Search

Objective:  Integrins are key regulators of various platelet functions. The pathophysiological importance of most platelet integrins has been investigated, with the exception of α5β1, a receptor for fibronectin. The aim of this study was to characterize the role of α5β1 in megakaryopoiesis, platelet function, and to determine its importance in hemostasis and arterial thrombosis., Approach and Results:  We generated a mouse strain deficient for integrin α5β1 on megakaryocytes and platelets (PF4Cre-α5 -/- ). PF4Cre-α5 -/- mice were viable, fertile, and presented no apparent signs of abnormality. Megakaryopoiesis appears unaltered as evidence by a normal megakaryocyte morphology and development, which is in agreement with a normal platelet count. Expression of the main platelet receptors and the response of PF4Cre-α5 -/- platelets to a series of agonists were all completely normal. Adhesion and aggregation of PF4Cre-α5 -/- platelets under shear flow on fibrinogen, laminin, or von Willebrand factor were unimpaired. In contrast, PF4Cre-α5 -/- platelets displayed a marked decrease in adhesion, activation, and aggregation on fibrillar cellular fibronectin and collagen. PF4Cre-α5 -/- mice presented no defect in a tail-bleeding time assay and no increase in inflammatory bleeding in a reverse passive Arthus model and a lipopolysaccharide pulmonary inflammation model. Finally, no defects were observed in three distinct experimental models of arterial thrombosis based on ferric chloride-induced injury of the carotid artery, mechanical injury of the abdominal aorta, or laser-induced injury of mesenteric vessels., Conclusion:  In summary, this study shows that platelet integrin α5β1 is a key receptor for fibrillar cellular fibronectin but is dispensable in hemostasis and arterial thrombosis., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Prevalence and burden of headache disorders in real-world settings is relatively unstudied. We explored the associations between passively collected activity data, headache burden, and quality of life in headache sufferers., Methods: Data from wearable activity tracking devices and daily short questionnaires were collected over 12 weeks to assess occurrence of headache, activity, quality of life and self-rated health. Variables were analyzed using a series of mixed-effects models and stratified based on headache type. Multiple linear and logistic regressions were used to analyze treatment preferences., Results: Behaviors inferred from activity tracker data suggested that individuals slept more, had reduced physical activity, and had lower maximum heart rate on days with headache. As headache-specific impact on quality of life increased, activity and maximum heart rate decreased and sleep increased. Headache days with higher self-rated health were associated with less napping, higher step count and maximum heart rate, correlating with increased activity. Migraineurs experienced greater burden in everyday life compared with tension-type headache sufferers., Conclusion: This study adds to existing evidence that activity trackers can be used to quantify headache burden in real-world settings and aid in understanding symptom management., (© 2021. The Author(s).)

Children admitted to hospital with an acute illness and concurrent severe malnutrition [complicated severe malnutrition (CSM)] have a high risk of dying. The biological processes underlying their mortality are poorly understood. In this case-control study nested within a multicenter randomized controlled trial among children with CSM in Kenya and Malawi, we found that blood metabolomic and proteomic profiles robustly differentiated children who died ( n = 92) from those who survived ( n = 92). Fatalities were characterized by increased energetic substrates (tricarboxylic acid cycle metabolites), microbial metabolites (e.g., propionate and isobutyrate), acute phase proteins (e.g., calprotectin and C-reactive protein), and inflammatory markers (e.g., interleukin-8 and tumor necrosis factor-α). These perturbations indicated disruptions in mitochondria-related bioenergetic pathways and sepsis-like responses. This study identified specific biomolecular disturbances associated with CSM mortality, revealing that systemic inflammation and bioenergetic deficits are targetable pathophysiological processes for improving survival of this vulnerable population.

Background: Breast cancer (BC) is the most common non-skin cancer affecting women but is extremely uncommon in the adolescent population. Genetic inheritance has been linked to <10% of BCs. CHEK2 is an uncommon genetic variant with a reported incidence of 0.3-1.6% in the general population and 4.9-5.7% in those with a family history of BC. Commonly, this mutation presents in females of European descent and is rare in North America., Case Presentation: A 19-year-old Caucasian female presented with breast pain and mass. She had an extensive family history of cancer, as well as a known CHEK2 gene mutation in 2 of her paternal aunts. Ultrasound and MRI confirmed a 4.5-cm mass with an enlarged right axillary lymph node. Image guided biopsy of the breast mass showed ER/PR-positive grade 1 invasive mucinous ductal cancer. Genetic testing confirmed an isolated CHEK2 mutation. After discussion by a multidisciplinary tumor board, the patient deferred bilateral mastectomy and underwent a right mastectomy with sentinel-lymph-node biopsy and immediate tissue-expander reconstruction. Final pathology confirmed ER/PR-positive Stage 1A (pT2 pN0 M0) invasive mucinous carcinoma. Chemotherapy was not recommended., Summary: Malignant adolescent breast masses are relatively rare and CHEK2 does not typically present at younger than 20 years of age. While there are many different differential diagnoses when evaluating an adolescent with a breast mass, we wish to increase providers' suspicion of malignancy, specifically in those individuals who have a strong family history of BC and the CHEK2 *1100delC mutation., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Background and Purpose: A large proportion of headache sufferers do not routinely seek medical care. App-based technologies permit the collection of real-world data over time and between countries that can help assess true burden of headache. This study used a mobile phone application to collect information on the real-world burden of self-diagnosed headache and to describe its impact on daily life in headache sufferers who do not routinely seek medical advice., Methods: This retrospective, non-interventional, cross-sectional study analysed self-reported data from users of the 'Migraine Buddy' app. The main objective was to describe self-reported characteristics of headache and migraine (triggers, duration, frequency), treatment patterns and impact on daily activity in headache sufferers from Australia, Brazil, France, Germany and Japan. Data including demographics, self-diagnosed episode type (headache/migraine), duration, potential triggers and impact on daily activity are reported. All analyses were exploratory and performed per country., Results: Self-reported data were collected from 60,474 users between August 2016 and August 2018. Approximately 90% of users were females; >60% were aged 24-45 years. Over one-third of users reported having two to five episodes of headache or migraine per month; impact included impaired concentration, being slower and missing work or social activities. Variations across countries were observed; within countries, episode characteristics were very similar for self-diagnosed headache versus migraine., Conclusions: Headache tracking was used to describe the experience, impact and self-management approaches of migraine and headache sufferers in a real-world setting. Headache disorders present a range of important issues for patients that deserve more study and reinforce the need for better approaches to management., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Supplementation with micronutrients, including vitamins, iron and zinc, is a key strategy to alleviate child malnutrition. However, association of gastrointestinal disorders with iron has led to ongoing debate over their administration. To better understand their impact on gut microbiota, we analyse the bacterial, protozoal, fungal and helminth communities of stool samples collected from a subset of 80 children at 12 and 24 months of age, previously enrolled into a large cluster randomized controlled trial of micronutrient supplementation in Pakistan (ClinicalTrials.gov identifier NCT00705445). We show that while bacterial diversity is reduced in supplemented children, vitamins and iron (as well as residence in a rural setting) may promote colonization with distinct protozoa and mucormycetes, whereas the addition of zinc appears to ameliorate this effect. We suggest that the risks and benefits of micronutrient interventions may depend on eukaryotic communities, potentially exacerbated by exposure to a rural setting. Larger studies are needed to evaluate the clinical significance of these findings and their impact on health outcomes., (© 2021. The Author(s).)

MicroRNAs are small noncoding RNAs that have important roles in the lactation process and milk biosynthesis. Some polymorphisms have been studied in various livestock species from the perspective of pathology or production traits. To target variants that could be the causal variants of dairy traits, genetic variants of microRNAs expressed in the mammary gland or present in milk and localized in dairy quantitative trait loci (QTLs) were investigated in bovine, caprine, and ovine species. In this study, a total of 59,124 (out of 28 millions), 13,427 (out of 87 millions), and 4761 (out of 38 millions) genetic variants in microRNAs expressed in the mammary gland or present in milk were identified in bovine, caprine, and ovine species, respectively. A total of 4679 of these detected bovine genetic variants are located in dairy QTLs. In caprine species, 127 genetic variants are localized in dairy QTLs. In ovine species, no genetic variant was identified in dairy QTLs. This study leads to the detection of microRNA genetic variants of interest in the context of dairy production, taking advantage of whole genome data to identify microRNA genetic variants expressed in the mammary gland and localized in dairy QTLs., (© 2021. The Author(s).)

Background: Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM., Methods: This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell's concordance index (C-index) and time-dependent area under the curve (tAUC)., Results: Inpatient case fatality ratio was 16.3% (n=127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77-0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74-0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively., Conclusions: This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children., Trial Registration: NCT02246296., (© 2021. The Author(s).)

Children with severe acute malnutrition (SAM) remain vulnerable after treatment at nutritional rehabilitation units (NRUs). The objective was to assess the concurrent pathways in a hypothesized model between caregiver body mass index (BMI), the home environment, and child nutritional status, and development (gross motor, fine motor, language, and social domains) in children with SAM following discharge from inpatient treatment. Structural equation modelling (SEM) was performed with data from a cluster-randomized controlled trial at the Moyo Nutritional Rehabilitation and Research Unit in Blantyre, Malawi. This approach was undertaken to explore simultaneous relationships between caregiver BMI, the home environment (Home Observation for Measurement of the Environment Inventory scores), child nutritional status (anthropometric indicators including weight-for-age z-scores [WAZ]), and child development (Malawi Developmental Assessment Tool (MDAT) z-scores as a latent variable) in children with SAM. These data were collected at participants' homes six months after discharge from NRU treatment. This analysis included 85 children aged 6-59 months with SAM and their caregivers recruited to the trial at the NRU and followed up successfully six months after discharge. The model with WAZ as the nutritional indicator fit the data according to model fit indices (χ2 = 28.92, p = 0.42). Caregiver BMI was predictive of better home environment scores (β = 0.23, p = 0.03) and child WAZ (β = 0.30, p = 0.005). The home environment scores were positively correlated with MDAT z-scores (β = 0.32, p = 0.001). Child nutritional status based on WAZ was also correlated with MDAT z-scores (β = 0.37, p<0.001). This study demonstrates that caregiver BMI could ultimately relate to child development in children with SAM, through its links to the home environment and child nutritional status., Competing Interests: The authors have declared that no competing interests exist.

Background: Children with severe acute malnutrition (SAM) who require nutritional rehabilitation unit (NRU) treatment often have poor developmental and nutritional outcomes following discharge. The Kusamala Program is a 4-d hospital-based counseling program for caregivers of children with SAM that integrates nutrition, water, sanitation, and hygiene and psychosocial stimulation, aimed at improving these outcomes., Objectives: The aim was to evaluate the effects of the Kusamala Program on child development and nutritional status in children with SAM 6 mo after NRU discharge. The other aim was to qualitatively understand perceptions and experiences of caregivers who participated in the intervention., Methods: A cluster-randomized controlled trial was conducted with caregivers and their children 6-59 mo of age with SAM admitted to the Moyo NRU in Blantyre, Malawi. The primary outcome of the trial was child development according to Malawi Developmental Assessment Tool (MDAT) composite z- scores of gross motor, fine motor, language, and social domains. A qualitative component with focus group discussions and in-depth interviews was also completed with a subset of caregivers who participated in the trial., Results: Sixty-eight caregivers and children were enrolled to clusters by week and randomly assigned to the comparison arm and 104 to the intervention arm. There were no differences in child development, with mean MDAT composite z -scores in the comparison arm of -1.2 (95% CI: -2.1, -0.22) and in the intervention arm of -1.1 (95% CI: -1.9, -0.40) ( P  = 0.93). The qualitative evaluation with 20 caregivers indicated that the 3 modules of the Kusamala Program were appropriate and that they applied many of the lessons learned at home as much as possible., Conclusions: The Kusamala Program did not result in improved developmental or nutritional outcomes, yet it was viewed positively by caregivers according to qualitative results. Future research should evaluate more intensive interventions for caregivers and children with SAM. This trial was registered at www.clinicaltrials.gov as NCT03072433., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Most studies on children evaluate longitudinal growth as an important health indicator. Different methods have been used to detect growth patterns across childhood, but with no comparison between them to evaluate result consistency. We explored the variation in growth patterns as detected by different clustering and latent class modelling techniques. Moreover, we investigated how the characteristics/features (e.g. slope, tempo, velocity) of longitudinal growth influence pattern detection., Methods: We studied 1134 children from The Applied Research Group for Kids cohort with longitudinal-growth measurements [height, weight, body mass index (BMI)] available from birth until 12 years of age. Growth patterns were identified by latent class mixed models (LCMM) and time-series clustering (TSC) using various algorithms and distance measures. Time-invariant features were extracted from all growth measures. A random forest classifier was used to predict the identified growth patterns for each growth measure using the extracted features., Results: Overall, 72 TSC configurations were tested. For BMI, we identified three growth patterns by both TSC and LCMM. The clustering agreement was 58% between LCMM and TS clusters, whereas it varied between 30.8% and 93.3% within the TSC configurations. The extracted features (n = 67) predicted the identified patterns for each growth measure with accuracy of 82%-89%. Specific feature categories were identified as the most important predictors for patterns of all tested growth measures., Conclusion: Growth-pattern detection is affected by the method employed. This can impact on comparisons across different populations or associations between growth patterns and health outcomes. Growth features can be reliably used as predictors of growth patterns., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

The objective of this study was to investigate the effects of feed restriction on mammary miRNAs and coding gene expression in midlactation cows. Five Holstein cows and 6 Montbéliarde cows underwent 6 days of feed restriction, during which feed allowance was reduced to meet 50% of their net energy for lactation requirements. Mammary biopsies were performed before and at the end of the restriction period. Mammary miRNA and mRNA analyses were performed using high-throughput sequencing and microarray analyses, respectively. Feed restriction induced a negative energy balance and decreased milk production and fat and protein yields in both breeds. Feed restriction modified the expression of 27 miRNAs and 374 mRNAs in mammary glands from Holstein cows, whereas no significant miRNA change was observed in Montbéliarde cows. Among the 27 differentially expressed miRNAs, 8 miRNAs were associated with dairy QTL. Analysis of target genes indicate that the 8 most abundantly expressed miRNAs control transcripts related to lipid metabolism, mammary remodeling and stress response. A comparison between the mRNAs targeted by the 8 most strongly expressed miRNAs and 374 differentially expressed mRNAs identified 59 mRNAs in common. The bioinformatic analyses of these 59 mRNAs revealed their implication in lipid metabolism and endothelial cell proliferation. These effects of feed restriction on mammary miRNAs and mRNAs observed in Holstein cows suggest a potential role of miRNAs in mammary structure and lipid biosynthesis that could explain changes in milk production and composition., Competing Interests: NO authors have competing interests.

Malnutrition impacts approximately 50 million children worldwide and is linked to 45% of global mortality in children below the age of five. Severe acute malnutrition (SAM) is associated with intestinal barrier breakdown and epithelial atrophy. Extracellular vesicles including exosomes (EVs; 30-150 nm) can travel to distant target cells through biofluids including milk. Since milk-derived EVs are known to induce intestinal stem cell proliferation, this study aimed to examine their potential efficacy in improving malnutrition-induced atrophy of intestinal mucosa and barrier dysfunction. Mice were fed either a control (18%) or a low protein (1%) diet for 14 days to induce malnutrition. From day 10 to 14, they received either bovine milk EVs or control gavage and were sacrificed on day 15, 4 h after a Fluorescein Isothiocyanate (FITC) dose. Tissue and blood were collected for histological and epithelial barrier function analyses. Mice fed low protein diet developed intestinal villus atrophy and barrier dysfunction. Despite continued low protein diet feeding, milk EV treatment improved intestinal permeability, intestinal architecture and cellular proliferation. Our results suggest that EVs enriched from milk should be further explored as a valuable adjuvant therapy to standard clinical management of malnourished children with high risk of morbidity and mortality.

Background: Lack of robust estimates of human-milk nutrient composition and influential maternal factors, such as body composition, are barriers to informing nutrition policies and programs., Objective: The objective was to understand the relation between maternal BMI and human-milk energy, fat, and/or total protein., Methods: Four electronic databases (MEDLINE, Embase, CINAHL, and Web of Science) were searched. Outcomes assessed were human-milk energy (kcal/L), fat (g/L), and total protein (g/L) from mothers 1 to 6 mo postpartum. Studies with data on maternal BMI or weight and height that quantified human-milk energy, fat, or protein between 1 and 6 mo postpartum were eligible. Random-effects meta-regression weighted by the inverse of the study-level SE was completed for each of the 3 outcomes. The certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach., Results: A total of 11,373 titles and abstracts were identified, and after full-text screening, 69 articles of 66 studies were included. Meta-regression results showed a positive association between maternal BMI and human-milk fat (β: 0.56 g/L; 95% CI: 0.034, 1.1; P = 0.04; I2 = 93.7%, n = 63 datapoints). There was no significant association between maternal BMI and human-milk energy (β: 3.9 kcal/L; 95% CI: -1.6, 9.5; P = 0.16, I2 = 93.3%, n = 40 datapoints) or total protein (β: 0.13 g/L; 95% CI: -0.16, 0.41; P = 0.37, I2 = 99.1%, n = 40 datapoints). The certainty of evidence for human-milk energy was low and the certainty of evidence for fat and total protein was very low., Conclusions: Meta-regression analysis of available literature suggested an association between maternal BMI and human-milk fat between 1 and 6 mo postpartum. Future studies are needed to confirm the relation between maternal BMI; variation in human-milk energy, fat, and protein content; and the implications for child growth and development. This review is registered with International Prospective Register of Systematic Reviews (PROSPERO 2018 CRD42018098808) at https://www.crd.york.ac.uk/prospero/., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: Severe Acute Malnutrition (SAM) in children is determined using anthropometry. However, bio-electrical impedance (BI) analysis could improve the estimation of altered body composition linked to edema and/or loss of lean body mass in children with SAM. We aimed to assess: 1) the changes in BI parameters during clinical stabilization and 2) whether BI parameters add prognostic value for clinical outcome beyond the use of anthropometry., Methods: This prospective observational study enrolled children, aged 6-60 months, that were admitted at Queen Elizabeth Central Hospital in Blantyre, Malawi, for complicated SAM (i.e., having either severe wasting or edematous SAM with a complicating illness). Height, weight, mid-upper arm circumference (MUAC), and BI were measured on admission and after clinical stabilization. BI measures were derived from height-adjusted indices of resistance (R/H), reactance (Xc/H), and phase angle (PA) and considered to reflect body fluids and soft tissue in BI vector analysis (BIVA)., Results: We studied 183 children with SAM (55% edematous; age 23.0 ± 12.0 months; 54% male) and 42 community participants (age 20.1 ± 12.3 months; male 62%). Compared to community participants, the BIVA of children with edematous SAM were short with low PA and positioned low on the hydration axis which reflects severe fluid retention. In contrast, children with severe wasting had elongated vectors with a PA that was higher than children with edematous SAM but lower than community participants. Their BIVA position fell within the top right quadrant linked to leanness and dehydration. BIVA from severely wasted and edematous SAM patients differed between groups and from community children both at admission and after stabilization (p < 0.001). Vector position shifted during treatment only in children with edematous SAM (p < 0.001) and showed a upward translation suggestive of fluid loss. While PA was lower in children with SAM, PA did not contribute more than anthropometry alone towards explaining mortality, length of stay, or time-to-discharge or time-to-mortality. The variability and heterogeneity in BI measures was high and their overall added predictive value for prognosis of individual children was low., Conclusions: BIVA did not add prognostic value over using anthropometry alone to predict clinical outcome. Several implementation challenges need to be optimized. Thus, in low-resource settings, the routine use of BI in the management of pediatric malnutrition is questionable without improved implementation., Competing Interests: Conflict of interest The authors have no competing interests to declare., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BACKGROUNDSevere acute malnutrition (SAM) is a major contributor to global mortality in children under 5 years. Mortality has decreased; however, the long-term cardiometabolic consequences of SAM and its subtypes, severe wasting (SW) and edematous malnutrition (EM), are not well understood. We evaluated the metabolic profiles of adult SAM survivors using targeted metabolomic analyses.METHODSThis cohort study of 122 adult SAM survivors (SW = 69, EM = 53) and 90 age-, sex-, and BMI-matched community participants (CPs) quantified serum metabolites using direct flow injection mass spectrometry combined with reverse-phase liquid chromatography. Univariate and sparse partial least square discriminant analyses (sPLS-DAs) assessed differences in metabolic profiles and identified the most discriminative metabolites.RESULTSSeventy-seven metabolite variables were significant in distinguishing between SAM survivors (28.4 ± 8.8 years, 24.0 ± 6.1 kg/m2) and CPs (28.4 ± 8.9 years, 23.3 ± 4.4 kg/m2) (mean ± SDs) in univariate and sPLS-DA models. Compared with CPs, SAM survivors had less liver fat; higher branched-chain amino acids (BCAAs), urea cycle metabolites, and kynurenine/tryptophan (KT) ratio (P < 0.001); and lower β-hydroxybutyric acid and acylcarnitine/free carnitine ratio (P < 0.001), which were both associated with hepatic steatosis (P < 0.001). SW and EM survivors had similar metabolic profiles as did stunted and nonstunted SAM survivors.CONCLUSIONAdult SAM survivors have distinct metabolic profiles that suggest reduced β-oxidation and greater risk of type 2 diabetes (BCAAs, KT ratio, urea cycle metabolites) compared with CPs. This indicates that early childhood SAM exposure has long-term metabolic consequences that may worsen with age and require targeted clinical management.FUNDINGHealth Research Council of New Zealand, Caribbean Public Health Agency, Centre for Global Child Health at the Hospital for Sick Children. DST is an Academic Fellow and a Restracomp Fellow at the Centre for Global Child Health. GBG is a postdoctoral fellow of the Research Foundation Flanders.

Aim: Among the Ehlers-Danlos syndromes, the hypermobile subtype (hEDS) is the most common. The variety, accumulation and duration of the painful symptoms make hEDS a chronic and highly disabling condition. Identifying drivers of pain and mobility disability in hEDS is necessary to provide adapted prevention and intervention programs. Methods: A cross-sectional sample of 75 adults with hEDS according to Villefranche criteria (67 women; 36 years, SD = 11.2) responded to self-assessment questionnaires regarding psychological (negative thoughts and emotions), health (pain, fatigue, diagnostic delay, body mass index, and mobility disability) and socio-demographic variables. Results: Forty-three percent of the participants suffer from severe pain, and two thirds suffer from a high level of mobility disability. Multivariate analyses show that delay of diagnosis, being professionally active and thoughts of helplessness are variables that increase the likelihood of severe pain, whereas age, fatigue, and body mass index predict mobility disability. Conclusion: These results confirm previous research concerning the high disease burden observed in hEDS patients, and highlight the importance of multidisciplinary management that includes nutritional and psychological advice to address this pathology. Increasing awareness of the clinical aspects of hEDS among physicians is necessary to reduce diagnostic delay and minimize negatives outcomes.Implications for RehabilitationA high proportion of patients with hypermobile Ehlers-Danlos syndrome suffer from severe pain (>42%) and a high level of mobility disability (>65%).Different psychosocial and health variables predict pain and mobility disability in patients with hypermobile Ehlers-Danlos syndrome.Awareness concerning the clinical picture of hypermobile Ehlers-Danlos syndrome among health care professionals is necessary to reduce diagnosis delay and the burden of the disease.

This study aimed to determine the associations of targeted metabolomics and hormone profiles data with lean mass index (LMI), which were estimated using bioelectrical impedance, in survivors of child severe malnutrition (SM) ( n = 69) and controls ( n = 77) in Malawi 7 years after being treated. Linear associations between individual metabolite or hormone and LMI were determined, including their interaction with nutrition status 7 years prior. Path analysis was performed to determine structural associations. Lastly, predictive models for LMI were developed using the metabolome and hormone profile by elastic net regularized regression (EN). Metabolites including several lipids, amino acids, and hormones were individually associated ( p < 0.05 after false discovery rate correction) with LMI. However, plasma FGF21 (Control: β = -0.02, p = 0.59; Case: β = -0.14, p < 0.001) and tryptophan (Control: β = 0.15, p = 0.26; Case: β = 0.70, p < 0.001) were associated with LMI among cases but not among controls (both interaction p -values < 0.01). Moreover, path analysis revealed that tryptophan mediates the association between child SM and LMI. EN revealed that most predictors of LMI differed between groups, further indicating altered metabolic mechanisms driving lean mass accretion among SM survivors later in life.

When miniaturizing fluidic circuitry, the solid walls of the fluid channels become increasingly important 1 because they limit the flow rates achievable for a given pressure drop, and they are prone to fouling 2 . Approaches for reducing the wall interactions include hydrophobic coatings 3 , liquid-infused porous surfaces 4-6 , nanoparticle surfactant jamming 7 , changes to surface electronic structure 8 , electrowetting 9,10 , surface tension pinning 11,12 and use of atomically flat channels 13 . A better solution may be to avoid the solid walls altogether. Droplet microfluidics and sheath flow achieve this but require continuous flow of the central liquid and the surrounding liquid 1,14 . Here we demonstrate an approach in which aqueous liquid channels are surrounded by an immiscible magnetic liquid, both of which are stabilized by a quadrupolar magnetic field. This creates self-healing, non-clogging, anti-fouling and near-frictionless liquid-in-liquid fluidic channels. Manipulation of the field provides flow control, such as valving, splitting, merging and pumping. The latter is achieved by moving permanent magnets that have no physical contact with the liquid channel. We show that this magnetostaltic pumping method can be used to transport whole human blood with very little damage due to shear forces. Haemolysis (rupture of blood cells) is reduced by an order of magnitude compared with traditional peristaltic pumping, in which blood is mechanically squeezed through a plastic tube. Our liquid-in-liquid approach provides new ways to transport delicate liquids, particularly when scaling channels down to the micrometre scale, with no need for high pressures, and could also be used for microfluidic circuitry.

Background: Despite a reduction of child mortality in low-income countries, acutely ill undernourished children still have an elevated risk of death. Those at highest risk are children with severe acute malnutrition (SAM) who often show metabolic dysregulation that remains poorly understood., Objective: We performed a pilot study to examine changes in urinary organic acids during nutritional rehabilitation of children with SAM, and to identify metabolites associated with the presence of edema or with mortality., Methods: This study included 76 children aged between 6 and 60 months, hospitalized for SAM at the Moyo Nutritional Rehabilitation and Research Unit in Blantyre, Malawi. Urine was collected at admission and 3 days after clinical stabilization and metabolomics were performed using gas chromatography-mass spectrometry. Metabolite concentrations were evaluated with both uni- and multivariate approaches., Results: Most metabolites increased 3 days after clinical stabilization, and total urinary concentration changed from 1.2 mM (interquartile range [IQR], 0.78-1.7) at admission to 3.8 mM (IQR, 2.1-6.6) after stabilization ( P < .0001). In particular, 6 metabolites showed increases: 3-hydroxybutyric, 4-hydroxyhippuric, p -hydroxyphenylacetic, oxoglutaric, succinic, and lactic acids. Urinary creatinine was low at both time points, but levels did increase from 0.63 mM (IQR, 0.2-1.2) to 2.6 mM (IQR,1.6-4.4; P < .0001). No differences in urinary profiles were found between children who died versus those who survived, nor between children with severe wasting or edematous SAM., Conclusions: Total urinary metabolites and creatinine increase after stabilization and may reflect partial recovery of overall metabolism linked to refeeding. The use of urinary metabolites for risk assessment should be furthered explored., Trial Registration: TranSAM study (ISRCTN13916953).

The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase Rab38 This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the cht mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for Rab32 , Rab38, and both genes. Single Rab38 inactivation mimicked cht mice, whereas single Rab32 inactivation had no effect in DGs, coat color, or lung morphology. By contrast, Rab32/38 double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content., (© 2019 by The American Society of Hematology.)

Background: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM., Methods: We followed-up children (n = 352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9·6 ± 1·6 years), siblings (n = 44, 10·5 ± 2·7 years), and age and sex-matched community controls (n = 37, 9·4 ± 1·8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index., Findings: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0·3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (β = 15·2, SE = 3·5, partial R 2  = 12%, p < 0·0001) and this relationship could be influenced by early childhood SAM (β = 17·4, SE = 7·7, partial R 2  = 2·8%, p = 0·025). No metabolites were associated with oedema status, duration of hospital stay, anthropometry measured during hospitalization, nor with changes in anthropometry since hospitalization., Interpretation: In this group of survivors, SAM was not associated with longer-term global metabolic changes 7 years after treatment. However, SAM may influence the relationship between current stunting and IGF1. Further risk markers for NCDs in SAM survivors may only be revealed by direct metabolic challenge or later in life., (Copyright © 2019. Published by Elsevier B.V.)

Fourteen species of the genus Boreophilia Benick are now recognized in North America. Boreophiliainsecuta (Eppelsheim), reported by Lohse (1990) from North America, is a misidentification of a new species, which is described here as B.neoinsecuta Klimaszewski, sp. n. , and the true B.insecuta (Epp.) does not occur in North America. An additional new species is found in Alaska, and described as B.beringi Klimaszewski & Brunke, sp. n. The following three species are synonymized (second name being valid): Boreophiliaherschelensis Klimaszewski & Godin, 2012, with Boreophiliavega (Fenyes, 1920); Boreophiliamanitobensis Lohse, 1990, with B.caseyi Lohse, 1990; and B.angusticornis (Bernahuer, 1907) with B.subplana (J Sahlberg, 1880), based on study of genital structures and external morphology. Athetagelida J Sahlberg, 1887, and Athetamunsteri Bernhauer, 1902, considered as Boreophilia in recent publications, are transferred to the genus Atheta Thomson, subgenus Dimetrota. Boreostibapiligera (J Sahlberg) is transferred to Boreophilia based on morphology and the results of our phylogenetic analysis. Boreophilianearctica is recorded from Alberta and B.nomensis is recorded from British Columbia for the first time. Each valid species is illustrated by color image of habitus, and black and white images of genitalia and tergite and sternite VIII. A new key to all Nearctic species of the genus is provided. DNA barcode data were available for nine of the 14 species, which we downloaded, analyzed, and used as additional evidence for the taxonomic conclusions reached herein.

Background: Children with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase., Methods and Findings: In a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2-5 days), which was similar between randomized groups (0.23 [95% CI -0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission, age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite., Conclusions: Empirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM., Trial Registration: ClinicalTrials.gov NCT02246296., Competing Interests: The authors have declared that no competing interests exist.

The ever-increasing use of next-generation sequencing technologies to explore the genome has generated large quantities of data in recent years. Numerous publications have described several thousand sequences of microRNAs, all species included. A new database (RumimiR) has been created from the literature to provide a detailed description of microRNAs for three ruminant species: cattle, goats and sheep. To date, 2887, 2733 and 5095 unique microRNAs from bovine, caprine and ovine species, respectively, are included. In addition to the most recent reference genomic position and sequence of each microRNA, this database contains details about the animals, tissue origins and experimental conditions mentioned in the publications. Identity to human or mouse microRNA is also indicated. The RumimiR database allows data filtering by selecting microRNAs on the basis of defined criteria such as animal status or tissue origin. For ruminant studies, RumimiR supplements the widely used miRBase database, by using complementary criteria to allow browsing and filtering, and integrates all newly described published sequences. The principal goal of this database is to provide easy access to all the ruminant microRNAs described in the literature., (© The Author(s) 2019. Published by Oxford University Press.)

Background: Due to a lack of systematic diagnostics, our understanding of the diversity and role of eukaryotic microbiota in human health is limited. While studies have shown fungal communities to be significant modulators of human health, information on the prevalence of taxa such as protozoa and helminths has been limited to a small number of species for which targeted molecular diagnostics are available. To probe the diversity of eukaryotic microbes and their relationships with other members of the microbiota, we applied in silico and experimental approaches to design a novel two-amplicon surveillance tool, based on sequencing regions of ribosomal RNA genes and their internal transcribed spacers. We subsequently demonstrated the utility of our approach by characterizing the eukaryotic microbiota of 46 hospitalized Malawian children suffering from Severe Acute Malnutrition (SAM)., Results: Through in silico analysis and validation on a diverse panel of eukaryotes, we identified 18S rRNA variable genetic regions 4 and 5 (18S V4 V5), together with a region encoding 28S rRNA variable genetic region 2 and the internal transcribed spacers (transITS), as optimal for the systematic classification of eukaryotes. Sequencing of these regions revealed protozoa in all stool samples from children with SAM and helminths in most, including several eukaryotes previously implicated in malnutrition and diarrheal disease. Clinical comparisons revealed no association between protozoan parasites and diarrhea or HIV reactivity. However, the presence of Blastocystis correlated with bacterial alpha diversity and increased abundance of specific taxa, including Sporobacter, Cellulosibacter, Oscillibacter, and Roseburia., Conclusion: We suggest this novel two-amplicon based strategy will prove an effective tool to deliver new insights into the role of eukaryotic microbiota in health and disease.

We report a case of spondylodiscitis caused by Bordetella holmesii, an emergent pathogen. This small Gram-negative rod was first known as a cause of invasive infections on asplenic patients. This case describes a spondylodiscitis due to this bacterium in an immunocompetent patient. This article underlines the interest of prolonged incubation for specimens in case of spondylodiscitis and shows us the contributions of mass spectrometry for easy and rapid identification of such bacterium., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Children admitted to nutritional rehabilitation units (NRUs) for inpatient treatment of severe acute malnutrition (SAM) are at high risk of poor developmental and nutritional outcomes. The Kusamala Program is an interactive hospital-based counseling program for primary caregivers of children with SAM that integrates three modules: nutrition and feeding; water, sanitation, and hygiene (WASH); and psychosocial stimulation. This mixed methods feasibility study aimed to evaluate the implementation of the Kusamala Program in an NRU setting and developmental outcomes in children with SAM 6 months after inpatient treatment., Methods: An internal pilot trial including the first 30 children and their primary caregivers enrolled to a cluster-randomized controlled trial of the Kusamala Program was performed. Barriers and enablers were identified in a qualitative study with a focus group discussion (FGD) and in-depth interviews (IDIs) with 12 hospital staff members, including five NRU nurses who deliver the Kusamala Program., Results: Results demonstrated high participant engagement (100%) and adherence (87%) of primary caregivers to the Kusamala Program. Potential barriers to implementation identified through the qualitative study were caregivers' perceived value of the program, prioritization of other ward activities, and shortages of staff. On the other hand, enablers to implementation were engaging other staff members, motivation and work ethic, and refresher training., Conclusions: This mixed methods study demonstrates the feasibility of implementing the Kusamala Program in a real NRU setting. The full cluster-randomized controlled trial will be completed to evaluate the effectiveness of the Kusamala Program., Trial Registration: ClinicalTrials.gov, NCT03072433. Registered on 7 March 2017-retrospectively registered., Competing Interests: Ethics approval for this study was obtained from the College of Medicine Research and Ethics Committee (P.04/16/1930) in Blantyre, Malawi, and the Research Ethics Board (1000053578) at the Hospital for Sick Children in Toronto, Canada. Consent was requested of all participants in the study; primary caregivers were asked to provide consent on behalf of themselves and their children.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Early postnatal-life malnutrition remains prevalent globally, and about 45% of all child deaths are linked to malnutrition. It is not clear whether survivors of childhood malnutrition suffer from long-term metabolic effects, especially when they are later in life exposed to a fat and carbohydrate rich obesogenic diet. The lack of knowledge around this dietary "double burden" warrants studies to understand the long-term consequences of children previously exposed to malnutrition. We hypothesized that an early-life nutritional insult of low protein consumption in mice would lead to long-term metabolic disturbances that would exacerbate the development of diet-induced insulin resistance and non-alcoholic fatty liver disease (NAFLD). We investigated the effects of feeding a low protein diet (4% wt/wt) immediately after weaning for four weeks and subsequent feeding of a high carbohydrate high fat feeding for 16 weeks on metabolic function and development of NAFLD. Mice exposed to early-life protein restriction demonstrated a transient glucose intolerance upon recovery by regular chow diet feeding. However, protein restriction after weaning in mice did not exacerbate an obesogenic diet-induced insulin resistance or progression to NAFLD. These data suggest that transient protein restriction in early-life does not exacerbate an obesogenic diet-induced NAFLD and insulin resistance., Competing Interests: The authors have declared that no competing interests exist.

Despite the frequent co-ocurrence of hypermobile Ehler-Danlos syndrome (hEDS) and pathological anxiety, little is known about the psychosocial and health implications of such comorbidity. Our aim was to explore the association between high levels of anxiety and psychosocial (catastrophizing, kinesiophobia, somatosensory amplification, social support and functioning), health (pain, fatigue, BMI, tobacco/alcohol use, depression, diagnosis delay, general health), and sociodemographic factors in people with hEDS. In this cross-sectional study, 80 hEDS patients were divided into two groups according to self-reported anxiety levels: low and high. Psychosocial, sociodemographic and health variables were compared between the groups. Forty-one participants reported a high level of anxiety (51.2%). No differences were found in the sociodemographic variables between high-anxious and low-anxious patients. The percentage of participants with severe fatigue and high depressive symptomatology was significantly higher in the high-anxious group (80.5 vs 56.4; 26.8 vs 12.8%, respectively). High-anxious hEDS patients also showed significantly higher levels of pain catastrophizing, somatosensory amplification as well as a poorer social functioning and general health. Multivariate analyses showed that somatosensory amplification, pain catastrophizing and poor social functioning are variables that increase the probability of belonging to the high-anxious group. Despite limitations, this first study comparing high-anxious versus low-anxious hEDS patients with respect to health aspects, highlight the importance of considering the psychosocial factors (many susceptible to modification), to improve the adjustment to this chronic condition and provide support to those affected through a biopsychosocial approach.

Background & Aims: Children with Severe Acute Malnutrition (SAM) often suffer from diarrhea, which is associated with increased mortality. The contribution of intestinal bacteria, parasites and viruses to morbidity such as diarrhea in SAM remains poorly understood. To evaluate their association with clinical outcomes, we detected stool pathogens in children with SAM at hospital admission and after clinical stabilization prior to discharge., Methods: 15 intestinal pathogens, fecal calprotectin and C-reactive protein (CRP) were determined at admission and after clinical stabilization in children aged 8-59 months (n = 47) hospitalized in Malawi for complicated SAM. Differences in fecal pathogens, intestinal and systemic inflammation, and clinical outcomes between time points were evaluated using the Wilcoxon Signed-Rank test or Wilcoxon rank-sum test., Results: On admission pathogens were present in nearly all children and after clinical stabilization many were cleared with only 55% of children still harboring a pathogen (89% vs. 55%, p = 0.001). Nosocomial infections were infrequent. The pathogens Giardia lamblia and Shigella spp. were most likely to persist. After clinical stabilization, fecal calprotectin was higher in children harboring a pathogen (median (IQR): 383 mg/kg (903-149 mg/kg) vs 140 mg/kg (300-71 mg/kg), p = 0.03). CRP did not correlate with fecal calprotectin levels nor was it associated with pathogen detection. Presence of stool pathogens was not associated with clinical outcomes such as diarrhea., Conclusions: Fecal pathogens were very common and cleared in most children with complicated SAM treated with antibiotics. The presence of stool pathogens after stabilization was associated with increased intestinal inflammation but not with clinical outcomes. (http://www.isrctn.com/ISRCTN13916953)., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Background: Severe acute malnutrition (SAM) is associated with high mortality rates and impairments in growth and development in children that do survive. There are complex nutritional, health, and behavioural risk factors involving severely malnourished children and their primary caregivers, requiring integrated intervention approaches., Methods: A cluster-randomized controlled trial at the Queen Elizabeth Central Hospital in Blantyre, Malawi will be conducted to evaluate the effectiveness of a 4-day hospital-based intervention programme directed at primary caregivers. This programme, titled the Kusamala Program, aims to improve developmental and nutritional outcomes in children with SAM. Up to six primary caregivers and their children will be enrolled to groups each week, which will be randomly allocated to intervention or comparison arms. The intervention package consists of interactive counselling on three modules: 1) nutrition and feeding; 2) water, sanitation, and hygiene (WASH); and 3) psychosocial stimulation. Data collection will be performed at enrolment, at discharge from hospital, and at 6 months following discharge. The primary outcome is child development assessed with the Malawi Developmental Assessment Tool (MDAT), a validated measure of gross and fine motor, language, and social development., Discussion: This intervention programme is unique because it utilizes primary caregivers' time spent in-hospital while children receive treatment for SAM. The programme has the potential to be effective in addressing multiple aspects of child, nutrition and development., Trial Registration: ClinicalTrials.gov, NCT03072433 . Registered on 7 March 2017.

Objective: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition., Study Design: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days., Results: Children treated with PERT for 28 days did not gain more weight than controls (13.7 ± 9.0% in controls vs 15.3 ± 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P <.01). Although the study was not powered to detect differences in mortality, mortality was significantly lower in the intervention group treated with pancreatic enzymes (18.6% vs 37.8%; P < .05). Children who died had low fecal fatty acid split ratios at admission. Exocrine pancreatic insufficiency was not improved by PERT, but children receiving PERT were more likely to be discharged with every passing day (P = .02) compared with controls., Conclusions: PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function., Trial Registration: ISRCTN.com: 57423639., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Thecturota tenuissima Casey, is reported for the first time from Canada, based on records from Ontario and Quebec. It was originally described from Rhode Island, USA, and no other records of this species in North America were published since that time. The specimens from Canada were captured by car netting. We provide here a redescription of this species and never before published images of habitus, tergite, and sternite VIII of both sexes, median lobe of aedeagus and spermatheca. The features distinguishing T. tenuissima from T. capito Casey (= pusio (Casey)), the only other species reported in Canada, are provided and illustrated.

Background: Approximately 50% of the deaths of children under the age of 5 can be attributed to undernutrition, which also encompasses severe acute malnutrition (SAM). Diarrhoea is strongly associated with these deaths and is commonly diagnosed solely based on stool frequency and consistency obtained through maternal recall. This trial aims to determine whether this approach is equivalent to a 'directly observed method' in which a health care worker directly observed stool frequency using diapers in hospitalised children with complicated SAM., Methods: This study was conducted at 'Moyo' Nutritional Rehabilitation Unit, Queen Elizabeth Central Hospital, Malawi. Participants were children aged 5-59 months admitted with SAM. We compared 2 days of stool frequency data obtained with next-day maternal-recall versus a 'gold standard' in which a health care worker observed stool frequency every 2 h using diapers. After study completion, guardians were asked their preferred method and their level of education., Results: We found poor agreement between maternal recall and the 'gold standard' of directly observed diapers. The sensitivity to detect diarrhoea based on maternal recall was poor, with only 75 and 56% of diarrhoea cases identified on days 1 and 2, respectively. However, the specificity was higher with more than 80% of children correctly classified as not having diarrhoea. On day 1, the mean stool frequency difference between the two methods was -0.17 (SD; 1.68) with limits of agreement (of stool frequency) of -3.55 and 3.20 and, similarly on day 2, the mean difference was -0.2 (SD; 1.59) with limits of agreement of -3.38 and 2.98. These limits extend beyond the pre-specified 'acceptable' limits of agreement (±1.5 stool per day) and indicate that the 2 methods are non-equivalent. The higher the stool frequency, the more discrepant the two methods were. Most primary care givers strongly preferred using diapers., Conclusions: This study shows lack of agreement between the assessment of stool frequency in SAM patients using maternal recall and direct observation of diapers. When designing studies, one should consider using diapers to determining diarrhoea incidence/prevalence in SAM patients especially when accuracy is essential., Trial Registration Number: ISRCTN11571116 (registered 29/11/2013).

Two genera, Apimela Mulsant & Rey and Gyronycha Casey (both Aleocharinae: Oxypodini: Meoticina), are recorded from New Brunswick and Canada for the first time. The following species are newly recorded or described as new in New Brunswick and Canada: Apimela fusciceps (Casey); A. canadensis Klimaszewski & Webster, sp. n .; and Gyronycha pseudoobscura Klimaszewski & Webster, sp. n. The genera are defined and the key for species identification is provided. Color habitus images and black and white images of the median lobe of the aedeagus, spermatheca, tergite, and sternite VIII are provided for all species occurring in Canada, and Apimela macella (Erichson), the type species of genus Apimela , and G. valens Casey, the type species of Gyronycha . New or additional habitat data are provided for the species treated in this contribution. The following new synonym is established: Gyronycha lepida Casey, 1911 (NC), is a synonym of G. fusciceps Casey, 1894 (NC).

The socially interactive therapeutic robot Paro is presented in the form of a soft toy. It can benefit patients suffering from Alzheimer's as well as nurses., (Copyright © 2016. Publié par Elsevier Masson SAS.)

Background: Mortality in children with severe acute malnutrition (SAM) remains high despite standardized rehabilitation protocols. Two forms of SAM are classically distinguished: kwashiorkor and marasmus. Children with kwashiorkor have nutritional edema and metabolic disturbances, including hypoalbuminemia and hepatic steatosis, whereas marasmus is characterized by severe wasting. The metabolic changes underlying these phenotypes have been poorly characterized, and whether homeostasis is achieved during hospital stay is unclear., Objectives: We aimed to characterize metabolic differences between children with marasmus and kwashiorkor at hospital admission and after clinical stabilization and to compare them with stunted and nonstunted community controls., Methods: We studied children aged 9-59 mo from Malawi who were hospitalized with SAM (n = 40; 21 with kwashiorkor and 19 with marasmus) or living in the community (n = 157; 78 stunted and 79 nonstunted). Serum from patients with SAM was obtained at hospital admission and 3 d after nutritional stabilization and from community controls. With the use of targeted metabolomics, 141 metabolites, including amino acids, biogenic amines, acylcarnitines, sphingomyelins, and phosphatidylcholines, were measured., Results: At admission, most metabolites (128 of 141; 91%) were lower in children with kwashiorkor than in those with marasmus, with significant differences in several amino acids and biogenic amines, including those of the kynurenine-tryptophan pathway. Several phosphatidylcholines and some acylcarnitines also differed. Patients with SAM had profiles that were profoundly different from those of stunted and nonstunted controls, even after clinical stabilization. Amino acids and biogenic amines generally improved with nutritional rehabilitation, but most sphingomyelins and phosphatidylcholines did not., Conclusions: Children with kwashiorkor were metabolically distinct from those with marasmus, and were more prone to severe metabolic disruptions. Children with SAM showed metabolic profiles that were profoundly different from stunted and nonstunted controls, even after clinical stabilization. Therefore, metabolic recovery in children with SAM likely extends beyond discharge, which may explain the poor long-term outcomes in these children. This trial was registered at isrctn.org as ISRCTN13916953., Competing Interests: 2 Author disclosures: V Di Giovanni, C Bourdon, DX Wang, S Seshadri, E Senga, CJ Versloot, W Voskuijl, RD Semba, I Trehan, R Moaddel, MI Ordiz, L Zhang, J Parkinson, MJ Manary, and RHJ Bandsma, no conflicts of interest., (© 2016 American Society for Nutrition.)

Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear., Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM., Design: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6-59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling., Results: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443-535 mg/kg feces) compared with 698 mg/kg feces (1438-244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112-22 ng/mL) compared with 2036 ng/mL (5800-149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831-131 ng/mL) compared with 3174 ng/mL (5819-357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation., Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of inflammatory changes in SAM, which may lead to improved therapies. This trial was registered at www.controlled-trials.com as ISRCTN13916953.

Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet α6β1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of α6β1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet α6β1. In vivo studies showed that the interplay between platelet α6β1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin α6β1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting α6β1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin α6β1 represents a promising target for antimetastatic therapies.

One hundred twenty species of aleocharine beetles (Staphylinidae) are recognized in the province of Saskatchewan. Sixty-five new provincial records, including twelve new species and one new North American record, are presented. Oligota inflata (Mannerheim), a Palearctic species, is newly recorded for North America. The following twelve species are described as new to science: Acrotona pseudopygmaea Klimaszewski & Larson, sp. n., Agaricomorpha pulchra Klimaszewski & Larson, sp. n. (new genus record for Canadian fauna), Aleochara elisabethae Klimaszewski & Larson, sp. n., Atheta (Dimetrota) larsonae Klimaszewski & Larson, sp. n., Atheta (Microdota) pseudopittionii Klimaszewski & Larson, sp. n., Atheta (Microdota) spermathecorum Klimaszewski & Larson, sp. n., Atheta (sensu lato) richardsoni Klimaszewski & Larson, sp. n., Brachyusa saskatchewanae Klimaszewski & Larson, sp. n., Dochmonota langori Klimaszewski & Larson, sp. n., Dochmonota simulans Klimaszewski & Larson, sp. n., Dochmonota websteri Klimaszewski & Larson, sp. n., and Oxypoda domestica Klimaszewski & Larson, sp. n. Colour images of habitus and black and white images of the median lobe of the aedeagus, spermatheca, and tergite and sternite VIII are presented for all new species, Oligota inflata Mannerheim and Dochmonota rudiventris (Eppelsheim). A new synonymy is established: Tetralina filitarsus Casey, syn. n. = Tetralina helenae Casey, now placed in the genus Brachyusa Mulsant & Rey.

Objectives: To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation., Study Design: We followed 89 children with severe acute malnutrition admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Stool and blood samples were taken on admission and 3 days after initial stabilization to determine exocrine pancreatic function via fecal elastase-1 (FE-1) and serum trypsinogen and amylase levels., Results: A total of 33 children (37.1%) had nonedematous severe acute malnutrition, whereas 56 (62.9%) had edematous severe acute malnutrition. On admission, 92% of patients showed evidence of pancreatic insufficiency as measured by FE-1 <200 μg/g of stool. Patients with edematous severe acute malnutrition were more likely to have low FE-1 (98% vs 82.8%, P = .026). FE-1 levels remained low in these individuals throughout the assessment period. Serum trypsinogen was elevated (>57 ng/mL) in 28% and amylase in 21% (>110 U/L) of children, suggesting pancreatic inflammation., Conclusion: Exocrine pancreatic insufficiency is prevalent in children with severe acute malnutrition and especially in children with edematous severe acute malnutrition. In addition, biochemical signs suggestive of pancreatitis are common in children with severe acute malnutrition. These results have implications for standard rehabilitation treatment of children with severe acute malnutrition who may benefit from pancreatic enzyme replacement therapy., Trial Registration: ISRCTN.com: 13916953., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Two new species, Atheta pseudovestita Klimaszewski & Langor, sp. n., Silusa prettyae Klimaszewski & Langor, sp. n., are described, and 16 new provincial records, including one new country record, of aleocharine beetles are presented for the province of Newfoundland and Labrador. Diagnostics, images of habitus and genital structures, distribution, bionomics information and new locality data are provided for the newly recorded species. A new checklist with 189 species of aleocharines recorded from the province is presented.

Objective: Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis., Design: An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified., Results: On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower., Conclusion: SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

A new species, Anomognathus athabascensis Klimaszewski, Hammond & Langor, sp. n., and nine new provincial records including one new country record of aleocharine beetles are presented for the province of Alberta. Diagnostics, images of habitus and genital structures, distribution, natural history information and new locality data are provided for the newly recorded species. A checklist for all recorded aleocharines from Alberta is updated.

This paper treats the discovery of new species and new records of aleocharine beetles for the province of New Brunswick. We report here 27 species new to science, one new North American record, six new Canadian records, and 29 new provincial records. The following are the new species: Acrotona brachyoptera Klimaszewski & Webster, sp. n., Acrotona sphagnorum Klimaszewski & Webster, sp. n., Atheta (Dimetrota) alphacrenuliventris Klimaszewski & Webster, sp. n., Atheta (Dimetrota) chartersensis Klimaszewski & Webster, sp. n., Atheta (Dimetrota) cranberriensis Klimaszewski & Webster, sp. n., Atheta (Dimetrota) bubo Klimaszewski & Webster, sp. n., Atheta (Dimetrota) mcalpinei Klimaszewski & Webster, sp. n., Atheta (Dimetrota) makepeacei Klimaszewski & Webster, sp. n., Atheta (Dimetrota) giguereae Klimaszewski & Webster, sp. n., Atheta (Dimetrota) petitcapensis Klimaszewski & Webster, sp. n., Atheta (sensu lato) pseudoschistoglossa Klimaszewski & Webster, sp. n., Atheta (sensu lato) sphagnicola Klimaszewski & Webster, sp. n., Atheta (sensu lato) thujae Klimaszewski & Webster, sp. n., Atheta (Pseudota) pseudoklagesi Klimaszewski & Webster, sp. n., Philhygra atypicalis Klimaszewski & Webster, sp. n., Schistoglossa (Schistoglossa) pelletieri Klimaszewski & Webster, sp. n., Thamiaraea corverae Klimaszewski & Webster, sp. n., Thamiaraea claydeni Klimaszewski & Webster, sp. n., Pleurotobia bourdonae Klimaszewski & Webster, sp. n., Pleurotobia brunswickensis Klimaszewski & Webster, sp. n., Agaricomorpha vincenti Klimaszewski & Webster, sp. n., Gyrophaena (Gyrophaena) aldersonae Klimaszewski & Webster, sp. n., Oligota polyporicola Klimaszewski & Webster, sp. n., Oligota sevogle Klimaszewski & Webster, sp. n., Hylota cryptica Klimaszewski & Webster, sp. n., Oxypoda sunpokeana Klimaszewski & Webster, sp. n., and Phloeopora gilbertae Klimaszewski & Webster, sp. n. The spermatheca of Dinaraea curtipenis Klimaszewski & Webster, Dinaraea longipenis Klimaszewski & Webster, and Dinaraea subdepressa (Bernhauer) are illustrated for the first time. Male specimens of Mniusa odelli Klimaszewski & Webster were confirmed and are illustrated. Color habitus images and black and white images of the median lobe of the aedeagus, the spermatheca, and tergite and sternite VIII are provided for all species. New or additional habitat data are provided for most of the species treated in this contribution.

Fourteen species of Liogluta Thomson are reported from Canada and Alaska. Three of these are described as new to science: Liogluta castoris Klimaszewski & Webster, sp. n.; Liogluta microgranulosa Klimaszewski & Webster, sp. n.; and Liogluta pseudocastoris Klimaszewski & Webster, sp. n. The previously unknown male of Liogluta gigantea Klimaszewski & Langor, Liogluta quadricollis (Casey), Liogluta wickhami (Casey), and female of Liogluta granulosa Lohse are described, and illustrated. Liogluta aloconotoides Lohse is synonymized with Liogluta terminalis (Casey). New provincial and state records are provided for six Liogluta species. A key to species, revised distribution with new provincial records, and new natural history data are provided.

This paper treats the discovery of new species and new records of Staphylinidae from the subfamilies Omaliinae, Proteininae, Tachyporinae, Oxytelinae, Scydmaeninae, Steninae, Euaesthetinae, Pseudopsinae, Paederinae, and Staphylininae for the province of New Brunswick and other provinces of Canada, and the USA. We report here two species new to science, three new North American records, nine new Canadian records, two new USA records, and 50 new provincial records. The following are the species new to science: Proteinus hughesi Webster & Davies, sp. n. and Proteinus sweeneyi Webster & Klimaszewski, sp. n. (Proteininae). Sepedophilus immaculatus (Stephens) and Carpelimus erichsoni (Sharp), Carpelimus mundus (Sharp) are newly recorded from North America. New Canadian records are as follows: Carpelimus difficilis (Casey), Carpelimus gracilis (Mannerheim), Carpelimus lacustris (Notman), Carpelimus probus (Casey), Carpelimus pusillus (Gravenhorst), Carpelimus rivularis (Motschulsky), Carpelimus spretus (Casey), Carpelimus weissi (Notman) (Oxytelinae), and Edaphus lederi Eppelsheim (Euaesthetinae). This is the first record of the genus Edaphus for Canada. Bledius basalis LeConte and Carpelimus obesus (Kiesenwetter) (Oxytelinae) are removed from the faunal list of New Brunswick. Proteinus acadiensis Klimaszewski and Proteinus pseudothomasi Klimaszewski are newly recorded from the USA and several provinces of Canada. Habitat data from New Brunswick are provided for most of the species treated in this contribution.

The ability of cellular fibronectin, found in the vessel wall in a fibrillar conformation, to regulate platelet functions and trigger thrombus formation remains largely unknown. In this study, we evaluated how parietal cellular fibronectin can modulate platelet responses under flow conditions. A fibrillar network was formed by mechanically stretching immobilised dimeric cellular fibronectin. Perfusion of anticoagulated whole blood over this surface resulted in efficient platelet adhesion and thrombus growth. The initial steps of platelet adhesion and activation, as evidenced by filopodia extension and an increase in intracellular calcium levels (419 ± 29 nmol/l), were dependent on integrins α5β1 and αIIbβ3. Subsequent thrombus growth was mediated by these integrins together with the GPIb-V-IX complex, GPVI and Toll-like receptor 4. The involvement of Toll-like receptor 4 could be conveyed via its binding to the EDA region of cellular fibronectin. Upon thrombus formation, the platelets became procoagulant and generated fibrin as revealed by video-microscopy. This work provides evidence that fibrillar cellular fibronectin is a strong thrombogenic surface which supports efficient platelet adhesion, activation, aggregation and procoagulant activity through the interplay of a series of receptors including integrins α5β1 and αIIbβ3, the GPIb-V-IX complex, GPVI and Toll-like receptor 4.