the ASC response to infection, the biological mechanisms underlying variability in its magnitude and the evolution and the B cell receptor in response to immune challenge. Nonetheless, there is potential of the ASC response to infection to be exploited as the basis for novel diagnostic tests to inform clinical care and public health priorities.
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http://dx.doi.org/10.3389/fimmu.2017.00630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451496PMC
June 2017

Anodal transcranial direct current stimulation over the primary motor cortex does not enhance the learning benefits of self-controlled feedback schedules.

Psychol Res 2018 May 27;82(3):496-506. Epub 2017 Feb 27.

School of Human Kinetics, University of Ottawa, Ottawa, ON, Canada.

A distinct learning advantage has been shown when participants control their knowledge of results (KR) scheduling during practice compared to when the same KR schedule is imposed on the learner without choice (i.e., yoked schedules). Although the learning advantages of self-controlled KR schedules are well-documented, the brain regions contributing to these advantages remain unknown. Identifying key brain regions would not only advance our theoretical understanding of the mechanisms underlying self-controlled learning advantages, but would also highlight regions that could be targeted in more applied settings to boost the already beneficial effects of self-controlled KR schedules. Here, we investigated whether applying anodal transcranial direct current stimulation (tDCS) to the primary motor cortex (M1) would enhance the typically found benefits of learning a novel motor skill with a self-controlled KR schedule. Participants practiced a spatiotemporal task in one of four groups using a factorial combination of KR schedule (self-controlled vs. yoked) and tDCS (anodal vs. sham). Testing occurred on two consecutive days with spatial and temporal accuracy measured on both days and learning was assessed using 24-h retention and transfer tests without KR. All groups improved their performance in practice and a significant effect for practicing with a self-controlled KR schedule compared to a yoked schedule was found for temporal accuracy in transfer, but a similar advantage was not evident in retention. There were no significant differences as a function of KR schedule or tDCS for spatial accuracy in retention or transfer. The lack of a significant tDCS effect suggests that M1 may not strongly contribute to self-controlled KR learning advantages; however, caution is advised with this interpretation as typical self-controlled learning benefits were not strongly replicated in the present experiment.
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http://dx.doi.org/10.1007/s00426-017-0846-xDOI Listing
May 2018

Not all choices are created equal: Task-relevant choices enhance motor learning compared to task-irrelevant choices.

Psychon Bull Rev 2017 12;24(6):1879-1888

School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada.

Lewthwaite et al. (2015) reported that the learning benefits of exercising choice (i.e., their self-controlled condition) are not restricted to task-relevant features (e.g., feedback). They found that choosing one's golf ball color (Exp. 1) or choosing which of two tasks to perform at a later time plus which of two artworks to hang (Exp. 2) resulted in better retention than did being denied these same choices (i.e., yoked condition). The researchers concluded that the learning benefits derived from choice, whether irrelevant or relevant to the to-be-learned task, are predominantly motivational because choice is intrinsically rewarding and satisfies basic psychological needs. However, the absence of a group that made task-relevant choices and the lack of psychological measures significantly weakened their conclusions. Here, we investigated how task-relevant and task-irrelevant choices affect motor-skill learning. Participants practiced a spatiotemporal motor task in either a task-relevant group (choice over feedback schedule), a task-irrelevant group (choice over the color of an arm-wrap plus game selection), or a no-choice group. The results showed significantly greater learning in the task-relevant group than in both the task-irrelevant and no-choice groups, who did not differ significantly. Critically, these learning differences were not attributed to differences in perceptions of competence or autonomy, but instead to superior error-estimation abilities. These results challenge the perspective that motivational influences are the root cause of self-controlled learning advantages. Instead, the findings add to the growing evidence highlighting that the informational value gained from task-relevant choices makes a greater relative contribution to these advantages than motivational influences do.
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http://dx.doi.org/10.3758/s13423-017-1250-7DOI Listing
December 2017

Intentional switches between coordination patterns are faster following anodal-tDCS applied over the supplementary motor area.

Brain Stimul 2017 Jan - Feb;10(1):162-164. Epub 2016 Nov 4.

School of Human Kinetics, University of Ottawa, Ottawa, ON, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2016.11.002DOI Listing
November 2016

Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children.

JAMA 2016 Aug 23-30;316(8):835-45

Section of Paediatrics, Division of Infectious Diseases, Department of Medicine, Imperial College London, London, United Kingdom.

Importance: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others.

Objective: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children.

Design, Setting, And Participants: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets.

Exposures: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis.

Main Outcomes And Measures: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group.

Results: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 100%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment.

Conclusions And Relevance: This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.
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http://dx.doi.org/10.1001/jama.2016.11236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997174PMC
September 2016

Measuring Investment in Learning: Can Electrocardiogram Provide an Indication of Cognitive Effort During Learning?

Percept Mot Skills 2016 Apr 25;122(2):375-94. Epub 2016 Feb 25.

Brock University, ON, Canada.

Heart rate variability (i.e., low frequency:high frequency ratio) was measured to differentiate invested cognitive effort during the acquisition and retention of a novel task. Participants (12 male, M = 25.1 year, SD = 3.6; 12 female, M = 22.8 year, SD = 1.1) were required to produce Braille equivalents of English letter primes on a standardized keyboard in proactive or retroactive conditions (groups, each n = 12). The correct Braille response was either provided before (i.e., proactively) or after (i.e., retroactively) the participant's response. During acquisition, participants in the proactive group demonstrated shorter study time, greater recall success, and reported lower cognitive investment. Participants in the proactive and retroactive groups did not statistically differ in heart rate variability. For retention, the retroactive group showed greater recall success, lower perceived cognitive effort investment, and lower heart rate variability. The results highlight the usefulness of heart rate variability in discriminating the cognitive effort invested for a recently acquired skill.
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http://dx.doi.org/10.1177/0031512516633348DOI Listing
April 2016

An interpolated activity during the knowledge-of-results delay interval eliminates the learning advantages of self-controlled feedback schedules.

Psychol Res 2017 Mar 18;81(2):399-406. Epub 2016 Feb 18.

School of Human Kinetics, University of Ottawa, 125 University Private, Ottawa, ON, Canada.

The learning advantages of self-controlled knowledge-of-results (KR) schedules compared to yoked schedules have been linked to the optimization of the informational value of the KR received for the enhancement of one's error-detection capabilities. This suggests that information-processing activities that occur after motor execution, but prior to receiving KR (i.e., the KR-delay interval) may underlie self-controlled KR learning advantages. The present experiment investigated whether self-controlled KR learning benefits would be eliminated if an interpolated activity was performed during the KR-delay interval. Participants practiced a waveform matching task that required two rapid elbow extension-flexion reversals in one of four groups using a factorial combination of choice (self-controlled, yoked) and KR-delay interval (empty, interpolated). The waveform had specific spatial and temporal constraints, and an overall movement time goal. The results indicated that the self-controlled + empty group had superior retention and transfer scores compared to all other groups. Moreover, the self-controlled + interpolated and yoked + interpolated groups did not differ significantly in retention and transfer; thus, the interpolated activity eliminated the typically found learning benefits of self-controlled KR. No significant differences were found between the two yoked groups. We suggest the interpolated activity interfered with information-processing activities specific to self-controlled KR conditions that occur during the KR-delay interval and that these activities are vital for reaping the associated learning benefits. These findings add to the growing evidence that challenge the motivational account of self-controlled KR learning advantages and instead highlights informational factors associated with the KR-delay interval as an important variable for motor learning under self-controlled KR schedules.
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http://dx.doi.org/10.1007/s00426-016-0757-2DOI Listing
March 2017

Self-controlled learning benefits: exploring contributions of self-efficacy and intrinsic motivation via path analysis.

J Sports Sci 2016 Sep 28;34(17):1650-6. Epub 2015 Dec 28.

a School of Human Kinetics , University of Ottawa , Ottawa , Canada.

Research has shown learning advantages for self-controlled practice contexts relative to yoked (i.e., experimenter-imposed) contexts; yet, explanations for this phenomenon remain relatively untested. We examined, via path analysis, whether self-efficacy and intrinsic motivation are important constructs for explaining self-controlled learning benefits. The path model was created using theory-based and empirically supported relationships to examine causal links between these psychological constructs and physical performance. We hypothesised that self-efficacy and intrinsic motivation would have greater predictive power for learning under self-controlled compared to yoked conditions. Participants learned double-mini trampoline progressions, and measures of physical performance, self-efficacy and intrinsic motivation were collected over two practice days and a delayed retention day. The self-controlled group (M = 2.04, SD = .98) completed significantly more skill progressions in retention than their yoked counterparts (M = 1.3, SD = .65). The path model displayed adequate fit, and similar significant path coefficients were found for both groups wherein each variable was predominantly predicted by its preceding time point (e.g., self-efficacy time 1 predicts self-efficacy time 2). Interestingly, the model was not moderated by group; thus, failing to support the hypothesis that self-efficacy and intrinsic motivation have greater predictive power for learning under self-controlled relative to yoked conditions.
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http://dx.doi.org/10.1080/02640414.2015.1130236DOI Listing
September 2016

Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats.

Dev Biol 2016 Jan 2;409(2):451-8. Epub 2015 Dec 2.

Department of Veterinary Medicine & Surgery, College of Veterinary Medicine, University of Missouri-Columbia, Columbia, MO 65211, USA; Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA 95776, USA.

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.
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http://dx.doi.org/10.1016/j.ydbio.2015.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724490PMC
January 2016

Judgments of learning are significantly higher following feedback on relatively good versus relatively poor trials despite no actual learning differences.

Hum Mov Sci 2016 Feb 19;45:63-70. Epub 2015 Nov 19.

School of Human Kinetics, University of Ottawa, Ottawa, Canada. Electronic address:

Studies have consistently shown that prospective metacognitive judgments of learning are often inaccurate because humans mistakenly interpret current performance levels as valid indices of learning. These metacognitive discrepancies are strongly related to conditions of practice. Here, we examined how the type of feedback (after good versus poor trials) received during practice and awareness (aware versus unaware) of this manipulation affected judgments of learning and actual learning. After each six-trial block, participants received feedback on their three best trials or three worst trials and half of the participants were made explicitly aware of the type of feedback they received while the other half were unaware. Judgments of learning were made at the end of each six-trial block and before the 24-h retention test. Results indicated no motor performance differences between groups in practice or retention; however, receiving feedback on relatively good compared to relatively poor trials resulted in significantly higher judgments of learning in practice and retention, irrespective of awareness. These results suggest that KR on relatively good versus relatively poor trials can have dissociable effects on judgments of learning in the absence of actual learning differences, even when participants are made aware of their feedback manipulation.
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http://dx.doi.org/10.1016/j.humov.2015.11.006DOI Listing
February 2016

Startle activation is additive with voluntary cortical activation irrespective of stimulus modality.

Neurosci Lett 2015 Oct 31;606:151-5. Epub 2015 Aug 31.

School of Human Kinetics, University of Ottawa, Ottawa, Canada. Electronic address:

When a startling acoustic stimulus (SAS) is presented during a simple reaction time (RT) task, it can trigger the prepared response through an involuntary initiation pathway. Previous research modelling the effects of presenting a SAS at various intervals following a non-startling auditory imperative signal (IS) suggested that involuntary initiation-related neural activation is additive with the voluntary initiation processes. The current study tested the predictions of this additive model when the SAS and IS are of different modalities by using a visual rather than auditory go-signal. Because voluntary RT latencies are delayed for visual stimuli compared to acoustic stimuli, it was hypothesised that the time course of additive activation would be similarly delayed. Participants performed 150 RT trials requiring a targeted 20° wrist extension task with a SAS presented 0-125 ms following a visual go-signal. Results were not different to those predicted by an additive model (p=0.979), yet were significantly different to those predicted by a horse-race model (p=0.037), indicating a joint contribution of voluntary and involuntary activation, even when the IS and SAS are of different modalities. Furthermore, the results indicated that voluntary RT differences due to stimulus modality are attributable to processes that occur prior to the increase in initiation-related activation.
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http://dx.doi.org/10.1016/j.neulet.2015.08.053DOI Listing
October 2015

Reduced motor preparation during dual-task performance: evidence from startle.

Exp Brain Res 2015 Sep 31;233(9):2673-83. Epub 2015 May 31.

School of Kinesiology, University of British Columbia, War Memorial Gymnasium 210-6081 University Boulevard, Vancouver, BC, V6T 1Z1, Canada,

Previous studies have used a secondary probe reaction time (RT) task to assess attentional demands of a primary task. The current study used a startling acoustic stimulus (SAS) in a probe RT paradigm to test the hypothesis that attentional resources would be directly related to limitations in response preparation. Participants performed an easy or difficult version of a continuous primary task that was either primarily motor in nature (pursuit tracking) or cognitive (counting backward). Concurrently, participants responded to an auditory cue as fast as possible by performing a wrist extension secondary movement. On selected trials, the auditory cue was replaced with a SAS (120 dB), which is thought to involuntarily trigger a prepared response and thus bypass any response initiation bottleneck that may be present when trying to perform two movements. Although startle trials were performed at a shorter latency, both non-startle and startle probe trials resulted in a delayed RT, as compared to single-task trials, consistent with reduced preparation of the secondary task. In addition, analysis of SAS trial RT when a startle indicator was present versus absent provided evidence that the secondary task was at a lowered state of preparation when engaged in the cognitive primary task as compared to a motor primary task, suggesting a facilitative effect on preparatory activation when both the primary and secondary tasks are motoric in nature.
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http://dx.doi.org/10.1007/s00221-015-4340-7DOI Listing
September 2015

Rapid diagnostic tests for dengue virus infection in febrile Cambodian children: diagnostic accuracy and incorporation into diagnostic algorithms.

PLoS Negl Trop Dis 2015 Feb 24;9(2):e0003424. Epub 2015 Feb 24.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.

Background: Dengue virus (DENV) infection is prevalent across tropical regions and may cause severe disease. Early diagnosis may improve supportive care. We prospectively assessed the Standard Diagnostics (Korea) BIOLINE Dengue Duo DENV rapid diagnostic test (RDT) to NS1 antigen and anti-DENV IgM (NS1 and IgM) in children in Cambodia, with the aim of improving the diagnosis of DENV infection.

Methodology And Principal Findings: We enrolled children admitted to hospital with non-localised febrile illnesses during the 5-month DENV transmission season. Clinical and laboratory variables, and DENV RDT results were recorded at admission. Children had blood culture and serological and molecular tests for common local pathogens, including reference laboratory DENV NS1 antigen and IgM assays. 337 children were admitted with non-localised febrile illness over 5 months. 71 (21%) had DENV infection (reference assay positive). Sensitivity was 58%, and specificity 85% for RDT NS1 and IgM combined. Conditional inference framework analysis showed the additional value of platelet and white cell counts for diagnosis of DENV infection. Variables associated with diagnosis of DENV infection were not associated with critical care admission (70 children, 21%) or mortality (19 children, 6%). Known causes of mortality were melioidosis (4), other sepsis (5), and malignancy (1). 22 (27%) children with a positive DENV RDT had a treatable other infection.

Conclusions: The DENV RDT had low sensitivity for the diagnosis of DENV infection. The high co-prevalence of infections in our cohort indicates the need for a broad microbiological assessment of non-localised febrile illness in these children.
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http://dx.doi.org/10.1371/journal.pntd.0003424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340051PMC
February 2015

Self-controlled feedback is effective if it is based on the learner's performance: a replication and extension of Chiviacowsky and Wulf (2005).

Front Psychol 2014 19;5:1325. Epub 2014 Nov 19.

School of Human Kinetics, Faculty of Health Sciences, University of Ottawa Ottawa, ON, Canada.

The learning advantages of self-controlled feedback schedules compared to yoked schedules have been attributed to motivational influences and/or information processing activities with many researchers adopting the motivational perspective in recent years. Chiviacowsky and Wulf (2005) found that feedback decisions made before (Self-Before) or after a trial (Self-After) resulted in similar retention performance, but superior transfer performance resulted when the decision to receive feedback occurred after a trial. They suggested that the superior skill transfer of the Self-After group likely emerged from information processing activities such as error estimation. However, the lack of yoked groups and a measure of error estimation in their experimental design prevents conclusions being made regarding the underlying mechanisms of why self-controlled feedback schedules optimize learning. Here, we revisited Chiviacowsky and Wulf's (2005) design to investigate the learning benefits of self-controlled feedback schedules. We replicated their Self-Before and Self-After groups, but added a Self-Both group that was able to request feedback before a trial, but could then change or stay with their original choice after the trial. Importantly, yoked groups were included for the three self-controlled groups to address the previously stated methodological limitation and error estimations were included to examine whether self-controlling feedback facilitates a more accurate error detection and correction mechanism. The Self-After and Self-Before groups demonstrated similar accuracy in physical performance and error estimation scores in retention and transfer, and both groups were significantly more accurate than the Self-Before group and their respective Yoked groups (p's < 0.05). Further, the Self-Before group was not significantly different from their yoked counterparts (p's > 0.05). We suggest these findings further indicate that informational factors associated with the processing of feedback for the development of one's error detection and correction mechanism, rather than motivational processes are more critical for why self-controlled feedback schedules optimize motor learning.
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http://dx.doi.org/10.3389/fpsyg.2014.01325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237043PMC
December 2014

Anodal transcranial direct current stimulation applied over the supplementary motor area delays spontaneous antiphase-to-in-phase transitions.

J Neurophysiol 2015 Feb 5;113(3):780-5. Epub 2014 Nov 5.

School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada;

Coordinated bimanual oscillatory movements often involve one of two intrinsically stable phasing relationships characterized as in-phase (symmetrical) or antiphase (asymmetrical). The in-phase mode is typically more stable than antiphase, and if movement frequency is increasing during antiphase movements, a spontaneous transition to the in-phase pattern occurs. There is converging neurophysiological evidence that the supplementary motor area (SMA) plays a critical role in the successful performance of these patterns, especially during antiphase movements. We investigated whether modulating the excitability of the SMA via offline transcranial direct current stimulation (tDCS) would delay the onset of anti-to-in-phase transitions. Participants completed two sessions (separated by ∼48 h), each consisting of a pre- and post-tDCS block in which they performed metronome-paced trials of rhythmic in- and antiphase bimanual supination-pronation movements as target oscillation frequency was systematically increased. Anodal or cathodal tDCS was applied over the SMA between the pre- and post-tDCS blocks in each session. Following anodal tDCS, participants performed the antiphase pattern with increased accuracy and stability and were able to maintain the coordination pattern at a higher oscillation frequency. Antiphase performance was unchanged following cathodal tDCS, and neither tDCS polarity affected the in-phase mode. Our findings suggest increased SMA excitability induced by anodal tDCS can improve antiphase performance and adds to the accumulating evidence of the pivotal role of the SMA in interlimb coordination.
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http://dx.doi.org/10.1152/jn.00662.2014DOI Listing
February 2015

Urinary antibiotic activity in paediatric patients attending an outpatient department in north-western Cambodia.

Trop Med Int Health 2015 Jan 16;20(1):24-8. Epub 2014 Oct 16.

Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Clinical Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, UK.

Objective: Antibiotic resistance is a prominent public and global health concern. We investigated antibiotic use in children by determining the proportion of unselected children with antibacterial activity in their urine attending a paediatric outpatient department in Siem Reap, Cambodia.

Methods: Caregiver reports of medication history and presence of possible infection symptoms were collected in addition to urine samples. Urine antibiotic activity was estimated by exposing bacteria to urine specimens, including assessment against multiresistant bacteria previously isolated from patients in the hospital (a methicillin-resistant Staphylococcus aureus (MRSA), a multiresistant Salmonella typhi and an extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolate).

Results: Medication information and urine were collected from 775 children. Caregivers reported medication use in 69.0% of children in the preceding 48 h. 31.7% samples showed antibacterial activity; 16.3% showed activity against a local multiresistant organism. No specimens demonstrated activity against an ESBL-producing E. coli.

Conclusions: Antibiotics are widely used in the community setting in Cambodia. Parents are often ill-informed about drugs given to treat their children. Increasing the regulation and training of private pharmacies in Cambodia may be necessary. Regional surveillance of antibiotic use and resistance is also essential in devising preventive strategies against further development of antibiotic resistance, which would have both local and global consequences.
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http://dx.doi.org/10.1111/tmi.12398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284023PMC
January 2015