Neurocognitive outcomes in neurofibromatosis clinical trials

Neurofibromatosis type 1 (NF1) is associated with neurocognitive deficits that can impact everyday functioning of children, adolescents, and adults with this disease. However, there is little agreement regarding measures to use as cognitive endpoints in clinical trials. This article describes the work of the Neurocognitive Committee of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration. The goal of this committee is to identify standardized and specific cognitive assessment tools for use in NF clinical trials. The committee first identified cognitive domains relevant to NF1 and prioritized attention as the first domain of focus given prior and current trends in NF1 cognitive clinical trials. Performance measures and behavioral rating questionnaires of attention were reviewed by the group using established criteria to assess patient characteristics, psychometric properties, and feasibility. The highest rated tests underwent side-by-side comparison. The Digit Span subtest from the Wechsler scales was given the highest ratings of the performance measures due to its good psychometrics, feasibility, utility across a wide age range, and extensive use in previous research. The Conners scales achieved the highest ratings of the behavioral questionnaires for similar reasons. Future articles will focus on other cognitive domains, with the ultimate goal of achieving agreement for cognitive endpoints that can be used across NF clinical trials

The relationship between a child's postural stability and manual dexterity

The neural systems responsible for postural control are separate from the neural substrates that underpin control of the hand. Nonetheless, postural control and eye-hand coordination are linked functionally. For example, a stable platform is required for precise manual control tasks (e.g. handwriting) and thus such skills often cannot develop until the child is able to sit or stand upright. This raises the question of the strength of the empirical relationship between measures of postural stability and manual motor control. We recorded objective computerised measures of postural stability in stance and manual control in sitting in a sample of school children (n = 278) aged 3–11 years in order to explore the extent to which measures of manual skill could be predicted by measures of postural stability. A strong correlation was found across the whole sample between separate measures of postural stability and manual control taken on different days. Following correction for age, a significant but modest correlation was found. Regression analysis with age correction revealed that postural stability accounted for between 1 and 10 % of the variance in manual performance, dependent on the specific manual task. These data reflect an interdependent functional relationship between manual control and postural stability development. Nevertheless, the relatively small proportion of the explained variance is consistent with the anatomically distinct neural architecture that exists for ‘gross’ and ‘fine’ motor control. These data justify the approach of motor batteries that provide separate assessments of postural stability and manual dexterity and have implications for therapeutic intervention in developmental disorders

Cortical functioning in children with developmental coordination disorder:a motor overflow study

This study examined brain activation in children with developmental coordination disorder (DCD) to reveal areas that may contribute to poor movement execution and/or abundant motor overflow. Using functional magnetic resonance imaging, 13 boys with DCD (mean age = 9.6 years ±0.8) and 13 typically developing controls (mean age = 9.3 years ±0.6) were scanned performing two tasks (finger sequencing and hand clenching) with their dominant hand, while a four-finger motion sensor recorded contralateral motor overflow on their non-dominant hand. Despite displaying increased motor overflow on both functional tasks during scanning, there were no obvious activation deficits in the DCD group to explain the abundant motor overflow seen. However, children with DCD were found to display decreased activation in the left superior frontal gyrus on the finger-sequencing task, an area which plays an integral role in executive and spatially oriented processing. Decreased activation was also seen in the left inferior frontal gyrus, an area typically active during the observation and imitation of hand movements. Finally, increased activation in the right postcentral gyrus was seen in children with DCD, which may reflect increased reliance on somatosensory information during the execution of complex fine motor tasks

Assessment of motor functioning in the preschool period

The assessment of motor functioning in young children has become increasingly important in recent years with the acknowledgement that motor impairment is linked with cognitive, language, social and emotional difficulties. However, there is no one gold standard assessment tool to investigate motor ability in children. The aim of the current paper was to discuss the issues related to the assessment of motor ability in young pre-school children and to provide guidelines on the best approach for motor assessment. The paper discusses the maturational changes in brain development at the preschool level in relation to motor ability. Other issues include sex differences in motor ability at this young age, and evidence for this in relation to sociological versus biological influences. From the previous literature it is unclear what needs to be assessed in relation to motor functioning. Should the focus be underlying motor processes or movement skill assessment? Several key assessment tools are discussed that produce a general measure of motor performance followed by a description of tools that assess specific skills, such as fine and gross motor, ball and graphomotor skills. The paper concludes with recommendations on the best approach in assessing motor function in pre-school children

Causal Pathways from Enteropathogens to Environmental Enteropathy: Findings from the MAL-ED Birth Cohort Study

Background Environmental enteropathy (EE), the adverse impact of frequent and numerous enteric infections on the gut resulting in a state of persistent immune activation and altered permeability, has been proposed as a key determinant of growth failure in children in low- and middle-income populations. A theory-driven systems model to critically evaluate pathways through which enteropathogens, gut permeability, and intestinal and systemic inflammation affect child growth was conducted within the framework of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study that included children from eight countries. Methods Non-diarrheal stool samples (N = 22,846) from 1253 children from multiple sites were evaluated for a panel of 40 enteropathogens and fecal concentrations of myeloperoxidase, alpha-1-antitrypsin, and neopterin. Among these same children, urinary lactulose:mannitol (L:M) (N = 6363) and plasma alpha-1-acid glycoprotein (AGP) (N = 2797) were also measured. The temporal sampling design was used to create a directed acyclic graph of proposed mechanistic pathways between enteropathogen detection in non-diarrheal stools, biomarkers of intestinal permeability and inflammation, systemic inflammation and change in length- and weight- for age in children 0–2 years of age. Findings Children in these populations had frequent enteric infections and high levels of both intestinal and systemic inflammation. Higher burdens of enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, were associated with elevated biomarker concentrations of gut and systemic inflammation and, via these associations, indirectly associated with both reduced linear and ponderal growth. Evidence for the association with reduced linear growth was stronger for systemic inflammation than for gut inflammation; the opposite was true of reduced ponderal growth. Although Giardia was associated with reduced growth, the association was not mediated by any of the biomarkers evaluated. Interpretation The large quantity of empirical evidence contributing to this analysis supports the conceptual model of EE. The effects of EE on growth faltering in young children were small, but multiple mechanistic pathways underlying the attribution of growth failure to asymptomatic enteric infections had statistical support in the analysis. The strongest evidence for EE was the association between enteropathogens and linear growth mediated through systemic inflammation

Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

Racism as a determinant of health: a systematic review and meta-analysis

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants.<br /

Phenomenon of declining blood pressure in elderly - high systolic levels are undervalued with Korotkoff method

<p>Abstract</p> <p>Background</p> <p>Systolic blood pressure (SBP) decline has been reported in octogenarians. The aim was to study if it could be observed while measuring SBP with two methods: Korotkoff (K-BP) and Strain-Gauge-Finger-Pletysmography (SG-BP), and which of them were more reliable in expressing vascular burden.</p> <p>Methods</p> <p>A cohort of 703 men from a population of Malmö, Sweden, were included in "Men born in 1914-study" and followed-up at ages: 68 and 81 years. 176 survivors were examined with K-BP and SG-BP at both ages, and 104 of them with Ambulatory Blood Pressure at age 81/82. Ankle Brachial Index (ABI) was measured on both occasions, and Carotid Ultrasound at age 81.</p> <p>Results</p> <p>From age 68 to 81, mean K-BP decreased in the cohort with mean 8.3 mmHg, while SG-BP increased with 13.4 mmHg. K-BP decreased in 55% and SG-BP in 31% of the subjects. At age 81, K-BP was lower than SG-BP in 72% of subjects, and correlated to high K-BP at age 68 (r = --.22; p < .05). SG-BP at age 81 was correlated with mean ambulatory 24-h SBP (r = .480; p < .0001), daytime SBP (r = .416; p < .0001), nighttime SBP (r = .395; p < .0001), and daytime and nighttime Pulse Pressure (r = .452; p < .0001 and r = .386; p < .0001). KB-BP correlated moderately only with nighttime SBP (r = .198; p = .044), and daytime and nightime pulse pressure (r = .225; p = .021 and r = .264; p = .007). Increasing SG-BP from age 68 to 81, but not K-BP, correlated with: 24-h, daytime and nighttime SBP, and mean daytime and nighttime Pulse Pressure. Increasing SG-BP was also predicted by high B-glucose and low ABI at age 68, and correlated with carotid stenosis and low ABI age 81, and the grade of ABI decrease over 13 years.</p> <p>Conclusion</p> <p>In contrast to K-BP, values of SG-BP in octogenarians strongly correlated with Ambulatory Blood Pressure. The SG-BP decline in the last decade was rare, and increasing SG-BP better than K-BP reflected advanced atherosclerosis. It should be aware, that K-BP underdetected 46% of subjects with SG-BP equal/higher than 140 mmHg at age 81, which may lead to biased associations with risk factors due to differential misclassification by age.</p

What Facilitates Return to Work? Patients Experiences 3 Years After Occupational Rehabilitation

Objective We have limited knowledge about the specific elements in an occupational rehabilitation programme that facilitate the process leading to return to work (RTW) as perceived by the patients. The aim of the study was to explore individual experiences regarding contributing factors to a successful RTW, 3 years after a resident occupational rehabilitation programme. Methods The study is based on interviews of 20 individuals who attended an occupational rehabilitation programme 3 years earlier. Ten informants had returned to work (RTW) and ten were receiving disability pension (DP). Data were analysed by systematic text condensation inspired by Giorgi’s phenomenological analysis. Results The core categories describing a successful RTW process included positive encounters, increased self-understanding and support from the surroundings. While the informants on DP emphasized being seen, heard and taken seriously by the professionals, the RTW group highlighted being challenged to increase self-understanding that promoted new acting in every-day life. Being challenged on self-understanding implied increased awareness of own identity, values and resources. Support from the surroundings included support from peer participants, employer and social welfare system. Conclusion Successful RTW processes seem to comprise positive encounters, opportunities for increased self-understanding and support from significant others. An explicit focus on topics like identity, own values and resources might improve the outcome of the rehabilitation process

Gender and age differences in the recurrence of sickness absence due to common mental disorders: a longitudinal study

Background: Common mental disorders (CMDs) are an important cause of sickness absence and long-term work disability. Although CMDs are known to have high recurrence rates, little is known about the recurrence of sickness absence due to CMDs. The aim of this study was to investigate the recurrence of sickness absence due to CMDs, including distress, adjustment disorders, depressive disorders and anxiety disorders, according to age, in male and female employees in the Netherlands. Methods: Data on sickness absence episodes due to CMDs were obtained for 137,172 employees working in the Dutch Post and Telecommunication companies between 2001 and 2007. The incidence density (ID) and recurrence density (RD) of sickness absence due to CMDs was calculated per 1000 person-years in men and women in the age-groups of < 35 years, 35-44 years, 45-54 years, and >= 55 years. Results: The ID of one episode of CMDs sickness absence was 25.0 per 1000 person-years, and the RD was 76.7 per 1000 person-years. Sickness absence due to psychiatric disorders (anxiety and depression) does not have a higher recurrence density of sickness absence due to any CMDs as compared to stress-related disorders (distress and adjustment disorders): 81.6 versus 76.0 per 1000 person-years. The ID of sickness absence due to CMDs was higher in women than in men, but the RD was similar. Recurrences were more frequent in women < 35 years and in women between 35 and 44 years of age. We observed no differences between age groups in men. Recurrences among employees with recurrent episodes occurred within 3 years in 90% of cases and the median time-to-onset of recurrence was 11 (10-13) months in men and 10 (9-12) months in women. Conclusions: Employees who have been absent from work due to CMDs are at increased risk of recurrent sickness absence due to CMDs and should be monitored after they return to work. The RD was similar in men and in women. In women < 45 years the RD was higher than in women >= 45 years. In men no age differences were observed