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Undernutrition remains a global struggle and is associated with almost 45% of deaths in children younger than 5 years. Despite advances in management of severe wasting (though less so for nutritional edema), full and sustained recovery remains elusive. Children with severe wasting and/or nutritional edema (also commonly referred to as severe acute malnutrition and part of the umbrella term "severe malnutrition") continue to have a high mortality rate. This suggests a likely multifactorial etiology that may include micronutrient deficiency. Micronutrients are currently provided in therapeutic foods at levels based on expert opinion, with few supportive studies of high quality having been conducted. This narrative review looks at the knowledge base on micronutrient deficiencies in children aged 6-59 months who have severe wasting and/or nutritional edema, in addition to highlighting areas where further research is warranted (See "Future Directions" section)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute.)

Background: Severe acute malnutrition (SAM) constitutes a substantial burden in African hospitals. Despite adhering to international guidelines, high inpatient mortality rates persist and the underlying contributing factors remain poorly understood., Objective: We evaluated the 10-year trend (2011-2021) in clinical factors and outcomes among children with severe wasting and/or nutritional edema at Malawi's largest nutritional rehabilitation unit (NRU)., Methods: This retrospective study analyzed trends in presentation and outcomes using generalized additive models. The association between clinical characteristics and mortality or readmission was examined and key features were also related to time to either mortality or discharge., Results: 1497 children (53%, females) were included. Median age at admission (23 months, IQR 14, 34) or anthropometry (i.e., weight-for-age, height-for-age and weight-for-height) did not change over the 10-years. But the prevalence of edema decreased by 40% whereas dehydration, difficulty breathing, and pallor became more common. Yearly HIV testing increased but positive-detection remained around 11%. Reporting of complete vaccination dropped by 49%, and no reduction in 'watch' antibiotic usage was detected. Overall admissions declined but mortality remained around 23% [95%CI; 21, 25], and deaths occurred earlier (5.6 days [95%CI; 4.6, 6.9] in 2011 vs. 3.5 days [95%CI; 2.5, 4.7] in 2021; p<0.001). Duration of hospitalization was shortened and readmissions surged from 4.9% [95%CI; 3.3, 7.4] in 2011 to 25% [95%CI; 18, 33] in 2021 (p<0.001). Age, wasting, having both dehydration and diarrhea, or having vomiting, cough, or difficulty breathing were associated with mortality but these associations did not show any interaction over time., Conclusion: Over 10 years, mortality risk remained high among hospitalized children with SAM and coincided with worsened clinical presentation at admission and increased readmission. Longitudinal data from major NRUs can identify shifts in clinical profiles or outcomes, and this information can be leveraged to promote earlier care-seeking, improved risk stratification, and implementation of more patient-centered treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chisala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Severe malnutrition is associated with infections, namely lower respiratory tract infections (LRTIs), diarrhea, and sepsis, and underlies the high risk of morbidity and mortality in children under 5 years of age. Dysregulations in neutrophil responses in the acute phase of infection are speculated to underlie these severe adverse outcomes; however, very little is known about their biology in this context. Here, in a lipopolysaccharide-challenged low-protein diet (LPD) mouse model, as a model of malnutrition, we show that protein deficiency disrupts neutrophil mitochondrial dynamics and ATP generation to obstruct the neutrophil differentiation cascade. This promotes the accumulation of atypical immature neutrophils that are incapable of optimal antimicrobial response and, in turn, exacerbate systemic pathogen spread and the permeability of the alveolocapillary membrane with the resultant lung damage. Thus, this perturbed response may contribute to higher mortality risk in malnutrition. We also offer a nutritional therapeutic strategy, nicotinamide, to boost neutrophil-mediated immunity in LPD-fed mice., Competing Interests: Declaration of interests A.F. is employed by Omega Laboratories, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background:  Participating in surveys can shape the perception of participants related to the study topic. Administering a vaccine hesitancy questionnaire can have negative impacts on participants' vaccine confidence. This is particularly true for online and cross-cultural data collection because culturally safe health education to correct misinformation is typically not provided after the administration of an electronic survey., Objective:  To create a culturally safe, online, COVID-19 vaccine confidence survey for Indigenous youth designed to collect authentic, culturally relevant data of their vaccine experiences, with a low risk of contributing to further vaccine confusion among participants., Methods:  Using the Aboriginal Telehealth Knowledge Circle consensus method, a team of academics, health care providers, policy makers, and community partners reviewed COVID-19 vaccine hesitancy surveys used in public health research, analyzed potential risks, and created a framework for electronic Indigenous vaccine confidence surveys as well as survey items., Results:  The framework for safer online survey items is based on 2 principles, a first do-no-harm approach and applying a strengths-based lens. Relevant survey domains identified in the process include sociodemographic information, participants' connection to their community, preferred sources for health information, vaccination uptake among family members and peers, as well as personal attitudes toward vaccines. A total of 44 survey items were developed, including 5 open-ended items to improve the authenticity of the data and the analysis of the experiences of Indigenous youth., Conclusions:  Using an Indigenous consensus method, we have developed an online COVID-19 vaccine confidence survey with culturally relevant domains and reduced the risk of amplifying misinformation and negative impacts on vaccine confidence among Indigenous participants. Our approach can be adapted to other online survey development in collaboration with Indigenous communities., (©Marion Maar, Caleigh Bourdon, Joahnna Berti, Emma Bisaillon, Lisa Boesch, Alicia Boston, Justin Chapdelaine, Alison Humphrey, Sandeep Kumar, Benjamin Maar-Jackson, Robert Martell, Bruce Naokwegijig, Davinder Preet Kaur, Sarah Rice, Barbara Rickaby, Mariette Sutherland, Maurianne Reade. Originally published in JMIR Formative Research (https://formative.jmir.org), 12.08.2024.)

Despite abundant evidence demonstrating that platelets foster metastasis, anti-platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subject syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the glycoprotein VI (GPVI) platelet-specific receptor in humanized mouse models efficiently reduce the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study demonstrates therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as a molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations., (© 2024. The Author(s).)

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries., Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia. Between November 2016 and January 2019, children were recruited at hospital admission and classified as: not-wasted (NW), moderately-wasted (MW), severely-wasted (SW), or having nutritional oedema (NO). We describe earlier (discharge to 45-days) and later (45- to 180-days) changes in length-for-age [LAZ], weight-for-age [WAZ], mid-upper arm circumference [MUACZ], weight-for-length [WLZ] z-scores, and clinical, nutritional, and socioeconomic correlates., Findings: We included 2472 children who survived to 180-days post-discharge: NW, 960 (39%); MW, 572 (23%); SW, 682 (28%); and NO, 258 (10%). During 180-days, LAZ decreased in NW (-0.27 [-0.36, -0.19]) and MW (-0.23 [-0.34, -0.11]). However, all groups increased WAZ (NW, 0.21 [95% CI: 0.11, 0.32]; MW, 0.57 [0.44, 0.71]; SW, 1.0 [0.88, 1.1] and NO, 1.3 [1.1, 1.5]) with greatest gains in the first 45-days. Of children underweight (<-2 WAZ) at discharge, 66% remained underweight at 180-days. Lower WAZ post-discharge was associated with age-inappropriate nutrition, adverse caregiver characteristics, small size at birth, severe or moderate anaemia, and chronic conditions, while lower LAZ was additionally associated with household-level exposures but not with chronic medical conditions., Interpretation: Underweight and poor linear growth mostly persisted after an acute illness. Beyond short-term nutritional supplementation, improving linear growth post-discharge may require broader individual and family support., Funding: Bill & Melinda Gates FoundationOPP1131320; National Institute for Health ResearchNIHR201813., Competing Interests: Members of the writing group declare having received support from the Bill and Melinda Gates Foundation (BMGF) for staff and research activities directly linked to this project which was paid to their universities or institutions (JAB, JLW, RHJB). Reimbursement for travel directly related to this project was also provided by BMGF and paid through the universities (JLW, JAB). JAB participated in a leadership role for the Commonwealth Association for Paediatic Gastroenterology & Nutrition (CAPGAN) and on a Data Safety Monitoring Board (DSMB) for a study regarding vitamin D., (© 2024 The Authors.)

There is scarce data on energy expenditure in ill children with different degrees of malnutrition. This study aimed to determine resting energy expenditure (REE) trajectories in hospitalized malnourished children during and after hospitalization. We followed a cohort of children in Bangladesh and Malawi (2-23 months) with: no wasting (NW); moderate wasting (MW), severe wasting (SW), or edematous malnutrition (EM). REE was measured by indirect calorimetry at admission, discharge, 14-and-45-days post-discharge. 125 children (NW, n = 23; MW, n = 29; SW, n = 51; EM, n = 22), median age 9 (IQR 6, 14) months, provided 401 REE measurements. At admission, the REE of children with NW and MW was 67 (95% CI [58, 75]) and 70 (95% CI [63, 76]) kcal/kg/day, respectively, while REE in children with SW was higher, 79 kcal/kg/day (95% CI [74, 84], p = 0.018), than NW. REE in these groups was stable over time. In children with EM, REE increased from admission to discharge (65 kcal/kg/day, 95% CI [56, 73]) to 79 (95% CI [72, 86], p = 0.0014) and was stable hereafter. Predictive equations underestimated REE in 92% of participants at all time points. Recommended feeding targets during the acute phase of illness in severely malnourished children exceeded REE. Acutely ill malnourished children are at risk of being overfed when implementing current international guidelines., (© 2024. The Author(s).)

Neutrophils are the most abundant innate immune cells. Multiple mechanisms allow them to engage a wide range of metabolic pathways for biosynthesis and bioenergetics for mediating biological processes such as development in the bone marrow and antimicrobial activity such as ROS production and NET formation, inflammation and tissue repair. We first discuss recent work on neutrophil development and functions and the metabolic processes to regulate granulopoiesis, neutrophil migration and trafficking as well as effector functions. We then discuss metabolic syndromes with impaired neutrophil functions that are influenced by genetic and environmental factors of nutrient availability and usage. Here, we particularly focus on the role of specific macronutrients, such as glucose, fatty acids, and protein, as well as micronutrients such as vitamin B3, in regulating neutrophil biology and how this regulation impacts host health. A special section of this review primarily discusses that the ways nutrient deficiencies could impact neutrophil biology and increase infection susceptibility. We emphasize biochemical approaches to explore neutrophil metabolism in relation to development and functions. Lastly, we discuss opportunities and challenges to neutrophil-centered therapeutic approaches in immune-driven diseases and highlight unanswered questions to guide future discoveries., Competing Interests: HU received research support or consultancy fees from Janssen, Eli Lilly, UCB Pharma, GSK, BMS/Celgene, MiroBio, OMass, and Mestag. AF is employed by Omega Laboratories Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Thind, Uhlig, Glogauer, Palaniyar, Bourdon, Gwela, Lancioni, Berkley, Bandsma and Farooqui.)

Based on the specimens housed primarily in the University of New Hampshire Insect Collection (UNH) and the Canadian National Collection (CNC), we present here a comprehensive faunal review of aleocharine beetles of the state and provide new distribution and natural history data. We report 252 species from New Hampshire belonging to some 74 genera in 15 tribes; 159 of these constitute new New Hampshire state records (NSR), of which 37 (excluding new species and including 1 New York record) constitute new country distribution records (NCR) for the USA. In addition, we provide 36 new state records for ME, with 5 of these species not yet known from NH, seven new state records for MA, two new state records for PA and VT, and one each for CT, DE, MI, NC, NY (also a NCR), OH, and OK. One new genus, Belladonna Klimaszewski and Chandler is erected, and nine species are described as new to science (alphabetical order): Agaricomorpha hampshirensis Klimaszewski and Chandler, sp. n., Atheta ellisi Klimaszewski and Chandler sp. n, Atheta monroe Klimaszewski and Chandler, sp. n., Atheta struyvei Klimaszewski and Chandler sp. n, Belladonna barryi Klimaszewski and Chandler, sp. n., Belladonna fortieri Klimaszewski and Chandler, sp. n., Colusa smetanai Klimaszewski and Chandler, sp. n., Philhygra pinkhami Klimaszewski and Chandler sp. n., and P. pseudomagniceps Klimaszewski and Chandler, sp. n. Undescribed females of Aleochara daviesi Klimaszewski and Brunke, and Silusa langori Klimaszewski, are described and illustrated. Illustrations of Atheta (Tetropla) tubericauda Bernhauer are provided for the first time, based on a male from New Hampshire. A new combination is proposed for Atheta (Dimetrota) mcalpinei Klimaszewski and Webster.

Copper pyrithione (CuPT) is used as a co-biocide in new antifouling paints but its toxicity remains little known. To compare the toxicity of copper-based compounds, rainbow trout (Oncorhynchus mykiss) larvae were exposed for 8-day to CuPT and CuSO 4 at equivalent copper concentrations. CuPT exposure led to the greatest accumulation of Cu in larvae. Exposure to 10 µg.L -1 CuPT induced 99% larval mortality but only 4% for CuSO 4 -exposed larvae. The larval development and growth were affected by CuPT (from 0.5 µg.L -1 Cu) but not by CuSO 4 . Lipid peroxidation was not induced by either contaminant. The expression of genes involved in oxidative stress defence, detoxification and copper transport was induced in larvae exposed to CuSO 4 and CuPT but at higher concentrations for CuPT. This study highlights the marked toxicity of CuPT for early life stages of fish and raises the question of the possible environmental risks of this antifouling compound., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Cachot Jerome reports financial support was provided by LabEx COTE., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Growth studies rely on longitudinal measurements, typically represented as trajectories. However, anthropometry is prone to errors that can generate outliers. While various methods are available for detecting outlier measurements, a gold standard has yet to be identified, and there is no established method for outlying trajectories. Thus, outlier types and their effects on growth pattern detection still need to be investigated. This work aimed to assess the performance of six methods at detecting different types of outliers, propose two novel methods for outlier trajectory detection and evaluate how outliers affect growth pattern detection., Methods: We included 393 healthy infants from The Applied Research Group for Kids (TARGet Kids!) cohort and 1651 children with severe malnutrition from the co-trimoxazole prophylaxis clinical trial. We injected outliers of three types and six intensities and applied four outlier detection methods for measurements (model-based and World Health Organization cut-offs-based) and two for trajectories. We also assessed growth pattern detection before and after outlier injection using time series clustering and latent class mixed models. Error type, intensity, and population affected method performance., Results: Model-based outlier detection methods performed best for measurements with precision between 5.72-99.89%, especially for low and moderate error intensities. The clustering-based outlier trajectory method had high precision of 14.93-99.12%. Combining methods improved the detection rate to 21.82% in outlier measurements. Finally, when comparing growth groups with and without outliers, the outliers were shown to alter group membership by 57.9 -79.04%., Conclusions: World Health Organization cut-off-based techniques were shown to perform well in few very particular cases (extreme errors of high intensity), while model-based techniques performed well, especially for moderate errors of low intensity. Clustering-based outlier trajectory detection performed exceptionally well across all types and intensities of errors, indicating a potential strategic change in how outliers in growth data are viewed. Finally, the importance of detecting outliers was shown, given its impact on children growth studies, as demonstrated by comparing results of growth group detection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The intestine of children with severe malnutrition (SM) shows structural and functional changes that are linked to increased infection and mortality. SM dysregulates the tryptophan-kynurenine pathway, which may impact processes such as SIRT1- and mTORC1-mediated autophagy and mitochondrial homeostasis. Using a mouse and organoid model of SM, we studied the repercussions of these dysregulations on malnutrition enteropathy and the protective capacity of maintaining autophagy activity and mitochondrial health., Methods: SM was induced through feeding male weanling C57BL/6 mice a low protein diet (LPD) for 14-days. Mice were either treated with the NAD + -precursor, nicotinamide; an mTORC1-inhibitor, rapamycin; a SIRT1-activator, resveratrol; or SIRT1-inhibitor, EX-527. Malnutrition enteropathy was induced in enteric organoids through amino-acid deprivation. Features of and pathways to malnutrition enteropathy were examined, including paracellular permeability, nutrient absorption, and autophagic, mitochondrial, and reactive-oxygen-species (ROS) abnormalities., Findings: LPD-feeding and ensuing low-tryptophan availability led to villus atrophy, nutrient malabsorption, and intestinal barrier dysfunction. In LPD-fed mice, nicotinamide-supplementation was linked to SIRT1-mediated activation of mitophagy, which reduced damaged mitochondria, and improved intestinal barrier function. Inhibition of mTORC1 reduced intestinal barrier dysfunction and nutrient malabsorption. Findings were validated and extended using an organoid model, demonstrating that resolution of mitochondrial ROS resolved barrier dysfunction., Interpretation: Malnutrition enteropathy arises from a dysregulation of the SIRT1 and mTORC1 pathways, leading to disrupted autophagy, mitochondrial homeostasis, and ROS. Whether nicotinamide-supplementation in children with SM could ameliorate malnutrition enteropathy should be explored in clinical trials., Funding: This work was supported by the Bill and Melinda Gates Foundation, the Sickkids Research Institute, the Canadian Institutes of Health Research, and the University Medical Center Groningen., Competing Interests: Declaration of interests All authors declare no conflicts interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Children admitted to hospital with complicated severe malnutrition (CSM) have high mortality despite compliance with standard WHO management guidelines. Limited data suggests a relationship between intestinal dysfunction and poor prognosis in CSM, but this has not been explicitly studied. This study aimed to evaluate the role of intestinal disturbances in CSM mortality., Methods: A case-control study nested within a randomized control trial was conducted among children hospitalized with CSM in Kenya and Malawi. Children who died (cases, n = 68) were compared with those who were discharged, propensity matched to the cases on age, HIV and nutritional status (controls, n = 68) on fecal metabolomics that targeted about 70 commonly measured metabolites, and enteropathy markers: fecal myeloperoxidase (MPO), fecal calprotectin, and circulating intestinal fatty acid binding protein (I-FABP)., Results: The fecal metabolomes of cases show specific reductions in amino acids, monosaccharides, and microbial fermentation products, when compared to controls. SCFA levels did not differ between groups. The overall fecal metabolomics signature moderately differentiates cases from controls (AUC = 0.72). Enteropathy markers do not differ between groups overall, although serum I-FABP is elevated in cases in a sensitivity analysis among non-edematous children. Integrative analysis with systemic data suggests an indirect role of intestinal inflammation in the causal path of mortality., Conclusions: Intestinal disturbances appear to have an indirect association with acute mortality. Findings of the study improve our understanding of pathophysiological pathways underlying mortality of children with CSM., (© 2023. Springer Nature Limited.)

Bipolar disorder (BD) is a chronic and severe psychiatric disorder associated with significant medical morbidity and reduced life expectancy. In this study, we assessed accelerated epigenetic aging in individuals with BD using various DNA methylation (DNAm)-based markers. For this purpose, we used five epigenetic clocks (Horvath, Hannum, EN, PhenoAge, and GrimAge) and a DNAm-based telomere length clock (DNAmTL). DNAm profiles were obtained using Infinium MethylationEPIC Arrays from whole-blood samples of 184 individuals with BD. We also estimated blood cell counts based on DNAm levels for adjustment. Significant correlations between chronological age and each epigenetic age estimated using the six different clocks were observed. Following adjustment for blood cell counts, we found that the six epigenetic AgeAccels (age accelerations) were significantly associated with the body mass index. GrimAge AgeAccel was significantly associated with male sex, smoking status and childhood maltreatment. DNAmTL AgeAccel was significantly associated with smoking status. Overall, this study showed that distinct epigenetic clocks are sensitive to different aspects of aging process in BD. Further investigations with comprehensive epigenetic clock analyses and large samples are required to confirm our findings of potential determinants of an accelerated epigenetic aging in BD., Competing Interests: Declaration of Competing Interest None to be declared in links with this study., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Longitudinal patterns of growth in early childhood are associated with health conditions throughout life. Knowledge of such patterns and the ability to predict them can lead to better prevention and improved health promotion in adulthood. However, growth analyses are characterized by significant variability, and pattern detection is affected by the method applied. Moreover, pattern labelling is typically performed based on ad hoc methods, such as visualizations or clinical experience. Here, we propose a novel pipeline using features extracted from growth trajectories using mathematical, statistical and machine-learning approaches to predict growth patterns and label them in a systematic and unequivocal manner., Methods: We extracted mathematical and clinical features from 9577 children growth trajectories embedded with machine-learning predictions of the growth patterns. We experimented with two sets of features (CAnonical Time-series Characteristics and trajectory features specific to growth), developmental periods and six machine-learning classifiers. Clinical experts provided labels for the detected patterns and decision rules were created to associate the features with the labelled patterns. The predictive capacity of the extracted features was validated on two heterogenous populations (The Applied Research Group for Kids and the 2004 Pelotas Birth Cohort, based in Canada and Brazil, respectively)., Results: Features predictive ability measured by accuracy and F1 score was ≥ 80% and ≥ 0.76 respectively in both cohorts. A small number of features (n = 74) was sufficient to distinguish between growth patterns in both cohorts. Slope, intercept of the trajectory, age at peak value, start value and change of the growth measure were among the top identified features., Conclusion: Growth features can be reliably used as predictors of growth patterns and provide an unbiased understanding of growth patterns. They can be used as tool to reduce the effort to repeat analysis and variability concerning anthropometric measures, time points and analytical methods, in the context of the same or similar populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth., Aim: The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6-23 months old children with severe wasting., Methods: We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial., Outcomes: The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety., Implications: These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial., Trial Registration: The trial has been registered on clinicaltrial.gov (NCT05737472)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Potani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: This study aimed to examine outcomes of a pilot program designed to increase inpatient medications for opioid use disorder (MOUD) induction and to support MOUD adherence after discharge., Methods: This retrospective cohort analysis examined Medicaid adults diagnosed with opioid use disorder discharged from 2 freestanding inpatient withdrawal management facilities between October 1, 2018, and December 31, 2019. Participants had ≥90 days of continuous Medicaid enrollment before and after admission. Odds ratios (ORs) examined associations of inpatient MOUD induction with discharge against medical advice, 7- and 30-day all-cause hospital readmission, and postdischarge MOUD adherence. Mixed-effect models examined changes associated with MOUD induction and postdischarge MOUD adherence in acute service utilization and opioid overdose in the 90-day postdischarge period., Results: Of the 2332 patients discharged, 493 started MOUD inpatient care (21.1%), with most initiating buprenorphine (76.5%). Induction of MOUD was associated with a lower likelihood of discharge against medical advice (OR, 0.49; 95% confidence interval [CI], 0.37-0.64), 30-day all-cause hospital readmission (OR, 0.61; 95% CI, 0.47-0.80), and higher odds of postdischarge MOUD adherence (OR, 3.83; 95% CI, 3.06-4.81). In the 90 days after discharge, MOUD adherent patients had significant reductions in emergency department visits for behavioral health, inpatient days, withdrawal management episodes, and opioid overdoses compared with the 90-day preadmission period., Conclusions: Inpatient MOUD induction is associated with a higher likelihood of short-term MOUD adherence after discharge, which in turn is associated with significant reductions in short-term service utilization and opioid overdose after discharge., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Child growth patterns assessment is critical to design public health interventions. However, current analytical approaches may overlook population heterogeneity. To overcome this limitation, we developed a growth trajectories clustering pipeline that incorporates a shape-respecting distance, baseline centering (i.e., birth-size normalized trajectories) and Gestational Age (GA)-correction to characterize shape-based child growth patterns. We used data from 3945 children (461 preterm) in the 2004 Pelotas Birth Cohort with at least 3 measurements between birth (included) and 11 years of age. Sex-adjusted weight-, length/height- and body mass index-for-age z-scores were derived at birth, 3 months, and at 1, 2, 4, 6 and 11 years of age (INTERGROWTH-21st and WHO growth standards). Growth trajectories clustering was conducted for each anthropometric index using k-means and a shape-respecting distance, accounting or not for birth size and/or GA-correction. We identified 3 trajectory patterns for each anthropometric index: increasing (High), stable (Middle) and decreasing (Low). Baseline centering resulted in pattern classification that considered early life growth traits. GA-correction increased the intercepts of preterm-born children trajectories, impacting their pattern classification. Incorporating shape-based clustering, baseline centering and GA-correction in growth patterns analysis improves the identification of subgroups meaningful for public health interventions., (© 2023. The Author(s).)

Pathogenic germline variants in the CHEK2 gene have been shown to cause a moderate increased risk of breast cancer. Here, we present a striking CHEK2 family with a biallelic carrier of two frameshift pathogenic variants, to draw attention and to encourage a comprehensive genetic and cancer risk education for biallelic carriers of CHEK2 pathogenic variants., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Severe COVID-19 has been associated with a high rate of thrombotic events but also of bleeding events, particularly when the level of prophylactic anticoagulation was increased. Data on the contribution of platelets to these thrombotic events are discordant between reports, while the involvement of platelets in bleeding events has never been investigated. The objective of the present study was to assess platelet function during the first week of ICU hospitalization in patients with severe COVID-19 pneumonia. A total of 35 patients were prospectively included and blood samples were drawn on day (D) 0, D2 and D7. COVID-19 pneumonia was severe with a median PaO 2 /FiO 2 ratio of 91 [68-119] on D0. Platelets from these patients showed evidence of pre-activation and exhaustion with a significant reduction in the surface expression of GPVI, GPIb and GPIIbIIIa, together with a decrease in serotonin content. Platelets from patients with severe COVID-19 were hyporesponsive with a reduced maximal aggregation response to several platelet agonists and decreased adhesion to immobilized fibrinogen. Aggregation of washed platelets and plasma substitution experiments indicated that a plasma factor was at least partially responsible for this hyporeactivity of platelets. Blood flow experiments showed that severe COVID-19 platelets formed smaller, less stable aggregates on a collagen-coated surface, which could explain why some patients develop bleeding events. These findings should prompt us to carefully evaluate the risks and benefits of high-dose prophylactic anticoagulation, and to decrease the level of anticoagulation once the initial phase of the disease has resolved. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04359992., Competing Interests: Declaration of competing interest CT reports personal fees paid by Sanofi for conference attendance., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+  dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+  pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+  pathway with NAD+  precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+  pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition., (© 2022. The Author(s).)

Severe malnutrition accounts for half-a-million deaths annually in children under the age of five. Despite improved WHO guidelines, inpatient mortality remains high and is associated with metabolic dysfunction. Previous studies suggest a correlation between hepatic metabolic dysfunction and impaired autophagy. We aimed to determine the role of mTORC1 inhibition in a murine model of malnutrition-induced hepatic dysfunction. Wild type weanling C57/B6 mice were fed a 18 or 1% protein diet for two weeks. A third low-protein group received daily rapamycin injections, an mTORC1 inhibitor. Hepatic metabolic function was assessed by histology, immunofluorescence, gene expression, metabolomics and protein levels. Low protein-fed mice manifested characteristics of severe malnutrition, including weight loss, hypoalbuminemia, hypoglycemia, hepatic steatosis and cholestasis. Low protein-fed mice had fewer mitochondria and showed signs of impaired mitochondrial function. Rapamycin prevented hepatic steatosis, restored ATP levels and fasted plasma glucose levels compared to untreated mice. This correlated with increased content of LC3-II, and decreased content mitochondrial damage marker, PINK1. We demonstrate that hepatic steatosis and disturbed mitochondrial function in a murine model of severe malnutrition can be partially prevented through inhibition of mTORC1. These findings suggest that stimulation of autophagy could be a novel approach to improve metabolic function in severely malnourished children., (© 2022. The Author(s).)

Background and Objectives: Acute illness with malnutrition is a common indication for hospitalization among children in low- and middle-income countries. We investigated the association between wasting recovery trajectories and neurodevelopmental outcomes in young children 6 months after hospitalization for an acute illness., Methods: Children aged 2 to 23 months were enrolled in a prospective observational cohort of the Childhood Acute Illness & Nutrition Network, in Uganda, Malawi, and Pakistan between January 2017 and January 2019. We grouped children on the basis of their wasting recovery trajectories using change in mid-upper arm circumference for age z-score. Neurodevelopment was assessed with the Malawi Developmental Assessment Tool (MDAT development-for-age z-score [DAZ]) at hospital discharge and after 6 months., Results: We included 645 children at hospital discharge (mean age 12.3 months ± 5.5; 55% male); 262 (41%) with severe wasting, 134 (21%) with moderate wasting, and 249 (39%) without wasting. Four recovery trajectories were identified: high-stable, n = 112; wasted-improved, n = 404; severely wasted-greatly improved, n = 48; and severely wasted-not improved, n = 28. The children in the severely wasted-greatly improved group demonstrated a steep positive MDAT-DAZ recovery slope. This effect was most evident in children with both wasting and stunting (interaction wasted-improved × time × stunting: P &lt; .001). After 6 months, the MDAT DAZ in children with wasting recovery did not differ from community children. In children who never recovered from wasting, there remained a significant delay in MDAT DAZ scores., Conclusions: Neurodevelopment recovery occurred in parallel with wasting recovery in children convalescing from acute illness and was influenced by stunting.

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.)

This study aimed to define the normative values of the DASH score in healthy individuals over 50 years of age. One hundred and twenty subjects equally representing both genders and six age categories (50-54, 55-59, 60-64, 65-69, 70-74 and 75-80 years), with no past medical history affecting the upper limb, were asked to complete the DASH questionnaire. A visual analogue scale for pain and an HAQ-DI questionnaire were also completed to confirm the absence of symptomatic untreated upper limb pathologies. In this series of a priori normal subjects, most had a DASH score greater than 0. Moreover, the DASH score was found to rise with age, with a statistically significant difference between women and men. The DASH questionnaire is widely accepted in the everyday medical practice as a tool to evaluate upper limb function. However, age adjustment of the DASH questionnaire is necessary to correctly evaluate the clinical status and progression of individuals over the age of 50., (Copyright © 2021 SFCM. Published by Elsevier Masson SAS. All rights reserved.)

Early life stages (ELS) of numerous marine invertebrates mustcope with man-made contaminants, including plastic debris, during their pelagic phase. Among the diversity of plastic particles, nano-sized debris, known as nanoplastics, can induce effects with severe outcomes in ELS of various biological models, including the Pacific oyster Crassostrea gigas . Here, we investigated the effects of a sub-lethal dose (0.1 µg mL -1 ) of 50 nm polystyrene nanobeads (nano-PS) with amine functions on oyster embryos (24 h exposure) and we assessed consequences on larval and adult performances over two generations of oysters. Only a few effects were observed. Lipid analyses revealed that first-generation (G1) embryos exposed to nano-PS displayed a relative increase in cardiolipin content (+9.7%), suggesting a potential modification of mitochondrial functioning. G1-larvae issued from exposed embryos showed decreases in larval growth (-9%) and lipid storage (-20%). No effect was observed at the G1 adult stage in terms of growth, ecophysiological parameters (clearance and respiration rates, absorption efficiency), or reproductive outputs (gonadic development, gamete quality). Second generation (G2) larvae issued from control G1 displayed a significant growth reduction after G2 embryonic exposure to nano-PS (-24%) compared to control (as observed at the first generation), while no intergenerational effect was detected on G2 larvae issued from G1 exposed embryos. Overall, the present experimental study suggests a low incidence of a short embryonic exposure to nano-PS on oyster phenotypes along the entire life cycle until the next larval generation.

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).

Metastasis is a major cause of death in cancer patients. The extracellular matrix molecule tenascin-C is a known promoter of metastasis, however the underlying mechanisms are not well understood. To further analyze the impact of tenascin-C on cancer progression we generated MMTV-NeuNT mice that develop spontaneous mammary tumors, on a tenascin-C knockout background. We also developed a syngeneic orthotopic model in which tumor cells derived from a MMTV-NeuNT tumor. Tumor cells were transfected with control shRNA or with shRNA to knockdown tenascin-C expression and, were grafted into the mammary gland of immune competent, wildtype or tenascin-C knockout mice. We show that stromal-derived tenascin-C increases metastasis by reducing apoptosis and inducing the cellular plasticity of cancer cells located in pulmonary blood vessels invasions (BVI), before extravasation. We characterized BVI as organized structures of tightly packed aggregates of proliferating tumor cells with epithelial characteristics, surrounded by Fsp1+ cells, internally located platelets and, a luminal monolayer of endothelial cells. We found extracellular matrix, in particular, tenascin-C, between the stromal cells and the tumor cell cluster. In mice lacking stromal-derived tenascin-C, the organization of pulmonary BVI was significantly affected, revealing novel functions of host-derived tenascin-C in supporting the integrity of the endothelial cell coat, increasing platelet abundance, tumor cell survival, epithelial plasticity, thereby promoting overall lung metastasis. Many effects of tenascin-C observed in BVI including enhancement of cellular plasticity, survival and migration, could be explained by activation of TGF-β signaling. Finally, in several human cancers, we also observed BVI to be surrounded by an endothelial monolayer and to express tenascin-C. Expression of tenascin-C is specific to BVI and is not observed in lymphatic vascular invasions frequent in breast cancer, which lack an endothelial lining. Given that BVI have prognostic significance for many tumor types, such as shorter cancer patient survival, increased metastasis, vessel occlusion, and organ failure, our data revealing a novel mechanism by which stromal tenascin-C promotes metastasis in human cancer, may have potential for diagnosis and therapy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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.)