Pain, self-regulation and temperament in high risk preterm newborns

Os recém-nascidos pré-termo são expostos a experiências dolorosas inevitáveis na Unidade de Terapia Intensiva Neonatal. Apesar de sua imaturidade biológica, esses podem tanto perceber quanto reagir à dor. A exposição repetida à dor exerce impacto negativo no desenvolvimento e pode aumentar a vulnerabilidade dos bebês, dificultando os processos autorregulatórios. A reatividade biocomportamental à dor é um indicador de autorregulação e associa-se ao temperamento da criança. Esses bebês necessitam de estratégias farmacológicas e não farmacológicas para alívio da dor. Além disso, devem ter um contexto de interações sincrônicas com os pais, adaptadas às suas características de temperamento. Os profissionais de saúde podem atuar como suporte de regulação externa para esses bebês promovendo alívio da dor e prevenindo problemas de desenvolvimento.High risk preterm newborns are exposed to unavoidable painful experiences in Neonatal Intensive Care Units. In spite of their biological immaturity, they are able to perceive and react to pain stimuli. Repetitive exposure to pain has a negative impact on the development and may increase the infant's vulnerability, affecting self-regulatory processes. Biobehavioral reactivity to pain is an indicator of self-regulation and it is associated to the child's temperament. Preterm infants need pharmacological and non-pharmacological strategies for pain relieving. Moreover, they need a context of synchronic interaction with their parents which must be adapted to their temperament characteristics. Health professionals may play an important role in supporting external regulation for those infants, promoting pain relief and preventing development problems.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Temperamento, comportamiento y experiencia dolorosa en la trayectoria del desarrollo del niño

O presente estudo teve por objetivo realizar uma revisão de estudos sobre as relações entre temperamento, comportamento e experiências dolorosas iniciais nas trajetórias de desenvolvimento de crianças, especialmente nas nascidas prematuras. Os estudos empíricos foram obtidos por meio das bases de dados PsycINFO e Medline. Os resultados mostraram que o temperamento foi preditor de padrões individuais de reação à dor e problemas de comportamento da criança, em diferentes idades. Além disso, as experiências precoces de dor em crianças nascidas prematuras podem afetar a reatividade do bebê, que por sua vez mostrou associação com dimensões do temperamento nos primeiros anos de vida.El objetivo del presente estudio fue realizar una revisión sobre las relaciones entre temperamento, comportamiento y experiencias dolorosas iniciales en la trayectoria del desarrollo de los niños, especialmente en los nacidos prematuros. Los estudios empíricos fueron obtenidos por medio de la base de datos PsycINFO y Medline. Los resultados muestran que el temperamento fue el definidor de los patrones individuales de las reacciones al dolor y problemas del comportamiento de los niños, en diferentes edades. También las experiencias precoces de dolor en niños nacidos prematuros pueden afectar la reactividad del recién nacido, que además mostró asociación con dimensiones del temperamento en los primeros años de vida.The objective of the present study was to review the studies about the relations among the temperament, behavior, and early painful experiences in children developmental pathways, especially with preterm born children. The empirical studies were obtained through the data bases PsycINFO and Medline. The results showed that the temperament was a predictor of the individual patterns of reaction to pain and to behavior problems at different ages. Moreover, the early painful experiences of children born preterm can influence infant's reactivity, which was in association to temperamental dimensions during the first years of life

NEONATAL CHARACTERISTICS AND TEMPERAMENT PREDICT BEHAVIOR PROBLEMS IN CHILDREN BORN PRETERM

Introduction: the preterm birth is a risk factor for child developmental and behavioral problems. Objective: to examine whether neonatal clinical characteristics of infants born preterm, as well as temperament assessed in toddlerhood, predict behavior problems during the preschool years. Methods: twenty-one children born preterm with very low birth weight were assessed longitudinally at three different ages: in the neonatal period, during toddlerhood, and in preschool. Medical charts were reviewed to assess infants’ clinical illness characteristics at the neonatal phase. Mothers fulfilled the Early Childhood Behavior Questionnaire for assessing temperament at the toddlerhood and the Child Behavior Checklist-1.5-5 for assessing children’s behavior problems at the preschool age. Results: very low birth weight associated with child temperament at the toddlerhood predicted behavior problems at the preschool age. High levels of excitement about expected pleasurable activities as well as low levels of inhibitory control increased the chance of exhibiting externalizing behavior problems. Otherwise, high levels of both gross and fine motor activation increased the chance of exhibiting internalizing behavior problems. Conclusion: prematurity associated with temperament of poor self-regulation in developmental processes comprises a multiple-risk condition for clinical behavior problems in the preschool age

Supplementation with green tea and oregano extracts on productive characteristics, blood metabolites, and antioxidant status of Jersey cows during the transition period

Plant extracts have been recognized as beneficial to human health and have been evaluated as feed additive for domestic and companion animals. This study evaluated oregano and green tea extracts fed to Jersey cows from approximately 21 d before calving to 21 d after calving on milk production, milk composition, and blood metabolites as well as investigated immunological and antioxidant attributes. Twenty-four Jersey cows with 441±27 kg of BW, 3.5±0.3 of body condition score (BCS), and 2.7±1.8 lactations were selected at approximately 28d before the expected parturition date and were randomly assigned to three treatments with eight cows each: without plant extracts in diet (control – CON), addition of 10g per day of oregano extract (OR), and addition of 5g per day of green tea extract (GT). Feed intake, BW, BCS, blood metabolites, hemogram as well as oxidative stress biomarkers were evaluated from approximately 3 weeks prepartum to 3 weeks postpartum (transition period) while milk production and composition were evaluated during the first 3 weeks of lactation. Plant extracts did not change BW, BCS, and DM intake (DMI) throughout the transition period, but OR increased in approximately 20% total digestive nutrients and metabolizable energy intake on days 15 and 16 postpartum compared with CON. In the prepartum, OR increased in 48% platelets count compared to the CON, while GT augmented in 142% eosinophils compared with CON. Oregano extract reduced the levels of reactive species in the erythrocytes in 40% during prepartum and postpartum compared with CON, while GT reduced its levels in 24 and 29% during prepartum and postpartum, respectively, when compared with CON. In the postpartum period, OR increased in 60% the carbonylated protein content compared with CON, while GT reduced in 45% the levels of reactive species in plasma compared with CON. During the postpartum, both extracts increased in 33% the concentration of reduced glutathione when compared with CON. Moreover, GT tended to decrease feed efficiency in 11% when compared with CON; OE reduced milk pH and somatic cell count when compared with CON. In conclusion, OE and GT did not expressively affect immunological attributes in blood but reduce some oxidative stress biomarkers without compromising productive traits of Jersey cows during the transition period

Plant extracts supplied to pre-weaned dairy calves influence their redox status

This study aimed to evaluate the effects of the separate provision of green and oregano tea extracts on the biomarkers of the redox state and health condition in pre-weaned Jersey calves from birth to 60 days of life. Two experiments following the complete randomized design with measures repeated in time were carried out using 38 Jersey calves (17 and 21 calves in experiments 1 and 2, respectively). Calves were distributed according to date of birth into one of three groups: control (CON) - with no addition of extracts; oregano extract (OE) - addition of 70 mg of oregano extract/kg of body weight (BW) and green tea extract (GT) - addition of 35 mg of green tea extract/kg of BW. Eight biomarkers of the redox state were evaluated on days 1, 30, and 60 after birth, and variables measured on day 1 were used as covariates. Body temperature and occurrence of diarrhea were evaluated every two days. Regarding the main results, the supply of oregano extract reduced the concentration of oxidizing biomarkers, such as DCFP (oxidation of dichlorofluorescein in plasma) and carbonyl, and increased the activity of antioxidant enzymes, such as GPx and catalase. Green tea extract only reduced DCFP and tended to improve catalase activity. Calves remained healthy (no fever and only a few days with diarrhea), and plant extracts did not improve their health condition. The addition of green tea and oregano extracts into the diet has a positive effect on redox status in pre-weaned Jersey calves

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons. A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB