Effects of Two Early Parenting Programmes on Child Aggression and Risk for Violence in Brazil: a Randomised Controlled Trial.

Violence is a major public health problem globally, with the highest rates in low- and middle-income countries (LMICs) in the Americas and southern Africa. Parenting programmes in high-income countries can diminish risk for violence, by reducing risk factors such as child aggression and harsh parenting, and increasing protective factors such as child cognitive development and school readiness. However, there is critical need to identify low-cost programmes with replicable benefits that work in real-world LMICs contexts. A three-arm, randomised, single-blind trial evaluated effects of two low-cost, group-based parenting programmes recommended for LMICs (ACT: Raising Safe Kids; DBS: dialogic book-sharing) on child aggression (primary outcome), child development, parenting, maltreatment, and stress. Participants were 369 children with medium-high levels of aggression (mean age 3.1 years at baseline) in poor households. Interventions were implemented in city health and education services in southern Brazil. Maternal reports, filmed observations, child tasks, and hair cortisol were assessed at baseline, 1-month post-intervention, and 8-month follow-up. Intention-to-treat analyses compared each of ACT and DBS with a control group. Three hundred sixty-eight (99.7%) participants completed follow-up assessments 8 months after the interventions. There was no effect of ACT (standardised mean difference, SMD 0.11, 95% CI - 0.05, 0.27) or DBS (SMD 0.05, 95% CI - 0.11, 0.21) on the primary outcome of child aggression. ACT reduced harsh parenting behaviour post-intervention (SMD - 0.23; 95% CI - 0.46, - 0.01), but not at follow-up. DBS improved book-sharing practices at both time points (e.g., maternal sensitivity at follow-up SMD 0.33; 95% CI 0.08, 0.57). There were no benefits of either programme for other parenting, child development, or stress outcomes. Two parenting programmes in Brazil had small effects on parenting practices but did not reduce child aggression or several other important risk/protective factors for violence. Effective early interventions that reduce violence in real-world LMIC settings are highly desirable but may be challenging to achieve.

Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases.

Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.

Effects of Breaking Up Sedentary Behavior With Short Bouts of Yoga and Tai-Chi on Glycemia, Concentration, and Well-Being.

BACKGROUND: Investigating the effects of breaking up sedentary behavior with short bouts of Yoga and Tai-Chi on glycemic control, concentration, and well-being in healthy individuals. METHODS: In this randomized balanced incomplete block study, 15 adults (age = 26 [2.50] y, 8 females) completed 2 of 3 protocols: uninterrupted sitting (Control), sitting interrupted with 3 minutes of Yoga every 30 minutes, or with 3 minutes of Tai-Chi every 30 minutes. Protocols lasted 7.5 hours and included a standardized diet. Glucose was measured every 30 minutes with a glucometer (Abbott FreeStyle Libre). Concentration and well-being were recorded with self-reported ecological momentary assessment. Area under the curve was calculated for glucose data. Statistical analyses were performed as a hierarchical repeated-measures model. RESULTS: Glucose area under the curve for the Yoga intervention (34.55 [3.12] mmol/L) was significantly lower than the Control (38.14 [3.18] mmol/L; P < .05). There was a trend toward lower glucose in the Tai-Chi group compared with the Control, but no significant differences were found (AUCTai-Chi = 36.64 [3.11] mmol/L; P = .57). Mean concentration in all groups decreased throughout the day, with the largest decrease in the Control. Well-being for the Yoga and Control groups decreased but increased with Tai-Chi. Concentration and well-being responses were not statistically significant between intervention groups. CONCLUSIONS: Breaking up sedentary behavior using 3-minute bouts of Yoga significantly lowers blood glucose in healthy individuals without compromising concentration or well-being. Tai-Chi did not provide the same significant effect on glucose levels but allowed better maintenance of concentration and well-being. These interventions provide effective ways to combat the deleterious effects of prolonged sedentary time while maintaining concentration and well-being.

Efficacy of a dialogic book-sharing intervention in a South African birth cohort: A randomized controlled trial.

OBJECTIVE: Evidence shows that dialogic book-sharing improves language development in young children in low-middle income countries (LMICs), particularly receptive and expressive language. It is unclear whether this intervention also boosts development of other neurocognitive and socio-emotional domains in children. Using a randomized controlled trial (RCT) nested in the Drakenstein Child Health Study (DCHS), a book-sharing intervention was implemented in caregivers of 3.5-year-old preschool children living in low-income South African communities. METHODS: 122 Caregivers and their children (mean age 3.5 years) were randomly assigned to an intervention group (n = 61) or waitlist control group (n = 61). A neurocognitive battery determined baseline receptive and expressive language, executive function, theory of mind, and behavior scores. RESULTS: No differences were observed between intervention and control groups on receptive and expressive language, or any of the neurocognitive or socio-emotional measures from baseline (3.5 years) to 4 months post-intervention administration (4 years). CONCLUSION: The benefits noted in prior literature of book-sharing in infants did not appear to be demonstrated at 4 months post-intervention, in children from 3.5 to 4 years of age. This suggests the importance of early intervention and emphasizes the need for further research on adaptation of book-sharing for older participants in a South African context. TRIAL REGISTRATION: retrospectively registered on 03/04/2022 PACTR202204697674974.

Small airway fibroblasts from patients with chronic obstructive pulmonary disease exhibit cellular senescence.

Small airway disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodeling. Parenchymal-derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAFs) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD. To investigate the senescent and fibrotic phenotype of SAF in COPD, SAFs were isolated from nonsmoker, smoker, and COPD lung resection tissue (n = 9-17 donors). Senescence and fibrotic marker expressions were determined using iCELLigence (proliferation), qPCR, Seahorse assay, and ELISAs. COPD SAFs were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent vs. 10% smallest/nonautofluorescent). The phenotype of the senescence-enriched population was investigated using RNA sequencing and pathway analysis. Markers of senescence were observed in COPD SAFs, including senescence-associated ß-galactosidase, SASP release, and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell sorting to enrich senescent COPD SAFs. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis, and mitochondrial dysfunction pathways. These data suggest COPD SAFs are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding of cellular senescence in SAFs may lead to potential therapies to limit SAD progression.NEW & NOTEWORTHY Fibroblasts and senescence are thought to play key roles in the pathogenesis of small airway disease and COPD; however, the characteristics of small airway-derived fibroblasts are not well explored. In this study we isolate and enrich the senescent small airway-derived fibroblast (SAF) population from COPD lungs and explore the pathways driving this phenotype using bulk RNA-seq.

A community-based child health and parenting intervention to improve child HIV testing, health, and development in rural Lesotho (Early Morning Star): a cluster-randomised, controlled trial.

BACKGROUND: When caregivers live in remote settings characterised by extreme poverty, poor access to health services, and high rates of HIV/AIDS, their caregiving ability and children's development might be compromised. We aimed to test the effectiveness of a community-based child health and parenting intervention to improve child HIV testing, health, and development in rural Lesotho. METHODS: We implemented a matched cluster-randomised, controlled trial in the Mokhotlong district in northeastern Lesotho with 34 community clusters randomly assigned to intervention or wait-list control groups within a pair. Eligible clusters were villages with non-governmental organisation partner presence and an active preschool. Participants were caregiver-child dyads, where the child was 12-60 months old at baseline. The intervention consisted of eight group sessions delivered at informal preschools to all children in each village. Mobile health events were hosted for all intervention (n=17) and control (n=17) clusters, offering HIV testing and other health services to all community members. Primary outcomes were caregiver-reported child HIV testing, child language development, and child attention. Assessments were done at baseline, immediately post-intervention (3 months post-baseline), and 12 months post-intervention. We assessed child language by means of one caregiver-report measure (MacArthur-Bates Communicative Development Inventory [CDI]) and used two observational assessments of receptive language (the Mullen Scales of Early Learning receptive language subscale, and the Peabody Picture Vocabulary Test 4th edn). Child attention was assessed by means of the Early Childhood Vigilance Task. Assessors were masked to group assignment. Analysis was by intention to treat. This trial was registered with ISRCTN.com, ISRCTN16654287 and is completed. FINDINGS: Between Aug 8, 2015, and Dec 10, 2017, 1040 children (531 intervention; 509 control) and their caregivers were enrolled in 34 clusters (17 intervention; 17 control). Compared with controls, the intervention group reported significantly higher child HIV testing at the 12-month follow-up (relative risk [RR] 1·46, 95% CI 1·29 to 1·65, p<0·0001), but not immediately post-intervention. The intervention group showed significantly higher child receptive language on the caregiver report (CDI) at immediate (effect size 3·79, 95% CI 0·78 to 6·79, p=0·028) but not at 12-month follow-up (effect size 2·96, 95% CI -0·10 to 5·98, p=0·056). There were no significant group differences for the direct assessments of receptive language. Child expressive language and child attention did not differ significantly between groups. INTERPRETATION: Integrated child health and parenting interventions, delivered by trained and supervised lay health workers, can improve both child HIV testing and child development. FUNDING: United States Agency for International Development (USAID) and the President's Emergency Plan for AIDS Relief (PEPFAR).

Anti-Factor-Xa and Activated Partial Thromboplastin Time Concordance and Outcomes in Adults Undergoing Extracorporeal Membrane Oxygenation: A Secondary Analysis of the Pilot Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation Randomized Trial.

OBJECTIVES: To determine the concordance between activated partial thromboplastin time (aPTT) and anti-factor-Xa (anti-Xa) in adults undergoing extracorporeal membrane oxygenation (ECMO) and to identify the factors associated with discordant paired aPTT/anti-Xa. DESIGN: Pre-planned secondary analysis of the Low-Dose Heparin in Critically Ill Patients Undergoing Extracorporeal Membrane Oxygenation pilot randomized unblinded, parallel-group controlled trial. SETTING: Two ICUs in two university hospitals. PATIENTS: Thirty-two critically ill patients who underwent ECMO and who had at least one paired aPTT and anti-Xa assay performed at the same time. INTERVENTIONS: We analyzed the concordance between aPTT and anti-Xa and identified factors associated with discordant paired aPTT/anti-Xa based on their respective therapeutic ranges. We also compared biological parameters between heparin resistance episode and no heparin resistance. MEASUREMENTS AND MAIN RESULTS: Of the 32 patients who were included in this study, 24 (75%) had at least one discordant paired aPTT/anti-Xa. Of the 581 paired aPTT/anti-Xa that were analyzed, 202 were discordant. The aPTT was relatively lower than anti-Xa in 66 cases (32.7%) or relatively higher than anti-Xa in 136 cases (67.3%). Thirty-three heparin resistance episodes were identified in six patients (19%). CONCLUSIONS: In these critically ill patients undergoing ECMO, one third of paired aPTT/anti-Xa measures was discordant. Coagulopathy and heparin resistance might be the reasons for discordance. Our results support the potential importance of routinely monitoring both tests in this setting.

Intimate partner violence victimisation and its association with maternal parenting (the 2015 Pelotas [Brazil] Birth Cohort): a prospective cohort study.

BACKGROUND: Intimate partner violence (IPV) is highly prevalent in low-income and middle-income countries and has been a major obstacle towards reaching global health targets for women and children. We aimed to investigate cross-sectional and longitudinal associations between IPV victimisation and maternal parenting practices of young children in a population-based birth cohort study in Brazil. METHODS: The 2015 Pelotas Birth Cohort is an ongoing, prospective cohort, including all hospital births occurring between Jan 1 and Dec 31, 2015, in the city of Pelotas, Brazil. When children were aged 4 years, mothers reported on emotional, physical, and sexual IPV victimisation in the past 12 months. Parenting outcomes were assessed through filming the mother and child in interactive tasks at age 4 years and maternal interviews at ages 4 years and 6-7 years. Interactive tasks were filmed at the Centre for Epidemiological Research facilities. Directly observed outcomes included negative (eg, coercive) and positive (eg, sensitivity and reciprocity) parenting interactions independently coded by a team of psychologists. Self-reported parenting was measured using the subscales on quality of parent-child relationship, positive encouragement, parental consistency, and coercive behaviour of the Parenting and Family Adjustment Scales questionnaire. Unadjusted and adjusted linear regression analyses were performed to assess the associations. FINDINGS: Of the 4275 livebirths enrolled in the cohort, 3730 mother-child dyads were included in our analytical sample at age 4 years and 3292 at age 6-7 years. After adjusting for all potential confounders, emotional IPV and physical or sexual IPV were associated with the following self-reported parenting outcomes: poor parent-child relationship quality (emotional IPV: p=0·011), lower parental consistency (emotional IPV: p<0·001, physical or sexual IPV: p=0·0053), and more coercive behaviour (emotional IPV: p<0·001, physical or sexual IPV: p=0·0071) at age 4 years. Associations were not observed for self-reported positive encouragement and filmed parenting outcomes in fully adjusted models. Longitudinally, IPV at age 4 years predicted similar outcomes when children were aged 6-7 years. INTERPRETATION: In this large cohort study, maternal IPV victimisation was consistently associated with poorer parent-child relationship, decreased parental consistency, and increased harsh parenting reported by mothers of young children. As well as initiatives to prevent IPV, parenting interventions focused on supporting the capacity of caregivers to provide nurturing care delivered at key stages early in the life course are crucial. FUNDING: Wellcome Trust. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids.

Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5 - /KRT17 + aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.

Autoantibodies are associated with disease progression in idiopathic pulmonary fibrosis.

Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention.