Procedural and declarative learning in dyslexia

The procedural deficit hypothesis claims that impaired procedural learning is at least partly responsible for the deficits in learning to read seen in children with developmental dyslexia. This study used a reading ability‐matched design to examine group differences in both procedural and declarative learning. Both children with dyslexia and typically developing children demonstrated procedural learning on a serial reaction time task, although learning in the typically developing group increased at a greater rate towards the end of the task compared with children with dyslexia. However, these results do not provide strong evidence for the procedural deficit hypothesis, because poorer procedural learning in the group with dyslexia may reflect impairments in motor learning, rather than sequence specific procedural learning. In addition, neither group showed a relationship between procedural learning and reading ability

Global health competencies and approaches in medical education: a literature review

<p>Abstract</p> <p>Background</p> <p>Physicians today are increasingly faced with healthcare challenges that require an understanding of global health trends and practices, yet little is known about what constitutes appropriate global health training.</p> <p>Methods</p> <p>A literature review was undertaken to identify competencies and educational approaches for teaching global health in medical schools.</p> <p>Results</p> <p>Using a pre-defined search strategy, 32 articles were identified; 11 articles describing 15 global health competencies for undergraduate medical training were found. The most frequently mentioned competencies included an understanding of: the global burden of disease, travel medicine, healthcare disparities between countries, immigrant health, primary care within diverse cultural settings and skills to better interface with different populations, cultures and healthcare systems. However, no consensus on global health competencies for medical students was apparent. Didactics and experiential learning were the most common educational methods used, mentioned in 12 and 13 articles respectively. Of the 11 articles discussing competencies, 8 linked competencies directly to educational approaches.</p> <p>Conclusions</p> <p>This review highlights the imperative to document global health educational competencies and approaches used in medical schools and the need to facilitate greater consensus amongst medical educators on appropriate global health training for future physicians.</p

Predictive value of cell-surface markers in infections in critically ill patients: protocol for an observational study (ImmuNe FailurE in Critical Therapy (INFECT) Study).

INTRODUCTION: Critically ill patients are at high risk of nosocomial infections, with between 20% and 40% of patients admitted to the intensive care unit (ICU) acquiring infections. These infections result in increased antibiotic use, and are associated with morbidity and mortality. Although critical illness is classically associated with hyperinflammation, the high rates of nosocomial infection argue for an importance of effect of impaired immunity. Our group recently demonstrated that a combination of 3 measures of immune cell function (namely neutrophil CD88, monocyte HLA-DR and % regulatory T cells) identified a patient population with a 2.4-5-fold greater risk for susceptibility to nosocomial infections. METHODS AND ANALYSIS: This is a prospective, observational study to determine whether previously identified markers of susceptibility to nosocomial infection can be validated in a multicentre population, as well as testing several novel markers which may improve the risk of nosocomial infection prediction. Blood samples from critically ill patients (those admitted to the ICU for at least 48 hours and requiring mechanical ventilation alone or support of 2 or more organ systems) are taken and undergo whole blood staining for a range of immune cell surface markers. These samples undergo analysis on a standardised flow cytometry platform. Patients are followed up to determine whether they develop nosocomial infection. Infections need to meet strict prespecified criteria based on international guidelines; where these criteria are not met, an adjudication panel of experienced intensivists is asked to rule on the presence of infection. Secondary outcomes will be death from severe infection (sepsis) and change in organ failure. ETHICS AND DISSEMINATION: Ethical approval including the involvement of adults lacking capacity has been obtained from respective English and Scottish Ethics Committees. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02186522; Pre-results.Innovate UK (formerly Technology Strategy Board) (Grant ID: 15457-108136), Becton Dickinson bioscience, NHS Lothian via the Edinburgh Health Services Research Unit, National Institute of Academic AnaesthesiaThis is the final version of the article. It first appeared from BMJ Publishing Group via http://dx.doi.org/10.1136/bmjopen-2016-01132

Oral language enrichment in preschool improves children's language skills : a cluster randomised controlled trial

Background. Oral language skills provide the foundation for formal education, yet many children enter school with language weaknesses. This study evaluated the efficacy of a new language enrichment programme, the Nuffield Early Language Intervention—Preschool (NELI Preschool), delivered to children in the year before they enter formal education. Methods. We conducted a preregistered cluster randomised controlled trial in 65 nursery schools in England (https://doi.org/10.1186/ISRCTN29838552). NELI Preschool consists of a 20-week whole-class language enrichment programme delivered by a teacher each day for 20 min. In addition, children with the weakest language skills in each class are allocated to receive additional targeted support delivered by classroom assistants (whole-class + targeted). The language skills of all children (n = 1,586) in participating classrooms were assessed using the LanguageScreen automated app (https://oxedandassessment.com/languagescreen/). Settings were then randomly allocated to an intervention or control group. The children with the weakest language in each class (whole-class + targeted children n = 438), along with four randomly selected children in each class allocated to the whole-class only programme (n = 288) were individually tested on a range of language measures. Results. Children receiving NELI Preschool made larger gains than children in the control group on an oral language latent variable (whole-class children d = .26; whole-class + targeted children d = .16). Conclusions. This study provides good evidence that whole-class intervention delivered in preschool can produce educationally significant improvements in children's language skills. The intervention is scaleable and relatively low cost. These findings have important implications for educational and social policy

Early PREdiction of Severe Sepsis (ExPRES-Sepsis) study: protocol for an observational derivation study to discover potential leucocyte cell surface biomarkers.

INTRODUCTION: Sepsis is an acute illness resulting from infection and the host immune response. Early identification of individuals at risk of developing life-threatening severe sepsis could enable early triage and treatment, and improve outcomes. Currently available biomarkers have poor predictive value for predicting subsequent clinical course in patients with suspected infection. Circulating leucocytes provide readily accessible tissues that reflect many aspects of the complex immune responses described in sepsis. We hypothesise that measuring cellular markers of immune responses by flow cytometry will enable early identification of infected patients at risk of adverse outcomes. We aim to characterise leucocyte surface markers (biomarkers) and their abnormalities in a population of patients presenting to the hospital emergency department with suspected sepsis, and explore their ability to predict subsequent clinical course. METHODS AND ANALYSIS: We will conduct a prospective, multicentre, clinical, exploratory, cohort observational study. To answer our study question, 3 patient populations will be studied. First, patients with suspected sepsis from the emergency department (n=300). To assess performance characteristics of potential tests, critically ill patients with established sepsis, and age and gender matched patients without suspicion of infection requiring hospital admission (both n=100) will be recruited as comparator populations. In all 3 groups, we plan to assess circulating biomarker profiles using flow cytometry. We will select candidate biomarkers by cross-cohort comparison, and then explore their predictive value for clinical outcomes within the cohort with suspected sepsis. ETHICS AND DISSEMINATION: The study will be carried out based on the principles in the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice. Ethics approval has been granted from the Scotland A Research Ethics Committee (REC) and Oxford C REC. On conclusion of this study, the results will be disseminated via peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02188992; Pre-results

Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study.

PURPOSE: Cellular immune dysfunctions, which are common in intensive care patients, predict a number of significant complications. In order to effectively target treatments, clinically applicable measures need to be developed to detect dysfunction. The objective was to confirm the ability of cellular markers associated with immune dysfunction to stratify risk of secondary infection in critically ill patients. METHODS: Multi-centre, prospective observational cohort study of critically ill patients in four UK intensive care units. Serial blood samples were taken, and three cell surface markers associated with immune cell dysfunction [neutrophil CD88, monocyte human leucocyte antigen-DR (HLA-DR) and percentage of regulatory T cells (Tregs)] were assayed on-site using standardized flow cytometric measures. Patients were followed up for the development of secondary infections. RESULTS: A total of 148 patients were recruited, with data available from 138. Reduced neutrophil CD88, reduced monocyte HLA-DR and elevated proportions of Tregs were all associated with subsequent development of infection with odds ratios (95% CI) of 2.18 (1.00-4.74), 3.44 (1.58-7.47) and 2.41 (1.14-5.11), respectively. Burden of immune dysfunction predicted a progressive increase in risk of infection, from 14% for patients with no dysfunction to 59% for patients with dysfunction of all three markers. The tests failed to risk stratify patients shortly after ICU admission but were effective between days 3 and 9. CONCLUSIONS: This study confirms our previous findings that three cell surface markers can predict risk of subsequent secondary infection, demonstrates the feasibility of standardized multisite flow cytometry and presents a tool which can be used to target future immunomodulatory therapies. TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT02186522).The study was funded by Innovate UK (Sepsis 2: 101193), BD Biosciences and the National Institute for Academic Anaesthesia. Dr Conway Morris is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z). Dr Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16- 011)

Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission

Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare – CD45RO+PD1hi CD4+ and CD8+ T cells, and CD27+CD86+CD21- B cells – further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+ memory T cells, memory CD8+CXCR5+ T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+ T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+ memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention

Early PREdiction of sepsis using leukocyte surface biomarkers: the ExPRES-sepsis cohort study.

PURPOSE: Reliable biomarkers for predicting subsequent sepsis among patients with suspected acute infection are lacking. In patients presenting to emergency departments (EDs) with suspected acute infection, we aimed to evaluate the reliability and discriminant ability of 47 leukocyte biomarkers as predictors of sepsis (Sequential Organ Failure Assessment score ≥ 2 at 24 h and/or 72 h following ED presentation). METHODS: In a multi-centre cohort study in four EDs and intensive care units (ICUs), we standardised flow-cytometric leukocyte biomarker measurement and compared patients with suspected acute infection (cohort-1) with two comparator cohorts: ICU patients with established sepsis (cohort-2), and ED patients without infection or systemic inflammation but requiring hospitalization (cohort-3). RESULTS: Between January 2014 and February 2016, we recruited 272, 59 and 75 patients to cohorts 1, 2, and 3, respectively. Of 47 leukocyte biomarkers, 14 were non-reliable, and 17 did not discriminate between the three cohorts. Discriminant analyses for predicting sepsis within cohort-1 were undertaken for eight neutrophil (cluster of differentiation antigens (CD) CD15; CD24; CD35; CD64; CD312; CD11b; CD274; CD279), seven monocyte (CD35; CD64; CD312; CD11b; HLA-DR; CD274; CD279) and a CD8 T-lymphocyte biomarker (CD279). Individually, only higher neutrophil CD279 [OR 1.78 (95% CI 1.23-2.57); P = 0.002], higher monocyte CD279 [1.32 (1.03-1.70); P = 0.03], and lower monocyte HLA-DR [0.73 (0.55-0.97); P = 0.03] expression were associated with subsequent sepsis. With logistic regression the optimum biomarker combination was increased neutrophil CD24 and neutrophil CD279, and reduced monocyte HLA-DR expression, but no combination had clinically relevant predictive validity. CONCLUSIONS: From a large panel of leukocyte biomarkers, immunosuppression biomarkers were associated with subsequent sepsis in ED patients with suspected acute infection. CLINICAL TRIAL REGISTRATION: NCT02188992.The study was funded by Innovate UK (Sepsis 2: 101193). Dr Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr Conway Morris is supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z)

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function